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Diabetes Mellitus

A 22- year-old diabetic comes to the Accident and Emergency department. She gives a 2-day history of vomiting and abdominal pain. She is drowsy and her breathing is deep and rapid. There is distinctive smell from her breath. She has been diagnosed with Diabetic ketoacidosis. Diabetic ketoacidosis is a complication of uncontrolled diabetes mellitus.

The TCA cycle in diabetes mellitus is suppressed and the excess Acetyl co A, resulting from fatty acid oxidation is channeled towards the pathway of ketogenesis.

Which of the following intermediates of TCA cycle is depleted in Type 1 Diabetes mellitus to suppress TCA cycle?

A) Succinate

B) Malate

C) α-Keto glutarate

D) Oxaloacetate

E) Pyruvate.

The correct answer is- D) – Oxaloacetate.

Two facts demand attention here-

1) TCA cycle suppression and

2) Basis of ketogenesis

In Diabetes mellitus, TCA cycle is in a state of suppression due to diminished availability of oxaloacetate which is channeled towards the pathway of gluconeogenesis.

The hyperglycemia in Insulin deficiency results from decreased utilization and excess pouring in of glucose. The processes of glucose utilization such as- Glycolysis, TCA cycle, HMP and glycogenesis occur at a diminished rate, whereas rates of gluconeogenesis and glycogen degradation are increased due to disturbed Insulin to Glucagon ratio in diabetes mellitus. Oxaloacetate is a common intermediate of  TCA cycle and gluconeogenesis. The utilization of oxaloacetate in the pathway of gluconeogenesis depletes the amount which is required for TCA cycle (Oxaloacetate acts as a catalyst; an optimum amount of oxaloacetate is required for the functioning of TCA cycle), therefore it undergoes in a state of suppression.

As glucose utilization is decreased in Diabetes mellitus, alternatively fatty acids are oxidized to compensate for the energy needs. Excess fatty acid oxidation results in:

i) Accumulation of NADH which further suppresses TCA cycle ( Excess of NADH decreases the catalytic activities of three NAD+ requiring enzymes of TCA cycle- Isocitrate dehydrogenase, Alpha ketoglutarate dehydrogenase and Malate dehydrogenase), and

Regulation of TCA cycle

Figure-1- Regulation of TCA cycle. Accumulation of NADH inhibits the activities of NAD + enzymes of TCA cycle, isocitrate dehydrogenase, Alpha keto glutarate dehydrogenase and Malate dehydrogenase. The activity of PDH complex is also decreased.

ii) Accumulation of Acetyl co A- The end product of fatty acid oxidation cannot be oxidized in TCA cycle at the same rate as that of its production, as a result , Acetyl co A is channeled either towards pathways of ketogenesis, or of cholesterol synthesis (figure-2).

TCA suppression

Figure-2- a) The rate of lipolysis is increased, fatty acids are oxidized to produce Acetyl CoA.

b) Due to non availability of oxaloacetate, which is diverted towards pathway of gluconeogenesis, TCA cycle is suppressed.

c) Acetyl co A is diverted towards pathway of ketogenesis. Acetone, acetoacetate and beta hydroxy butyrate are the three ketone bodies

d) Accumulated ketone bodies, (being acidic in nature and also as they deplete the alkali reserve) cause acidosis.

In Type 1 Diabetes mellitus, the onset of the disease is abrupt, which is why the body switches abruptly from glucose utilization to fatty acid oxidation for energy needs.  Acetyl co A resulting from excess fatty acid oxidation saturates TCA cycle and the other alternative pathways resulting in ketogenesis. This is the reason ketoacidosis is far more commonly found in type 1diabetes mellitus than type 2 diabetes.

The similar situation is observed in prolonged fasting or starvation. Diabetes mellitus and starvation depict a similar metabolic state, in both the conditions, the cells are deprived of glucose and switch to alternative fuels for their energy needs. The basis of ketosis is thus the same in both conditions.

As regards other options:

A) Succinate-Succinate is an intermediate of TCA cycle, but it is not depleted in Diabetes mellitus.

B) Malate- Similarly malate and C) α-Keto glutarate are also not depleted in Diabetes mellitus.

E) Pyruvate depletion does not directly affect the functioning of TCA cycle, of course pyruvate is also diverted towards glucose production, but there are other sources available, in any case TCA cycle activity is not affected.

Thus the most logical option is Oxaloacetate which is the most important regulator of TCA cycle, depletion of which suppresses TCA cycle.






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Management of Type 2 Diabetes Mellitus

The goals of therapy for type 2 DM are similar to those in type 1. While glycemic control tends to dominate the management of type 1 DM, the care of individuals with type 2 DM must also include attention to the treatment of conditions associated with type 2 DM (obesity, hypertension, dyslipidemia, cardiovascular disease) and detection/management of DM-related complications. DM-specific complications may be present in up to 20–50% of individuals with newly diagnosed type 2 DM. Reduction in cardiovascular risk is of paramount importance as this is the leading cause of mortality in these individuals.

Pharmacological Interventions

Hypoglycemic agents

If the patient is not able to achieve target glycemic control with weight management and exercise, then pharmacologic therapy is indicated.

Based on their mechanisms of action, glucose-lowering agents are subdivided into agents that increase insulin secretion, reduce glucose production, increase insulin sensitivity, and enhance GLP-1 action. Glucose-lowering agents (with the exception of α-glycosidase inhibitors and an amylin analogue) are ineffective in type 1 DM and should not be used for glucose management of severely ill individuals with type 2 DM. Insulin is sometimes the initial glucose-lowering agent.

1) Insulin Secretagogues

Insulin Secretagogues stimulate insulin secretion by interacting with the ATP-sensitive potassium channel on the beta cells. These drugs are most effective in individuals with type 2 DM of relatively recent onset (<5 years), who have residual endogenous insulin production.  Various examples of Insulin Secretagogues are as follows-

a) Sulfonylurea—first generation

  • Chlorpropamide
  • Tolazamide
  • Tolbutamide

b ) Sulfonylurea—second generation

  • Glimepiride
  • Glipizide
  • Glipizide (extended release)
  • Glyburide
  • Glyburide (micronized)

c) Nonsulfonylureas

  • Repaglinide
  •  Nateglinide

Insulin Secretagogues are generally well tolerated. All of these agents, however, have the potential to cause profound and persistent hypoglycemia, especially in elderly individuals. Hypoglycemia is usually related to delayed meals, increased physical activity, alcohol intake, or renal insufficiency.

2) Biguanides

Metformin is representative of this class of agents. It reduces hepatic glucose production through an undefined mechanism and improves peripheral glucose utilization slightly.

Metformin reduces fasting plasma glucose and insulin levels, improves the lipid profile, and promotes modest weight loss.The major toxicity of metformin, lactic acidosis, can be prevented by careful patient selection.

3) α-Glycosidase Inhibitors

α -Glycosidase inhibitors (acarbose and miglitol) reduce postprandial hyperglycemia by delaying glucose absorption; they do not affect glucose utilization or insulin secretion. Postprandial hyperglycemia, secondary to impaired hepatic and peripheral glucose disposal, contributes significantly to the hyperglycemic state in type 2 DM. These drugs, taken just before each meal, reduce glucose absorption by inhibiting the enzyme that cleaves oligosaccharides into simple sugars in the intestinal lumen. The major side effects (diarrhea, flatulence, abdominal distention) are related to increased delivery of oligosaccharides to the large bowel and can be reduced somewhat by gradual upward dose titration. α-Glucosidase inhibitors may increase levels of sulfonylureas and increase the incidence of hypoglycemia.

4) Thiazolidinediones

Thiazolidinediones reduce insulin resistance. These drugs bind to the PPAR-γ (peroxisome proliferator-activated receptor- γ) nuclear receptor. The PPAR- γ receptor is found at highest levels in adipocytes but is expressed at lower levels in many other tissues. Agonists of this receptor regulate a large number of genes, promote adipocyte differentiation, reduce hepatic fat accumulation, and appear to reduce insulin resistance indirectly by enhancing fatty acid storage and possibly by increasing adiponectin levels Thiazolidinediones promote a redistribution of fat from central to peripheral locations. Circulating insulin levels decrease with use of the thiazolidinediones, indicating a reduction in insulin resistance

Rosiglitazone, Pioglitazone belong to this category.

5) Glucagon like peptide–1 agonists

GLP-1 agonists (ie, exenatide, liraglutide) mimic the endogenous incretin GLP-1; they stimulate glucose-dependent insulin release, reduce glucagon, and slow gastric emptying. The use of a GLP-1 in addition to metformin and/or a sulfonylurea may result in modest weight loss

6) Amylinomimetics

Pramlintide acetate is an amylin analog that mimics the effects of endogenous amylin, which is secreted by pancreatic beta cells. This agent delays gastric emptying, decreases postprandial glucagon release, and modulates appetite.

7) Insulin Therapy in Type 2 DM

Insulin should be considered as the initial therapy in type 2 DM, particularly in lean individuals or those with severe weight loss, in individuals with underlying renal or hepatic disease that precludes oral glucose-lowering agents, or in individuals who are hospitalized or acutely ill. Insulin therapy is ultimately required by a substantial number of individuals with type 2 DM because of the progressive nature of the disorder and the relative insulin deficiency that develops in patients with long-standing diabetes.

Non pharmacological Interventions

a) Weight reduction

Treatment is directed toward achieving weight reduction, and prescribing a diet is only one means to this end. Behavior modification to achieve adherence to the diet—as well as increased physical activity to expend energy—is also required.

b) Diet

A well-balanced, nutritious diet remains a fundamental element of therapy. The American Diabetes Association (ADA) recommends about 45–65% of total daily calories in the form of carbohydrates; 25–35% in the form of fat (of which less than 7% are from saturated fat), and 10–35% in the form of protein. In patients with type 2 diabetes, limiting the carbohydrate intake and substituting some of the calories with monounsaturated fats, such as olive oil, rapeseed (canola) oil, or the oils in nuts and avocados, can lower triglycerides and increase HDL cholesterol. Patients with type 1 diabetes or type 2 diabetes who take insulin should be taught “carbohydrate counting,” so they can administer their insulin bolus for each meal based on its carbohydrate content. In obese individuals with diabetes, an additional goal is weight reduction by caloric restriction).

The current recommendations for both types of diabetes continue to limit cholesterol to 300 mg daily, and individuals with LDL cholesterol more than 100 mg/dL should limit dietary cholesterol to 200 mg daily. High protein intake may cause progression of renal disease in patients with diabetic nephropathy; for these individuals, a reduction in protein intake to 0.8 kg/day (or about 10% of total calories daily) is recommended.

c) Dietary fiber

Plant components such as cellulose, gum, and pectin are indigestible by humans and are termed dietary “fiber.” Insoluble fibers such as cellulose or hemicellulose, as found in bran, tend to increase intestinal transit and may have beneficial effects on colonic function. In contrast, soluble fibers such as gums and pectins, as found in beans, oatmeal, or apple skin, tend to retard nutrient absorption rates so that glucose absorption is slower and hyperglycemia may be slightly diminished. Although its recommendations do not include insoluble fiber supplements such as added bran, the ADA recommends food such as oatmeal, cereals, and beans with relatively high soluble fiber content as staple components of the diet in diabetics. High soluble fiber content in the diet may also have a favorable effect on blood cholesterol levels.

d) Artificial and other sweeteners

Aspartame (NutraSweet) consists of two major amino acids, aspartic acid and phenylalanine, which combine to produce a sweetener 180 times as sweet as sucrose. A major limitation is that it is not heat stable, so it cannot be used in cooking. Saccharin (Sweet ‘N Low), Sucralose (Splenda), and Acesulfame potassium (Sweet One) are other “artificial” sweeteners that can be used in cooking and baking.

Fructose represents a “natural” sugar substance that is a highly effective sweetener, induces only slight increases in plasma glucose levels, and does not require insulin for its metabolism. However, because of potential adverse effects of large amounts of fructose on raising serum cholesterol, triglycerides, and LDL cholesterol, it does not have any advantage as a sweetening agent in the diabetic diet. This does not preclude, however, ingestion of fructose-containing fruits and vegetables or fructose-sweetened foods in moderation.

Sugar alcohols, also known as polyols or polyalcohol, are commonly used as sweeteners and bulking agents. They occur naturally in a variety of fruits and vegetables but are also commercially made from sucrose, glucose, and starch. Examples are sorbitol, xylitol, mannitol, lactitol, isomalt, maltitol, and hydrogenated starch hydrolysates (HSH). They are not as easily absorbed as sugar, so they do not raise blood glucose levels as much. Therefore, sugar alcohols are often used in food products that are labeled as “sugar-free,” such as chewing gum, lozenges, hard candy, and sugar-free ice cream. However, if consumed in large quantities, they will raise blood glucose and can cause bloating and diarrhea.


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Differential Diagnosis

Hyperglycemia Secondary to Other Causes

Secondary hyperglycemia has been associated with various disorders of insulin target tissues (liver, muscle, and adipose tissue). Other secondary causes of carbohydrate intolerance include endocrine disorders—often specific endocrine tumors—associated with excess production of growth hormone, glucocorticoids, catecholamines, glucagon, or somatostatin. With excess of glucocorticoids, catecholamines, or glucagon, increased hepatic output of glucose is a contributory factor; in the case of catecholamines, decreased insulin release is an additional factor in producing carbohydrate intolerance, and with excess somatostatin production it is the major factor.

Secondary causes of hyperglycemia

A)Hyperglycemia due to tissue insensitivity to insulin  

 1) Hormonal tumors (acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma)

 2) Pharmacologic agents (corticosteroids, sympathomimetic drugs, niacin)

 3) Liver disease (cirrhosis, Hemochromatosis)

 4) Muscle disorders (myotonic dystrophy)

 5) Adipose tissue disorders (Lipodystrophy, truncal obesity)

  6) Insulin receptor disorders (acanthosis nigricans syndromes, Leprechaunism)

B)Hyperglycemia due to reduced insulin secretion 

1) Hormonal tumors (somatostatinoma, pheochromocytoma)

 2) Pancreatic disorders (pancreatitis, Hemosiderosis, Hemochromatosis

 3) Pharmacologic agents (thiazide diuretics, phenytoin, pentamidine)

A rare syndrome of extreme insulin resistance associated with acanthosis nigricans afflicts either young women with androgenic features as well as insulin receptor mutations or older people, mostly women, in whom a circulating immunoglobulin binds to insulin receptors and reduces their affinity to insulin.

Medications such as diuretics, phenytoin, niacin, and high-dose corticosteroids can produce hyperglycemia that is reversible once the drugs are discontinued or when diuretic-induced hypokalemia is corrected. Chronic pancreatitis or subtotal pancreatectomy reduces the number of functioning B cells and can result in a metabolic derangement very similar to that of genetic type 1 diabetes except that a concomitant reduction in pancreatic A cells may reduce glucagon secretion so that relatively lower doses of insulin replacement are needed. Insulin-dependent diabetes is occasionally associated with Addison’s disease and autoimmune thyroiditis (Schmidt’s syndrome, or polyglandular failure syndrome). This occurs more commonly in women and represents an autoimmune disorder in which there are circulating antibodies to adrenocortical and thyroid tissue, thyroglobulin, and gastric parietal cells.

Nondiabetics Glycosuria

Nondiabetic Glycosuria (renal Glycosuria) is a benign asymptomatic condition wherein glucose appears in the urine despite a normal amount of glucose in the blood, either basally or during a glucose tolerance test. Its cause may vary from an autosomally transmitted genetic disorder to one associated with dysfunction of the proximal renal tubule (Fanconi’s syndrome, chronic renal failure), or it may merely be a consequence of the increased load of glucose presented to the tubules by the elevated glomerular filtration rate during pregnancy. As many as 50% of pregnant women normally have demonstrable sugar in the urine, especially during the third and fourth months. This sugar is practically always glucose except during the late weeks of pregnancy, when lactose may be present.

Management of Type 1 Diabetes Mellitus

The goals of therapy for type 1 or type 2 DM are to: (1) eliminate symptoms related to hyperglycemia, (2) reduce or eliminate the long-term micro vascular and macro vascular complications of DM, and (3) allow the patient to achieve as normal a lifestyle as possible.

Because individuals with type 1 DM partially or completely lack endogenous insulin production, administration of basal, exogenous insulin is essential for regulating glycogen breakdown, gluconeogenesis, lipolysis, and ketogenesis. Likewise, insulin replacement for meals should be appropriate for the carbohydrate intake and promote normal glucose utilization and storage.

Insulin regimens

Two therapeutic regimens are currently in use- Standard and Intensive insulin treatment.

1) Standard treatment versus Intensive treatment

Standard treatment which has its therapeutic goal the clinical well being of the patient, typically consists of one or two daily injections of insulin. Mean blood glucose obtained are typically in the 225 to 275 mg/dl range, with an HbA1c of eight to nine percent of the total hemoglobin (The rate of formation of HbA1c is proportional to the average blood glucose concentration over the previous several months. Thus, HbA1c provides a measure of how well the treatment has normalized blood glucose in the diabetic over time.)

In contrast to standard therapy,

Intensive diabetes management has the goal of achieving euglycemia or near-normal glycemia. This approach requires multiple resources including thorough and continuing patient education, comprehensive recording of plasma glucose measurements and nutrition intake by the patient, and a variable insulin regimen that matches glucose intake and insulin dose. Insulin regimens usually include multiple-component insulin regimens, multiple daily injections (MDI), or insulin infusion devices. Mean blood glucose levels of 150 mg/dl can be achieved, with HbA1c 7% of the total hemoglobin. The patients on intensive therapy showed a 60% reduction in the long term complications of diabetes-retinopathy, nephropathy and neuropathy- compared with patients receiving standard care. This confirms that the complications of diabetes are related to an elevation of plasma glucose.

Insulin Preparations

Insulin is indicated for type 1 diabetes as well as for type 2 diabetic patients with insulinopenia whose hyperglycemia does not respond to diet therapy either alone or combined with other hypoglycemic drugs.

With the development of highly purified human insulin preparations, immunogenicity has been markedly reduced, thereby decreasing the incidence of therapeutic complications such as insulin allergy, immune insulin resistance, and localized lipoatrophy at the injection site. However, the problem of achieving optimal insulin delivery remains unsolved with the present state of technology. It has not been possible to reproduce the physiologic patterns of intraportal insulin secretion with subcutaneous injections of short-acting or longer-acting insulin preparations. Even so, with the help of appropriate modifications of diet and exercise and careful monitoring of capillary blood glucose levels at home, it has often been possible to achieve acceptable control of blood glucose by using various mixtures of short- and longer-acting insulins injected at least twice daily or portable insulin infusion pumps.

Human insulin is produced by recombinant DNA techniques (biosynthetic human insulin) as Humulin (Eli Lilly) and as Novolin (Novo Nordisk). It is dispensed as either regular (R) or NPH (N) formulations. Five analogs of human insulin—three rapidly acting (insulin lispro, insulin aspart, insulin glulisine) and two long-acting (insulin glargine and insulin detemir)—have been approved by the FDA for clinical use 

Insulins can be classified as short-acting or long-acting The short-acting preparations are regular insulin and the rapidly acting insulin analogs They are dispensed as clear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf life. The long-acting preparations are NPH insulin and the long-acting insulin analogs. NPH insulin is dispensed as a turbid suspension at neutral pH with protamine in phosphate buffer. The long-acting insulin analogs are also dispensed as clear solutions.

Mixed insulin preparations

Since intermediate insulins require several hours to reach adequate therapeutic levels, their use in patients with type 1 diabetes requires supplements of regular or rapidly acting insulin analogs preprandially. For convenience, regular or rapidly acting insulin analogs and NPH insulin may be mixed together in the same syringe and injected subcutaneously in split dosage before breakfast and supper.

Summary of bioavailability characteristics of insulins

Insulin Preparations Onset of Action Peak Action Effective Duration
Insulins lispro, aspart, glulisine 5–15 minutes 1–1.5 hours 3–4 hours
Human regular 30–60 minutes 2 hours 6–8 hours
Human NPH 2–4 hours 6–7 hours 10–20 hours
Insulin glargine 1.5 hours Flat ~24 hours
Insulin detemir 1 hour Flat 17 hours

Methods of insulin administration

1) Insulin syringes and needles

Plastic disposable syringes are available in 1-mL, 0.5-mL, and 0.3-mL sizes.(Figure-1)







Figure-1- Showing Insulin syringe

2) Insulin pen injector devices

Insulin pens eliminate the need for carrying insulin vials and syringes. Cartridges of insulin lispro, insulin aspart, insulin glargine, regular insulin, NPH insulin, and 70% NPH/30% regular insulin are available for reusable pens (Figure-2).





Figure-2- showing prefilled insulin pen.

3) Insulin pumps

Insulin infusion pumps are used for subcutaneous delivery of insulin. (Figure-3).These pumps are small (about the size of a pager) and very easy to program. They offer many features, including the ability to set a number of different basal rates throughout the 24 hours and to adjust the time over which bolus doses are given.












Figure-3- showing insulin pump

4) Inhaled insulin

A novel method for delivering a pre-prandial powdered form of insulin by inhalation (Exubera) has been approved by the FDA.

5) Islet cell transplantation is a minimally invasive procedure, wide application of this procedure for the treatment of type 1 diabetes is limited by the dependence on multiple donors and the requirement for potent long-term immunotherapy.

A judicious balance of the size and frequency of meals with moderate regular exercise can often stabilize the insulin dosage in diabetics. A reasonable aim of therapy is to approach normal glycemic excursions without provoking severe or frequent hypoglycemia. What has been considered “acceptable” control includes blood glucose levels of 90–130 mg/dL before meals and after an overnight fast, and levels no higher than 180 mg/dL 1 hour after meals and 150 mg/dL 2 hours after meals. Glycohemoglobins levels should be no higher than 1% above the upper limit of the normal range.

Complications of Insulin Therapy

Hypoglycemia, Insulin allergy, immune insulin resistance and Lipodystrophy at the injection site are some of the complications of insulin therapy.

Hypoglycemia in type 1 diabetes

One of the therapeutic goals of diabetes is to decrease blood glucose levels in an effort to minimize the development of the long-term complications of the disease. However, appropriate dosage is difficult to achieve in all patients, and hypoglycemia caused by excess insulin is the most common complication of insulin therapy, occurring in more than 90 % of the patients. The frequency of hypoglycemic episodes, coma and seizures is particularly high with intensive treatment regimens designed to achieve tight control of blood glucose. In normal individuals, hypoglycemia triggers a compensatory secretion of counter regulatory hormones, most notably glucagon and epinephrine, which promote hepatic production of glucose. However patients with type 1 diabetes also develop a deficiency of glucagon secretion. This defect occurs early in the disease and is almost universally present four years after diagnosis. These patients thus rely on epinephrine secretion to prevent severe hypoglycemia. However as the disease progresses, type 1 diabetes patients show diabetic autonomic neuropathy and impaired ability to secrete epinephrine in response to hypoglycemia. The combined deficiency of glucagon and epinephrine secretion creates a condition sometimes called “Hypoglycemia unawareness”. Thus patients with long standing diabetes are particularly vulnerable to hypoglycemia. Hypoglycemia can also be caused by strenuous exercise. Exercise promotes glucose uptake in to muscles and decreases the need for exogenous insulin. Patients should therefore check blood glucose levels before or after intensive exercise to prevent or abort hypoglycemia.

Around ¼ of all patients who get type 1 diabetes develop what is known as a ‘honeymoonperiod within days or weeks of the onset of treatment. It is as if the patient has gone into remission and it can be confusing for the patient as it would appear that the condition has corrected itself. Some patients actually require no insulin during this phase and this may last for weeks or months. It is usually best to keep treating with insulin even if the requirements are negligible, to avoid possible insulin allergy upon re-exposure and also to maintain a treatment regimen and not give false hope to the patient.

Other Agents that Improve Glucose Control

The role of amylin, a 37-amino-acid peptide co secreted with insulin from pancreatic beta cells, in normal glucose homeostasis is uncertain. However, based on the rationale that patients who are insulin deficient are also amylin deficient, an analogue of amylin (pramlintide) was created and found to reduce postprandial glycemic excursions in type 1 and type 2 diabetic patients taking insulin.

Besides insulin therapy, life long dietary and life style modifications are required to be done to achieve euglycemia.

Stem cell therapy

Stem cell therapy is one of the most promising treatments for the near future. It is expected that this kind of therapy can ameliorate or even reverse some diseases.

Prognosis- Prognosis of patients with type 1 diabetes can be markedly improved by optimal care.


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Chronic Complications of Diabetes Mellitus

Chronic complications can be divided into vascular and non-vascular complications.

The vascular complications of DM are further subdivided into micro vascular (retinopathy, neuropathy, and nephropathy) and macro vascular complications [coronary artery disease (CAD), peripheral arterial disease (PAD), cerebrovascular disease]. Nonvascular complications include problems such as gastroparesis, infections, and skin changes. Long-standing diabetes may be associated with hearing loss.

The risk of chronic complications increases as a function of the duration of hyperglycemia; they usually become apparent in the second decade of hyperglycemia. Since type 2 DM often has a long asymptomatic period of hyperglycemia, many individuals with type 2 DM have complications at the time of diagnosis.

Mechanisms of Complications

Following prominent theories, which are not mutually exclusive, have been proposed to explain how hyperglycemia might lead to the chronic complications of DM.

1) Advanced Glycosylation End Products

Increased intracellular glucose leads to the formation of advanced glycosylation end products (AGEs) via the nonenzymatic glycosylation of intra and extra cellular proteins. Nonenzymatic glycosylation results from the interaction of glucose with amino groups on proteins. AGEs have been shown to cross-link proteins (e.g., collagen, extracellular matrix proteins), accelerate atherosclerosis, promote glomerular dysfunction, reduce nitric oxide synthesis, induce endothelial dysfunction, and alter extracellular matrix composition and structure (Figure-1).The serum level of AGEs correlates with the level of glycemia, and these products accumulate as glomerular filtration rate declines.

Figure-1-Pathogenic effects of advanced glycation end products (AGEs). By binding and crosslinking extracellular matrix, e.g. collagen, AGEs induce vascular stiffness and increased vascular permeability. The interaction with AGE receptors (e.g. RAGE) induces endothelial dysfunction by reducing nitric oxide (NO) release ,  promoting inflammatory reactions, and oxidative stress. Binding to lipoproteins increases the uptake of e.g. low density lipoproteins (LDL) by macrophages, which may lead to the formation of foam cells.

2) Sorbitol pathway

Hyperglycemia increases glucose metabolism via the Sorbitol pathway. Intracellular glucose is predominantly metabolized by phosphorylation and subsequent glycolysis, but when increased, some glucose is converted to sorbitol by the enzyme aldose reductase. Increased sorbitol concentration alters redox potential, increases cellular osmolality, generates reactive oxygen species, and likely leads to other types of cellular dysfunction.


Figure-2- showing  mechanism of sorbitol formation from Glucose. (SDH- Sorbitol dehydrogenase catalyzes conversion of sorbitol to fructose, but this enzyme  is absent in most of the tissues.)

3) Activation of protein kinase C (PKC)

A third hypothesis proposes that hyperglycemia increases the formation of diacylglycerol leading to activation of protein kinase C (PKC). Among other actions, PKC alters the transcription of genes for fibronectin, type IV collagen, contractile proteins, and extracellular matrix proteins in endothelial cells and neurons. Inhibitors of PKC are being studied in clinical trials.

4) Hexosamine pathway

A fourth theory proposes that hyperglycemia increases the flux through the hexosamine pathway, which generates fructose-6-phosphate, a substrate for O-linked glycosylation and proteoglycan production. The hexosamine pathway may alter function by glycosylation of proteins such as endothelial nitric oxide synthase or by changes in gene expression of transforming growth factor β (TGF- β) or plasminogen activator inhibitor-1 (PAI-1).

Growth factors appear to play an important role in DM-related complications, and their production is increased by most of these proposed pathways.

5) Oxidative stress

Hyperglycemia leads to increased production of reactive oxygen species or Superoxide in the mitochondria; these compounds may activate all four of the pathways described above. (Figure-3). Although hyperglycemia serves as the initial trigger for complications of diabetes, it is still unknown whether the same pathophysiological processes are operative in all complications or whether some pathways predominate in certain organs.

Figure-3- showing implications of hyperglycemia

Vascular complications

1) Micro vascular complications

A) Ocular Complications

DM is the leading cause of blindness between the ages of 20 and 74 in the United States. Blindness is primarily the result of progressive diabetic retinopathy and clinically significant macular edema.

a) Diabetic retinopathy

Diabetic retinopathy is classified into two stages: nonproliferative and proliferative. Nonproliferative diabetic retinopathy usually appears late in the first decade or early in the second decade of the disease and is marked by retinal vascular micro aneurysms, blot hemorrhages, and cotton wool spots .Mild nonproliferative retinopathy progresses to more extensive disease, characterized by changes in venous vessel caliber, intraretinal microvascular abnormalities, and more numerous micro aneurysms and hemorrhages (Figure-4)

Figure-4 – showing Diabetic retinopathy

The appearance of neovascularization in response to retinal hypoxia is the hallmark of proliferative diabetic retinopathy These newly formed vessels appear near the optic nerve and/or macula and rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment. Clinically significant macular edema can occur when only nonproliferative retinopathy is present.

Duration of DM and degree of glycemic control are the best predictors of the development of retinopathy; hypertension is also a risk factor. Nonproliferative retinopathy is found in almost all individuals who have had DM for >20 years (25% incidence with 5 years, and 80% incidence with 15 years of type 1 DM). Although there is genetic susceptibility for retinopathy, it confers less influence than either the duration of DM or the degree of glycemic control.


The most effective therapy for diabetic retinopathy is prevention. Intensive glycemic and blood pressure control will delay the development or slow the progression of retinopathy in individuals with either type 1 or type 2 DM.  Laser photocoagulation is very successful in preserving vision. Proliferative retinopathy is usually treated with panretinal laser photocoagulation, whereas macular edema is treated with focal laser photocoagulation.

b) Diabetic cataract

Premature cataracts occur in diabetic patients (Figure-5) and seem to correlate with both the duration of diabetes and the severity of chronic hyperglycemia. Nonenzymatic glycosylation of lens protein contributes to the premature occurrence of cataracts.

Figure-5 – showing Diabetic cataract

c) Glaucoma

Glaucoma occurs in approximately 6% of persons with diabetes. It is responsive to the usual therapy for open-angle disease. Neovascularization of the iris in diabetics can predispose to closed-angle glaucoma, but this is relatively uncommon except after cataract extraction, when growth of new vessels has been known to progress rapidly, involving the angle of the iris and obstructing outflow.

B) Renal Complications

Diabetic nephropathy- Diabetic nephropathy (nephropatia diabetica), also known as Kimmelstiel-Wilson syndrome, and intercapillary glomerulonephritis, is a progressive kidney disease, caused by angiopathy of capillaries in the kidney glomeruli, and it is characterized by Nephrotic syndrome and diffuse glomerulosclerosis. It is due to long standing diabetes mellitus, and is a prime cause for dialysis in many Western countries.


Like other microvascular complications, the pathogenesis of diabetic nephropathy is related to chronic hyperglycemia.The mechanisms by which chronic hyperglycemia leads to End Stage Renal Disease ( ESRD), though incompletely defined, involve the effects of soluble factors (growth factors, angiotensin II, Endothelin, AGEs), hemodynamic alterations in the renal microcirculation (glomerular hyper filtration or hyper perfusion, increased glomerular capillary pressure), and structural changes in the glomerulus (increased extracellular matrix, basement membrane thickening, mesangial expansion, fibrosis). Some of these effects may be mediated through angiotensin II receptors.

The earliest detectable change in the course of diabetic nephropathy is a thickening in the glomerulus. At this stage, the kidney may start allowing more albumin than normal in the urine (albuminuria), and this can be detected by sensitive medical tests for albumin. This stage is called “microalbuminuria”. After 5–10 years of type 1 DM, ~40% of individuals begin to show microalbuminuria. Microalbuminuria is defined as 30–300 mg/d of albumin in a 24-h collection of urine. As diabetic nephropathy progresses, increasing numbers of glomeruli are destroyed by nodular glomerulosclerosis. Although the appearance of microalbuminuria in type 1 DM, is an important risk factor for progression to overt proteinuria (in>300 mg/d), only ~50% of individuals will progress to macroalbuminuria over the next 10 years. In some individuals with type 1 diabetes and microalbuminuria of short duration, the microalbuminuria regresses. Once macroalbuminuria is present, there is a steady decline in GFR (Glomerular Filtration Rate), and ~50% of individuals reach ESRD (End Stage Renal Disease) in 7–10 years. Once macroalbuminuria develops, blood pressure rises slightly and the pathologic changes are likely to be irreversible. At this stage, a kidney biopsy clearly shows diabetic nephropathy.

Clinical Manifestations

Kidney failure provoked by glomerulosclerosis leads to fluid filtration deficits and other disorders of kidney function. There is an increase in blood pressure and fluid retention in the body causing edema. Other complications may be arteriosclerosis of the renal artery and proteinuria.

Throughout its early course, diabetic nephropathy has no symptoms. They develop in late stages and may be a result of excretion of high amounts of protein in the urine or due to renal failure:

  • edema: swelling, usually around the eyes in the mornings; later, general body swelling may result, such as swelling of the legs
  • foamy appearance or excessive frothing of the urine (caused by the proteinuria)
  • unintentional weight gain (from fluid accumulation)
  • anorexia
  • nausea and vomiting
  • malaise
  • fatigue
  • headache
  • frequent hiccups
  • generalized itching

Laboratory Diagnosis

The first laboratory abnormality is a positive microalbuminuria test. Most often, the diagnosis is suspected when a routine urinalysis of a person with diabetes shows too much protein in the urine (proteinuria). The urinalysis may also show glucose in the urine, especially if blood glucose is poorly controlled. Serum creatinine and BUN may increase as kidney damage progresses. Dyslipidemia is a common associated finding. A Renal biopsy confirms the diagnosis.

The nephropathy that develops in type 2 DM differs from that of type 1 DM in the following respects:

(1) microalbuminuria or macroalbuminuria may be present when type 2 DM is diagnosed, reflecting its long asymptomatic period;

(2) hypertension more commonly accompanies microalbuminuria or macroalbuminuria in type 2 DM; and

(3) microalbuminuria may be less predictive of diabetic nephropathy and progression to macroalbuminuria in type 2 DM. 


The optimal therapy for diabetic nephropathy is prevention by control of glycemia. As a part of comprehensive diabetes care, microalbuminuria detection, and measurement of the serum creatinine to estimate GFR, should be done at an early stage, when effective therapies can be instituted.

Interventions effective in slowing progression from microalbuminuria to macroalbuminuria include: (1) normalization of glycemia, (2) strict blood pressure control, and (3) administration of ACE inhibitors (Angiotensin-converting enzyme inhibitors), or ARBs( Angiotensin II receptor blockers),Dyslipidemia should also be treated. Modest restriction of protein and fat intake is recommended. Once macroalbuminuria ensues, the likelihood of ESRD is very high. Survival after the onset of ESRD is shorter in the diabetic population compared to nondiabetics with similar clinical features. Dialysis may be necessary once end-stage renal disease develops. At this stage, a kidney transplantation must be considered. Another option for type 1 diabetes patients is a combined kidney-pancreas transplant.

C) Diabetic Neuropathy

Diabetic neuropathy occurs in ~50% of individuals with long-standing type 1 and type 2 DM. It may manifest as polyneuropathy, mononeuropathy, and/or autonomic neuropathy. Both myelinated and unmyelinated nerve fibers are lost.

a) Polyneuropathy/Mononeuropathy

The most common form of diabetic neuropathy is distal symmetric polyneuropathy. It most frequently presents with distal sensory loss, but up to 50% of patients do not have symptoms of neuropathy. Loss of function appears in a stocking-glove pattern. Hyperesthesia, paresthesias, and dysesthesia also may occur. Symptoms may include a sensation of numbness, tingling, sharpness, or burning that begins in the feet and spreads proximally. Neuropathic pain develops in some of these individuals, occasionally preceded by improvement in their glycemic control. Pain typically involves the lower extremities, is usually present at rest, and worsens at night. Both an acute (lasting <12 months) and a chronic form of painful diabetic neuropathy have been described. As diabetic neuropathy progresses, the pain subsides and eventually disappears, but a sensory deficit in the lower extremities persists. Physical examination reveals sensory loss, loss of ankle reflexes, and abnormal position sense.

Mononeuropathy (dysfunction of isolated cranial or peripheral nerves) is less common than polyneuropathy in DM and presents with pain and motor weakness in the distribution of a single nerve. A vascular etiology has been suggested, but the pathogenesis is unknown.

b) Autonomic Neuropathy

Individuals with long-standing type 1 or 2 DM may develop signs of autonomic dysfunction involving the cholinergic, noradrenergic, and peptidergic (peptides such as pancreatic polypeptide, substance P, etc.) systems. DM-related autonomic neuropathy can involve multiple systems, including the cardiovascular, gastrointestinal, genitourinary, and metabolic systems. Autonomic neuropathy may reduce counterregulatory hormone release, leading to an inability to sense hypoglycemia appropriately thereby subjecting the patient to the risk of severe hypoglycemia and complicating efforts to improve glycemic control. Anhidrosis of the feet can promote dry skin with cracking, which increases the risk of foot ulcers.

Diabetic nerve damage can affect the nerves that are important for penile erection, causing erectile dysfunction .Erectile dysfunction can also be caused by poor blood flow to the penis from diabetic blood vessel disease.

Diabetic neuropathy can also affect nerves to the stomach and intestines, causing nausea, weight loss, diarrhea, and other symptoms of gastroparesis (delayed emptying of food contents from the stomach into the intestines, due to ineffective contraction of the stomach muscles).

Diabetic Neuropathy: Treatment

Despite advances in the understanding of the metabolic causes of neuropathy, treatments aimed at interrupting these pathological processes have been limited. Thus, with the exception of tight glucose control, treatments are for reducing pain and other symptoms.

Options for pain control include tricyclic antidepressants (TCAs), serotonin reuptake inhibitors (SSRIs) and antiepileptic drugs (AEDs).


The mechanisms of diabetic neuropathy are poorly understood. At present, treatment alleviates pain and can control some associated symptoms, but the process is generally progressive.

As a complication, there is an increased risk of injury to the feet because of loss of sensation. Small infections can progress to ulceration and this may require amputation.

c) Diabetic gangrene

The incidence of gangrene of the feet in diabetics(Figure-6) is 30 times more than that in age-matched controls. The factors responsible for its development, in addition to peripheral vascular disease, are small vessel disease, peripheral neuropathy with loss of both pain sensation and neurogenic inflammatory responses, and secondary infection.

Figure-6-showing Diabetic foot

The peripheral sensory neuropathy interferes with normal protective mechanisms and allows the patient to sustain major or repeated minor trauma to the foot, often without knowledge of the injury. Motor and sensory neuropathy lead to abnormal foot muscle mechanics and to structural changes in the foot (hammer toe, claw toe deformity, prominent metatarsal heads, Charcot joint). Autonomic neuropathy results in anhidrosis and altered superficial blood flow in the foot, which promote drying of the skin and fissure formation. PAD and poor wound healing impede the resolution of minor breaks in the skin, allowing them to enlarge and to become infected.

Approximately 15% of individuals with DM develop a foot ulcer (great toe or MTP areas are most common), and a significant subset will ultimately undergo amputation (14–24% risk with that ulcer or subsequent ulceration). Risk factors for foot ulcers or amputation include: male sex, diabetes >10 years’ duration, peripheral neuropathy, abnormal structure of foot (bony abnormalities, callus, and thickened nails), peripheral arterial disease, and smoking, history of previous ulcer or amputation, and poor glycemic control.


The optimal therapy for foot ulcers and amputations is prevention through identification of high-risk patients, education of the patient, and institution of measures to prevent ulceration. Despite preventive measures, foot ulceration and infection are common and represent a serious problem. Due to the multifactorial pathogenesis of lower extremity ulcers, management of these lesions is multidisciplinary.

Agents that reduce peripheral blood flow such as tobacco and propranolol should be avoided. Control of other risk factors such as hypertension is essential. Cholesterol-lowering agents are useful as adjunctive therapy when early ischemic signs are detected and when dyslipidemia is present. Patients should be advised to seek immediate medical care if a diabetic foot ulcer develops. Improvement in peripheral blood flow with endarterectomy and bypass operations is possible in certain patients.

2) Large vessel diseases (Macro vascular complications)

Atherosclerosis and its effects produce the large vessel diseases.

a) Involvement of the coronary vessels can produce myocardial infarction,

b) Involvement of cerebral vessels can produce ‘stroke’.

c) Peripheral vascular disease-Atherosclerosis is markedly accelerated in the larger arteries. It is often diffuse, with localized enhancement in certain areas of turbulent blood flow, such as at the bifurcation of the aorta or other large vessels. Clinical manifestations of peripheral vascular disease include ischemia of the lower extremities, impotence, and intestinal angina.

Non vascular complications

Skin and Mucous Membrane Complications

Chronic pyogenic infections of the skin may occur, especially in poorly controlled diabetic patients. Eruptive xanthomas can result from hypertriglyceridemia, associated with poor glycemic control. An unusual lesion termed necrobiosis lipoidica diabeticorum is usually located over the anterior surfaces of the legs or the dorsal surfaces of the ankles. They are oval or irregularly shaped plaques with demarcated borders and a glistening yellow surface and occur in women two to four times more frequently than in men.

Fungal infections are also very common in diabetics. Candidal infection can produce erythema and edema of intertriginous areas below the breasts, in the axillas, and between the fingers. It causes vulvovaginitis in most chronically uncontrolled diabetic women with persistent glucosuria and is a frequent cause of pruritus.While antifungal creams containing miconazole or clotrimazole offer immediate relief of vulvovaginitis, recurrence is frequent unless glucosuria is reduced.

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Complications of Diabetes Mellitus (DM)

Acute Complications of DM

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are acute complications of diabetes. DKA was formerly considered a hallmark of type 1 DM, but it also occurs in individuals who lack immunologic features of type 1 DM and who can subsequently be treated with oral glucose-lowering agents (these obese individuals with type 2 DM are often of Hispanic or African-American descent). HHS is primarily seen in individuals with type 2 DM. Both disorders are associated with absolute or relative insulin deficiency, volume depletion, and acid-base abnormalities. DKA and HHS exist along a continuum of hyperglycemia, with or without ketosis. Both disorders are associated with potentially serious complications if not promptly diagnosed and treated.

1) Diabetic Keto- acidosis

Diabetic Ketoacidosis (DKA) is a state of inadequate insulin levels resulting in high blood sugar and accumulation of organic acids and ketones in the blood. It is a potentially life-threatening complication in patients with diabetes mellitus. It happens predominantly in type 1 diabetes mellitus, but it can also occur in type 2 diabetes mellitus under certain circumstances.


DKA most frequently occurs in known diabetics. It may also be the first presentation in patients who had not previously been diagnosed as diabetics. There is often a particular underlying problem that has led to the DKA episode. This may be intercurrent illness (pneumonia, influenza, gastroenteritis, a urinary tract infection), pregnancy, inadequate insulin administration (e.g. defective insulin pen device), myocardial infarction (heart attack), stroke or the use of cocaine. Young patients with recurrent episodes of DKA may have an underlying eating disorder, or may be using insufficient insulin for fear that it will cause weight gain. In 5% of cases, no cause for the DKA episode is found.

Diabetic ketoacidosis may occur in those previously known to have diabetes mellitus type 2 or in those who on further investigations turn out to have features of type 2 diabetes (e.g. obesity, strong family history); this is more common in African, African-American and Hispanic people. Their condition is then labeled “ketosis-prone type 2 diabetes“.


DKA results from relative or absolute insulin deficiency combined with counter regulatory hormone excess (Glucagon, Catecholamines, cortisol, and growth hormone). The decreased ratio of insulin to Glucagon promotes Gluconeogenesis, glycogenolysis, and Ketone body formation in the liver, as well as increases in substrate delivery from fat and muscle (free fatty acids, amino acids) to the liver.

The combination of insulin deficiency and hyperglycemia reduces the hepatic level of fructose-2,6-phosphate, which alters the activity of phosphofructokinase and fructose-1,6-bisphosphatase. Glucagon excess decreases the activity of pyruvate kinase, whereas insulin deficiency increases the activity of phosphoenolpyruvate carboxykinase. These changes shift the handling of pyruvate toward glucose synthesis and away from glycolysis. The increased levels of glucagon and catecholamines in the face of low insulin levels promote glycogenolysis. Insulin deficiency also reduces levels of the GLUT4 glucose transporter, which impairs glucose uptake into skeletal muscle and fat and reduces intracellular glucose metabolism

Normally, the free fatty acids released by adipolysis are converted to triglycerides or VLDL in the liver. However, in DKA, hyperglucagonemia alters hepatic metabolism to favor Ketone body formation, through activation of the enzyme carnitine palmitoyl Transferase I. This enzyme is crucial for regulating fatty acid transport into the mitochondria, where beta oxidation and conversion to ketone bodies occur.

The ketone bodies, however, have a low pH and therefore turn the blood acidic (metabolic acidosis). The body initially buffers this with the bicarbonate buffering system, but this is quickly overwhelmed and other mechanisms to compensate for the acidosis, such as hyperventilation to lower the blood carbon dioxide levels. This hyperventilation, in its extreme form, may be observed as Kussmaul respiration. Ketones, too, participate in osmotic diuresis and lead to further electrolyte losses. As a result of the above mechanisms, the average adult DKA patient has a total body water shortage of about 6 liters (or 100 ml/kg), in addition to substantial shortages in sodium, potassium, chloride, phosphate, magnesium and calcium. Glucose levels usually exceed 13.8 mmol/l or 250 mg/dl.

Increased lactic acid production also contributes to the acidosis. The increased free fatty acids increase triglyceride and VLDL production. VLDL clearance is also reduced because the activity of insulin-sensitive lipoprotein lipase in muscle and fat is decreased. Most commonly, DKA is precipitated by increased insulin requirements, as might occur during a concurrent illness. Occasionally, complete omission of insulin by the patient with type 1 DM precipitates DKA.

Clinical manifestations- The symptoms of an episode of diabetic ketoacidosis usually evolve over the period of about 24 hours. Predominant symptoms are nausea and vomiting, pronounced thirst, excessive urine production and abdominal pain that may be severe. Hyperglycemia is always present .In severe DKA, breathing becomes labored and of a deep, gasping character (a state referred to as “Kussmaul respiration“). The abdomen may be tender to the point that an acute abdomen may be suspected, such as acute pancreatitis, appendicitis or gastrointestinal perforation. Coffee ground vomiting (vomiting of altered blood) occurs in a minority of patients; this tends to originate from erosions of the esophagus. In severe DKA, there may be confusion, lethargy, stupor or even coma (a marked decrease in the level of consciousness).

On physical examination there is usually clinical evidence of dehydration, such as a dry mouth and decreased skin turgor. If the dehydration is profound enough to cause a decrease in the circulating blood volume, tachycardia (a fast heart rate) and low blood pressure may be observed. Often, a “ketotic” odor is present, which is often described as “fruity”. If Kussmaul respiration is present, this is reflected in an increased respiratory rate.

Small children with DKA are relatively prone to cerebral edema (swelling of the brain tissue), which may cause headache, coma, loss of the pupillary light reflex, and progress to death. It occurs in 0.7–1.0% of children with DKA, and has been described in young adults, but is overall very rare in adults. It carries 20–50% mortality.





















Figure- showing causes and consequences of DKA



Diabetic Ketoacidosis may be diagnosed when the combination of hyperglycemia (high blood sugars), ketones on urinalysis and acidosis are demonstrated. Arterial blood gas measurement is usually performed to demonstrate the acidosis; this requires taking a blood sample from an artery. In addition to the above, blood samples are usually taken to measure urea and creatinine (measures of kidney function, which may be impaired in DKA as a result of dehydration) and electrolytes. Furthermore, markers of infection (complete blood count, C-reactive protein) and acute pancreatitis (amylase and lipase) may be measured. Given the need to exclude infection, chest radiography and urinalysis are usually performed.

If cerebral edema is suspected because of confusion, recurrent vomiting or other symptoms, computed tomography may be performed to assess its severity and to exclude other causes such as stroke.


The main aims in the treatment of diabetic ketoacidosis are replacing the lost fluids and electrolytes while suppressing the high blood sugars and ketone production with insulin.

Fluid replacement– The amount of fluid depends on the estimated degree of dehydration. If dehydration is so severe, rapid infusion of saline is recommended to restore circulating volume.

Insulin is usually given continuously.

Potassium levels can fluctuate severely during the treatment of DKA, because insulin decreases potassium levels in the blood by redistributing it into cells. Serum potassium levels are initially often mildly raised even though total body potassium is depleted. Hypokalemia often follows treatment. This increases the risk of irregularities in the heart rate. Therefore, continuous observation of the heart rate is recommended, as well as repeated measurement of the potassium levels and addition of potassium to the intravenous fluids once levels fall below 5.3 mmol/l. If potassium levels fall below 3.3 mmol/l, insulin administration may need to be interrupted to allow correction of the hypokalemia.


Sodium bicarbonate solution is administered to rapidly improve the acid levels in the blood.

Cerebral edema– administration of fluids is slowed; intravenous Mannitol and hypertonic saline (3%) are used.

2) Hyperglycemic Hyperosmolar State (HHS)

Clinical Features-

HHS occurs in elderly individuals with type 2 DM, with a several week history of polyuria, weight loss, and diminished oral intake that culminates in mental confusion, lethargy, or coma.

The physical examination reveals-

  • Profound dehydration and hyperosmolality
  • Hypotension, tachycardia, and altered mental status.
  • Nausea, vomiting, abdominal pain and the Kussmaul respirations characteristic of DKA are absent.
  • HHS is often precipitated by a serious, concurrent illness such as myocardial infarction or stroke.
  • Sepsis, pneumonia, and other serious infections are frequent precipitants and should be sought.


Relative insulin deficiency and inadequate fluid intake are the underlying causes of HHS. Insulin deficiency increases hepatic glucose production (through glycogenolysis and gluconeogenesis) and impairs glucose utilization in skeletal muscle. Hyperglycemia induces an osmotic diuresis that leads to intravascular volume depletion, which is exacerbated by inadequate fluid replacement. The absence of ketosis in HHS is not completely understood. Presumably, the insulin deficiency is only relative and less severe than in DKA. Lower levels of counterregulatory hormones and free fatty acids have been found in HHS than in DKA in some studies. It is also possible that the liver is less capable of ketone body synthesis or that the insulin/glucagon ratio does not favor ketogenesis.

Laboratory Abnormalities and Diagnosis

Most notable are the marked hyperglycemia [plasma glucose may be >55.5 mmol/L (1000 mg/dL)], hyperosmolality (>350 mosmol/L), and prerenal azotemia. The measured serum sodium may be normal or slightly low despite the marked hyperglycemia. The corrected serum sodium is usually increased [add 1.6 meq to measured sodium for each 5.6-mmol/L (100 mg/dL) rise in the serum glucose]. In contrast to DKA, acidosis and ketonemia are absent or mild. A small anion gap metabolic acidosis may be present secondary to increased lactic acid. Moderate ketonuria, if present, is secondary to starvation.

Treatment-In HHS, fluid losses and dehydration are usually more pronounced than in DKA due to the longer duration of the illness. The patient with HHS is usually older, more likely to have mental status changes, and more likely to have a life-threatening precipitating event with accompanying co morbidities. Even with proper treatment, HHS has a substantially higher mortality than DKA (up to 15% in some clinical series).

3) Lactic acidosis

Type 1 lactic acidosis occurs in hypoxic individuals and is due to an excessive production of lactate by peripheral tissues. Hypoxia is not a feature of lactic acidosis which occurs due to impaired metabolism of lactate in the liver. Both are characterized by extreme metabolic acidosis. There is high anion gap with low or absent ketones and high lactate levels.


Large amount of intravenous sodium bicarbonate is needed to correct the acidosis. Alternatively the patient may be dialyzed against a bicarbonate containing solution.


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Laboratory Findings


a) Glucosuria

Glycosuria allows for a good first-line screening test for diabetes mellitus. Normally glucose does not appear in urine until the plasma glucose rises above 10 mmol/L or more. But in certain individuals due to low renal threshold glucose may be present despite normal blood glucose levels. Conversely renal threshold increases with age so many diabetics may not have Glycosuria despite high blood sugar levels.

A specific and convenient method to detect glucosuria is the paper strip impregnated with glucose oxidase and a chromogen system (Clinistix, Diastix), which is sensitive to as little as 0.1% glucose in urine. Diastix can be directly applied to the urinary stream, and differing color responses of the indicator strip reflect glucose concentration.

A normal renal threshold for glucose as well as reliable bladder emptying is essential for interpretation.


Qualitative detection of ketone bodies can be accomplished by nitroprusside tests (Acetest or Ketostix). Although these tests do not detect Beta-hydroxybutyric acid, which lacks a ketone group, the semiquantitative estimation of ketonuria thus obtained is nonetheless usually adequate for clinical purposes. Ketone bodies may be present in normal subject as a result of simple prolonged fasting.

c) Microalbuminuria

Microalbuminuria may be defined as an albumin excretion rate intermediate between normality (2.5-25 mg/day) and macroalbuminuria (250mg/day). The small increase in urinary albumin excretion is not detected by simple albumin stick tests and requires confirmation by careful quantization in a 24 hr. urine specimen. The importance of micro- albuminuria in the diabetic patient is that it is a signal of early reversible renal damage. Performing an albumin-to-creatinine ratio is probably easiest.

Unlike type 1 diabetes mellitus, in which microalbuminuria is a good indicator of early kidney damage, microalbuminuria is a common finding (even at diagnosis) in type 2 diabetes mellitus and is a risk factor for macro vascular (especially coronary heart) disease. It is a weaker predictor for future kidney disease in type 2 diabetes mellitus.

2) Blood Testing Procedures

a) Glucose tolerance test

Methodology and normal fasting glucose

Plasma or serum from venous blood samples has the advantage over whole blood of providing values for glucose that are independent of Haemtocrit and that reflect the glucose concentration to which body tissues are exposed. For these reasons, and because plasma and serum are more readily measured on automated equipment, they are used in most laboratories. If serum is used or if plasma is collected from tubes that lack an agent to block glucose metabolism (such as fluoride), samples should be refrigerated and separated within 1 hour after collection. The glucose concentration is 10–15% higher in plasma or serum than in whole blood because structural components of blood cells are absent.

Fasting blood Glucose

Fasting blood glucose is measured after an overnight fast of 10 hrs. Fasting blood glucose estimation is better than random blood glucose. FPG < 5.6 mmol/L (100 mg/dL) is considered normal; (2) FPG = 5.6–6.9 mmol/L (100–125 mg/dL) is defined as IFG; and (3) FPG >7.0 mmol/L (126 mg/dL) warrants the diagnosis of DM.

Criteria for laboratory confirmation of diabetes mellitus

If the fasting plasma glucose level is 126 mg/dL or higher on more than one occasion, further evaluation of the patient with a glucose challenge is unnecessary. However, when fasting plasma glucose is less than 126 mg/dL in suspected cases, a standardized oral glucose tolerance test may be done .

75 g of glucose dissolved in 300 mL of water is given after an overnight fast to a person who has been receiving at least 150–200 g of carbohydrate daily for 3 days before the test. The data is interpreted as follows-

The Diabetes Expert Committee criteria for evaluating the standard oral glucose tolerance test.

For proper evaluation of the test, the subjects should be normally active and free from acute illness. Medications that may impair glucose tolerance include diuretics, contraceptive drugs, glucocorticoids, niacin, and phenytoin should be avoided on that day.

Random blood Glucose

Random is defined as without regard to time since the last meal.

RBG measurement is required only during emergency. The current criteria for the diagnosis of DM emphasize that the FPG is the most reliable and convenient test for identifying DM in asymptomatic individuals. A random plasma glucose concentration >11.1 mmol/L (200 mg/dL) accompanied by classic symptoms of DM (polyuria, polydipsia, weight loss) is sufficient for the diagnosis of DM

b) Glycated hemoglobin (Hb1C) measurements

Hemoglobin becomes glycated by ketoamine reactions between glucose and other sugars and the free amino groups on the alpha and beta chains. Only glycation of the N-terminal valine of the beta chain imparts sufficient negative charge to the hemoglobin molecule to allow separation by charge dependent techniques. These charge separated hemoglobin are collectively referred to as hemoglobin A1 (HbA1). The major form of HbA1 is hemoglobin A1c (HbA1c) where glucose is the carbohydrate. HbA1c comprises 4–6% of total hemoglobin A1. The remaining HbA1 species contain fructose-1, 6 bisphosphate (HbA1a1); glucose-6-phosphate (HbA1a2); and unknown carbohydrate moiety (HbA1b). The hemoglobin A1c fraction is abnormally elevated in diabetic persons with chronic hyperglycemia.

Methods for measuring HbA1c include electrophoresis, cation-exchange chromatography, boronate affinity chromatography, and immunoassays. Office-based immunoassays using capillary blood give a result in about 9 minutes and this allows for immediate feedback to the patients regarding their glycemic control.

Since glycohemoglobins circulate within red blood cells whose life span lasts up to 120 days, they generally reflect the state of glycemia over the preceding 8–12 weeks, thereby providing an improved method of assessing diabetic control. Measurements should be made in patients with either type of diabetes mellitus at 3- to 4-month intervals so that adjustments in therapy can be made.

In patients monitoring their own blood glucose levels, HbA1c values provide a valuable check on the accuracy of monitoring.

Use of HbA1c for screening is controversial. Sensitivity in detecting known diabetes cases by HbA1c measurements is only 85%, indicating that diabetes cannot be excluded by a normal value. On the other hand, elevated HbA1c assays are fairly specific (91%) in identifying the presence of diabetes.

The accuracy of HbA1c values can be affected by hemoglobin variants or derivatives; the effect depends on the specific hemoglobin variant or derivative and the specific assay used. Immunoassays that use an antibody to the glycated amino terminus of beta globin do not recognize the terminus of the gamma globin of hemoglobin F. Thus, in patients with high levels of hemoglobin F, immunoassays give falsely low values of HbA1c. Cation-exchange chromatography separates hemoglobin species by charge differences. Hemoglobin variants that co-elute with HbA1c can lead to an overestimation of the HbA1c value. Chemically modified derivatives of hemoglobin such as carbamoylation (in renal failure) or Acetylation (high-dose aspirin therapy) can similarly co-elute with HbA1c by some assay methods.

Any condition that shortens erythrocyte survival or decreases mean erythrocyte age (eg, recovery from acute blood loss, hemolytic anemia) will falsely lower HbA1c irrespective of the assay method used. Alternative methods such as fructosamine should be considered for these patients. Vitamins C and E are reported to falsely lower test results possibly by inhibiting glycation of hemoglobin.

c) Serum fructosamine

Serum fructosamine is formed by nonenzymatic glycosylation of serum proteins (predominantly albumin). Since serum albumin has a much shorter half-life than hemoglobin, serum fructosamine generally reflects the state of glycemic control for only the preceding 1–2 weeks. Reductions in serum albumin (eg, nephrotic state or hepatic disease) will lower the serum fructosamine value. When abnormal hemoglobins or hemolytic states affect the interpretation of glycohemoglobins or when a narrower time frame is required, such as for ascertaining glycemic control at the time of conception in a diabetic woman who has recently become pregnant, serum fructosamine assays offer some advantage. Normal values vary in relation to the serum albumin concentration and are 1.5–2.4 mmol/L when the serum albumin level is 5 g/dL.

d) Self-monitoring of blood glucose

Capillary blood glucose measurements performed by patients themselves, as outpatients, are extremely useful. In type 1 patients in whom “tight” metabolic control is attempted, they are indispensable. There are several paper strip (glucose oxidase, glucose dehydrogenase, or hexokinase) methods for measuring glucose on capillary blood samples. A reflectance photometer or an amperometric system is then used to measure the reaction that takes place on the reagent strip.

e) Lipid profile

Circulating lipoproteins are just as dependent on insulin as is the plasma glucose. In type 1 diabetes, moderately deficient control of hyperglycemia is associated with only a slight elevation of LDL cholesterol and serum triglycerides and little if any change in HDL cholesterol. Once the hyperglycemia is corrected, lipoprotein levels are generally normal. However, in obese patients with type 2 diabetes, a distinct “diabetic dyslipidemia” is characteristic of the insulin resistance syndrome. Its features are a high serum triglyceride level (300–400 mg/dL), a low HDL cholesterol (less than 30 mg/dL), and a qualitative change in LDL particles, producing a smaller dense particle whose membrane carries supranormal amounts of free cholesterol. These smaller dense LDL particles are more susceptible to oxidation, which renders them more atherogenic. Since a low HDL cholesterol is a major feature predisposing to macrovascular disease, the term “dyslipidemia” has preempted the term “hyperlipidemia,” which mainly denoted the elevated triglycerides. Measures designed to correct the obesity and hyperglycemia, such as exercise, diet, and hypoglycemic therapy, are the treatment of choice for diabetic dyslipidemia, and in occasional patients in whom normal weight was achieved, all features of the lipoprotein abnormalities cleared

f) Additional Tests

In addition to the standard laboratory evaluation, the patient should be screened for DM-associated conditions (e.g., kidney, liver and thyroid dysfunction). Individuals at high risk for cardiovascular disease should be screened for asymptomatic CAD by appropriate cardiac stress testing, when indicated.

The classification of the type of DM may be facilitated by laboratory assessments. Serum insulin or C-peptide measurements do not always distinguish type 1 from type 2 DM, but a low C-peptide level confirms a patient’s need for insulin. Many individuals with new-onset type 1 DM retain some C-peptide production.

 Insulin levels generally are high early in the course of type 2 diabetes mellitus and gradually wane over time. Stimulated C-peptide concentrations (after a standard meal challenge such as Sustacal or after glucagon) are somewhat preserved until late in the course of type 2 diabetes mellitus. Absence of a C-peptide response to carbohydrate ingestion may indicate total beta cell failure.

Measurement of islet cell antibodies at the time of diabetes onset may be useful if the type of DM is not clear based on the characteristics described above. Antibodies to insulin, islet cells, or Glutamic acid decarboxylase (GAD) are absent in type 2 diabetes mellitus.

Latent autoimmune diabetes of adults, or LADA, is a form of slow-onset type 1 diabetes that occurs in middle-aged (usually white) adults. It can be differentiated from type 2 diabetes by measuring anti-GAD65 antibodies. Such patients may respond to insulin secretagogue for a brief period (months).

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Pathophysiology of Type 2 Diabetes Mellitus

Type 2 DM is characterized by impaired insulin secretion, insulin resistance, excessive hepatic glucose production, and abnormal fat metabolism. Obesity, particularly visceral or central (as evidenced by the hip-waist ratio), is very common in type 2 DM. In the early stages of the disorder, glucose tolerance remains near-normal, despite insulin resistance, because the pancreatic beta cells compensate by increasing insulin output .As insulin resistance and compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable to sustain the hyperinsulinemia state. Impaired Glucose Tolerance (IGT), characterized by elevations in postprandial glucose, then develops. A further decline in insulin secretion and an increase in hepatic glucose production lead to overt diabetes with fasting hyperglycemia. Ultimately, beta cell failure may ensue.

Abnormal Muscle and Fat Metabolism

Insulin resistance, the decreased ability of insulin to act effectively on target tissues (especially muscle, liver, and fat), is a prominent feature of type 2 DM and results from a combination of genetic susceptibility and obesity. Insulin resistance is relative, however, since supernormal levels of circulating insulin will normalize the plasma glucose. Insulin resistance impairs glucose utilization by insulin-sensitive tissues and increases hepatic glucose output; both effects contribute to the hyperglycemia. Increased hepatic glucose output predominantly accounts for increased FPG levels, whereas decreased peripheral glucose usage results in postprandial hyperglycemia. In skeletal muscle, there is a greater impairment in glycogen formation than in glucose metabolism through Glycolysis. Glucose metabolism in insulin-independent tissues is not altered in type 2 DM.

The precise molecular mechanism leading to insulin resistance in type 2 DM has not been elucidated. Insulin receptor levels and tyrosine kinase activity in skeletal muscle are reduced, but these alterations are most likely secondary to hyperinsulinemia and are not a primary defect. Therefore, “postreceptor” defects in insulin-regulated phosphorylation/dephosphorylation may play the predominant role in insulin resistance. For example, a PI-3-kinase signaling defect may reduce translocation of GLUT4 to the plasma membrane. Other abnormalities include the accumulation of lipid within skeletal myocytes, which may impair mitochondrial oxidative phosphorylation and reduce insulin-stimulated mitochondrial ATP production. Impaired fatty acid oxidation and lipid accumulation within skeletal myocytes may generate reactive oxygen species such as lipid peroxides. Of note, not all insulin signal transduction pathways are resistant to the effects of insulin (e.g., those controlling cell growth and differentiation using the mitogenic-activated protein kinase pathway). Consequently, hyperinsulinemia may increase the insulin action through these pathways, potentially accelerating diabetes-related conditions such as atherosclerosis.

The obesity accompanying type 2 DM, particularly in a central or visceral location, is thought to be part of the pathogenic process. The increased adipocyte mass leads to increased levels of circulating free fatty acids and other fat cell products .For example, adipocytes secrete a number of biologic products (nonesterified free fatty acids, retinol-binding protein 4, leptin, TNF-α, resistin, and adiponectin). In addition to regulating body weight, appetite, and energy expenditure, adipokines also modulate insulin sensitivity. The increased production of free fatty acids and some adipokines may cause insulin resistance in skeletal muscle and liver. For example, free fatty acids impair glucose utilization in skeletal muscle, promote glucose production by the liver, and impair beta cell function. In contrast, the production by adipocytes of adiponectin, an insulin-sensitizing peptide, is reduced in obesity and this may contribute to hepatic insulin resistance. Adipocyte products and adipokines also produce an inflammatory state and may explain why markers of inflammation such as IL-6 and C-reactive protein are often elevated in type 2 DM.

Impaired Insulin Secretion

Insulin secretion and sensitivity are interrelated. In type 2 DM, insulin secretion initially increases in response to insulin resistance to maintain normal glucose tolerance. Initially, the insulin secretory defect is mild and selectively involves glucose-stimulated insulin secretion Eventually, the insulin secretory defect progresses to a state of grossly inadequate insulin secretion.

The reason(s) for the decline in insulin secretory capacity in type 2 DM is unclear. The assumption is that a second genetic defect—superimposed upon insulin resistance—leads to beta cell failure. Islet amyloid polypeptide or amylin is co secreted by the beta cell and forms the amyloid fibrillar deposit found in the islets of individuals with long-standing type 2 DM. Whether such islet amyloid deposits are a primary or secondary event is not known. The metabolic environment of diabetes may also negatively impact islet function. For example, chronic hyperglycemia paradoxically impairs islet function (“glucose toxicity”) and leads to a worsening of hyperglycemia. Improvement in glycemic control is often associated with improved islet function. In addition, elevation of free fatty acid levels (“lipotoxicity”) and dietary fat may also worsen islet function. Beta cell mass is decreased in individuals with long-standing type 2 diabetes.

Increased Hepatic Glucose and Lipid Production

In type 2 DM, insulin resistance in the liver reflects the failure of hyperinsulinemia to suppress gluconeogenesis, which results in fasting hyperglycemia and decreased glycogen storage by the liver in the postprandial state. Increased hepatic glucose production occurs early in the course of diabetes, though likely after the onset of insulin secretory abnormalities and insulin resistance in skeletal muscle. As a result of insulin resistance in adipose tissue and obesity, free fatty acid (FFA) flux from adipocytes is increased, leading to increased lipid [very low density lipoprotein (VLDL) and triglyceride] synthesis in hepatocytes. This lipid storage or steatosis in the liver may lead to nonalcoholic fatty liver disease and abnormal liver function tests. This is also responsible for the dyslipidemia found in type 2 DM [elevated triglycerides, reduced high-density lipoprotein (HDL), and increased small dense low-density lipoprotein (LDL) particles].

Risk Factors for Type 2 Diabetes Mellitus

  • Family history of diabetes (i.e., parent or sibling with type 2 diabetes)
  • Obesity (BMI >25 kg/m2)
  • Habitual physical inactivity
  • Race/ethnicity (e.g., African-American, Latino, Native American, Asian American, Pacific Islander)
  • Previously identified IFG or IGT
  • History of GDM or delivery of baby >4 kg (>9 lb)
  • Hypertension (blood pressure >140/90 mmHg)
  • HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level >250 mg/dL (2.82 mmol/L)
  • Polycystic ovary syndrome or acanthosis nigricans
  • History of vascular disease

Symptoms and Signs

Type 1 diabetes

1)      Polyuria-Increased urination is a consequence of osmotic diuresis secondary to sustained hyperglycemia. This results in a loss of glucose as well as free water and electrolytes in the urine.

2)      Thirst (Polydipsia) is a consequence of the hyperosmolar state, as is blurred vision, which often develops as the lenses are exposed to hyperosmolar fluids.

3)      Weight loss despite normal or increased appetite is a common feature of type 1 when it develops sub acutely. The weight loss is initially due to depletion of water, glycogen, and triglycerides; thereafter, reduced muscle mass occurs as amino acids are diverted to form glucose and ketone bodies.

4)      Lowered plasma volume produces symptoms of postural hypotension.Total body potassium loss and the general catabolism of muscle protein contribute to the weakness.

5)      Paresthesias may be present at the time of diagnosis, particularly when the onset is sub acute. They reflect a temporary dysfunction of peripheral sensory nerves, which clears as insulin replacement restores glycemic levels closer to normal, suggesting neurotoxicity from sustained hyperglycemia. When absolute insulin deficiency is of acute onset, the above symptoms develop abruptly.

6)       Ketoacidosis exacerbates the dehydration and hyperosmolality by producing anorexia and nausea and vomiting, interfering with oral fluid replacement. The patient’s level of consciousness can vary depending on the degree of hyperosmolality. When insulin deficiency develops relatively slowly and sufficient water intake is maintained, patients remain relatively alert and physical findings may be minimal. When vomiting occurs in response to worsening ketoacidosis, dehydration progresses and compensatory mechanisms become inadequate to keep serum osmolality below 320–330 mOsm/L. Under these circumstances, stupor or even coma may occur. The fruity breath odor of acetone further suggests the diagnosis of diabetic ketoacidosis.

7)      Hypotension in the recumbent position is a serious prognostic sign.

8)      Loss of subcutaneous fat and muscle wasting are features of more slowly developing insulin deficiency. In occasional patients with slow, insidious onset of insulin deficiency, subcutaneous fat may be considerably depleted.

Type 2 Diabetes Mellitus

1)      While many patients with type 2 diabetes present with increased urination and thirst, many others have an insidious onset of hyperglycemia and are asymptomatic initially. This is particularly true in obese patients, whose diabetes may be detected only after Glycosuria or hyperglycemia is noted during routine laboratory studies.

2)      Occasionally, type 2 patients may present with evidence of neuropathic or cardiovascular complications because of occult disease present for some time prior to diagnosis.

3)       Chronic skin infections are common. Generalized pruritus and symptoms of vaginitis are frequently the initial complaints of women. Diabetes should be suspected in women with chronic Candida vulvovaginitis as well as in those who have delivered large babies (> 9 lb, or 4.1 kg) or have had polyhydramnios, preeclampsia, or unexplained fetal losses.

4)      Obese diabetics may have any variety of fat distribution; however, diabetes seems to be more often associated in both men and women with localization of fat deposits on the upper segment of the body (particularly the abdomen, chest, neck, and face) and relatively less fat on the appendages, which may be quite muscular. Standardized tables of waist-to-hip ratio indicate that ratios of “greater than 0.9” in men and “greater than 0.8” in women are associated with an increased risk of diabetes in obese subjects.

5)      Mild hypertension is often present in obese diabetics.

6)       Eruptive xanthomas on the flexor surface of the limbs and on the buttocks and Lipemia retinalis due to hyperchylomicronemia can occur in patients with uncontrolled type 2 diabetes who also have a familial form of hypertriglyceridemia.

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Etiology of Type 2 Diabetes Mellitus

This represents a heterogeneous group of conditions that used to occur predominantly in adults, but it is now more frequently encountered in children and adolescents. More than 90% of all diabetic persons in the United States are included under this classification. Circulating endogenous insulin is sufficient to prevent ketoacidosis but is inadequate to prevent hyperglycemia in the face of increased needs owing to tissue insensitivity (insulin resistance).

Genetic considerations

Genetic and environmental factors combine to cause both the insulin resistance and the beta cell loss. Most epidemiologic data indicate strong genetic influences, since in monozygotic twins over 40 years of age, concordance develops in over 70% of cases within a year whenever type 2 diabetes develops in one twin. Individuals with a parent with type 2 DM have an increased risk of diabetes; if both parents have type 2 DM, the risk approaches 40%. Insulin resistance, as demonstrated by reduced glucose utilization in skeletal muscle, is present in many nondiabetic, first-degree relatives of individuals with type 2 DM. The disease is polygenic and multifactorial since in addition to genetic susceptibility, environmental factors (such as obesity, nutrition, and physical activity) modulate the phenotype. The mechanisms by which these genetic alterations increase the susceptibility to type 2 diabetes are not clear.

Environmental factors

Obesity is the most important environmental factor causing insulin resistance. The degree and prevalence of obesity varies among different racial groups with type 2 diabetes. Visceral obesity, due to accumulation of fat in the omental and mesenteric regions, correlates with insulin resistance; subcutaneous abdominal fat seems to have less of an association with insulin insensitivity. Exercise may affect the deposition of visceral fat as suggested by CT scans of Japanese wrestlers, whose extreme obesity is predominantly subcutaneous. Their daily vigorous exercise program prevents accumulation of visceral fat, and they have normal serum lipids and euglycemia despite daily intakes of 5000–7000 kcal and development of massive subcutaneous obesity.

Several adipokines, secreted by fat cells, can affect insulin action in obesity. Two of these, leptin and adiponectin, seem to increase sensitivity to insulin, presumably by increasing hepatic responsiveness.Two others—tumor necrosis factor-α, which inactivates insulin receptors, and the newly discovered peptide, resistin—interfere with insulin action on glucose metabolism and have been reported to be elevated in obese animal models. Mutations or abnormal levels of these adipokines may contribute to the development of insulin resistance in human obesity.

Other Specific Types of Diabetes Mellitus

Maturity-onset diabetes of the young (MODY)

This subgroup is a relatively rare monogenic disorder characterized by non–insulin-dependent diabetes with autosomal dominant inheritance and an age at onset of 25 years or younger. Patients are nonobese, and their hyperglycemia is due to impaired glucose-induced secretion of insulin. Six types of MODY have been described. Except for MODY 2, in which a Glucokinase gene is defective, all other types involve mutations of a nuclear transcription factor that regulates islet gene expression.

MODY 2 is quite mild, associated with only slight fasting hyperglycemia and few if any microvascular diabetic complications. It generally responds well to dietary modifications or low doses of oral hypoglycemic agents. MODY 3—the most common form—accounts for two-thirds of all MODY cases. The clinical course is similar to that of idiopathic type 2 diabetes in terms of microangiopathy and failure to respond to oral agents with time.

Diabetes due to mutant insulins

This is a very rare subtype of nonobese type 2 diabetes, with no more than ten families having been described. Since affected individuals were heterozygous and possessed one normal insulin gene, diabetes was mild, did not appear until middle age, and showed autosomal dominant genetic transmission. There is generally no evidence of clinical insulin resistance, and these patients respond well to standard therapy.

Diabetes due to mutant insulin receptors

Defects in one of their insulin receptor genes have been found in more than 40 people with diabetes, and most have extreme insulin resistance associated with acanthosis nigricans. In very rare instances when both insulin receptor genes are abnormal, newborns present with a leprechaun-like phenotype and seldom live through infancy.

Diabetes mellitus associated with a mutation of mitochondrial DNA

Since sperm do not contain mitochondria, only the mother transmits mitochondrial genes to her offspring. Diabetes due to a mutation of mitochondrial DNA that impairs the transfer of Leucine or lysine into mitochondrial proteins has been described. Most patients have a mild form of diabetes that responds to oral hypoglycemic agents; some have a nonimmune form of type 1 diabetes. Two-thirds of patients with this subtype of diabetes have a hearing loss, and a smaller proportion (15%) had a syndrome of myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).

Wolfram’s syndrome

Wolfram’s syndrome is an autosomal recessive neurodegenerative disorder first evident in childhood. It consists of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, hence the acronym DIDMOAD. It is due to mutations in a gene named WFS1, which encodes a 100.3 KDa transmembrane protein localized in the endoplasmic reticulum. The function of the protein is not known.

Transient or permanent neonatal diabetes

Onset < 6 months of age, may be caused by several genetic mutations and requires treatment with insulin. Mutations in subunits of the ATP-sensitive potassium channel subunits are the major causes of permanent neonatal diabetes. Although these activating mutations impair glucose-stimulated insulin secretion, these individuals may respond to sulfonylureas and improve their glycemic control and can be treated with these agents. Homozygous Glucokinase mutations cause a severe form of neonatal diabetes.

Insulin Resistance Syndrome (Syndrome X; Metabolic Syndrome)

Twenty-five percent of the general nondiabetic obese population has insulin resistance of a magnitude similar to that seen in type 2 diabetes. These insulin-resistant nondiabetic individuals are at much higher risk for developing type 2 diabetes than insulin-sensitive persons. In addition to diabetes, these individuals have increased risk for elevated plasma triglycerides, lower high-density lipoproteins (HDLs), and higher blood pressure—a cluster of abnormalities termed syndrome X. These associations have now been expanded to include small, dense, low-density lipoprotein (LDL), hyperuricemia, abdominal obesity, prothrombotic state with increased levels of plasminogen activator inhibitor type 1 (PAI-1), and proinflammatory state.These clusters of abnormalities significantly increase the risk of atherosclerotic disease.

Pathophysiology of Type 1 Diabetes

Although other islet cell types [alpha cells (glucagon-producing), delta cells (somatostatin-producing), or PP cells (pancreatic polypeptide-producing)] are functionally and embryologically similar to beta cells and express most of the same proteins as beta cells, they are inexplicably spared from the autoimmune process.

Pathologically, the pancreatic islets are infiltrated with lymphocytes (in a process termed insulitis). After all beta cells are destroyed, the inflammatory process abates, the islets become atrophic, and most immunologic markers disappear. The precise mechanisms of beta cell death are not known but may involve the formation of nitric oxide metabolites, apoptosis, and direct CD8+ T cell cytotoxicity. The autoimmune destruction of pancreatic β-cells leads to a deficiency of insulin secretion. It is this loss of insulin secretion that leads to the metabolic derangements associated with IDDM.

In addition to the loss of insulin secretion, the function of pancreatic α-cells is also abnormal. There is excessive secretion of glucagon in IDDM patients. Normally, hyperglycemia leads to reduced glucagon secretion. However, in patients with IDDM, glucagon secretion is not suppressed by hyperglycemia. The resultant inappropriately elevated glucagon levels exacerbate the metabolic defects due to insulin deficiency .The most pronounced example of this metabolic disruption is that patients with IDDM rapidly develop diabetic ketoacidosis in the absence of insulin administration. Particularly problematic for long term IDDM patients is an impaired ability to secrete glucagon in response to hypoglycemia. This leads to potentially fatal hypoglycemia in response to insulin treatment in these patients.

Although insulin deficiency is the primary defect in IDDM, in patients with poorly controlled IDDM there is also a defect in the ability of target tissues to respond to the administration of insulin. There are multiple biochemical mechanisms that account for this impairment of tissues to respond to insulin. Deficiency in insulin leads to elevated levels of free fatty acids in the plasma as a result of uncontrolled lipolysis in adipose tissue. Free fatty acids suppress glucose metabolism in peripheral tissues such as skeletal muscle. This impairs the action of insulin in these tissues, i.e. the promotion of glucose utilization.

Additionally, insulin deficiency decreases the expression of a number of genes necessary for target tissues to respond normally to insulin such as Glucokinase in liver and the GLUT 4 class of glucose transporters in adipose tissue. The major metabolic derangements which result from insulin deficiency in IDDM are impaired glucose, lipid and protein metabolism.

Glucose Metabolism: Uncontrolled IDDM leads to increased hepatic glucose output. First, liver glycogen stores are mobilized then hepatic gluconeogenesis is used to produce glucose. Insulin deficiency also impairs non-hepatic tissue utilization of glucose. In particular in adipose tissue and skeletal muscle, insulin stimulates glucose uptake. This is accomplished by insulin-mediated movement of glucose transporter proteins to the plasma membrane of these tissues. Reduced glucose uptake by peripheral tissues in turn leads to a reduced rate of glucose metabolism. In addition, the level of hepatic Glucokinase is regulated by insulin. Therefore, a reduced rate of glucose phosphorylation in hepatocytes leads to increased delivery to the blood. Other enzymes involved in anabolic metabolism of glucose are affected by insulin (primarily through covalent modifications). The combination of increased hepatic glucose production and reduced peripheral tissues metabolism leads to elevated plasma glucose levels. When the capacity of the kidneys to absorb glucose is surpassed, Glycosuria ensues. Glucose is an osmotic diuretic and an increase in renal loss of glucose is accompanied by loss of water and electrolytes, termed polyuria. The result of the loss of water (and overall volume) leads to the activation of the thirst mechanism (polydipsia). The negative caloric balance which results from the glucosuria and tissue catabolism leads to an increase in appetite and food intake (polyphagia).

Lipid Metabolism: One major role of insulin is to stimulate the storage of food energy following the consumption of a meal. This energy storage is in the form of glycogen in hepatocytes and skeletal muscle. Additionally, insulin stimulates hepatocytes to synthesize triglycerides and storage of triglycerides in adipose tissue. In opposition to increased adipocyte storage of triglycerides is insulin-mediated inhibition of lipolysis. In uncontrolled IDDM there is a rapid mobilization of triglycerides leading to increased levels of plasma free fatty acids. The free fatty acids are taken up by numerous tissues (however, not the brain) and metabolized to provide energy. Free fatty acids are also taken up by the liver.

Normally, the levels of malonyl-CoA are high in the presence of insulin. These high levels of malonyl-CoA inhibit carnitine palmitoyl Transferase I, the enzyme required for the transport of fatty acyl-CoA’s into the mitochondria where they are subject to oxidation for energy production. Thus, in the absence of insulin, malonyl-CoA levels fall and transport of fatty acyl-CoA’s into the mitochondria increases. Mitochondrial oxidation of fatty acids generates acetyl-CoA which can be further oxidized in the TCA cycle. However, in hepatocytes the majority of the acetyl-CoA is not oxidized by the TCA cycle but is metabolized into the ketone bodies, Acetoacetate and β-hydroxybutyrate. These ketone bodies leave the liver and are used for energy production by the brain, heart and skeletal muscle. In IDDM, the increased availability of free fatty acids and ketone bodies exacerbates the reduced utilization of glucose furthering the ensuing hyperglycemia. Production of ketone bodies, in excess of the body’s ability to utilize them leads to ketoacidosis. In diabetics, this can be easily diagnosed by smelling the breath. A spontaneous breakdown product of acetoacetate is acetone which is volatilized by the lungs producing a distinctive odor.

Normally, plasma triglycerides are acted upon by lipoprotein lipase (LPL), an enzyme on the surface of the endothelial cells lining the vessels. In particular, LPL activity allows fatty acids to be taken from circulating triglycerides for storage in adipocytes. The activity of LPL requires insulin and in its absence a hypertriglyceridemia results.

Protein Metabolism: Insulin regulates the synthesis of many genes, either positively or negatively that then affect overall metabolism. Insulin has a global effect on protein metabolism, increasing the rate of protein synthesis and decreasing the rate of protein degradation. Thus, insulin deficiency will lead to increased catabolism of protein. The increased rate of proteolysis leads to elevated concentrations in plasma amino acids. These amino acids serve as precursors for hepatic and renal gluconeogensis. In liver, the increased gluconeogenesis further contributes to the hyperglycemia seen in IDDM.



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Diabetes Mellitus


Diabetes mellitus is a syndrome with disordered metabolism and inappropriate hyperglycemia due to either a deficiency of insulin secretion or to a combination of insulin resistance and inadequate insulin secretion to compensate.

Several distinct types of DM exist and are caused by a complex interaction of genetics and environmental factors. Depending on the etiology of the DM, factors contributing to hyperglycemia include reduced insulin secretion, decreased glucose utilization, and increased glucose production. The metabolic dysregulation associated with DM causes secondary pathophysiologic changes in multiple organ systems that impose a tremendous burden on the individual with diabetes and on the health care system.


DM is classified on the basis of the pathogenic process that leads to hyperglycemia, as opposed to earlier criteria such as age of onset or type of therapy. The two broad categories of DM are designated type 1 and type 2 .Both types of diabetes are preceded by a phase of abnormal glucose homeostasis as the pathogenic processes progresses. Type 1 diabetes is the result of complete or near-total insulin deficiency. Type 2 DM is a heterogeneous group of disorders characterized by variable degrees of insulin resistance, impaired insulin secretion, and increased glucose production. Distinct genetic and metabolic defects in insulin action and/or secretion give rise to the common phenotype of hyperglycemia in type 2 DM and have important potential therapeutic implications. Type 2 DM is preceded by a period of abnormal glucose homeostasis classified as impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).

Etiologic Classification of Diabetes Mellitus

I. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)

  A. Immune-mediated

  B. Idiopathic

II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly insulin secretory defect with insulin resistance)

A. Nonobese

B. Obese

III. Other specific types of diabetes

 A. Genetic defects of  cell function characterized by mutations in:

    1. Hepatocyte nuclear transcription factor (HNF) 4 α (MODY 1)-

    { MODY, maturity onset diabetes of the young}

    2. Glucokinase (MODY 2)

    3. HNF-1 α (MODY 3)

    4. Insulin promoter factor-1 (IPF-1; MODY 4)

    5. HNF-1β (MODY 5)

    6. NeuroD1 (MODY 6)

    7. Mitochondrial DNA

    8. Subunits of ATP-sensitive potassium channel

    9. Proinsulin or insulin conversion

 B. Genetic defects in insulin action

    1. Type A insulin resistance

    2. Leprechaunism

    3. Rabson-Mendenhall syndrome

    4. Lipodystrophy syndromes

C. Diseases of the exocrine pancreas—pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy, mutations in carboxyl ester lipase

D. Endocrinopathies—Acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma

E. Drug- or chemical-induced—Vacor, pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, , β -adrenergic agonists, thiazides, phenytoin, α-interferon, protease inhibitors, clozapine

F. Infections—congenital rubella, cytomegalovirus, coxsackie

G. Uncommon forms of immune-mediated diabetes—”stiff-person” syndrome, anti-insulin receptor antibodies

H. Other genetic syndromes sometimes associated with diabetes—Down’s syndrome, Klinefelter’s syndrome, Turner’s syndrome, Wolfram’s syndrome, Friedreich’s ataxia, Huntington’s chorea, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome

IV. Gestational diabetes mellitus (GDM)

Source: Adapted from American Diabetes Association, 2007.

The terms insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) are obsolete. Since many individuals with type 2 DM eventually require insulin treatment for control of glycemia.

Age is not a criterion in the classification system. Although type 1 DM most commonly develops before the age of 30, an autoimmune beta cell destructive process can develop at any age. It is estimated that between 5 and 10% of individuals who develop DM after age 30 have type 1 DM. Likewise, type 2 DM more typically develops with increasing age but is now being diagnosed more frequently in children and young adults, particularly in obese adolescents.

Etiology of Type 1 Diabetes

The global incidence of type 1 diabetes is increasing (approximately 3% each year).This form of diabetes is immune-mediated in over 90% of cases and idiopathic in less than 10%. The rate of pancreatic B cell destruction is quite variable, being rapid in some individuals and slow in others.

A) Immune-mediated type 1 diabetes mellitus

Approximately one-third of the disease susceptibility is due to genes and two-thirds to environmental factors.

Genes that are related to the HLA locus contribute about 40% of the genetic risk. About 95% of patients with type 1 diabetes possess either HLA-DR3 or HLA-DR4.The other important gene that contributes to about 10% of the genetic risk is found at the 5′ polymorphic region of the insulin gene. This polymorphic region affects the expression of the insulin gene in the thymus and results in depletion of insulin-specific T lymphocytes. 16 other genetic regions of the human genome have been identified as being important to pathogenesis but less is known about them.

Children of diabetic parents are at increased lifetime risk for developing type 1 diabetes. A child whose mother has type 1 diabetes has a 3% risk of developing the disease and a 6% risk if the child’s father has it. The risk in siblings is related to the number of HLA haplotypes that the sibling shares with the diabetic parent. If one haplotype is shared, the risk is 6% and if two haplotypes are shared, the risk increases to 12–25%. The highest risk is for identical twins, where the concordance rate is 25–50%.

Some patients with a milder expression of type 1 diabetes mellitus initially retain enough B cell function to avoid ketosis, but as their B cell mass diminishes later in life, dependence on insulin therapy develops. Up to 15% of “type 2” diabetic patients may actually have this mild form of type 1 diabetes (latent autoimmune diabetes of adulthood; LADA).

Environment- Which environmental factor is responsible for the increased risk is not known. There have been a number of different hypotheses including infections with certain viruses (rubella, Coxsackie B4) and consumption of cow’s milk. None of these factors has so far been confirmed as the culprit.

Types of Auto antibodies (Immunological Markers)

1. Islet cell cytoplasmic antibodies: The primary antibodies found in 90% of type 1 diabetics are against islet cell cytoplasmic proteins (termed ICCA, islet cell cytoplasmic antibodies). In non-diabetics ICCA frequency is only 0.5%–4%. The presence of ICCA is a highly accurate predictor of future development of IDDM, the titer of the ICCA tends to decline over time.

2. Islet cell surface antibodies: Auto antibodies directed against cell-surface antigens (ICSA) have also been described in as many as 80% of type 1 diabetics. Similar to ICCA, the titer of ICSA declines over time. Some patients with type 2 diabetes have been identified that are ICSA positive.

3. Specific antigenic targets of islet cells: Antibodies to Glutamic acid decarboxylase (GAD) have been identified in over 80% of patients newly diagnosed with IDDM. Like ICCA, anti-GAD antibodies decline over time in type 1 diabetics. The presence of anti-GAD antibodies is a strong predictor of the future development of IDDM in high-risk populations. Anti-insulin antibodies (IAA) have been identified in IDDM patients and in relatives at risk to develop IDDM. These IAA are detectable even before the onset of insulin therapy in type 1 diabetics. IAA are detectable in around 40% of young children with IDDM.

B) Idiopathic type 1 diabetes mellitus

Less than 10% of subjects have no evidence of pancreatic B cell autoimmunity to explain their insulinopenia and ketoacidosis. This subgroup has been classified as “idiopathic type 1 diabetes” and designated as “type 1B.” Although only a minority of patients with type 1 diabetes fall into this group, most of these are of Asian or African origin. 

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Insulin Biosynthesis, Secretion, and Action


Insulin is produced in the beta cells of the pancreatic islets. It is initially synthesized as a single-chain 86-amino-acid precursor polypeptide, preproinsulin. Subsequent Proteolytic processing removes the amino terminal signal peptide, giving rise to proinsulin. Proinsulin is structurally related to insulin-like growth factors I and II, which bind weakly to the insulin receptor. Cleavage of an internal 31-residue fragment from proinsulin generates the C peptide and the A (21 amino acids) and B (30 amino acids) chains of insulin, which are connected by disulfide bonds (Figure-1)The mature insulin molecule and C peptide are stored together and co secreted from secretory granules in the beta cells. Because the C peptide is cleared more slowly than insulin, it is a useful marker of insulin secretion and allows discrimination of endogenous and exogenous sources of insulin in the evaluation of hypoglycemia.

Figure-1-showing the synthesis of Insulin


Glucose is the key regulator of insulin secretion by the pancreatic beta cell, although amino acids, ketones, various nutrients, gastrointestinal peptides, and neurotransmitters also influence insulin secretion. Glucose levels > 3.9 mmol/L (70 mg/dL) stimulate insulin synthesis, primarily by enhancing protein translation and processing. Glucose stimulation of insulin secretion begins with its transport into the beta cell by the GLUT2 glucose transporter. Glucose phosphorylation by glucokinase is the rate-limiting step that controls glucose-regulated insulin secretion. Further metabolism of glucose-6-phosphate via Glycolysis generates ATP, which inhibits the activity of an ATP-sensitive K+ channel. This channel consists of two separate proteins: one is the binding site for certain oral hypoglycemic (e.g., sulfonylureas, meglitinides); the other is an inwardly rectifying K+ channel protein Inhibition of this K+ channel induces beta cell membrane depolarization, which opens voltage-dependent calcium channels (leading to an influx of calcium), and stimulates insulin secretion. (See figure-2)

Figure-2- showing mechanism of secretion of insulin

Insulin secretory profiles reveal a pulsatile pattern of hormone release, with small secretory bursts occurring about every 10 min, superimposed upon greater amplitude oscillations of about 80–150 min. Incretins are released from neuroendocrine cells of the gastrointestinal tract following food ingestion and amplify glucose-stimulated insulin secretion and suppress glucagon secretion (Figure-3). Glucagon-like peptide 1 (GLP-1), the most potent incretin, is released from L cells in the small intestine and that stimulates insulin secretion only when the blood glucose is above the fasting level. Incretin analogues, such as exena-tide, are being used to enhance endogenous insulin secretion.

Figure-3- showing Insulin release. The release is more marked after oral glucose load due to the release of Incretins from GIT.


Once insulin is secreted into the portal venous system, ~50% is degraded by the liver. Unextracted insulin enters the systemic circulation where it binds to receptors in target sites.

Figure-4 -showing the structure of Insulin receptor.The receptor is composed of two extracellular α-subunits that are each linked to a ß-subunit and to each other by disulfide bonds.

Insulin binding to its receptor stimulates intrinsic tyrosine kinase activity (See figure -5) leading to receptor autophosphorylation and the recruitment of intracellular signaling molecules, such as insulin receptor substrates (IRS). IRS and other adaptor proteins initiate a complex cascade of phosphorylation and dephosphorylation reactions, resulting in the widespread metabolic and mitogenic effects of insulin. As an example, activation of the phosphatidylinositol-3′-kinase (PI-3-kinase) pathway stimulates translocation of glucose transporters (e.g., GLUT4) to the cell surface, an event that is crucial for glucose uptake by skeletal muscle and fat. Activation of other insulin receptor signaling pathways induces glycogen synthesis, protein synthesis, lipogenesis, and regulation of various genes in insulin-responsive cells.

Figure-5- showing the  mechanism of action of Insulin

Glucose homeostasis reflects a balance between hepatic glucose production and peripheral glucose uptake and utilization. Insulin is the most important regulator of this metabolic equilibrium, but neural input, metabolic signals, and other hormones (e.g., glucagon) result in integrated control of glucose supply and utilization.

In the fasting state, low insulin levels increase glucose production by promoting hepatic Gluconeogenesis and glycogenolysis and reduce glucose uptake in insulin-sensitive tissues (skeletal muscle and fat), thereby promoting mobilization of stored precursors such as amino acids and free fatty acids (lipolysis). Glucagon, secreted by pancreatic alpha cells when blood glucose or insulin levels are low, stimulates glycogenolysis and gluconeogenesis by the liver and renal medulla.

Figure-6- showing glucose homeostasis mediated by Insulin

Postprandially, the glucose load elicits a rise in insulin and fall in glucagon, leading to a reversal of these processes( Figure-6). Insulin, an anabolic hormone, promotes the storage of carbohydrate and fat and protein synthesis. The major portion of postprandial glucose is utilized by skeletal muscle, an effect of insulin-stimulated glucose uptake. Other tissues, most notably the brain, utilize glucose in an insulin-independent fashion.

Insulin and Lipid Metabolism

The metabolic pathways for utilization of fats and carbohydrates are deeply and intricately intertwined. Considering insulin’s profound effects on carbohydrate metabolism, it stands to reason that insulin also has important effects on lipid metabolism, including the following:

Fatty acid synthesis-Insulin promotes synthesis of fatty acids in the liver. insulin is stimulatory to synthesis of glycogen in the liver. However, as glycogen accumulates to high levels (roughly 5% of liver mass), further synthesis is strongly suppressed.

When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.

Fatty acid oxidation-Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids.

Synthesis of Glycerol-Insulin facilitates entry of glucose into adipocytes, and within those cells, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride within the adipocyte. By these mechanisms, insulin is involved in further accumulation of triglyceride in fat cells.

From a whole body perspective, insulin has a fat-sparing effect. Not only does it drive most cells to preferentially oxidize carbohydrates instead of fatty acids for energy, insulin indirectly stimulates accumulation of fat in adipose tissue.

Figure-7 -showing the effect of Insulin of fatty acid synthesis and oxidation. Insulin inhibits hormone sensitive lipase and hence inhibits adipolysis.

Other Notable Effects of Insulin

 Amino acid metabolism-In addition to insulin’s effect on entry of glucose into cells, it also stimulates the uptake of amino acids, again contributing to its overall anabolic effect. When insulin levels are low, as in the fasting state, the balance is pushed toward intracellular protein degradation.

Electrolyte balance-Insulin also increases the permeability of many cells to potassium, magnesium and phosphate ions. The effect on potassium is clinically important. Insulin activates sodium-potassium ATPases in many cells, causing a flux of potassium into cells. Under certain circumstances, injection of insulin can kill patients because of its ability to acutely suppress plasma potassium concentrations.

Insulin Deficiency and Excess Diseases

Diabetes mellitus, the most important metabolic disease ,is an insulin deficiency state. Two principal forms of this disease are recognized:

Type I or insulin-dependent diabetes mellitus is the result of a frank deficiency of insulin. The onset of this disease typically is in childhood. It is due to destruction pancreatic beta cells, most likely the result of autoimmunity to one or more components of those cells. Many of the acute effects of this disease can be controlled by insulin replacement therapy. Maintaining tight control of blood glucose concentrations by monitoring, treatment with insulin and dietary management will minimize the long-term adverse effects of this disorder on blood vessels, nerves and other organ systems, allowing a healthy life.

Type II or non-insulin-dependent diabetes mellitus begins as a syndrome of insulin resistance. That is, target tissues fail to respond appropriately to insulin. Typically, the onset of this disease is in adulthood. Despite monumental research efforts, the precise nature of the defects leading to type II diabetes have been difficult to ascertain, and the pathogenesis of this condition is plainly multifactorial. Obesity is clearly a major risk factor, but in some cases of extreme obesity in humans and animals, insulin sensitivity is normal. Because there is not, at least initially, an inability to secrete adequate amounts of insulin, insulin injections are not useful for therapy. Rather the disease is controlled through dietary therapy and hypoglycemic agents.

Hyperinsulinemia or excessive insulin secretion is most commonly a consequence of insulin resistance, associated with type 2 diabetes or the metabolic syndrome. More rarely, hyperinsulinemia results from an insulin-secreting tumor (insulinoma) in the pancreas. Hyperinsulinemia due to accidental or deliberate injection of excessive insulin is dangerous and can be acutely life-threatening because blood levels of glucose drop rapidly and the brain becomes starved for energy (insulin shock).

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Q.1- What is the biochemical basis for the followings in Diabetes mellitus

a) Weight loss

b) Paresthesias

c) Increased susceptibility to infections

d) Non healing ulcers

e) Blindness

f) Hypoglycemia

g) Lactic acidosis

h) Ketosis

i) Hypercholesterolemia

j) High risk for IHD

Q- 2 What is Glycated hemoglobin? What is its significance in the diagnosis of Diabetes mellitus?

Q.3- What is the cause of Hypokalemia upon insulin administration in diabetics?

Q.4.- What is Maturity onset diabetes mellitus of young (MODY)?

Q.5-What is LADA (Latent Auto immune diabetes mellitus of Adults)?

Q.6- What are the important differences between Type 1 and Type 2 diabetes mellitus?

Q.7- What is the cause of insulin resistance in type 2 diabetes mellitus?

Q.8-A 35 year- old woman reported with classical symptoms of polyuria, Polyphagia and Polydipsia. Her fasting blood glucose was 190 mg/dl. She was diagnosed with Diabetes mellitus and was started with oral hypoglycemic drugs. A week later her blood glucose was repeated and was found to be 234 mg/dl.  What could be the reason for increasing blood glucose level despite glucose lowering therapy? Which investigation should be carried out for further diagnosis?

Q.9-What is the significance of estimating c-peptide levels?

Q.10- What are diabetes prone states?

Q.11-What are the secondary causes of diabetes mellitus?

Q.12- What is the significance of detecting microalbuminuria in diabetes mellitus?

Q.13-What is the biochemical basis for impaired glucose uptake in skeletal muscles and adipose tissue in diabetes mellitus?

Q.14- What is the biochemical basis for complications in diabetes mellitus?

Q.15- What are the acute complications of diabetes mellitus?

Q.16-What are late onsets or chronic complications of diabetes mellitus?

Q.17-What is meant by “Advanced glycation end products”?

Q.18- What are the metabolic alterations brought about in the absence of insulin in diabetes mellitus?

Q.19- Enumerate the different tests carried out for the diagnosis of diabetes mellitus?

Q.20 Suggest a healthy diet for a diabetic patient? What is the role of dietary fiber?

Q.21- What is the treatment for diabetic ketoacidosis?

Q.22- What should be the fasting and post load blood glucose values for a person to be declared as  having impaired glucose tolerance?

Q.23- What are the indication for carrying out oral glucose tolerance test ?

Q.24 -What is the criteria for the laboratory diagnosis of diabetes mellitus after oral glucose tolerance test?

Q.25- What is the significance of serum fructosamine estimation in diabetes mellitus?

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