Managed Care - October 2008 - (Page 39) However, we now know that these diagnostic criteria focus on only a small part of the disease process. The two main physiologic abnormalities of type 2 diabetes are insulin resistance and β-cell dysfunction. Insulin resistant cells fail to respond to circulating insulin. As a result, skeletal muscle is unable to properly utilize plasma glucose, and the liver inappropriately synthesizes glucose. Adipose tissue, in particular, and visceral fat stores enlarge and further contribute to insulin resistance. Plasma glucose levels rise, necessitating increased insulin secretion from pancreatic β-cells. There is a period prior to the onset of symptoms in which the β-cells can keep up with the enhanced demand for insulin secretion (see figure 1). The compensatory increase in circulating insulin prevents elevation of glucose levels. Eventually, however, increasing end-organ insulin resistance coupled with β-cell exhaustion leads to the development of hyperglycemia (DeFronzo 1988, Goldstein 2002). Insulin resistance alone does not result in the development of diabetes. When insulin resistance first occurs, insulin secretion increases so that normal glucose tolerance is maintained. When insulin demand outstrips the capacity of insulin production by β-cells, glucose tolerance is impaired. During this period of insulin resistance and hyperinsulinemia, pathophysiologic alterations to large and small blood vessels are hastening the development of diabetic complications (DeFronzo 1988, Weyer 2001). There are two main components of β-cell dysfunction. These include secretory defects in which cells show a diminished acute insulin response to glucose, a reduced ability to compensate for insulin resistance, and inhibited potentiation of non-glucosestimulated insulin secretion. Deficiencies in the glucose-sensing mechanism of β-cells result in a reduced ability to detect and respond to oscillations in glucose levels and a shift in the relationship between glucose levels and insulin secretion (Polonsky 1996). There is tremendous overlap between type 2 diabetes and the metabolic syndrome. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) describes metabolic syndrome as a constellation of risk factors that includes abdominal or visceral obesity; atherogenic dyslipidemia (elevated triglycerides, small dense LDL particles, and low HDL-cholesterol); elevated blood pressure; insulin resistance; and prothrombotic and proinflammatory states (Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults 2001, Grundy 2004). Visceral adiposity is closely associated with insulin resistance and elevated levels of free fatty acids. These conditions stimulate hepatic apolipoprotein B secretion and hepatic lipase activity, contributing to the dyslipidemia that is characteristic of both the metabolic syndrome and type 2 diabetes (Brunzell 1999). Hypertension, a defining component of the metabolic syndrome, is extremely common in patients with insulin resistance and/or diabetes. In addition, levels of proinflammatory cytokines including tumor necrosis factor-α interleukinFIGURE 1 Natural history of type 2 diabetes 350 300 250 200 150 100 50 250 Relative function 200 150 100 50 0 Glucose (mg/dL) 6, and C-reactive protein are elevated in insulin-resistant, obese individuals; their presence predicts the subsequent development of diabetes and cardiovascular disease. The complications of insulin resistance and type 2 diabetes lead to staggering morbidity and mortality. Approximately 65 percent of deaths in people with diabetes are due to cardiovascular disease and stroke. Mortality due to cardiovascular disease is elevated up to fourfold among adults with diabetes compared to those without diabetes. The risk of cerebrovascular incident is similarly elevated among people with diabetes and lower-limb amputations are rampant in this population. Hypertension is also extremely common. It is critical for people with diabetes to be treated both to ameliorate hyperglycemia and to minimize the impact of cardiovascular pathology. Interventions may include controlling blood pressure, aggressive management of dyslipidemia, use of antiplatelet agents, and encouraging smoking cessation. Microvascular changes result in compromised function in the kidneys, eyes, and nervous system. Diabetic retinopathy is the leading cause of new cases of blindness among adults ages 20 to 74, and diabetic nephropathy is the leading cause of Post-meal glucose Obesity — inactivity genetics Fasting glucose Insulin resistance Pre-diabetes (IFG, IGT) metabolic syndrome −15 −10 −5 Diabetes diagnosis 5 Insulin response 10 15 20 25 30 0 Onset OCTOBER 2008 / MANAGED CARE 39
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