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.

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...

Tuberculosis (TB) remains an eminent global burden with one third of the world’s population latently infected with Mycobacterium tuberculosis (M. tb). Individuals with compromised immune systems are especially vulnerable to M. tb infection. In fact, individuals with Type 2 Diabetes Mellitus (T2DM) are two to three times more susceptible to TB than those without T2DM. In this study, we report that individuals with T2DM have lower levels of glutathione (GSH) due to compromised levels of GSH synthesis and metabolism enzymes. Transforming growth factor beta (TGF-β), a cytokine that is known to decrease the expression of the catalytic subunit of glutamine-cysteine ligase (GCLC) was found in increased levels in the plasma samples from individuals with T2DM, explaining the possible underlying mechanism that is responsible for decreased levels of GSH in individuals with T2DM. Moreover, increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-17 (IL-17) were observed in plasma samples isolated from individuals with T2DM. Increased levels of IL-6 and IL-17 was accompanied by enhanced production of free radicals further indicating an alternative mechanism for the decreased levels of GSH in individuals with T2DM. Augmenting the levels of GSH in macrophages isolated from individuals with T2DM resulted in improved control of M. tb infection. Furthermore, cytokines that are responsible for controlling M. tb infection at the cellular and granuloma level such as tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), interferon-gamma (IFN-γ), and interleukin-12 (IL-12), were found to be compromised in plasma samples isolated from individuals with T2DM. On the other hand, interleukin-10 (IL-10), an immunosuppressive cytokine was increased in plasma samples isolated from individuals with T2DM. Overall, these findings suggest that lower levels of GSH in individuals with T2DM lead to their increased susceptibility to M. tb infection.

Cytokines are signaling biomolecules that serve as key regulators of our immune system. CD4+ T-cells can be grouped into 2 major categories based on their cytokine profile: T-helper 1 (TH1) subset and T-helper 2 (TH2) subset. Protective immunity against HIV infection requires TH1-directed CD4 T-cell responses, mediated by cytokines, such as interleukin-1β (IL-1β), IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Cytokines released by the TH1 subset of CD4 T-cells are considered important for mediating effective immune responses against intracellular pathogens such as Mycobacterium tuberculosis (M. tb). Oxidative stress and redox imbalance that occur during HIV infection often lead to inappropriate immune responses. Glutathione (GSH) is an antioxidant present in nearly all cells and is recognized for its function in maintaining redox homeostasis. Our laboratory previously reported that individuals with HIV infection have lower levels of GSH. In this study, we report a link between lower levels of GSH and dysregulation of TH1- and TH2-associated cytokines in the plasma samples of HIV-positive subjects. Furthermore, we demonstrate that supplementing individuals with HIV infection for 13 weeks with liposomal GSH (lGSH) resulted in a significant increase in the levels of TH1 cytokines, IL-1β, IL-12, IFN-γ, and TNF-α. lGSH supplementation in individuals with HIV infection also resulted in a substantial decrease in the levels of free radicals and immunosuppressive cytokines, IL-10 and TGF-β, relative to those in a placebo-controlled cohort. Finally, we determined the effects of lGSH supplementation in improving the functions of immune cells to control M. tb infection by conducting in vitro assays using peripheral blood mononuclear cells collected from HIV-positive individuals at post-GSH supplementation. Our studies establish a correlation between low levels of GSH and increased susceptibility to M. tb infection through TH2-directed response, which may be relieved with lGSH supplementation enhancing the TH1 response.

The purpose of this study was to examine the response of pancreatic ␤-cells to changes in insulin sensitivity in women at high risk for type 2 diabetes. Oral glucose tolerance tests (OGTTs) and frequently sampled intravenous glucose tolerance tests (FSIGTs) were conducted on Latino women with impaired glucose tolerance and a history of gestational diabetes before and after 12 weeks of treatment with 400 mg/day troglitazone (n = 13) or placebo (n = 12). Insulin sensitivity was assessed by minimal model analysis, and ␤-cell insulin release was assessed as acute insulin responses to glucose (AIR g ) and tolbutamide (AIR t ) during FSIGTs and as the 30-min incremental insulin response (30-min dINS) during OGTTs. ␤-Cell compensation for insulin resistance was assessed as the product (disposition index) of minimal model insulin sensitivity and each of the 3 measures of ␤-cell insulin release. In the placebo group, there was no significant change in insulin sensitivity or in any measure of insulin release, ␤-cell compensation for insulin resistance, or glucose tolerance. Troglitazone treatment resulted in a significant increase in insulin sensitivity, as reported previously. In response, AIR g did not change significantly, so that the disposition index for AIR g increased significantly from baseline (P = 0.004) and compared with placebo (P = 0.02). AIR t (P = 0.001) and 30-min dINS (P = 0.02) fell with improved insulin sensitivity during troglitazone treatment, so that the disposition index for each of these measures of ␤-cell function did not change significantly from baseline (P > 0.20) or compared with placebo (P > 0.3). Minimal model analysis revealed that 89% of the change from baseline in insulin sensitivity during troglitazone treatment was accounted for by lowered plasma insulin concentrations. Neither oral nor intravenous glucose tolerance changed significantly from baseline or compared with placebo during troglitazone treatment. The predominant response of ␤-cells to improved insulin sensitivity in women at high risk for type 2 diabetes was a reduction in insulin release to maintain nearly constant glucose tolerance. Diabetes 49:782-788, 2000