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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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