The role of islet secretory function in the development of diabetes in the GK Wistar rat

Summary Insulin secretion and glucose metabolism were compared in islets isolated from GK Wistar rats (a non-obese, spontaneous model of non-insulin-dependent diabetes mellitus) and control Wistars aged 8 and 14 weeks. By 8 weeks of age, GK Wistar rats were clearly diabetic as indicated by non-fasting plasma glucose concentrations and impaired glucose tolerance. Islet insulin content was not significantly different to controls at either age. In islets from 14-week-old GK Wistar rats glucose-stimulated insulin release (6–16 mmol/l glucose) was significantly reduced to 25–50% of controls in static incubations (p<0.001). In perifusion, glucose-stimulated insulin release was reduced by 90% for first phase (p<0.01) and by 75% for second phase (p<0.05). The responses to arginine and 2 Ketoisocaproate in islets were similar to those in controls. In contrast, islets isolated from 8-week-old GK Wistar rats exhibited no significant reduction in glucose-stimulated insulin secretion in static incubations. In perifusion, although both first and second phases of glucose-stimulated insulin release were slightly reduced, these were not significantly different to controls. Islets from 8-week-old GK Wistar rats failed however to respond to stimulation by glyceraldehyde. Raising the medium glucose concentration to 16 mmol/l significantly increased rates of glucose utilisation ([³H] H₂O production from 5-[³H] glucose) and oxidation ([¹⁴C] CO₂ production from U-[¹⁴C] glucose) in islets isolated from 8-week-old control and GK Wistar rats, respectively. The rates of oxidation were not significantly different at stimulatory glucose concentrations whereas the rates of utilisation were significantly higher in islets from the diabetic animals (p<0.05). Production of [³H] H₂O from 2-[³H] glycerol metabolism was increased (p<0.05) at 2 mmol/l glucose but was not significantly different to controls at 16 mmol/l glucose in islets from 8-week-old GK Wistar rats. This data would suggest that abnormalities in islet function are present in 8-week-old diabetic animals although these do not seriously impair glucose-stimulated insulin release from isolated islets. This in turn would indicate that a defect in the glucose signalling pathway in beta cells is not a primary cause of the diabetes of GK Wistar rats and that deterioration of the secretory response is the consequence of some factor associated with the diabetic condition.Abbreviations KIC 2 Ketoisocaproate - BSA bovine serum albumin - GLUT glucose transporter