R. Fussgänger

Effects of synthetic rat C-peptide in normal and diabetic rats

SummaryThe effects of synthetic rat C-peptide 1 and C-peptide 2 on plasma insulin and blood glucose concentrations in the rat were studied. Infusion of rat C-peptide (500μg·h-1· kg-1) diminished glucose induced increase of plasma insulin by 56% (15.2±0.9 versus 6.6± 0.6 ng/ml, p<0.01, mean±SEM). Somatostatin infused at a rate of 50 μg·h-1·kg-1 body weight inhibited glucose-induced insulin secretion by 33%. In the presence of a mixture of both C-peptides or somatostatin, blood glucose after intravenous glucose was higher than in the control experiments. In alloxan-diabetic rats, C-peptide (160 μg/kg) significantly increased and prolonged the hypoglycaemic effect of exogenous insulin. It is suggested that C-peptide may not be a biologically inert substance.

Hyperglucagonemia of the isolated perfused pancreas of diabetic mice (db/db)

SummaryDiabetes mellitus is held to be accompanied by inappropriately high levels of plasma glucagon relative to blood glucose concentrations. This has been interpreted as indicating lack of insulin. To establish glucagon release in presence of high levels of endogenous insulin, the effects of both glucose and arginine were studied in the isolated perfused pancreas of genetically diabetic mice (db/db). Stimulation with glucose 2.75 mM or glucose plus arginine 8.25 mM exhibited a pronounced hyperglucagonemia. Following glucose 8.25 mM, however, there was no depression of glucagon secretion. Despite excessive high levels of endogenous insulin, there was a pattern of rather non-suppressible glucagon release. Lack of insulin per se, therefore, is unlikely to be the sole cause of hyperglucagonemia in this type of genetic animal diabetes mellitus.

Insulin secretion and biosynthesis in sucrose fed rats

SummaryLong term feeding of a sucrose rich diet to rats is accompanied by a decreased glucose assimilation rate, despite high plasma insulin levels. Hyperinsulinism is at least partially based on a relative obesity, with increased amounts of abdominal- and retroperitoneal fat tissue, but unchanged total body weight compared to starch fed controls. The secretory pattern of insulin release was studied following glucose, arginine, fructose and sulfonylurea administration in the isolated perfused pancreas of sucrose and isocaloric starch fed rats. In addition, isolated islets of Langerhans were used to demonstrate the effects of glucose on insulin secretion and the incorporation of H-3 leucine into the proinsulin and insulin fraction of islet proteins. Following 11 mM glucose, the dynamics of insulin release in the isolated perfused pancreas of sucrose fed rats is characterized by a markedly elevated, late plateau-like response, usually seen only at higher glucose concentrations. Hyperinsulinism, as compared to starch fed controls, can also be demonstrated following arginine and the sulfonylurea HB-419, whereas fructose has no effect in the presence of low glucose concentrations. During incubation of the pancreatic islets, the hyperinsulinism in sucrose-, compared to starch fed rats, is more pronounced at 11 mM glucose than at 5.5 mM glucose. The incorporation of H-3 leucine into the proinsulin-insulin fraction of islet proteins in sucrose compared to starch fed rats, however, is significantly greater with glucose 5.5 mM than at high glucose level. In sucrose fed rats, secretion and biosynthesis of insulin thus appear to be elevated but closely linked only at physiological glucose concentration.

Influence of Insulin and Glybenclamid on the Intestinal Disaccharidases of Subtotally Pancreatectomized Rats

88 days after subtotal pancreatectomy the activities of intestinal disaccharidases and the RNA/DNA ratio were investigated and compared to normal rats. The activities of these enzymes rise after pancreatectomy. Insulin and glybenclamid cause a decrease of the elevated enzyme levels almost to normal range.

DYNAMICS OF INSULIN SECRETION: COMPARISON OF VARIOUS IN VITRO PREPARATIONS *

SUMMARY All preparations examined displayed qualitatively rather than quantitatively different patterns of response to tolbutamide as compared to HB 419. The rapidly occurring but short-lasting enhancement of the insulin secretion brought about by tolbutamide contrasted to the delayed but more persisting stimulation provoked by HB 419. Tolbutamide interferred with the glucose-induced insulin secretion, resulting in an inhibition of the release after withdrawal of the drug. HB 419, on the other hand, did not inhibit but rather potentiated the effect of glucose, except when the sugar was present in the highest concentrations. Furthermore, when the insulin secretion was stimulated by repeated pulses of sulfonylurea, a refractory state occurred more rapidly when tolbutamide was used, as compared to HB 419. In the presence of low glucose concentrations (60 mg%), neither drug stimulated the insulin release more than did pulses of high glucose concentration (200 mg%). The observed synergism between glucose and HB 419 is in accordance with the great blood-sugar-lowering capacity and the high plasma insulin levels induced by the new compound, when given together with glucose to normal human subjects ( Raptis et al., 1969 ). Also, elderly diabetic subjects, unresponsive to tolbutamide, not only showed increased concentrations of insulin in plasma and moderate hypoglycemia after treatment with HB 419 alone, but also displayed a clear rise of immunoreactive insulin and lower blood sugar values when given a combination of HB and oral glucose ( Raptis et al., 1969 ; Chandalia et al., 1969 ). This response might not be due to the greater molar efficiency of the new compound as compared to tolbutamide but to some specific interaction with the glucose metabolism and/or energy production in the β-cell. It should be mentioned that intestinal hormones like glucagon (Melani et al., 1966, 1967 ; Simpson et al., 1966 ) and secretin ( Raptis et al., 1968, 1969 ; Deckert, 1968 ) have similar effects in diabetic subjects which are unresponsive to glucose alone.