Metabolic Changes in Type-2 Diabetes Mellitus - Assignment Example

Metabolic Changes in Type-2 Diabetes Mellitus Introduction Diabetes mellitus can be defined as a group of clinical syndromes characterized by hyperglycemia arising as a result of absolute or relative insulin deficiency (Edwards, 724). There are basically 2 types of diabetes mellitus. While type-1 is due to absolute insulin deficiency as a result of pancreatic beta-cell destruction, there is relative insulin deficiency in type-2 as a result of combination of peripheral resistance to insulin action and an inadequate secretory response by the beta cells (Kumar, p.1190). Type 2 diabetes is the most common form of diabetes constituting 90% of diabetic population (Ramachandran, p.1471). Since the etiology of both the conditions is different, the metabolic changes are also different. The literature review elaborated in this article will deal with metabolic changes in type-2 diabetes mellitus. Metabolic changes in type-2 diabetes mellitus The main metabolic defects in type-2 diabetes mellitus are decreased ability of the peripheral tissues to respond to insulin and inadequate secretion of insulin by beta cells of pancreas which are the only source of insulin production in the body. Of the two, in most of the cases, the first defect to develop is insulin resistance which is defined as resistance to the effects of insulin on glucose uptake, metabolism and storage (Kumar, p.1195). This defect further leads to decreased uptake of glucose in muscle and adipose tissues. Both the defects must be present for the development of hyperglycemia. Most of the obese patients have insulin resistance, but only those with an inability to increase beta-cell production of insulin develop diabetes (Votey, eMedicine). The impaired insulin secretion in type-2 diabetes is due to beta cell dysfunction (DeFronzo, p.117). The beta cells fail to adapt themselves for the long-term demands of peripheral insulin resistance and increased insulin secretion (Kumar, p.1196). In type-2, this dysfunction is both quantitative and qualitative. There is loss of normal pulsatile, oscillating pattern of insulin secretion and the rapid first phase of insulin secretion which is a normal response to elevated plasma glucose is attenuated. There is also decrease in beta cell mass, islet degeneration and deposition of islet amyloid (Kumar, p.1196). Infact, studies have established the onset of insulin resistance much before the manifestations of hyperglycemia (DeFronzo, p.117). The pancreas beta-cell function declines gradually over time already before the onset of clinical hyperglycaemia (Stumvoll, p.1333). The factors which probably lead to insulin resistance are increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for beta-cell dysfunction (Stumvoll, 1333). The fasting insulin levels in patients with type-2 diabetes may be either normal or increased and the basal insulin levels increased (DeFronzo, p.117). As the glucose concentration of the blood increases, the insulin levels also increase initially but after a certain range, beyond 140mg/dl, the insulin secretion is not sustained and the fasting insulin concentration declines precipitously. It is at this point that hepatic glucose production begins to rise and the hormone will not be able to suppress hepatic gluconeogenesis (Kumar, p.1196). Thus the natural history of type-2 diabetes can be described as that starting with normal glucose tolerance, insulin resistance, and compensatory hyperinsulinemia with progression to impaired glucose tolerance (IGT) and overt diabetes mellitus and it can be said that hyperinsulinemia precedes the development of type 2 diabetes and hyperinsulinemia is a strong predictor of the development type 2 diabetes (Edwards, 724). Lipotoxicity is an acquired cause of the progressive decline in beta cell function as individuals progress from impaired glucose tolerance to overt type 2 diabetes mellitus. Various studies have shown the association between obesity and insulin resistance. It has been reported that central obesity is more associated with diabetes. Reasons for this relationship could be that there is an inverse correlation between fasting plasma free fatty acids (FFAs) and insulin sensitivity. The short term exposure to increases in free fatty acids stimulates insulin secretion. Also, the level of intracellular triglycerides is markedly increased in muscle and liver tissues in obese individuals because the increased circulating FFAs are deposited in these organs (Kumar, 1195). Raised FFAs and intracellular triglycerides are potent inhibitors of insulin signalling. Another aspect is that there is dysregulation of adipokine secretion which further contributes to the insulin resistance (Kumar, 1195). In all cases of diabetes, there is decreased anabolism and increased catabolism. When the concentration of the glucose in plasma exceeds renal threshold (usually 180mg/dl), glucose can be spotted in urine and this is known as glycosuria. Glycosuria causes polyuria due to more absorption of water into the tubules along with glucose. Polyuria leads to polydipsia. The severity of polyuria and polydipsia is dependent upon the degree of glycosuria. If the development of hyperglycemia is gradual over many years, the renal threshold also increases. Such patients may not have obvious symptoms of diabetes, namely polyuria and polydipsia. In the progression from normal glucose tolerance to abnormal glucose tolerance, postprandial glucose levels first increase and eventually fasting hyperglycemia occurs due to hepatic gluconeogenesis (Votey, eMedicine). Though most of the patients with type-2 diabetes present with polyuria and polydipsia, some may present with recurrent infections or non-healing wounds. In some others there may not be any symptoms at all and they are diagnosed during routine tests. Rarely, diabetic ketoacidosis may be the first presentation of diabetes. This condition is actually more common in type-1 diabetes and infact rare in type-2 diabetes. Ketoacidosis occurs due to lipolysis. Lipolysis occurs because, the increased glucose levels are unable to enter target cells and since these cells need energy, they burn the fat. Lipolysis leads to increase in fatty acids in the blood. These are taken up by the liver and metabolism in the liver yields acetoacetic acid and hydroxybutyric acid. Both these compounds are known as ketone bodies. These are utilized for energy but when the rate of production increases, hyperketonemia results causing metabolic acidosis and dehydration. Increased lipolysis can cause weight loss and increased gluconeogenesis can cause wasting (Edwards, 724). The long-term complications of diabetes mellitus result from the damaging effect of hyperglycemia on the blood vessels which eventually leads to disease of the eyes (retinopathy), nerves (neuropathy), and kidneys (nephropathy) (Kumar, 1195). Tissues like nerves, lenses, kidneys and blood vessels do not require insulin for transport of glucose. Hyperglycemia leads to increased intracellular glucose in these tissues. The glucose is then metabolized by aldose reductase to sortibitol and then fructose. This process uses NADPH which gradually gets depleted which leads to oxidative stress in the cells. Thus damage to the organs occurs (Kumar, p.1195). Intracellular hyperglycemia stimulates the de novo synthesis of diacyl glycerol from glycolytic intermediates. This causes activation of protein kinase C. Activation of protein kinase C leads to neovascularisation in retina and diabetic retinopathy, increased depositon of extra cellular matrix, fibrinolysis and production of pro-inflammatory cytokines (Kumar, p.1195). Conclusion Diabetes mellitus type-2 occurs due to metabolic defects in insulin production and also insulin sensitivity. These defects lead to the development of hyperglycemia. As the glucose levels go beyond the renal threshold, glycosuria starts occurring which leads to polyuria and polydipsia. On the other hand, hyperglycemia causes gluconeogenesis and further increase in glucose levels in the blood. Lipolysis also occurs which can rarely cause ketoacidosis. Thus hyperglycemia has both anabolic and catabolic effects. In certain tissues like nerves, lenses, kidneys and blood vessels which do not require insulin for transport of glucose, there is loading of cells with glucose. This glucose is metabolized into sorbitol during which process depletion of NADPH leads to oxidative stress and injury to the cells. Chronic injury cause diabetic complications in the form of retinopathy, neuropathy and nephropathy. References DeFronzo, RA. “Pathogenesis of type 2 diabetes mellitus: metabolic and molecular implications for identifying diabetes genes.” Diabetes , 1997, pgs.117-269. Edwards, CRW, Baird, JD, Frier, BM, Sfepherd, J and Toft, AD. " Endocrine and metabolic diseases, including diabetes mellitus." In: Davidsons Principles and Practice of Medicine. 17th edition. New York: Chuchill Livingstone, pgs.724-735. Kumar, Vinay, Abbas, Abul and Fausto, Nelson. Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Saunders Publishers, 2007, pgs. 1195 Ramachandran, A, Snehalatha, C and Vishwanathan, V. “Burden of Type-2 Diabetes and its complications- The Indian Scenario.” Current Science, 2002, 83(12), pgs. 1471-1475. Stumvoll M, Goldstein BJ, van Haeften TW. “Type 2 diabetes: principles of pathogenesis and therapy.” Lancet, 2005, 365(9467), pgs. 1333-46 Votey, SR. “Diabetes Mellitus, Type 2 - A Review.” eMedicine from WebMD, 2005. 13th Nov., 2007 Read More