We have previously reported that newly diagnosed Type-1 diabetic patient sera potently suppressed insulin secretion from a clonal rat pancreatic -cell line (BRIN BD11) but did not alter cell viability. Here, we report that apoptosis in BRIN BD11 cells incubated in various sera types (fetal calf serum (FCS), normal human serum and Type-1 diabetic patient) was virtually undetectable. Although low levels of necrosis were detected, these were not significantly different between cells incubated in sera from different sources. ATP levels were reduced by approximately 30% while nitrite production increased twofold from BRIN BD11 cells incubated for 24 h in the presence of Type-1 diabetic patient sera compared with normal human sera. Additionally, ATP levels were reduced by approximately 40% and DNA fragmentation increased by more than 20-fold in BRIN BD11 cells incubated in FCS in the presence of a pro-inflammatory cytokine cocktail (interleukin-1 , tumour necrosis factor-and interferon-), compared with cells incubated in the absence of cytokines. Nitric oxide production from BRIN BD11 cells was markedly increased (up to 10-fold) irrespective of sera type when the cytokine cocktail was included in the incubation medium.Type-1 diabetic patient sera significantly (P<0·001) raised basal levels of intracellular free Ca 2+ concentration ([Ca 2+ ] i ) in BRIN BD11 cells after a 24-h incubation. The alteration in [Ca 2+ ] i concentration was complement dependent, as removal of the early complement components C1q and C3 resulted in a significant reduction (P<0·01) of sera-induced [Ca 2+ ] i changes. We propose that the mechanism of Type-1 diabetic patient sera-induced inhibition of insulin secretion from clonal -cells may involve complement-stimulated elevation of [Ca 2+ ] i which attenuates the nutrient-induced insulin secretory process possibly by desensitizing the cell to further changes in Ca 2+ .
Administration of the compound M&B 39890A lowered serum glucose levels significantly (p less than 0.001) in genetically obese mice, while no effect on serum insulin levels was observed. In in vitro experiments with isolated rat islets of Langerhans M&B 39890A inhibited arginine-stimulated glucagon release at all concentrations tested (0.5, 5.0 and 50 mumol/l). Insulin secretion was not inhibited by M&B 39890A (0.5 and 5.0 mumol/l), but was slightly decreased at 50 mumol/l. M&B 39890A (5 mumol/l) also inhibited glucagon secretion in vitro in the presence of 2 mmol/l, 6 mmol/l and 20 mmol/l glucose, while exerting no effect on insulin secretion. These results suggest that the hypoglycaemic action of M&B 39890A may be due to its direct and selective effect on glucagon secretion; this appears to operate by a mechanism different to that of glucose.
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