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ABSTRACT

  • β-Cell dysfunction is an integral component of the pathogenesis of the hyperglycemia of type 2 diabetes mellitus. This dysfunction is associated with decreased insulin secretion as well as a decline in the release of the newly identified β-cell secretory product islet amyloid polypeptide (IAPP or amylin). Production of these hormones by the islet β-cell requires the packaging of their respective propeptides (proinsulin and proIAPP) into secretory granules, where they undergo processing by the proprotein convertases (proconvertase 1/3 (PC1/3) and proconvertase 2 (PC2)) to yield their mature products insulin and IAPP and the inert C-peptide, the latter as a byproduct of proinsulin processing. Proinsulin processing is incomplete, and small amounts of proinsulin are released along with insulin and C-peptide when secretory granule exocytosis is stimulated by glucose and nonglucose secretagogues.

  • Glucose-induced exocytosis of the secretory granule requires entry of glucose into the cell via the facilitative glucose transporter Glut-2 followed by its phosphorylation by glucokinase. The subsequent metabolism of glucose results in the production of adenosine triphosphate(ATP), which raises the ATP/adenosine diphosphate (ADP) ratio within the cell and closes the specific ATP-sensitive potassium channel. In the case of the nonglucose secretagogues, these act via the membrane phosphodiesterases or by activation of adenylate cyclase through the guanine-nucleotide binding proteins (G-proteins). All of these mechanisms are dependent on the mobilization of calcium from the extracellular space or from intracellular stores.

  • Glucose directly stimulates insulin secretion in a complicated manner involving at least two phases. In addition to stimulating insulin release directly, glucose also potentiates the β-cell response to other secretagogues. The secretory responsiveness of the β-cell is also modulated by other factors including the sensitivity of the peripheral tissues to insulin. The nature of this modulation is compatible with a feedback loop such that β-cell function increases reciprocally as insulin sensitivity declines. Knowledge of the nature of this relationship is important in the interpretation of β-cell-function testing in vivo.

  • In type 2 diabetes, β-cell dysfunction is manifest as an absence of the early (first) phase of glucose-induced insulin and IAPP secretion and a reduction in the later (second) phase response. In addition, the ability of glucose to potentiate the β-cell’s response to nonglucose secretagogues is diminished. Finally, oscillatory insulin release is also abnormal in subjects with type 2 diabetes. Many of these changes in β-cell function can be demonstrated in subjects at high risk of developing type 2 diabetes at a time when their glucose tolerance is essentially normal. These individuals include women with a history of gestational diabetes or with polycystic ovary syndrome, older subjects, first-degree relatives of individuals with type 2 diabetes, and subjects with impaired glucose tolerance (IGT).

  • The etiology of the β-cell dysfunction of type 2 diabetes is incompletely understood. Both genetic and environmental factors are important. Islet mass is reduced by the deposition of islet amyloid which predominantly replaces β-cells. These amyloid deposits are comprised primarily of IAPP. A single amino acid substitution in IAPP has been described in a ...

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