GLUCAGON-RESPONSE TO HYPOGLYCEMIA IS IMPROVED BY INSULIN-INDEPENDENT RESTORATION OF NORMOGLYCEMIA IN DIABETIC RATS

The aim of this study was to determine whether the impaired glucagon r esponse to insulin-induced hypoglycemia in the diabetic rat can be imp roved by correction of hyperglycemia independent of insulin. Four grou ps of age-matched male Sprague-Dawley rats (246 +/- 13 g BW) were stud ied: 1) normal controls (NC; n = 7); 2) diabetic, untreated (DU; n = 6 ); 3) diabetic, treated for 5-7 days using sustained release (2-3 U/da y) insulin implants (DI; n = 6); and 4) diabetic, treated for 3-4 days with phlorizin (0.4 g/kg), given sc twice daily (DP; n = 7). Diabetes was induced by a single injection of streptozotocin (65 mg/kg). Basal plasma glucose was 7.4 +/- 0.3 mM in NC, but rose to 14.5 +/- 2.2 mM in DU. Basal hyperglycemia was corrected with phlorizin and insulin tr eatments (5.5 +/- 0.5 and 6.7 +/- 0.8 mM, respectively). NC rats respo nded to insulin-induced hypoglycemia with a rapid and marked increase in glucagon (peak, 2059 +/- 311 pg/ml). The glucagon response was blun ted in DU (635 +/- 180 pg/ml) and was partially improved by prolonged normalization of glycemia in DP (1335 +/- 295 pg/ml; P < 0.05). Plasma somatostatin levels in all diabetic groups were 2- to 3-fold higher i n the basal state, but were not different during hypoglycemia, than th ose in NC rats. Compared to levels in NC rats, diabetes resulted in de creased insulin, but elevated glucagon and somatostatin concentrations in the pancreatic tissue. Treatment with both insulin and phlorizin r eversed the changes in the pancreatic content of both glucagon and som atostatin. Pancreatic proglucagon messenger RNA did not show significa nt differences among the four groups in either state. Insulin treatmen t in the DI group resulted in a delayed and much smaller increase in t he glucagon response (740 +/- 138 pg/ml) to hypoglycemia despite norma lization of glycemia. We, therefore, conclude that in streptozotocin-d iabetic rats, the impaired glucagon responsiveness to hypoglycemia is significantly improved by insulin-independent correction of hyperglyce mia, suggesting the importance of normoglycemia per se in maintaining, at least in part, the glucose sensitivity of pancreatic alpha-cells.