β-Cell Insensitivity to Glucose in the GK Rat, a Spontaneous Nonobese Model for Type II Diabetes

Abstract

In early 1988, a colony of GK rats was started in Paris with progenitors issued from F35 of the original colony reported by Goto and Kakisaki. When studied longitudinally up to 8 mo, GK rats showed as early as 1 mo (weaning) significantly higher basal plasma glucose (9 mM) and insulin levels (doubled), altered glucose tolerance (intravenous glucose), and a very poor insulin secretory response to glucose in vivo compared with Wistar controls. Males and females were similarly affected. Studies of in vitro pancreatic function were carried out with the isolated perfused pancreas preparation. Compared with nondiabetic Wistar rats, GK rats at 2 mo showed a significantly increased basal insulin release, no insulin response to 16 mM glucose, and hyperresponse to 19 mM arginine. Pancreatic insulin stores were only 50% of that in Wistar rats. Perfusion of GK pancreases for 50 or 90 min with buffer containing no glucose partially improved the insulin response to 16 mM glucose and markedly diminished the response to 19 mM arginine, whereas the responses by Wistar pancreases were unchanged. These findings are similar to those reported in rats with non-insulin-dependent diabetes induced by neonatal streptozocin administration and support the concept that chronic elevation in plasma glucose may be responsible, at least in part, for the beta-cell desensitization to glucose in this model. The GK rat seems to be a valuable model for identifying the etiology of beta-cell desensitization to glucose.

The NSY mouse: a new animal model of spontaneous NIDDM with moderate obesity

“…Several animal models for NIDDM have been described. Although recent studies have revealed impaired insulin secretion in GK rats [5][6][7], most of the animal models for NIDDM are characterized by obesity, hyperinsulinaemia and islet hypertrophy [8].…”

“…Several animal models for NIDDM have been described. Although recent studies have revealed impaired insulin secretion in GK rats [5][6][7], most of the animal models for NIDDM are characterized by obesity, hyperinsulinaemia and islet hypertrophy [8].The NSY (Nagoya-Shibata-Yasuda) mouse is a spontaneous model of NIDDM with moderate obesity that was established by selective breeding for glucose intolerance from a non-diabetic JcI:ICR mouse colony [9]. Previous studies suggested that NSY mice develop renal lesions similar to diabetic nephro-…”

Src activation generates reactive oxygen species and impairs metabolism–secretion coupling in diabetic Goto–Kakizaki and ouabain-treated rat pancreatic islets

“…One of the characteristics of type 2 diabetes is that the insulin secretory response of beta cells to glucose is selectively impaired [41]. In the GK rat, a genetic model of type 2 diabetes mellitus [42], glucose-induced insulin secretion is selectively impaired [43]. On single-channel recording, the glucose sensitivity of the beta cell K ATP channel is remarkably reduced in GK rats, while the inhibitory effect of ATP on channel activity is not significantly different in control and GK rats [5].…”

Altered Functions of Ion Channels in Diabetic β Cells

“…L-type Ca2+ channel activities were increased upon depolarizations, which might be related to augmented insulin response to non-glucose depolarization stimuli found in GK p cells (2). This increased L-type Ca2+ channel activity seems to be still insufficient to compensate for ," poor closure of K A~ channels by glucose and thus resultant glucose-induced insulin secretion might be diminished.…”

“…Although insights into the nature of diabetic p cells have been obtained using neonatally-streptozotocin-induced diabetic rats (NSZ rats) (1,3,5), precise pathophysiological knowledge of the GK rat p cells would facilitate our understanding of human NIDDM, because this genetically occurring NIDDM model rat has been reported to resemble human NIDDM in many respects (2). Since major glucose sensing mechanism in p cells involves K A T~ channels and L-type Ca2+ channels, we focus on functional alterations in these channels in GK p cells.…”