Autocrine effect of insulin on insulin secretion
Rodent and human pancreatic β cells possess the various components of the insulin signaling system, including insulin receptor, insulin-like growth factor-1 (IGF-1) receptor, insulin receptor substrates (IRS-1 and IRS-2), phosphatidylinositol 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1), and protein kinase B (PKB)/Akt [52,110–112]. It has been shown that insulin binds to the insulin receptors on the surface of β cells and induces phosphorylation of the insulin receptors and IRSs,modulating its own secretion [51,52,113,114]. This effect of insulin is involved especially in the 1st phase of GIIS in mice [52,113].
PI3K is a key component that transmits the insulin signal to downstream targets, and is shown to mediate regulated exocytosis in skeletal muscle and adipose tissues . Three classes of mammalian PI3Ks have been identified based on their domain structures, differences in catalytic activity, and modes of regulation . Class IA PI3K in mouse pancreatic β cells contributes to normal regulation of GIIS through the maintenance of expression levels of SNARE proteins and the control of intracellular Ca2+ levels [54,117,118]. Class II PI3K-C2α is also activated by insulin in mouse insulinoma cells and promotes GIIS via PKBα/Akt1, an isoform of PKB/Akt . Knockdown of PI3K-C2α impairs insulin granule exocytosis in rat insulinoma cells . The expression level of PI3K-C2α mRNA in islets of type 2 diabetic patients is decreased compared to that in nondiabetic individuals, suggesting that downregulation of PI3K-C2α may be a feature of type 2 diabetes .
Pathophysiology of pancreatic beta cells
Beta-Cell mass and function in type 2 diabetes
Type 2 diabetes is characterized by impaired insulin secretion and/or insulin resistance. However, insulin secretory capacity is the major determinant in the development of type 2 diabetes, as neither hyperglycemia nor glucose intolerance develops in insulin-resistant patients as long as sufficient insulin is secreted from β cells in a timely fashion in response to various stimuli. Impaired insulin secretion may be due to β-cell dysfunction, reduced β-cell mass, or both. Loss of β-cell mass in type 2 diabetes patients has been reported . However, surgical and chemical reductions of β-cell volume induce functional adaptation of the normal β cell to prevent a rise in fasting glucose or reduction in the 1st phase of insulin secretion [122,123], suggesting that β-cell dysfunction is closely associated with the pathogenesis and pathophysiology of type 2 diabetes.
Abnormalities in the dynamics of insulin secretion
Abnormal dynamics of insulin secretion selective for glucose stimulation, especially the acute phase of the insulin response, is already reduced in the early stage of type 2 diabetes, patients with IGT, and their first-degree relatives [124,125]. As the early phase of insulin secretion is determined by the RRP, a reduction in its size and/or impairment of signaling for exocytosis of the insulin granules from the RRP may well develop in IGT and the early stage of type 2 diabetes. The RRP is completely depleted and the RP is markedly reduced in the fully developed stage of type 2 diabetes. Signaling mechanisms underlying exocytosis of insulin granules from the RRP and the RP may also be defective in type 2 diabetes.
Although the pulsatile nature of insulin secretion is maintained in patients with type 2 diabetes, with a number of pulses similar to that in healthy control subjects, the pulses after meals are less frequent, irregular, and have a significantly lower amplitude, resulting in a marked disruption of the dynamics of post-meal insulin secretion . A loss of coordinated insulin secretory responses to oscillatory glucose infusion is found in subjects with IGT, indicating a defect in the ability of the β cells to properly sense and respond to parallel changes in the plasma glucose level . Thus, abnormalities in the dynamics of insulin secretion may be an early manifestation of β-cell dysfunction preceding the development of overt type 2 diabetes.
Mechanisms of insulin secretion in pancreatic β cells have been extensively studied for decades, and many intracellular signals that trigger or amplify insulin secretion have been identified. Glucose metabolism is essential for both the triggering and amplifying pathways of insulin secretion. Besides glucose, lipid metabolism in β cells is also implicated in insulin secretion. Many molecules associated with the exocytotic machinery of insulin granules have been identified recently. Advances in technologies of imaging and mass spectrometry enable us to visualize insulin granule dynamics in living β cells and to analyze cellular proteins and metabolites in a comprehensive manner. Clarification of the molecular and cellular mechanisms of insulin secretion should provide a basis for identifying novel therapeutic targets as well as deeper understating of the pathogenesis and pathophysiology of diabetes.