Effect of Pioglitazone on Pancreatic β-Cell Function and Diabetes Risk in Hispanic Women With Prior Gestational Diabetes

Abstract

The Pioglitazone In Prevention Of Diabetes (PIPOD) study was conducted to evaluate ␤-cell function, insulin resistance, and the incidence of diabetes during treatment with pioglitazone in Hispanic women with prior gestational diabetes who had completed participation in the Troglitazone In Prevention Of Diabetes (TRIPOD) study. Women who completed the TRIPOD study were offered participation in the PIPOD study for a planned 3 years of drug treatment and 6 months of postdrug washout. Oral glucose tolerance tests were performed annually on pioglitazone and at the end of the postdrug washout. Intravenous glucose tolerance tests (IVGTTs) for assessment of insulin sensitivity and ␤-cell function were conducted at baseline, after 1 year on pioglitazone, and at the end of the postdrug washout. Of 95 women who were not diabetic at the end of the TRIPOD study, 89 enrolled in the PIPOD study, 86 completed at least one follow-up visit, and 65 completed all study visits, including the postdrug tests. Comparison of changes in ␤-cell compensation for insulin resistance across the TRIPOD and PIPOD studies revealed that pioglitazone stopped the decline in ␤-cell function that occurred during placebo treatment in the TRIPOD study and maintained the stability of ␤-cell function that had occurred during troglitazone treatment in the TRIPOD study. The risk of diabetes, which occurred at an average rate of 4.6% per year, was lowest in women with the largest reduction in total IVGTT insulin area after 1 year of treatment. The similarity of findings between the PIPOD and TRIPOD studies support a class effect of thiazolidinedione drugs to enhance insulin sensitivity, reduce insulin secretory demands, and preserve pancreatic ␤-cell function, all in association with a relatively low rate of type 2 diabetes, in Hispanic women with prior gestational diabetes. Diabetes 55:517-522, 2006 T ype 2 diabetes frequently results from progressive failure of pancreatic ␤-cells in a setting of chronic insulin resistance (1-6). In the Troglitazone In Prevention Of Diabetes (TRIPOD) study (7), we found that treatment of insulin resistance with the thiazolidinedione drug, troglitazone, improved insulin sensitivity and reduced the incidence of type 2 diabetes in Hispanic women with prior gestational diabetes. Protection from diabetes was closely related to the degree to which endogenous insulin requirements were reduced soon after initiation of troglitazone treatment. Moreover, women who were protected from diabetes during troglitazone treatment had stable ␤-cell function and insulin resistance for nearly 5 years. These findings provided evidence that reducing the secretory demands that are placed in pancreatic ␤-cells by chronic insulin resistance can preserve ␤-cell function and slow or stop progression to type 2 diabetes. Troglitazone was withdrawn from clinical use in 2000. The Pioglitazone In Prevention Of Diabetes (PIPOD) study was conducted to assess the effect of a currently available thiazolidinedione drug, pioglitazone, on pancreatic ␤-cell functi...

Pioglitazone does not enhance the effectiveness of lifestyle modification in preventing conversion of impaired glucose tolerance to diabetes in Asian Indians: results of the Indian Diabetes Prevention Programme-2 (IDPP-2)

“…This was in contrast to reports that pioglitazone [9], troglitazone [6,8] and rosiglitazone [7] are highly effective preventive agents in different populations. Troglitazone was found to be highly effective in reducing the incidence of diabetes in individuals with IGT [6] and in women with a history of GDM [8], but these studies had to be terminated prematurely because of hepatic toxicity of the drug.…”

“…Insulin sensitisers such as metformin [3,4] and the glitazones [6,7] have also been useful in the primary prevention of diabetes in people with IGT and in women with a history of gestational diabetes (GDM) [8,9], in different ethnic groups. Results of the Actos Now for Prevention of Diabetes (ACT NOW) study, presented in the 68th Annual Meeting of the American Diabetes Association in June 2008, showed that pioglitazone produced a remarkable reduction (81%) in conversion of IGT to diabetes in a mean period of 2.6 years, in the US population [10].…”

Prevalence of type 2 diabetes among women with a previous history of gestational diabetes mellitus

“…Women with a history of GDM also constitute a high-risk population. Women who developed GDM and were treated with pioglitazone in the Pioglitazone in Prevention of Diabetes study had stable pancreatic b-cell function and a relatively low subsequent incidence of diabetes [10].…”

The metabolic consequences of sleep deprivation

“…DI values of 2,000 and above are typical of subjects with normal glucose tolerance while DI values under 1,000 have been reported in populations at high risk for type 2 diabetes, such as Hispanic women with prior gestational diabetes. 24 In the sleep debt condition, the DI was 40% lower than after sleep recovery and 3 of the 11 subjects had DI values under 1,000. Table 2 compares the glucose tolerance (K G ) values observed in these healthy young men at the end of the sleep debt condition and when fully rested to values obtained in different subject populations using the same ivGTT protocol and mathematical analysis.…”