The Stimulus‐Secretion Coupling of Glucose‐Induced Insulin Release

Abstract

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.)...

Presence of fructokinase in pancreatic islets

“…Although unable to stimulate insulin secretion by itself, fructose is known to augment the release of insulin induced by glucose or other secretagogues [1][2][3][4]. According to the fuel hypothesis, the effect of nutrient secretagogues is related to the rate at which they are metabolized in islet cells [5].…”

“…According to the fuel hypothesis, the effect of nutrient secretagogues is related to the rate at which they are metabolized in islet cells [5]. Fructose is indeed metabolized in pancreatic islets, though at a maximal rate roughly 5-fold lower than that of D-glucose [2][3][4]6].…”

Metabolism of glucose and mannose anomers in pancreatic islets

“…In the case of D-glucose, it was already reported 6 years ago that the rates of lactate output and glucose oxidation were higher in islets exposed to the athan to the ¡3-anomer, the difference apparently being attributable to the astereospecificity of phosphoglucose isomerase (Malaisse et a/., 1976).…”

Anomeric Specificity of Glucose Metabolism in Health and Disease

“…The first demonstration of an anomeric difference of D-glucose metabolism in intact cells was established in 1976 in rat pancreatic islets exposed to either α-or β-D-glucose (3,4). The rate of glycolysis was found to be higher in islets exposed to α-rather than to β-D-glucose.…”