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

TLDR

Type 2 diabetes often develops from progressive β‑cell failure in the setting of chronic insulin resistance. The study tested whether long‑term improvement of insulin resistance could preserve β‑cell function and prevent diabetes in high‑risk Hispanic women. Women with prior gestational diabetes were randomized to placebo or troglitazone (400 mg/day) in a double‑blind trial, with fasting glucose, OGTTs, IVGTTs, and follow‑up tests performed to track metabolic changes. Troglitazone lowered annual diabetes incidence from 12.1 % to 5.4 %, preserved β‑cell compensation, and its protective effect persisted 8 months after treatment cessation, demonstrating that reducing insulin demand protects β‑cells.

Abstract

Type 2 diabetes frequently results from progressive failure of pancreatic β-cell function in the presence of chronic insulin resistance. We tested whether chronic amelioration of insulin resistance would preserve pancreatic β-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 double-blind 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 β-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 β-cell function and appeared to be mediated by a reduction in the secretory demands placed on β-cells by chronic insulin resistance.