Type 2 diabetes (T2D) is characterized by chronic hyperglycemia resulting from a deficiency in insulin signaling, because of insulin resistance and/or defects in insulin secretion; it is also associated with increases in glucagon and endogenous glucose production (EGP). Gliflozins, including dapagliflozin, are a new class of approved oral antidiabetic agents that specifically inhibit sodium-glucose co-transporter 2 (SGLT2) function in the kidney, thus preventing renal glucose reabsorption and increasing glycosuria in diabetic individuals while reducing hyperglycemia. However, gliflozin treatment in subjects with T2D increases both plasma glucagon and EGP by unknown mechanisms. In spite of the rise in EGP, T2D patients treated with gliflozin have lower blood glucose levels than those receiving placebo, possibly because of increased glycosuria; however, the resulting increase in plasma glucagon levels represents a possible concerning side effect, especially in a patient population already affected by hyperglucagonemia. Here we demonstrate that SGLT2 is expressed in glucagon-secreting alpha cells of the pancreatic islets. We further found that expression of SLC5A2 (which encodes SGLT2) was lower and glucagon (GCG) gene expression was higher in islets from T2D individuals and in normal islets exposed to chronic hyperglycemia than in islets from non-diabetics. Moreover, hepatocyte nuclear factor 4-α (HNF4A) is specifically expressed in human alpha cells, in which it controls SLC5A2 expression, and its expression is downregulated by hyperglycemia. In addition, inhibition of either SLC5A2 via siRNA-induced gene silencing or SGLT2 via dapagliflozin treatment in human islets triggered glucagon secretion through KATP channel activation. Finally, we found that dapagliflozin treatment further promotes glucagon secretion and hepatic gluconeogenesis in healthy mice, thereby limiting the decrease of plasma glucose induced by fasting. Collectively, these results identify a heretofore unknown role of SGLT2 and designate dapagliflozin an alpha cell secretagogue.

The release of insulin evoked by nutrients in the pancreatic beta-cell is attributed to either the activation of a stereospecific receptor by the nutrient molecule itself or the generation of one or more signal(s) through the intracellular metabolism of the nutrient secretagogue. The first of these hypotheses is apparently supported by the fact the nonmetabolized amino acids, especially the L-leucine analogue b(-)2-amino-bicyclo[2,2,1]heptane-2-carbocyclic acid (BCH), stimulate insulin release. However, we now report evidence in support of the second hypothesis. We present data consistent with the idea that BCH induces insulin release through the allosteric activation of glutamate dehydrogenase. This is compatible with the fuel hypothesis, which states that the secretory response to nutrient secretagogues depends always on an increase of catabolic fluxes in the islet cells.

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The diabetogenic agent alloxan exerts a preferential cytotoxic effect on the pancreatic B cell. The determinants of such a tissue specificity were investigated. Alloxan accumulated rapidly in liver and pancreatic islets but much more slowly in muscle. The activity of glutathione peroxidase and the resistance to exogenous peroxide were -20 times higher in liver and kidney than in islets, intermediate values being found in exocrine pancreas and muscle. These findings suggest that the selective cytotoxicity of alloxan to the pancreatic B cell is attributable to the conjunction oftwo features: a rapid cellular uptake ofthe drug and an exquisite sensitivity of the B cell to peroxide.

1 . The possible significance of the insular sorbitol pathway in glucose-induced insulin release was investigated.2. Glucose, but neither fructose nor galactose, stimulated sorbitol synthesis by isolated islets. Aldose reductase inhibitors such as 2,4-dimethylglutaric and 3,3-tetramethylene glutaric acid abolished the glucose-induced sorbitol formation, but failed to affect glucose-induced insulin release.About 75 % of the sorbitol formed by the islets was recovered in the incubation medium, the efflux of sorbitol occurring independently of insulin release. Exogenous fructose and sorbitol exerted a modest insulinotropic action characterized by a shift to the left of the sigmoidal curve relating insulin release to glucose concentration. The relative insulinotropic potency of glucose (1 00 %), fructose (16%) and sorbitol (7%) paralleled their rate of oxidation by the isolated islets.3. These data suggest that metabolism through the sorbitol pathway plays little role in the process of glucose-induced insulin release, although exogenous sorbitol exerts a modest insulinotropic action.In the present series of investigations, we have reached the tentative conclusion that the insulinotropic action of glucose is mediated through an inhibition of calcium outward transport across the plasma membrane of the /?-cell [l], leading to the cytosolic accumulation of calcium [2,3] and subsequent activation of a microtubular-microfilamentous system controlling the migration and extrusion of secretory granules [4-61. In this sequence of events, a critical step which remains to be elucidated concerns the modality of glucose recognition by the /?-cell and the link between such a process and the subsequent modification of cation transport across the cell membrane. As reviewed in detail elsewhere [7,8], the intimate nature and properties of the glucosensor device in the pancreatic /?-cell are indeed still a matter of debate, especially as far as the possible participation of different pathways of glucose metabolism in the mechanism of glucose identification is concerned. For instance, the recent description ofan insular sorbitol pathway [9] has led to speculations as to the possible role of sorbitol in the control of insulin secretion [lo]. The present report aims at characterizing the metabolism of sorbitol in isolated islets and its possible involvement in the process of glucose-induced insulin release. ~~This paper is the XVIIIth of a series. MATERIALS AND METHODS Sorbitol Formation by Isolated IsletsPaired groups of 95 to 180 islets each, obtained from fed female albino rats [ll], were incubated for 90 and occasionally 180 min at 37 "C in 1 .O ml bicarbonate-buffered medium [12], equilibrated against a mixture of 0, (95%) and C 0 2 (5%) and containing albumin (5 mg/ml; fraction V, Sigma Chemical Co., St. Louis, U.S.A.) and, as required, glucose, galactose, fructose, mannoheptulose, glutaric acid, 2,4-dimethylglutaric acid (Koch-Light Lab., Colnbrook, England) and 3,3-tetramethyleneglutaric acid (gift of Dr K. Gabbay, Boston, U.S.A.)...