A single injection of streptozotocin into mice produced an extensive necrosis of the beta cells resulting in permanent diabetes. The histological changes in the islets were similar to those described after the injection of alloxan. The regenerative capacity of beta cells which survived the cytotoxic injury was limited.Hypoglycemia induced by an injection of insulin or hyperglycemia induced by glucose injections sensitized the beta cells to streptozotocin. In contrast, injection of insulin antibody effectively protected the beta cells from the cytotoxic injury.Streptozotocin caused widespread necrosis of the beta cells of the guinea pig and the obese hyperglycemic mouse. Both these species had proven resistant to the diabetogenic effect of alloxan.Diabetic guinea pigs were observed for eight months, without reversion of the diabetic syndrome. DIABETES 18: 606-11, September, 1969. Until recently alloxan was the most effective compound for the induction of experimental diabetes in animals. In 1963 Rakieten 1 reported that streptozotocin, a by-product of the bacterium Streptomyces achromogenes possessing antibacterial and antitumoral properties, 2 caused diabetes in dogs and rats. The initial observation attributed the diabetic syndrome to destruction of the beta cells of the pancreatic islets. Later experimental work with rats by Arison et al. 3 favored an inhibition of insulin synthesis without cell necrosis as the diabetogenic mechanism.We became interested in the experimental diabetes induced by streptozotocin for the following reasons:(a) The suggestion of a permanent biochemical lesion without necrosis of beta cells required reinvestigation because of its implications in the physiology and biochemistry of insulin secretion.(b) We wanted to test the effect of hyperglycemia From the Banting and Best
This study contributes to a fuller understanding of the dynamics and time relationships of follicular growth and loss in the guinea pig ovary and provides new morphogenetic information on the atretic process. It would be valuable for the design of experiments on endocrine and paracrine interactions involved in follicular growth and atresia.
A specially developed clamping procedure permitted the easy, complication-free removal of splenic pancreas from rats. Using this biopsy procedure pancreatic tissue was removed from 50- to 90-day-old BB rats to study in a retrospective experimental design the time at which insulitis appears in BB rats, which develop acute, overt diabetes before the age of 120 days. Islets in biopsies taken 18–53 days before the onset of diabetes showed normal structure and were free from any mononuclear infiltrations. Biopsies removed between 2 and 9 days before onset of diabetes in contrast showed widespread insulitis. In five rats in which the biopsy preceded the manifestation of diabetes by 11–16 days, only a small number of pancreatic islets showed small focal mononuclear cell infiltrations. Most of the islets in these five rats had a normal histologic appearance.
Thus the lesions within the islets develop rapidly starting about 2–3 wk before overt diabetes. As revealed by autoradiography, pancreatic beta-cells still surviving at the time of onset of diabetes show a modest increase in replicative activity. Replicative activity of mononuclear inflammatory cells also was observed, suggesting that their accumulation within the islet tissue may result in part from local replication.
Inosine and guanosine were potent stimuli of proinsulin biosynthesis ([3H]leucine incorporation) in isolated pancreatic islets of the rat. The effect was nearly abolished by formycin B, an inhibitor of purine nucleoside phosphorylase, but not by D-mannoheptulose. The corresponding bases had no effect on the rate of proinsulin biosynthesis. D-ribose enhance proinsulin biosynthesis at low concentrations )0.3-0.6mM) but concentrations above 5 mM were ineffective. The effect of all three compounds was highly specific for proinsulin biosynthesis, since incorporation of [3H]leucine into other islet proteins was not significantly stimulated. The data strongly indicate that metabolic signals regulate modulation of proinsulin biosynthesis in the beta cells.
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