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Rosiglitazone, But Not Glyburide, Reduces Circulating Proinsulin and the Proinsulin:Insulin Ratio in Type 2 Diabetes

Scientific Affairs (S.A.S.), Diabetes, GlaxoSmithKline, Harlow, Essex, CM19 5AW, United Kingdom; and Cardiovascular and Metabolism Clinical Development (L.E.P., N.B., M.I.F.), GlaxoSmithKline, King of Prussia, Pennsylvania 19406

Address all correspondence and requests for reprints to: Stephen A. Smith, GlaxoSmithKline, New Frontiers Science Park (South), Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom. E-mail: stephen.a.smith{at}gsk.com.

An elevation in the ratio of proinsulin (PI) to immunoreactive insulin (IRI) is inversely related to ß-cell function in type 2 diabetes, and increased PI is an independent risk factor for coronary heart disease. An objective of the present studies was to assess the effects of the thiazolidinedione insulin sensitizer, rosiglitazone, on indirect markers of ß-cell function and cardiovascular risk in people with type 2 diabetes by measuring plasma PI and the PI:IRI ratio. Parameters of insulin processing, including plasma PI and PI:IRI ratios, were determined in type 2 diabetes patients enrolled in two randomized double-blind studies comparing the effects of rosiglitazone (4 or 8 mg/d) with placebo (study 1, 26-wk treatment) or the sulfonylurea glyburide (study 2, 52-wk treatment). Treatment with rosiglitazone for 26 wk (study 1) produced significant dose-dependent decreases in both plasma PI concentrations (18–29%) and the PI:IRI ratio compared with baseline (7–14%) and placebo (19–29%) (P < 0.001). A significant increase in the PI:IRI ratio in placebo-treated patients occurred (P < 0.001). In study 2, rosiglitazone also significantly reduced both plasma PI and the PI:IRI ratio compared with baseline (P < 0.001). In contrast, glyburide significantly increased both plasma PI (45%; P < 0.001) and the PI:IRI ratio (10%) (P < 0.05 vs. baseline). These results show that rosiglitazone and glyburide have differential effects on absolute PI levels and the PI:IRI ratio in people with type 2 diabetes.

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