Endocrine Pancreas and Type 2 Diabetes

From the previous discussions, it is clear that the endocrine pancreas is a complexly regulated organ that integrates incoming impulses of nutrient, hormonal, and neural nature. The endocrine pancreas converts these impulses to an optimal secretion of the islet hormones mainly for the regulation of carbohydrate homeostasis. An example of the consequences that follow derangement of the endocrine pancreas is type 2 diabetes. A primary event during the development of this disease is a reduced action of insulin on the activation of peripheral insulin receptors.156 This results in a compensatory increase in insulin secretion, which explains the hyperinsulinemia that accompanies states with peripheral insulin insensitivity, such as obesity. The relation between

Insulin sensitivity

FIGURE 78-3. Schematic illustration of the relation between insulin sensitivity and insulin secretion. During progression to insulin resistance (i.e., low insulin sensitivity), insulin secretion is increased in a compensatory manner. The relation between the two variables is nonlinear and best described by a hyperbolic function. If insulin secretion is adequate in relation to insulin sensitivity, normal glucose tolerance (NGT) remains. However, if the B cells fail to compensate insulin resistance adequately, impaired glucose tolerance or type 2 diabetes develops.

Insulin sensitivity

FIGURE 78-3. Schematic illustration of the relation between insulin sensitivity and insulin secretion. During progression to insulin resistance (i.e., low insulin sensitivity), insulin secretion is increased in a compensatory manner. The relation between the two variables is nonlinear and best described by a hyperbolic function. If insulin secretion is adequate in relation to insulin sensitivity, normal glucose tolerance (NGT) remains. However, if the B cells fail to compensate insulin resistance adequately, impaired glucose tolerance or type 2 diabetes develops.

insulin sensitivity and insulin secretion is tightly regulated, and careful mathematic analyses have shown that the relation displays a curvilinear function that is best fit by a hyperbolic function (Fig.78-3),157458 as first demonstrated by Bergman and collaborators in the early 1980s.157 Hence, when insulin resistance develops, normal islet function ensures adequate hyperinsulinemia. These patients thus have normo-glycemia and hyperinsulinemia. This is, for example, seen in the many subjects with obesity, who have insulin resistance but have compensated with a sufficient increase in insulin secretion to avoid glucose intolerance.

However, in patients who proceed to type 2 diabetes, there is a defect in glucose action on the B cells, leading to impaired glucose-stimulated insulin secretion, making it impossible for the B cells to compensate fully for the peripheral insulin insensitivity. This leads to hyperglycemia and diabetes.19159 Hence, the main defect in type 2 diabetes is defective beta cells; insulin resistance can be regarded as a risk factor because it may unmask the defective islet function. Also, the ability of the A cells to respond properly with inhibition of glucagon secretion when the glucose level is increased is impaired in diabetes.159 This leads to hyperglucagonemia, which, together with the insufficient hyperinsulinemia, increases the hepatic glucose output and reduces the glucose uptake in peripheral tissues, which are the metabolic signs of type 2 diabetes. Central to the disease is the inability of the B cells to respond normally to increased glucose levels. This may be due both to impaired function of the individual B cells and to reduced number of B cells, for example, through apop-tosis.160 The cellular biology basis for this defect is still poorly understood. For the development of type 2 diabetes, furthermore, it has been demonstrated that it is mainly the first, initial, phase of insulin secretion that is of importance.161 Hence, appropriate early treatment of the disease is augmentation of the first or early phase of insulin secretion (the first 10 to 15 minutes) after meal ingestion, which is instituted by rapid secretagogues such as nateglinide and repaglinide121 together with improvement of insulin resistance by life style intervention and drugs such as metformin and thiazolidinediones.

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