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.Please help "Biochemistry for Medics" by CLICKING ON THE ADVERTISEMENTS above!
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 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.
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 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.
Please help "Biochemistry for Medics" by CLICKING ON THE ADVERTISEMENTS above!