In vivo and in vitro increased pancreatic beta-cell sensitivity to glucose in normal rats submitted to a 48-h hyperglycaemic period

Abstract

We investigated the importance of the level and the duration of glucose stimulation on the in vivo and in vitro insulin response to glucose in normal rats previously submitted to hyperglycaemia. Rats were made hyperglycaemic by a 48-h glucose infusion. Glucose-induced insulin secretion was investigated in vivo by a 20-min hyperglycaemic clamp and in vitro by the isolated perfused pancreas technique, 3 h after the end of the in vivo glucose infusion. In glucose-infused rats, as compared to controls, in vivo incremental plasma insulin values above baseline integrated over the 20-min hyperglycaemic clamp (delta I) were five times higher during 8 mmol/l glucose clamp, only two times higher in 11 mmol/l glucose clamp and no different in 16.5 mmol/l. Compared to the controls, in vitro incremental plasma insulin concentration above baseline integrated over a 20-min period (delta I) in glucose-infused rats was 16 times higher in response to 2.8 mmol/l glucose, two times higher in response to 5.5 mmol/l, similar in response to 8.3 mmol/l and significantly lower in response to 16.5 mmol/l. In conclusion, our data suggest that a 48-h hyperglycaemic period results in an increased response of the pancreatic beta cell to low glucose. The response is immediately maximal and can not be increased with higher glucose concentrations. This situation could explain the apparent minimal effect of high concentrations on in vitro insulin secretion in previously hyperglycaemic rats and may provide insights into the sequence of events leading to the impairment of beta-cell function in Type 2 (non-insulin-dependent) diabetes mellitus.

Hyperglycaemia but not hyperlipidaemia causes beta cell dysfunction and beta cell loss in the domestic cat

“…In contrast to previous models using rodents, in which glucose was infused for 2-4 days [9][10][11][12][13][14], we show that severe beta cell dysfunction is rapidly induced by sustained hyperglycaemia in cats. Plasma insulin markedly declined by day 2 of glucose infusion and was below baseline by day 10.…”

“…Several groups used a variety of glucose and lipid infusion protocols to investigate the direct effects of hyperglycaemia and hyperlipidaemia on beta cells in vivo [9][10][11][12][13][14][15][16][17][18][19]. In previous studies performed in rodents, glucose and lipid solutions were administered at a constant rate and for only 2-4 days.…”

Effect of forty-eight-hour glucose infusion into rats on islet ion fluxes, ATP/ADP ratio and redox ratios of pyridine nucleotides

“…Long term exposure of pancreatic islets to high glucose in vitro or by glucose infusion has been shown to cause sensitization and/or desensitization of insulin release (Leahy et al 1986, Bolaffi et al 1988, Marynissen et al 1990, Timmers et al 1990, Bedoya & Jeanrenaud 1991a, Thams 1991, Davalli et al 1992, Eizirik et al 1992, Purello et al 1992, Thibault et al 1993. The respective effects seem to depend on the glucose concentration employed (Leahy et al 1986) and the duration of glucose action (Bedoya & Jeanrenaud 1991a).…”

Prolonged exposure of human beta cells to elevated glucose levels results in sustained cellular activation leading to a loss of glucose regulation.

“…This concept has been documented in animal models of hyperglycemia (7)(8)(9)(10)(11) as well as in cultured islet cell preparations (12)(13)(14)(15). It is still unclear whether the deleterious effects of persistently high glucose concentrations are the consequence of a glucose-induced toxicity (1)(2)(3)(4)(5), desensitization (5,6,12,13), hyperactivation (16,17), or exhaustion (1,2,18) of the ␤ cells. In a recent study on rat islet ␤ cells, we found that chronic exposure to elevated glucose levels induces a prolonged state of ␤ cell activation and glucose hypersensitivity rather than a glucotoxicity or glucose desensitization (19).…”