Non-obese diabetic mice aged 30 to 60 days were treated orally with Cyclosporin at doses of 25, 15 and 2.5 mg/kg every 2 days until 160 days of age. Diabetes developed in 12 out of 18 oil-treated mice (67%), with partial to complete Langerhans' islet destruction associated with lymphocytic infiltration. The non-obese diabetic mice showed a plasma glucose concentration of 6.62 +/- 0.92 mmol/l (mean +/- SD) at 50 days of age. The plasma glucose level of oil-treated non-obese diabetic mice gradually increased after 130 days of age and reached 14.0 to 19.0 mmol/l at 160 days of age, while Cyclosporin-treated non-obese diabetic mice showed neither clear increase of plasma glucose levels nor development of insulitis. The cumulative incidence of diabetes in Cyclosporin-treated mice was significantly lower than that in oil-treated mice (p less than 0.01). Subsequently, Cyclosporin treatment was started after development of glucose intolerance. Twenty-five mg/kg of Cyclosporin was administered every 2 days for 35 days. Cyclosporin appeared to have little therapeutic effect on diabetes in non-obese diabetic mice.
Aims/IntroductionPemafibrate is a novel selective peroxisome proliferator‐activated receptor‐α modulator with potent triglyceride‐lowering and high‐density lipoprotein cholesterol‐raising effects. We showed that pemafibrate decreased the homeostatic model assessment for insulin resistance in patients with dyslipidemia. To investigate how pemafibrate improves insulin sensitivity, we used a hyperinsulinemic‐euglycemic clamp technique to determine the splanchnic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance.Materials and MethodsA total of 27 patients with hypertriglyceridemia and insulin resistance were randomly assigned to receive pemafibrate (0.4 mg/day, b.i.d.) or placebo treatment for 12 weeks. The hyperinsulinemic‐euglycemic clamp test combined with oral glucose loading was carried out at weeks 0 and 12 to evaluate the splanchnic and peripheral glucose uptake.ResultsPemafibrate, but not the placebo, significantly increased the splanchnic glucose uptake rate from baseline (19.6 ± 5.9% with P = 0.005 and 2.1 ± 7.4% with P = 0.78, respectively), although no significant difference between the groups was observed (P = 0.084). Conversely, peripheral glucose uptake rate was not significantly altered. Pemafibrate, compared with the placebo, significantly decreased plasma triglycerides (−61.4 ± 16.4% vs −2.5 ± 41.4%, P = 0.001), free fatty acids (−24.8 ± 23.2% vs 2.0 ± 26.8%, P = 0.016) and gamma‐glutamyl transpeptidase (−30 ± 46 vs 10 ± 19 U/L, P = 0.009) levels, and significantly increased fibroblast growth factor 21 (457.7 ± 402.1 vs −41.7 ± 37.4 pg/mL, P = 0.007) levels.ConclusionsPemafibrate increased splanchnic glucose uptake from baseline in patients with hypertriglyceridemia.
It has been reported that insulin secretion decreases during hypoxia both in vitro and in vitro, while an increase in glucagon secretion is found only in vivo. The effect of acute hypoxia on the secretion of glucagon and insulin was studied in the perfused rat pancreas. Phentolamine, an alpha-adrenergic blocker, was perfused during the period of hypoxia to elucidate the role of alpha-adrenergic stimulation. Sodium ATP and dibutyryl cAMP were also administered to study their effects on insulin and glucagon responses during hypoxia. In the present experiments, insulin secretion was suppressed while glucagon secretion was increased during hypoxia. Phentolamine did not cause any change in insulin of glucagon secretion. When dibutyryl cAMP was added, the increased glucagon secretion was reduced to the basal level, whereas the decreases in insulin secretion were not altered. The addition of sodium ATP reversed the hypoxia-induced decrease in insulin and the increase in glucagon secretion. These results suggest that a decrease in ATP production, which leads to impaired cAMP generation, pays a role in, and that alpha-adrenergic stimulation does not participate in the changes in, insulin and glucagon secretion during hypoxia in vitro.
Summary.Human pancreatic A-, B-and D-cell clonal strains, named JHPG-1, JHPI-1 and JHPS-1, were established successfully from adult and fetal pancreata by the single cell plating feeder layer method using a modified Rose's chamber. This is the first time that insulin-, glucagon-and somatostatin-producing clonal strains have been separated into continuous clonal cell lines.The cultured cells are epithelial in nature, free of fibroblast contamination, and can be cloned. Under the phase-contrast microscope, the B-cell clone (JHPI-1) was generally oval or round in shape, the A-cell clone (JHPG-1) was bipolar, and the D-cell clone (JHPS-1) was nerve-like with cytoplasmic processes. By the use of immunocytochemical techniques, insulin-, glucagon-and somatostatin-like immunoreactivities were detected in each clone respectively.By radioimmunoassay it was revealed that each clone produced a single pancreatic hormone.The B-cell clone especially, was found to secrete insulin amply and continuously, for over 150 days. The glucagon release responses by the A-cell clone to insulin and glucose were also studied.The clonal strains obtained in this study provide useful systems for the investigation of the cell-biological aspects of human islet cells in vitro.
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