Genetically diabetic mice (C57BL/KsJ-db/db) were used as a model to study the development of defects of insulin secretion in relation to common metabolic indicators (body weight, serum glucose and insulin, and islet insulin contant). Consistent with the idea of a protective effect of oestrogen on the pancreatic β-cell, the female diabetic mice survived longer than the males. In males, while serum insulin decreased in the later stages of the disease, serum glucose increased progressively with age. Perfusion of the diabetic pancreases revealed a rise and subsequent fall with age of the basal insulin released at 3 mm glucose. Despite previous reports of β-cell hyperplasia, progressive impairment of the insulin response to 20 mm glucose, or to 20 mm glucose and 1 mm 3-isobutyl-1-methylxanthine, was seen with increasing age in experiments with perfused pancreas or microdissected islets. Islet content of insulin also decreased progressively with age in the diabetic animals.

Therefore, to characterize pancreatic islet function, dynamic insulin and glucagon release from normal and nonketotic diabetic hamster pancreases in response to glucose (300 mg/100 ml) and theophylline (10 mM), infused singly and together, was studied in vitro.20-min glucose infusions of normal hamster pancreases caused biphasic insulin release, consisting of a rapid first peak and a gradually rising second phase, similar to that reported for man in vivo. Both phases were significantly reduced in the diabetic pancreases. Theophylline alone stimulated similar nonphasic insulin release in both the normal and the diabetic pancreases. Glucose and theophylline together caused greater insulin release than either stimulant alone in both normals and diabetics; however, the diabetic response was still subnormal.Glucose suppressed glucagon release from normal pancreases; suppression was significantly impaired in diabetics. Theophylline stimulated nonphasic glucagon release in both the normals and diabetics. Glucose partially suppressed the theophylline-stimulated release in both groups.Insulin/glucagon molar ratios of the diabetics were consistently subnormal, although individual hormone levels often overlapped into the normal range.This work was presented in part at the Western Section of the American Federation for Clinical Research, Carmel, Calif., 2 February 1973 (Clin. Res. 21: 273)

A clinical syndrome, characterized by acute diabetic ketoacidosis associated with a toxic neuropathy, developed in five men who intentionally ingested a recently introduced rodenticide (Vacor) containing N-3-pyridylmethyl-N'-p-nitrophenyl urea (RH-787). A 7-yr-old boy, who accidentally ingested this poison, died within 14 h. Marked insulinopenia, without a reduction in glucagon levels, suggested a specific beta-cytotoxic effect, which was supported after autopsy in three cases by histopathologic evidence of extensive beta cell destruction. Lethal effects in rats prevented investigation of RH-787's diabetogenicity in vivo; however, studies in isolated rat islets confirmed a direct inhibitory effect, which was prevented by concomitant incubation with nicotinamide, suggesting a mechanism of action similar to that of streptozotocin. We detected islet cell-surface antibodies in two of four patients studied. These findings indicate that this nongenetic, acquired form of insulinopenic diabetes, which has persisted in the surviving patients for up to 3 yr, presents a unique opportunity to test in man the concept that hyperglycemia and the accompanying metabolic consequences of insulinopenia can induced diabetic microangiopathy in the absence of genetic predisposition.

Some data in the literature suggest that heightened activity of the pineal gland may be diabetogenic. The onset of insulin-dependent diabetes mellitus is highest during the winter months and at puberty when melatonin levels are also greatest. To study the direct effects of pineal hormones on insulin release, hand-dissected ob/ob-mouse islets of Langerhans were incubated in vitro with melatonin (1 nmol/l to 100 mumol/l) or arginine vasotocin (1 pmol/l to 10 mumol/l) and D-glucose (3 or 20 mmol/l for 1 hr. Melatonin did not affect basal or glucose-stimulated insulin release. Arginine vasotocin (AVT) did not affect basal insulin release, but at presumably pharmacological levels (1 and 10 mumol/l) the peptide significantly increased glucose-stimulated insulin release. We conclude that melatonin and AVT at physiological concentrations have no direct effect on islet insulin release, and that any diabetogenic effect of the pineal gland must occur via suppression of insulin action or via production of a metabolite or hormone that suppresses insulin release.