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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #131: Pathogenesis of Type 2 Diabetes Mellitus Part 2

Jun 26, 2018

Natural history of type 2 diabetes

The natural history of T2DM has been well described in multiple populations [1,3,22–32] and is reviewed in references [1] and [3]. Individuals destined to develop T2DM inherit a set of genes from their parents that make their tissues resistant to insulin [1–3,33–37] and the insulin resistance is aggravated by weight gain and physical inactivity. Hepatic insulin resistance is manifested by an overproduction of glucose during the basal state despite the presence of fasting hyperinsulinemia [38] and an impaired suppression of hepatic glucose production (HGP)


in response to insulin [39], as occurs following a meal [40]. Muscle insulin resistance [6,36,39,41] is manifest by impaired glucose uptake following ingestion of a carbohydrate meal and results in postprandial hyperglycemia [40]. The origin of the insulin resistance can be traced to the genetic background [2,34,42]. However, the epidemic of diabetes that has enveloped Westernized countries primarily results from the epidemic of obesity and physical inactivity [43]. Both obesity [44] and decreased physical activity [45] are insulin-resistant states and, when added to the genetic burden of the insulin resistance, place a major stress on the pancreatic β cells to augment their secretion of insulin to offset the defect in insulin action [1–3]. Initially the β cells augment their secretion of insulin to offset the insulin resistance and glucose tolerance remains normal [46]. However, with time the β cells begin to fail and initially the postprandial plasma glucose levels and subsequently the fasting plasma glucose concentration rise, leading to the onset of overt diabetes [1–3,47,48]. Collectively, the insulin resistance In muscle and liver and β-cell failure have been referred to as the Triumvirate [1] (Figure 25.1). The resultant hyperglycemia and poor metabolic control may cause a further decline in insulin sensitivity, but it is the progressive β-cell failure that determines the rate of disease progression.

Although the relative contributions of insulin resistance and β-cell failure to the development of\ T2DM may vary amongst different ethnic groups [49], progressive β-cell failure superimposed upon a background of insulin resistance represent the core pathophysiologic defects responsible for the development of overt diabetes [1–3,50].

The natural history of T2DM described above [1–3] is depicted by a prospective 6-year study carried out by Felber and colleagues [26] (Figure 25.2). Subjects had a euglycemic insulin clamp to measure tissue sensitivity to insulin and an oral glucose tolerance test (OGTT) to provide a measure of glucose tolerance and β-cell function. As lean subjects gain weight, insulin sensitivity declines but glucose tolerance remains normal because of the compensatory increase in insulin secretion.With time the obese normal glucose-tolerant (NGT) individuals progress to impaired glucose tolerance (IGT) in association with a further reduction in insulin sensitivity. However, the rise in plasma glucose concentration is modest because of a further compensatory increase in insulin secretion. However, people with IGT are in a very precarious position, since they are maximally or near maximally insulin resistant, and their β-cell function is severely impaired even though, in absolute terms, their plasma insulin response is increased (see subsequent 140 discussion). With time the β cells cannot continue to produce these very large amounts of insulin and the obese IGT individual progresses to overt diabetes. The decline in glucose tolerance is associated with a marked decrease in insulin secretion without further or minimal change in insulin sensitivity (Figure 25.2). This characteristic rise in insulin response to insulin resistance and hyperglycemia, followed by a subsequent decline, has been referred to as Starling’s curve of the pancreas [1] and is characteristic of the natural history of T2DM in many diverse ethnic populations [1–3,22–32,51,52].

A similar pattern of insulin secretion has been observed during the development of diabetes in primates [53,54]. The aging primate becomes obese and a high percentage develop typical T2DM.The earliest detectable abnormality (preceding the onset of diabetes mellitus) is a decrease in tissue sensitivity to insulin with a compensatory increase in fasting and glucose-stimulated plasma insulin concentrations. With time, the high rate of insulin secretion cannot be maintained, the β cell starts on the downward slope of Starling’s curve and fasting hyperglycemia and glucose intolerance ensue.