Altered Secretory Responsiveness of Brin-BD11 Cells Cultured under Hyperglycaemic Conditions is not Readily Reversed by Subsequent Culture in Lower Glucose Concentrations

Abstract

The complex interaction of nutrient stimuli on the pancreatic B-cell results in the appropriate amount of insulin being secreted to maintain glucose homeostasis. In non-insulin-dependent diabetes mellitus (NIDDM), defects in the regulatory mechanisms of in sulin secretion make a major contribution to the metabolic disorders associated with the disease (Kahn and Porte, 1990). Possible molecular mechanisms underlying pancreatic B-cell dysfunction in NIDDM include site-specific defects in the stimulus-secretion pathway and alterations of B-cell function consequent to changes in external influences on the B-cell (Flatt et al., 1994). Studies in man and experimental animals both in vivo and in vitro have indicated that long-term exposure to a hyperglycaemic environment results in a gradual impairment of insulin secretion (Leahy et al., 1992; McClenaghan et al., 1996; Barnett et al., 1993, 1994). Such observations support the concept of glucose toxicity and the view of hyperglycaemia as an inducer, as well as a consequence of B-cell dysfunction (Unger and Grundy, 1985). Recent studies indicate that there may be species variation in the susceptibility to the detrimental effects of a hyperglycaemic environment (Eizirik and Sandier, 1992; Eizirik et al., 1989). These observations raise two important considerations. Firstly, species differences may reflect differences in endogenous mechanisms which protect against the effects of glucose toxicity. Secondly, the deleterious effects of hyperglycaemia may be manifest in genetically susceptible B-cells where increased functional strain is imposed on existing weakspots in the insulin secretory pathway. In this study we investigated the effects of hyperglycaemia on insulin secretory responsiveness of the novel clonal B-cell line, BRIN-BD11 (Flatt et al., 1993). Possible reversal of the glucose toxic effects by subsequent culture at lower glucose concentrations were also examined.