Failure of chronic hyperinsulinemia to suppress pancreatic glucagon in vivo in the rat

To determine the effects of chronic hyperinsulinemia on glucagon release, rats were made hyperinsulinemic for 14 days by supplementation of drinking water with sucrose (10%; sucrose-fed) to increase endogenous release or by implantation of osmotic minipumps (subcutaneous, s.c; or intraperitoneal, i.p.) to deliver exogenous insulin (6 U/day). Both s.c. and i.p. rats also had sucrose in the drinking water to prevent hypoglycemia. Plasma insulin levels were significantly elevated in sucrose-fed, s.c, and i.p. rats. However, glucose levels were significantly elevated in sucrose-fed rats only. Surprisingly, plasma glucagon concentrations were elevated in i.p. and s.c. rats and were not suppressed in sucrose-fed rats. Inverse relationships were found between the plasma levels of insulin and glucose (n = 65; r = −0.42, p < 0.0001) and between glucose and glucagon (n = 73; r = −0.46, p < 0.0001). However, unexpectedly, a positive correlation between insulin and glucagon (n = 65; r = 0.47, p < 0.0001) was established. As suppression of plasma glucagon levels below basal was not observed in any of the hyperinsulinemic or hyperglycemic rats, we wished to establish further whether pancreatic glucagon release could be suppressed below basal levels in the rat by another means. Thus, high doses of somatostatin (50–100 μg∙kg−1∙min−1) were infused for 45 min into normal rats without or with a concomitant hyperinsulinemic, hyperglycemic glucose clamp. Somatostatin fully suppressed insulin, but although plasma glucagon levels were decreasd by somatostatin infusion relative to saline-infused animals, there was still no suppression below basal levels. Thus, the rat A cells are less sensitive to somatostatin than are those of other species. The results of this study demonstrate that chronic endogenous or exogenous hyperinsulinemia does not inhibit glucagon secretion, even in the presence of hyperglycemia. Factors other than insulin may therefore play an important role in the regulation of the pancreatic A cell in the chronic hyperinsulinemic rat.Key words: glycemia, insulin, glucagon, somatostatin, very low density lipoprotein.