Insulin Production and Glucose Metabolism in Isolated Pancreatic Islets of Rats With NIDDM BERNARD PORTHA, MARIE-HELENE GIROIX, PATRICIA SERRADAS, NILS WELSH, CLAES HELLERSTROM, ABDULLAH SENER, AND WILLY J. MALAISSE Rats with non-insulin-dependent diabetes mellitus (NIODM) induced by neonatal injection of streptozocin are known to have a deficient insulin response to glucose. To evaluate to what extent this glucose insensitivity can be attributed to a pertubation of the islet glucose metabolism, we estimated the rates of glucose phosphorylation, glucose utilization, oxygen consumption, and glucose oxidation in islets isolated from normal and NIDDM rats and compared these values with rates of islet insulin biosynthesis and release in vitro. The data confirm that islets from rats with NIDDM display a deficient response to glucose of both insulin biosynthesis and release that is still present after an overnight culture of the islets at 5.5 mM glucose. Furthermore, they show that islets of these rats have 1) normal low- and high-/C m glucose- phosphorylating activities and no major alteration of the glucose utilization rate, 2) decreased insulin release in response to glyceraldehyde, 3) decreased rates of basal respiration and glucose oxidation and a markedly reduced stimulation by glucose of both islet oxygen consumption and glucose oxidation, and 4) decreased glucose-stimulated net 45 Ca uptake. We conclude that the relative unresponsiveness to glucose of islets from NIDDM rats is associated with, and perhaps due to, a deficient islet glucose metabolism. This defect is not due to gross alterations in the glycolytic pathway but probably reflects alteration in the islet mitochondria function. Diabetes 37:1226-33, 1988 W e previously described an experimental model of non-insulin-dependent diabetes mellitus (NIDDM) induced in the neonatal rat by a sin- gle streptozocin injection (1,2). In adult life, these animals are characterized by a deficient insulin re- sponse to glucose and a diminished pancreatic insulin con- tent (2). They also show a selective lack of sensitivity of the p-cells to glucose (3) with preservation of the response to nonglucose secretagogues, which appears similar to that in humans with type II diabetes (NIDDM; 4,5) and in the pre- diabetic phase of human type I (insulin-dependent) diabe- tes, as recently reported (6). The reason for the glucose insensitivity is presently un- known. Although the mechanism by which glucose stimulates insulin release from the pancreatic p-cell is not completely understood, most evidence suggests that an increased rate of glucose metabolism is necessary for initiation of glu- cose-stimulated insulin release (7-9). In islets isolated from rats with NIDDM, the p-cells exhibit poor sensitivity to glu- cose (10,11). It is not known, however, to what extent this deficient insulin response reflects changes in islet glucose metabolism. In this study, we measured several parameters of glucose metabolism in pancreatic islets isolated from rats with NIDDM. The values were correlated to the rates of insulin biosynthesis and release by islets isolated from similar rats. MATERIALS AND METHODS Animals. On the day of birth, albino Wistar rats received an injection of streptozocin (STZ; 100|xg/g i.v.) dissolved in 25 |xl of citrate buffer (50 mM, pH 4.5). The injection was given through the saphenous vein made directly accessible by transcutaneous puncture as previously described (1). Each litter was limited to eight rats. In control litters, new- borns received only citrate buffer. Four days after birth, all the STZ-injected neonates exhibited glycosuria, scoring 3 + values when estimated with Clinistix (Ames, Miles, Slough, UK). This neonatal diabetes subsequently developed into an NIDDM state in the adult rat and remained stable and chronic as previously described (2). Animals were weaned 21 days after birth and were subsequently fed a commercial pelleted From the Laboratoire de Physiologie du Developpement, University Paris 7, Paris, France; the Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and the Laboratory of Experimental Medicine, Brussels Free University, Brussels, Belgium. Address correspondence and reprint requests to Dr. Bernard Portha, La- boratoire de Physiologie du Developpement, UA 307 (CNRS), Universite Paris 7, Tour 54-2, Place Jussieu, F-75251 Paris Cedex 05, France. Received for publication 25 September 1987 and accepted in revised form 26 February 1988. 1226 DIABETES, VOL. 37, SEPTEMBER 1988 Downloaded from http://diabetesjournals.org/diabetes/article-pdf/37/9/1226/356322/37-9-1226.pdf by guest on 04 November 2022