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.