Glucose Stimulated Insulin Secretion

Glucose uptake into the pancreatic p-cell is the initial step in glucose-stimulated insulin secretion (GSIS). This glucose transport is mediated by GLUT2, a low-affinity (Km = 17mmol/l) glucose transporter [16]. Glucose is then phosphorylated by the high-KM glucokinase, which is rate-limiting for glucose metabolism and of insulin release and is therefore viewed as a glucose sensor. This sensor couples changes in physiological glucose concentration in the pancreatic p-cells and in the liver to the intermediary metabolism, i.e. glycolysis, the citrate cycle and respiratory-chain phosphorylation and increases the ATP levels in the p-cells. Changes in the ATP/ADP ratio within the p-cells inhibits ATP-sensitive K+ channels (subunits Kir6.2 and SUR1), resulting in activation of voltage-gated Ca2+ channels which triggers the release of insulin granules. Exocytosis of insulin-containing secretory vesicles in pancreatic p-cells is crucial to maintenance of plasma glucose levels [17].

Decreased expression and cell surface localization of GLUT2 occurs simultaneously with the loss of GSIS in numerous animal models of type 2 diabetes [18]. The significant role of GLUT2 for the regulation of GSIS was confirmed by the Slc2a2 null mice which lack a first phase of insulin secretion. However, a second phase of secretion was still present and dependent on glucose metabolism [7]. As mentioned above, Slc2a2—/— mice are diabetic and die around weaning.

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