Adaptation of pCell Mass to Insulin Resistance Mechanisms of Growth and Proliferation

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Although changes in P-cell function are observed under conditions of increased secretory demand, the volume of P-cells also increases. In rodents fed a high-fat diet for 12 months to induce obesity and insulin resistance, islet size increases as a result of an increase in the number of P-cells rather than a change in P-cell size, and new islets do not form [36]. NEFAs rather than glucose may mediate this increase in P-cell mass [for review, see 30, 37]. In contrast, human studies suggest that P-cell volume is increased by about 50% in healthy obese individuals, which, however seems to be more dependent on hypertrophy of existing cells than proliferation [38, 39]. Interestingly, in the long-term increased dietary fat feeding study in rats, P-cell mass increased but glucose-induced insulin release did not, which indicates a dissociation between P-cell mass and the secretory function [36]. Increased signaling by insulin and/or insulin-like growth factor 1 (IGF-1) could also underlie the modulation of islet mass. Activation of the insulin/IGF-1 receptor leads to phosphorylation of IRS-2 and downstream signaling through pathways including PI3K/protein kinase-B (PKB/Akt) and Ras, leading to activation of the mitogen-activated protein (MAP) kinases ERK-1 and ERK-2 [40]. IRS-2 appears to play a key role in the cellular processes associated with increased P-cell proliferation, neogenesis and survival.

Finally, the incretin GLP-1 is an insulin secretagogue but is also a p-cell mitogen, capable of increasing p-cell proliferation and reducing p-cell apoptosis in animal models through several pathways, including transactivation of the epidermal growth factor receptor and stimulation of the IRS-2 pathway [35]. Whether GLP-1 has similar effects in humans is not known. Finally, neural signaling could also contribute to increased p-cell mass.

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