EFFECTS OF CHRONICALLY ELEVATED GLUCOSE-LEVELS ON THE FUNCTIONAL-PROPERTIES OF RAT PANCREATIC BETA-CELLS

This study examines the effects of chronically elevated glucose levels on the survival and function of purified rat beta-cells. Prolonged ex posure (9 days) of beta-cell aggregates to 20 mmol/l glucose did not l ead to cell losses, but reduced the amount of insulin secreted in resp onse to glucose. This decrease was not caused by cellular desensitizat ion but resulted from the lower cellular insulin content after a prolo nged imbalance between stimulated rates of insulin synthesis and relea se, Virtually all beta-cells exhibited a state of metabolic and biosyn thetic activation, which was maintained for at least 2 h in glucose-de pleted media, Their rates of protein and insulin synthesis were amplif ied by glucose, reaching (half-) maximal stimulation at lower glucose concentrations (2 and 5 mmol/l, respectively) than control cells cultu red at 10 mmol/l glucose (5 and 10 mmol/l, respectively), As for insul in release, the net glucose effect on insulin synthesis was markedly r educed as compared with that in control cells. This was also the case after culture at 6 mmol/l glucose. In the latter condition, the lower glucose-inducible activities were caused by cellular desensitization, with 50% of the beta-cells unresponsive to glucose and the other 50% r esponding with a lower sensitivity (half-maximal stimulation at 7 mmol /l glucose), Comparison of beta-cells cultured at the three glucose co ncentrations indicated that prolonged exposure to elevated glucose lev els increases the number of degranulated cells, of cells with a high p roportion of immature insulin granules, and of cells with glycogen dep osition-morphologic features previously described in conditions of hyp erglycemia. It is concluded that chronic exposure (9 days) of rat beta -cells to elevated glucose levels induces a prolonged state of beta-ce ll activation and glucose hypersensitivity rather than a glucotoxicity or glucose desensitization. This shift in the functional state of the beta-cell population is responsible for a reduced insulin release in response to glucose, as observed in other conditions of prolonged expo sure to high glucose levels.