Adult F1 hybrids of male GK and female Wistar control rats exhibit mild, spontaneous non-insulin-dependent diabetes mellitus characterized by impaired glucose-induced insulin secretion. Using isolated pancreatic islets of hybrid rats, we first studied whether impaired glucose-induced insulin response is present not only in adult but also in neonatal rats. Furthermore, we investigated whether the impaired glucose-induced insulin response can be restored by long-term normalization of glycemia. Both 1-week- and 2- to 3-month-old hybrid rats had similar body weights but increased fed blood glucose levels (P < 0.05) compared with age-matched control rats. At 5.5 mmol/1 glucose, insulin release was two- to threefold lower in isolated islets of hybrid than in control rats of both age groups (P < 0.05). At 16.7 mmol/1 glucose, insulin secretion from hybrid islets was ∼25% of that from control islets of both 1-week- and 2- to 3-month-old rats. For the second objective, batches of 250 islets from hybrid or control rats were transplanted under the kidney capsule of athymic, normoglycemic nude mice and maintained there for 4 weeks. Perfusion of kidneys demonstrated that glucose-induced (16.7 mmol/l) insulin secretion was impaired markedly in hybrid grafts compared with that in control grafts (0.66 ± 0.23 vs. 1.8 ± 0.38 pmol/20 min; P < 0.01), whereas stimulation by 20 mmol/l arginine resulted in similar insulin responses in both groups. The volumes of the grafted islets were similar in kidneys bearing either control or hybrid islets. In conclusion, in hybrid rats the insulin response to glucose is impaired already at neonatal age. This impairment was not restored by long-term maintenance of the hybrid islets in a normoglycemic environment, whereas the arginine effect was intact. These findings suggest that the primary defect resides in the stimulus-secretion coupling for glucose in the β-cell and that hyperglycemia (glucotoxicity) does not play a major role in sustaining this selective β-cell defect.

This content is only available via PDF.