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Homeostasis of blood glucose is maintained by hormone secretion from the pancreatic islets of Langerhans. Glucose stimulates insulin secretion from beta-cells but suppresses the release of glucagon, a hormone that raises blood glucose, from alpha-cells. The mechanism by which nutrients stimulate insulin secretion has been studied extensively: ATP has been identified as the main messenger and the ATP-sensitive potassium channel as an essential transducer in this process. By contrast, much less is known about the mechanisms by which nutrients modulate glucagon secretion. Here we use conventional pancreas perfusion and a transcriptional targeting strategy to analyse cell-type-specific signal transduction and the relationship between islet alpha- and beta-cells. We find that pyruvate, a glycolytic intermediate and principal substrate of mitochondria, stimulates glucagon secretion. Our analyses indicate that, although alpha-cells, like beta-cells, possess the inherent capacity to respond to nutrients, secretion from alpha-cells is normally suppressed by the simultaneous activation of beta-cells. Zinc released from beta-cells may be implicated in this suppression. Our results define the fundamental mechanisms of differential responses to identical stimuli between cells in a microorgan.

Glucagon, secreted from islet ␣-cells, mobilizes liver glucose. During hyperglycemia, glucagon secretion is inhibited by paracrine factors from other islet cells, but in type 1 and type 2 diabetic patients, this suppression is lost. We investigated the effects of ␤-cell secretory products zinc and insulin on isolated rat ␣-cells, intact islets, and perfused pancreata. Islet glucagon secretion was markedly zinc sensitive (IC 50 ‫؍‬ 2.7 mol/l) more than insulin release (IC 50 ‫؍‬ 10.7 mol/l). Glucose, the mitochondrial substrate pyruvate, and the ATP-sensitive K ؉ channel (K ATP channel) inhibitor tolbutamide stimulated isolated ␣-cell electrical activity and glucagon secretion. Zinc opened K ATP channels and inhibited both electrical activity and pyruvate (but not arginine)-stimulated glucagon secretion in ␣-cells. G lucagon, a hormone secreted from ␣-cells in the pancreatic islets, is critical for blood glucose homeostasis. It is the major counterpart to insulin, released during hypoglycemia to induce hepatic glucose output, but suppressed when postprandial hyperglycemia stimulates ␤-cell insulin secretion (1). In both type 1 (lacking ␤-cells) and type 2 (impaired insulin secretion) diabetic patients, normal inhibition of glucagon release is perturbed, causing hyperglucagonemia, thus aggravating the diabetic state (1-3). The mechanism by which hyperglycemia inhibits ␣-cell glucagon release is poorly understood but may involve paracrine signals from other islet cell types. This concept is supported by reports that 1) functional ␤-cells are required in rats and dogs for high glucose inhibition of glucagon secretion (4 -6), 2) type 1 diabetic patients exhibit hyperglucagonemia (2), and 3) overactive ␤-cells can prevent the glucagon response to hypoglycemia in humans (7) or other secretagogues in rat (6). Paracrine signaling between islet cell types is subject to microcirculation. In rats, the blood supply first reaches the ␤-cells in the islet core and then the mantle, where ␣ and somatostatin secreting ␦-cells are located (8). Little is known about islet microcirculation in humans, but it appears that ␤-cell-derived insulin does inhibit glucagon release in the perfused pancreas (9). Mouse islet microcirculation remains uncharacterized; in fact, ␣-cell activity may be less influenced by insulin secretion and instead regulated predominantly by the neuronal system (10,11).Candidate paracrine inhibitors of glucagon secretion include insulin (12) and recently zinc (6). Zinc cocrystalizes with insulin in ␤-cell granules (13) and is released from isolated mouse ␤-cells on exposure to high glucose (14). The mechanisms by which these paracrine factors may block glucagon release are unknown, as ␣-cell stimulus-secretion coupling remains largely uncharacterized. Glucagon secretion involves calcium influx through voltage-dependent calcium channels (15) and can be induced by pyruvate (6), a secretagogue unable to stimulate insulin secretion on account of the tissue-specific nature of the uptake mechanism (16). Pyruvate is rele...

We studied the effect of gap junctional coupling on the excitability of ␤-cells in slices of pancreas, which provide a normal environment for islet cells.

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