Preservation of Pancreatic β-Cell Function and Prevention of Type 2 Diabetes by Pharmacological Treatment of Insulin Resistance in High-Risk Hispanic Women

Abstract

Type 2 diabetes frequently results from progressive failure of pancreatic ␤-cell function in the presence of chronic insulin resistance. We tested whether chronic amelioration of insulin resistance would preserve pancreatic ␤-cell function and delay or prevent the onset of type 2 diabetes in high-risk Hispanic women. Women with previous gestational diabetes were randomized to placebo (n ‫؍‬ 133) or the insulin-sensitizing drug troglitazone (400 mg/day; n ‫؍‬ 133) administered in doubleblind fashion. Fasting plasma glucose was measured every 3 months, and oral glucose tolerance tests (OGTTs) were performed annually to detect diabetes. Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and 3 months later to identify early metabolic changes associated with any protection from diabetes. Women who did not develop diabetes during the trial returned for OGTTs and IVGTTs 8 months after study medications were stopped. During a median follow-up of 30 months on blinded medication, average annual diabetes incidence rates in the 236 women who returned for at least one follow-up visit were 12.1 and 5.4% in women assigned to placebo and troglitazone, respectively (P < 0.01). Protection from diabetes in the troglitazone group 1) was closely related to the degree of reduction in endogenous insulin requirements 3 months after randomization, 2) persisted 8 months after study medications were stopped, and 3) was associated with preservation of ␤-cell compensation for insulin resistance. Treatment with troglitazone delayed or prevented the onset of type 2 diabetes in high-risk Hispanic women. The protective effect was associated with the preservation of pancreatic ␤-cell function and appeared to be mediated by a reduction in the secretory demands placed on ␤-cells by chronic insulin resistance.

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.…”

“…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. Presently, the safety of rosiglitazone in the prevention or treatment of type 2 diabetes mellitus is being debated as there is a possibility that it increases cardiovascular risk in some individuals [16,17].…”

“…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].…”

Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia

“…Second, the current data also suggest that chronic hypoadiponectinaemia could provide a therapeutic target for risk modification in this patient population. In this respect, it is of interest to note that thiazolidinedione therapy, which has been shown to preserve beta cell function and significantly reduce the risk of developing type 2 diabetes in women with a history of GDM [37], is also known to increase adiponectin levels [38]. It thus emerges that a pathophysiological relationship between hypoadiponectinaemia and diabetic risk following GDM could hold important clinical implications.…”

Does WHI tell us how to prevent diabetes?

“…Also, very few patients have succeeded in maintaining weight loss over the longer term without the type of support available in the DPP. Medications such as metformin, troglitazone and acarbose have also been studied in terms of diabetes prevention [4,5,6]. Although effective, they have had significantly less impact than intensive lifestyle changes alone and may simply postpone the inevitable presentation of diabetes in individuals at risk.…”