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...

Context: Impairments in the pituitary-gonadal axis with aging are associated with loss of muscle mass and function and accumulation of upper body fat. Objectives: We tested the hypothesis that physiological supplementation with testosterone and GH together improves body composition and muscle performance in older men. Design, Setting, and Participants: One hundred twenty-two community-dwelling men 70.8 4.2 yr of age with body mass index of 27.4 3.4 kg/m 2 , testosterone of 550 ng/dl or less, and IGF-I in lower adult tertile (167 ng/dl) were randomized to receive transdermal testosterone (5 or 10 g/d) during a Leydig cell clamp plus GH (0, 3, or 5 g/kg d) for 16 wk. Main Outcome Measures: Body composition by dual-energy x-ray absorptiometry, muscle performance , and safety tests were conducted. Results: Total lean body mass increased (1.0 1.7 to 3.0 2.2 kg) as did appendicular lean tissue (0.4 1.4 to 1.5 1.3 kg), whereas total fat mass decreased by 0.4 0.9 to 2.3 1.7 kg as did trunk fat (0.5 0.9 to 1.5 1.0 kg) across the six treatment groups and by dose levels for each parameter (P 0.0004 for linear trend). Composite maximum voluntary strength of upper and lower body muscles increased by 14 34 to 35 31% (P 0.003 in the three highest dose groups) that correlated with changes in appendicular lean mass. Aerobic endurance increased in all six groups (average 96 137sec longer). Systolic and diastolic blood pressure increased similarly in each group with mean increases of 12 14 and 8 8 mm Hg, respectively. Other predictable adverse events were modest and reversible. Conclusions: Supplemental testosterone produced significant gains in total and appendicular lean mass, muscle strength, and aerobic endurance with significant reductions in whole-body and trunk fat. Outcomes appeared to be further enhanced with GH supplementation. (J Clin Endocrinol Metab A lterations in body composition, physical function, and sub-strate metabolism occur with advancing age. Loss of skeletal muscle mass (sarcopenia) (1, 2) contributes to declines in muscle strength and function along with diminished quality of life (3). In the Baltimore Longitudinal Aging Study, quadriceps strength decreased about 30% between 50-70 yr of age (4). In the Copenhagen Heart Study, leg strength in 80-yr-olds was 20-30% lower than in 70-yr-olds (5, 6). Substantial losses in

OBJECTIVETo identify factors associated with declining β-cell compensation for insulin resistance.RESEARCH DESIGN AND METHODSIn a cohort of Hispanic women with recent gestational diabetes mellitus, oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs), and bioelectrical impedance measurements were performed at 15-month intervals for up to 5 years, or until fasting plasma glucose exceeded 140 mg/dl (7.8 mmol/l). Data were analyzed to identify predictors of declining β-cell compensation for insulin resistance (the disposition index [DI]) and to examine the mechanism of weight gain and changes in circulating levels of selected adipokines and inflammatory markers on β-cell compensation decline.RESULTSA total of 60 nondiabetic women had a median of four sets of OGTT + IVGTT during a median follow-up of 52 months. Fourteen of the women developed diabetes. None of the baseline characteristics were significantly predictive of a decline in DI. There were significant univariate associations between declining DI and weight gain (specifically fat gain), declining adiponectin and rising C-reactive protein. Multivariate analysis showed that the weight gain was the most significant factor associated with declining DI. The amount of association between weight gain and declining DI was explained 31% by changes in adiponectin and C-reactive protein and 40% by changes in insulin resistance.CONCLUSIONSThese results identify weight gain as the strongest factor associated with declining β-cell compensation for insulin resistance in Hispanic women at high risk for type 2 diabetes. Such effect may be mediated through at least two effects: alterations in adipokine levels and increasing insulin resistance.

Context: Biomarkers that predict musculoskeletal response to anabolic therapies should expedite drug development. During collagen synthesis in soft lean tissue, N-terminal propeptide of type III procollagen (P3NP) is released into circulation. We investigated P3NP as a biomarker of lean body mass (LBM) and muscle strength gains in response to testosterone and GH. Design: Community-dwelling older men received GnRH agonist plus 5 or 10 g testosterone gel plus 0, 3, or 5 g recombinant human GH daily. P3NP levels were measured at baseline and wk 4, 8, 12, and 16.LBMandappendicularskeletalmusclemass(ASM)weremeasuredbydual-energyx-rayabsorptiometry. Results: One hundred twelve men completed treatment; 106 underwent serum P3NP measurements. P3NP levels were higher at wk 4 than baseline (6.61 2.14 vs. 4.51 1.05, P 0.0001) and reached plateau by wk 4 in men receiving testosterone alone. However, wk 8 P3NP levels were higher than wk 4 levels in men receiving testosterone plus recombinant human GH. Increases in P3NP from baseline to wk 4 and 16 were significantly associated with gains in LBM (r 0.26, P 0.007; r 0.53, P 0.001) and ASM (r 0.17, P 0.07; r 0.40, P 0.0001). Importantly, for participants receiving only testosterone, P3NP increases at wk 4 and 16 were related to muscle strength gains (r 0.20, P 0.056 and r 0.36, P 0.04). In stepwise regression, change in P3NP explained 28 and 30% of the change in ASM and LBM, respectively, whereas change in testosterone but not IGF-I and age provided only small improvements in the models. Conclusion: Early changes in serum P3NP levels are associated with subsequent changes in LBM and ASM during testosterone and GH administration. Serum P3NP may be a useful early predictive biomar-ker of anabolic response to GH and testosterone. (J Clin Endocrinol Metab 94: 4224-4233, 2009) T he past decade has witnessed substantial pharmaceutical and academic investment in the development of function promoting anabolic therapies that improve physical function and health-related outcomes (1). The leading function promoting anabolic molecules that are under development , androgens, myostatin inhibitors, and GH, are potential promyogenic agents that are expected to improve physical function primarily by increasing skeletal muscle mass. Considering the enormous resources required for conducting large efficacy trials, serum biomar

OBJECTIVEGlucokinase (GCK) and glucose-6-phosphatase catalytic subunit 2 (G6PC2) regulate the glucose-cycling step in pancreatic β-cells and may regulate insulin secretion. GCK rs1799884 and G6PC2 rs560887 have been independently associated with fasting glucose, but their interaction on glucose-insulin relationships is not well characterized.RESEARCH DESIGN AND METHODSWe tested whether these variants are associated with diabetes-related quantitative traits in Mexican Americans from the BetaGene Study and attempted to replicate our findings in Finnish men from the METabolic Syndrome in Men (METSIM) Study.RESULTSrs1799884 was not associated with any quantitative trait (corrected P > 0.1), whereas rs560887 was significantly associated with the oral glucose tolerance test 30-min incremental insulin response (30′ Δinsulin, corrected P = 0.021). We found no association between quantitative traits and the multiplicative interaction between rs1799884 and rs560887 (P > 0.26). However, the additive effect of these single nucleotide polymorphisms was associated with fasting glucose (corrected P = 0.03) and 30′ Δinsulin (corrected P = 0.027). This additive association was replicated in METSIM (fasting glucose, P = 3.5 × 10−10 30′ Δinsulin, P = 0.028). When we examined the relationship between fasting glucose and 30′ Δinsulin stratified by GCK and G6PC2, we noted divergent changes in these quantitative traits for GCK but parallel changes for G6PC2. We observed a similar pattern in METSIM.CONCLUSIONSOur data suggest that variation in GCK and G6PC2 have additive effects on both fasting glucose and insulin secretion.