Search

The autoregulation of insulin secretion was studied using perifused and incubated pancreatic islets of normal (obOb) mice and of their obese-hyperglycemic (obob) littermates. Islets secreted more insulin when they were perifused than when they were incubated and insulin was allowed to accumulate in the medium. When rat insulin was added to the incubation medium in the concentration of 250 μU/ml, the secretory activity of the normal islets was suppressed almost completely. The concentration of exogenous insulin required to inhibit the islets of obese mice was higher and increased with the age of the animals, until it reached a value that was 20 to 30 times greater than that found in the circulating blood. Similar concentrations may well exist in the extracellular fluid of the pancreatic islets. It is possible that while insulin resistance of the peripheral tissues may be responsible for the hyperglycemia of the obob mice, the progressive loss of insulin sensitivity of their pancreatic islets and, consequently, of the normal autoregulation of insulin secretion, may play a role in the progressive hyperinsulinism and, hence, of the obesity characteristic of these animals.

Significant quantities of A cell and total glucagon were found in the systemic blood of eviscerated rats, especially following arginine infusion. These findings and the hyperglucagonemia previously observed in depancreatized and in eviscerated animals, prompted us to look for glucagon sources other than the pancreas and the gastrointestinal tract. Significant amounts of immunoreactive glucagon (IRG) were extracted from rat submaxillary and parotid gland tissue using a modification of the method of Kenny. This IRG could be measured with an antiglucagon serum specific for pancreatic or A cell glucagon and with an antiserum that crossreacts with extracts of intestinal mucosa. Intravenous injections of submaxillary gland extracts caused a significant increase in blood glucose in normal, but not in eviscerated rats. A-V differences in glucagon concentration between aorta and facial vein suggest that the salivary glands release glucagon into the circulation. Similarly, A-V differences between the blood of the aorta and of the renal vein suggest that the kidneys remove glucagon from the circulation in normal, but not in eviscerated rats. Indeed, the kidneys of eviscerated rats may release previously stored glucagon into the blood. No glucagon was found in the saliva. Glucagon release by the salivary glands and the kidneys may contribute to the hyperglucagonemia characteristic of depancreatized and eviscerated animals.

The ability of dispersed islet cells in a perifusion system to secrete glucagon and insulin in response to physiologic stimuli was investigated. Normal hamster islets were isolated by coUagenase digestion and the cells dispersed by sequential digestion with coUagenase and trypsin. Following a 50-min period of equilibrium in buffer with high glucose concentrations (5.0 mg/ml), glucagon secretion was stimulated by glucopenia and subsequently, inhibited by increasing the concentration of glucose. The responsiveness to glucose inhibition was significantly less in dispersed islet cells than in intact islets. However, the dispersed islet cells showed a significantly greater response to arginine. Glucagon secretion by dispersed islet cells was stimulated to tolbutamide and epinephrine but somatostatin had no effect. Dispersed islet cell preparations did not augment insulin secretion in response to glucose but did secrete more insulin in response to arginine. Intact islets secreted insulin in response to glucose but not arginine. We conclude that A cells in cell suspension do not need direct contact or an intact intra-islet environment in order to respond to glucose, arginine, epinephrine, or tolbutamide but the extent of response may be influenced by paracrine effects. However, paracrine relationships may be important in determining the response of B cells to secretagogues.

The effect of acute and chronic ingestion of aspartame was studied in normal and streptozotocin-induced diabetic rats. In both groups, a single dose of aspartame caused an increase of approximately 12% in liver tryptophan oxygenase (TO) activity. In diabetic animals, the sweetener caused a decrease in blood and brain tryptophan and an increase in serum glucose and glucagon. Chronic ingestion of aspartame also caused increase in TO activity in both groups. It caused a decrease in fasting serum insulin in normal animals and an increase in serum glucose in diabetic animals. Aspartame may adversely affect the capacity to control glucose metabolism in the diabetic.

Tolbutamide and glibenclamide (glyburide) were administered to normal hamsters, mice or rats in daily doses proportional to their body weight and equivalent to those used in human therapy. The animals were sacrificed after 6 to 8 weeks of treatment. Pieces of pancreas or isolated pancreatic islets were incubated or perifused in a medium containing glucose or tolbutamide, with or without Ieucine-114C or glucose-U-14C. The results indicate that the B cells of sulfonylurea treated animals synthesized and released less insulin and oxidized less glucose than those of insulin or saline treated controls. Accordingly, at least in the glibenclamide treated animals, the tolerance for glucose and the insulinogenic response to a glucose load in vivo were suppressed. Although insular function tended to return, to normal after treatment was discontinued, the results reported in this paper do not support the generally accepted view that the lasting therapeutic effectiveness of the sulfonylureas is due to a beta-cytotrophic action.