Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic ␤ cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican-American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPAR␥ coactivator 1-␣ and-␤ (PGC1-␣͞PPARGC1 and PGC1-␤͞PERC), coactivators of NRF-1 and PPAR␥-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.I nsulin resistance precedes and predicts the development of type 2 diabetes mellitus (DM) (1, 2). Defects in insulin signal transduction, gene expression, and muscle glycogen synthesis, and accumulation of intramyocellular triglycerides have all been identified as potential mediators of insulin resistance in high-risk individuals (1, 3-7). However, the molecular pathogenesis of DM remains unknown. Mouse data highlight the importance of glucose uptake into muscle but suggest a role for novel mechanisms, distinct from insulin signaling pathways (8). The importance of genetic risk factors is exemplified by the high concordance of DM in identical twins, the strong influence of family history and ethnicity on risk, and the identification of DNA sequence alterations in both rare and common forms of DM (9). Environmental factors, including obesity, inactivity, and aging, also play critical roles in DM risk. Because both genotype and environment converge to influence cellular function via gene and protein expression, we hypothesize that alterations in expression define a phenotype that parallels the metabolic evolution of DM and provides potential clues to pathogenesis. We used high-density oligonucleotide arrays to identify genes differentially expressed in skeletal muscle from nondiabetic and type 2 diabetic subjects. Because hyperglycemia per se can modulate expression, we also evaluated gene expression in insulin-resistant subjects at high risk for DM (''prediabetes'') on the basis of family history of DM and Mexican-American ethnicity (10). We demonstrate that prediabetic and diabetic muscle is characterized by decreased expressi...

The multifactorial mechanisms promoting weight loss and improved metabolism following Roux-en-Y gastric bypass (GB) surgery remain incompletely understood. Recent rodent studies suggest that bile acids can mediate energy homeostasis by activating the G-protein coupled receptor TGR5 and the type 2 thyroid hormone deiodinase. Altered gastrointestinal anatomy following GB could affect enterohepatic recirculation of bile acids. We assessed whether circulating bile acid concentrations differ in patients who previously underwent GB, which might then contribute to improved metabolic homeostasis. We performed cross-sectional analysis of fasting serum bile acid composition and both fasting and post-meal metabolic variables, in three subject groups: (i) post-GB surgery (n = 9), (ii) without GB matched to preoperative BMI of the index cohort (n = 5), and (iii) without GB matched to current BMI of the index cohort (n = 10). Total serum bile acid concentrations were higher in GB (8.90 ± 4.84 µmol/l) than in both overweight (3.59 ± 1.95, P = 0.005, Ov) and severely obese (3.86 ± 1.51, P = 0.045, MOb). Bile acid subfractions taurochenodeoxycholic, taurodeoxycholic, glycocholic, glycochenodeoxycholic, and glycodeoxycholic acids were all significantly higher in GB compared to Ov (P < 0.05). Total bile acids were inversely correlated with 2-h post-meal glucose (r = −0.59, P < 0.003) and fasting triglycerides (r = −0.40, P = 0.05), and positively correlated with adiponectin (r = −0.48, P < 0.02) and peak glucagon-like peptide-1 (GLP-1) (r = 0.58, P < 0.003). Total bile acids strongly correlated inversely with thyrotropic hormone (TSH) (r = −0.57, P = 0.004). Together, our data suggest that altered bile acid levels and composition may contribute to improved glucose and lipid metabolism in patients who have had GB.

A robust insulin secretory response was associated with postprandial hypoglycemia in patients after GB presenting with NG. Increased incretin levels may contribute to the increased insulin secretory response.