A Link between Insulin Resistance and Hyperinsulinemia: Inhibitors of Phosphatidylinositol 3-Kinase Augment Glucose-Induced Insulin Secretion from Islets of Lean, But Not Obese, Rats¹

Abstract

Wortmannin (5-100 nM), a specific phosphatidyinositol 3-kinase inhibitor, augmented 8 mM glucose-induced insulin secretion from control Sprague Dawley rat islets in a dose-dependent manner. This effect persisted after its removal from the perifusion medium; however, this augmenting effect was reduced by the calcium channel inhibitor nitrendipine or by lowering the glucose level to 3 mM. Wortmannin amplified insulin release induced by the combination of 6 -8 mM glucose plus 1 M carbachol; however, it had no effect on phorbol ester-or ␣-ketoisocaproate-induced insulin secretion. The potentiating action of wortmannin on 8 mM glucose-induced release was duplicated by LY294002. Wortmannin had no effect on glucose usage rates or inositol phosphate accumulation in [ 3 H]inositol-prelabeled

Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus

“…What reinforces the controversy around this concept of whether short-term autocrine actions of insulin affect its own secretion are the different experimental outcomes reported by investigators. Early studies observed inhibitory actions of exogenous insulin on insulin secretion [88][89][90][91][92][93], whereas others reported no effects [94][95][96][97][98]; in contrast, recent studies demonstrated that insulin enhances its own secretion following glucose stimulation [75,[99][100][101][102][103]. These discrepancies surrounding short term insulin action on insulin secretion might be due to differences in the experimental preparations used in these studies, such as different concentrations and/or incubation times with exogenous insulin and whether stimulatory concentrations of glucose were present or absent in incubation medium.…”

Defective insulin secretion in pancreatic β cells lacking type 1 IGF receptor

“…Nevertheless, the role of growth factor signaling through PI 3-kinase as related to insulin secretion remains poorly understood. Additional difficulties arise because, against expectation, knockout of the gene encoding the p85α subunit of PI 3-kinase results in increased insulin secretion (27), consistent with studies using PI 3-kinase inhibitors (28). Because of the known relationship between IGF and PI 3-kinase signaling and results indicating that IGFs inhibit insulin secretion (29)(30)(31), we sought to examine in mutant mice the contribution of type 1 IGF receptor (IGF1R) function to insulin secretion and β cell proliferation, which could differ from that of the IR pathway.…”

Insulin feedback action on pancreatic β‐cell function

“…The concept that insulin affects its own secretion is not new, however, the area is still controversial and currently under discussion. Historically, insulin secretion was suggested to be inhibited by secreted insulin [3–7], but on the other hand, similar models used by others fail to support this concept [12–14]. Most interestingly, recent data suggest that secreted insulin may have a positive effect on insulin exocytosis [9–11,27,28,42].…”

“…Moreover, there are data showing an increased glucose‐stimulated insulin release after inhibition of PI3 kinase or in islets of p85 −/− mice [6,15,54,55], indeed suggesting that insulin has a negative effect on β‐cell stimulus–secretion coupling. Interestingly, Eto et al [54] report that inhibition of PI3 kinase did not interfere with the secretion‐triggered pathway including glucose oxidation, ATP content or [Ca 2+ ] i , but suggest the effect to be distal to the increase in [Ca 2+ ] i .…”

“…Experimentally, with regard to the effect of insulin upon insulin secretion for example, all possible outcomes like negative feedback [3–8], positive feedback [9–11], and no effect at all [12–15] have been reported. Moreover, while historically insulin was exclusively discussed as a negative signal [2–7,16], recent data provide evidence for a positive role of insulin in several cellular processes that include the regulation of gene transcription [17–23], translation [18,24–26], Ca 2+ flux [9–11,27,28], insulin secretion [9–11] and the potential role of insulin action in β‐cell survival [29]. One of the major points discussed as a source for controversial results and conceptual disagreement was the question whether the observed insulin effect upon β‐cell function is a direct one or rather secondary, mediated by factors of non‐β‐cell origin.…”