IMPACT OF DIABETIC INHERITANCE ON GLUCOSE-TOLERANCE AND INSULIN-SECRETION IN SPONTANEOUSLY DIABETIC GK-WISTAR RATS

The impact of genetic factors and maternal diabetes on glucose toleran ce and pancreatic beta-cell function was studied in first generation ( F1) offspring generated in crosses between the spontaneously diabetic Goto-Kakizaki (GK)-Wistar rat and normoglycemic control Wistar rats (W ). The (GK x W) F1 hybrids were offspring of either male GK (mGK) and female Wistar (fW) (mGK x fW) or male Wister (mW) and female GK (fGK) (mW x fGK) rats. Already at 8 days of age, blood glucose levels were e levated in GK (7.6 +/- 0.5 vs. 4.8 +/- 0.3 mM in W; P < 0.001) and in F1 rats (6.0 +/- 0.3 in mGK x fW and 6.6 +/- 0.4 mM in mW x fGK; both P < 0.01 vs. W). In 2-month-old male rats, glucose (2 g/kg, intraperit oneally) markedly increased blood glucose levels after 60 min in GK ra ts (18.1 +/- 0.6 vs. 5.5 +/- 0.3 mM in W; P < 0.001) and moderately in creased levels in F1 rats (9.9 +/- 0.9 in mGK x fW and 11.6 +/- 1.0 mM in mW x fGK, both P < 0.01 vs. W). Similar patterns were obtained in female rats. Repeated backcrossing of F1 with W rats successively impr oved glucose tolerance. In perfused pancreases of male rats, the 20-mi n insulin response to 16.7 mM glucose was -7.44 +/- 5.18 pmol in GK ra ts, 71.57 +/- 12.25 pmol in W rats, 9.00 +/- 0.89 pmol in mGK x fW rat s, and 18.20 +/- 3.97 pmol in mW x fGK rats. In female W rats, the glu cose-induced insulin response was significantly lower than in males (P < 0.05). However, as in males, insulin responses to glucose were impa ired in both GK and F1 female rats. Arginine-induced insulin release w as similar in all groups. In mGK x fW, glucose-stimulated somatostatin release was 50% of that in W rats, whereas arginine-stimulated respon ses of glucagon and somatostatin were not different from W rats. Pancr eatic contents of insulin and glucagon were similar in mGK x fW and W rats, whereas somatostatin content was lower in mGK x fW rats (P < 0.0 5). In conclusion, the diabetic state in GK and F1 rats was evident ea rly in life. Hybrid rats were intermediate between W and GK rats with regard to glucose tolerance and glucose-stimulated insulin response in vitro, but had normal pancreatic insulin content. Results of repeated backcrossing of F1 rats with W rats showed that genes in > 1 locus co ntribute to the diabetic state. Furthermore, the absence of significan t differences between impact of maternal and paternal origin of the GK genes for glucose intolerance suggests that hyperglycemia in utero do es not influence the severity of diabetes in the F1 offspring.