Fluctuations in insulin sensitivity occur during the normal life cycle, with insulin resistance being observed during puberty, pregnancy, and with ageing. On the other hand, increased physical activity and increased carbohydrate intake are associated with enhanced insulin sensitivity. Hence P-cells are markedly adaptable in their ability to regulate insulin release in a very precise manner. Obviously, the P-cell is fundamental to ensuring that in healthy subjects, plasma glucose levels remain within a narrow physiological range [for review, see 30].
In healthy individuals, there is a feedback loop between the insulin-sensitive tissues and the P-cells, with P-cells increasing insulin supply in response to demand by the liver, muscles and adipose tissue. The relationship between insulin sensitivity and insulin levels is reciprocal and hyperbolic . In response to changes in insulin sensitivity, insulin release increases or decreases reciprocally to maintain normal glucose tolerance. Insulin sensitivity is almost always decreased in obesity and insulin-resistant individuals, whether lean or obese, have greater insulin responses and lower hepatic insulin clearance than insulin-sensitive individuals. In contrast, individuals with high risk of developing T2D display inadequate insulin release for any level of insulin sensitivity at any stage of the disease and even when they have normal glucose tolerance, suggesting that p-cell function has already being decreased before the development of hyperglycemia . Hence, failure of this feedback loop seems to contribute to the development of DM.
Another important implication of this feedback loop is that assessment of p-cell function requires knowledge of both insulin sensitivity and the insulin response, in other words the interpretation of the p-cell's secretory response to a given stimulus must take into account the prevailing degree of insulin sensitivity. This ability of the p-cell to adapt to changes in insulin sensitivity seems to result from (1) the functional responsiveness of the cell and (2) p-cell mass. In response to the insulin resistance observed in obesity, puberty and pregnancy, human p-cells can increase insulin release to levels 4- to 5-fold higher than in insulin-sensitive individuals, whereas p-cell volume is only enhanced by about 50%. In individuals with normal p-cells, glucose tolerance is preserved during these periods of insulin resistance as the decrease in insulin sensitivity is matched by a compensatory increase in insulin release. In contrast, in groups of people with T2D and those at increased risk of developing T2D, the decline in insulin sensitivity is not matched by a reciprocal increase in the insulin response. Instead, the insulin response also declines, which is compatible with the idea of p-cell dysfunction .
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