Glucoregulatory Mechanisms Following Hypophysectomy in Diabetic Dogs with Residual Insulin Secretion

Abstract

It is known that in pancreatectomized dogs completely deprived of insulin, hypophysectomy normalizes plasma glucagon and prevents ketoacidosis, but rarely normalizes glucose levels. The present study concerns diabetic dogs with only partial insulin deficiency in whom we studied the effects of hypophysectomy on glucoregulatory mechanisms. Eleven dogs were alloxanized and hypophysectomized 2-3 wk later. Withholding exogenous insulin from alloxan-diabetic dogs resulted in hypoinsuiinemia (6 ± 1 |xU/ml), hyperglucagonemia (341 ± 44 pg/ml), elevated plasma FFA levels (1442 ± 1 2 5 jxeq/ml), hyperglycemia (333 ± 27 mg/dl), increased hepatic glucose production (Ra, 4.2 ± 0.3 mg/kg/min) and decreased clearance of glucose (CR, 1.8 ± 0.1 ml/kg/min). After hypophysectomy, glucagon and FFA fell to normal in 7 of 11 hypophysectomized alloxan-diabetic dogs (106 ± 7), while 4 remained hyperglycemic (337 ± 28 mg/dl). Normoglycemia was the result of a reduced Ra to subnormal in the presence of unaltered glucose clearance. However, normoglycemia could not be equated with normal metabolism: glucose turnover was well below normal, and peripheral glucose uptake was impaired. The sensitivity of the liver to glucagon was investigated by infusing somatostatin alone (ST, 0.24 jig/kg/min) and with replacement (1 mg/kg/min) or with excess of glucagon (3.6 ng/kg/min). Even in hypophysectomized dogs, glucagon suppression resulted in a sustained decrease in Ra and plasma glucose. Glucagon replacement restored glucose kinetics and excess of glucagon led to hyperglycemia (300 ± 20 mg/dl). This was due to a prompt rise in Ra which, however, plateaued at levels lower than in diabetic dogs, suggesting that normalization of glucagon following hypophysectomy is an important but not the sole factor responsible for the marked reduction in Ra. The persistence of hyperglycemia in four diabetic dogs was attributed to a diminished effect of the hypophysectomy: in spite of hyperglycemia, Ra was not lower than in normoglycemic dogs, it was insensitive to glucagon suppression, and glucose clearance was more impaired than in normoglycemic dogs. It is hypothesized, therefore, that these dogs had a smaller residual insulin reserve than normoglycemic hypophysectomized dogs. Thus a critical amount of insulin may be indispensible for the maintenance of normoglycemia.In conclusion, in alloxan-diabetic dogs, hypophysectomy can fully normalize postabsorptive glycemia, due to suppression of glucose production. Normoglycemia is, however, associated with an abnormally low glucose turnover. Hyperglucagonemia is important but not the sole factor responsible for diabetic overproduction of glucose. Hypophysectomy does not abolish the hepatic sensitivity to glucagon in insulin-deficient dogs. Persistence of hyperglycemia in some dogs after hypophysectomy is associated with less effective suppression of glucose production and with a very low glucose clearance. DIABETES 32:26-34, January 1983.

Paradoxical Reduction in Pancreatic Glucagon with Normalization of Somatostatin and Decrease in Insulin in Normoglycemic Alloxan-Diabetic Dogs: A Putative Mechanism of Glucagon Irresponsiveness to Hypoglycemia*

“…This was surprising because plasma insulin in our A-D dogs in postabsorptive state is decreased by only 50% (Table 1), as also observed previously (4,23). It is possible that, with few surviving B cells, the rate of release of insulin is so rapid that most of the B cells are degranulated.…”

“…In several animal models of diabetes, low plasma insulin and high plasma glucagon and somatostatin concentrations have been observed (4)(5)(6)(7)(8)(9). In streptozotocindiabetic rats and monkeys, these hormonal alterations were consistent with changes in the content of these hormones and the number of respective cells in the pancreatic islets (5,8).…”

“…Diabetic dogs were studied 4-6 weeks after alloxan. Details of the procedure and animal care are described in a previous report from this laboratory (4).…”

Odyssey between Scylla and Charybdis through storms of carbohydrate metabolism and diabetes: a career retrospective

“…We demonstrated that this is due to a decrease of glucose production, which is partly due to normalization of glucagon secretion (101). The Sireks, who had emigrated from Slovakia, introduced me to Prof. C. H. Best, and I owe it to them that I was invited to Toronto as a post-doc, and the rest is history.…”