Effect of chronic rosiglitazone, metformin and glyburide treatment on β‐cell mass, function and insulin sensitivity in mZDF rats

Abstract

Here we investigate the effect of rosiglitazone (RSG), metformin (MET) and glyburide (GLIB) on plasma glucose levels, beta-cell mass, function and insulin sensitivity in 10-week-old diabetic male Zucker diabetic fatty (mZDF) rats using quantitative morphometry and a mathematical model beta-cell mass, insulin and glucose kinetics (betaIG). At treatment start, 10-week-old diabetic mZDF rats were severely hyperglycaemic and had very low beta-cell function (insulin secretory capacity). RSG treatment significantly lowered plasma glucose levels in 67% of the mZDF rats. MET was effective at lowering plasma glucose levels in 33% of the mZDF rats, while GLIB was completely ineffective at lowering blood glucose levels in 10-week-old mZDF rats. RSG treatment prevented the fall in beta-cell mass after 6-8 weeks of treatment accompanied by a significant decrease in beta-cell death while MET treatment had no effect on beta-cell mass. RSG treatment increased insulin sensitivity 10-fold, increased beta-cell function fivefold and modestly increased beta-cell mass 1.4-fold. MET treatment increased insulin sensitivity fourfold, with no significant effect on beta-cell function or mass. Although RSG treatment was highly successful in lowering plasma glucose levels, the 33% of mZDF rats that did not respond to the treatment had significantly lower beta-cell function prior to treatment start compared with the responder group. Thus, the low level of beta-cell function at treatment start may explain why none of these agents were completely effective at lowering blood glucose levels in 10-week-old diabetic mZDF rats. Nevertheless, these data suggest that the preservation of beta-cell mass and improvement in beta-cell function play a role in the overall beneficial effect of RSG in 10-week-old diabetic mZDF rats.