The aim of this study was to determine whether the impaired glucagon response to insulin-induced hypoglycemia in the diabetic rat can be improved by correction of hyperglycemia independent of insulin. Four groups of age-matched male Sprague-Dawley rats (246 +/- 13 g BW) were studied: 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/day) 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 treatments (5.5 +/- 0.5 and 6.7 +/- 0.8 mM, respectively). NC rats responded to insulin-induced hypoglycemia with a rapid and marked increase in glucagon (peak, 2059 +/- 311 pg/ml). The glucagon response was blunted 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 in the basal state, but were not different during hypoglycemia, than those in NC rats. Compared to levels in NC rats, diabetes resulted in decreased insulin, but elevated glucagon and somatostatin concentrations in the pancreatic tissue. Treatment with both insulin and phlorizin reversed the changes in the pancreatic content of both glucagon and somatostatin. Pancreatic proglucagon messenger RNA did not show significant differences among the four groups in either state. Insulin treatment in the DI group resulted in a delayed and much smaller increase in the glucagon response (740 +/- 138 pg/ml) to hypoglycemia despite normalization of glycemia. We, therefore, conclude that in streptozotocin-diabetic rats, the impaired glucagon responsiveness to hypoglycemia is significantly improved by insulin-independent correction of hyperglycemia, suggesting the importance of normoglycemia per se in maintaining, at least in part, the glucose sensitivity of pancreatic alpha-cells.