Severe Diabetes Induced in Subtotally Depancreatized Dogs by Sustained Hyperglycemia

Abstract

Chronic clamping of plasma glucose levels at greater than or equal to 250 mg/dl in four partially depancreatized but previously nondiabetic dogs was followed within 2 wk by persistent hyperglycemia and glycosuria of less than or equal to 500 g/day, ketonuria, and weight loss. Three of the four dogs required daily insulin injections to control these catabolic manifestations. There was no evidence of spontaneous improvement of the severe diabetic state during the 39-69 days of observation after discontinuation of intravenous glucose infusion. Impairment of intravenous glucose tolerance, loss of the insulin response to glucose and arginine, fasting hyperglucagonemia, exaggerated glucagon responsiveness to arginine, and a significant reduction in sensitivity to insulin were characteristic of all diabetic dogs. Morphometric analysis of the endocrine pancreas revealed a profound reduction in the number and size of identifiable islets of the hyperglycemic dogs compared with islets from their own pancreases resected months earlier and with those from pancreatic remnants of eight subtotally depancreatized control dogs that had not been subjected to chronic hyperglycemic clamping. The reduction in number and size of islets of the hyperglycemic dogs was largely the consequence of depletion of insulin-containing cells and was similar to that of dogs with long-standing alloxan-induced diabetes. In the eight control dogs, clinical evidence of diabetes did not develop during a follow-up period of 193-296 days. In this group, there was no evidence of diminution of intravenous glucose tolerance, of the insulin response to glucose or arginine, or of insulin sensitivity as determined by an acute hyperinsulinemic hyperglycemic clamp. The number and size of islets and number of beta-cells in pancreatic remnants from these dogs did not differ morphometrically from those of the pancreatic segment that had been resected. We conclude that in subtotally depancreatized but nondiabetic dogs, maintenance of constant hyperglycemia of greater than or equal to 250 mg/dl by means of intravenous glucose infusion causes a severe, persistent, and often insulin-requiring diabetic state that does not occur in the absence of the hyperglycemia.

Plasma C-Peptide Levels and Clinical Remissions in Recent-Onset Type I Diabetic Patients Treated With Cyclosporin A and Insulin

“…In our study, initial insulin dosages were the same, and the metabolic control obtained was similar in both groups for the duration of the study. All these studies emphasize the possibility that strict control can induce partial recovery in p-cell function, due to the metabolic (17)(18)(19)(20)(21) and/or immunologic (26) beneficial effects of euglycemia.…”

“…However, remission can result from an actual recovery of islet function, a correction of the insulin resistance of untreated insulinopenic diabetic patients (12)(13)(14)(15)(16), or both. On the other hand, aggressive insulin therapy alone drastically improves islet function and reverses insulin resistance of tissues (17)(18)(19)(20)(21)(22). When immunosuppressive treatments are combined with insulin and a remission then occurs, the actual contribution of immunosuppression to these results may be questioned.…”

Type II Diabetes, Glucose “Non-Sense,” and Islet Desensitization

“…This conclusion was reinforced by Leahy et al (18) and Rossetti et al (19), who reported data suggesting that chronic postpancreatectomy exposure of residual fJ-cells to higher than normal glucose concentrations causes insulin secretory defects. Imamura et al (20) also observed adverse effects of hyperglycemia on residual pancreatic function after pancreatectomy. On the other hand, Ward et al (21) reported defective arginineinduced insulin secretion 6 wk after partial pancreatectomy when glucose-induced insulin secretion remained normal; however, the animals were not hyperglycemic postoperatively.…”

Natural History of β-Cell Dysfunction in NIDDM

“…Alternatively, could these observations be secondary to glucose intolerance? In animals, it has been reported that long-term severe hyperglycemia has a cytotoxic effect on (3-cells, but the relevance of this observation to NIDDM is unclear (59,60).…”