Most POPs were positively but not significantly associated with incident diabetes. PCB151 was significantly predictive and HCB was significantly protective for diabetes. Among participants with diabetes, low-chlorine PCBs increase the risk of ESRD and death without ESRD, whereas several PSTs predict death without ESRD.

BackgroundIn rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown.ObjectiveTo compare BDNF concentrations of subjects with loss-of-function (LOF) and gain-of-function (GOF) MC4R variants to those of controls with common sequence MC4R.MethodsCirculating BDNF was measured in two cohorts with known MC4R sequence: 148 subjects of Pima Indian heritage ([mean±SD]: age 15.7±6.5y, BMI-Z 1.63±1.03), and 69 subjects of Hispanic heritage (10.8±3.6y, BMI-Z 1.57±1.07). MC4R variants were characterized in vitro by cell surface expression, receptor binding, and cAMP response after agonist administration. BDNF single nucleotide polymorphisms (SNPs) rs12291186, rs6265, and rs7124442 were also genotyped.ResultsIn the Pima cohort, no significant differences in serum BDNF was observed for 43 LOF-subjects versus 65 LOF-matched controls [age-, sex-, and BMI-matched] (P=0.29), or 20 GOF-subjects versus 20 GOF-matched controls (P=0.40). Serum BDNF was significantly associated with genotype for BDNF rs12291186 (P=0.006) and rs6265 (P=0.009), but not rs7124442 (P=0.99); BDNF SNPs did not interact with MC4R status to predict serum BDNF. In the Hispanic cohort, plasma BDNF was not significantly different among 21 LOF-subjects, 20 GOF-subjects, and 28 controls (P=0.79); plasma BDNF was not predicted by BDNF genotype or BDNF-x-MC4R genotype interaction.ConclusionsCirculating BDNF concentrations were not significantly associated with MC4R functional status, suggesting that peripheral BDNF does not directly reflect hypothalamic BDNF secretion and/or that MC4R signaling is not a significant regulator of the bulk of BDNF expression in humans.

Skeletal muscle insulin resistance manifests shortly after high-fat feeding, yet mechanisms are not known. Here we set out to determine whether excess skeletal muscle membrane cholesterol and cytoskeletal derangement known to compromise glucose transporter (GLUT)4 regulation occurs early after high-fat feeding. We fed 6-wk-old male C57BL/6NJ mice either a low-fat (LF, 10% kcal) or a high-fat (HF, 45% kcal) diet for 1 wk. This HF feeding challenge was associated with an increase, albeit slight, in body mass, glucose intolerance, and hyperinsulinemia. Liver analyses did not reveal signs of hepatic insulin resistance; however, skeletal muscle immunoblots of triad-enriched regions containing transverse tubule membrane showed a marked loss of stimulated GLUT4 recruitment. An increase in cholesterol was also found in these fractions from HF-fed mice. These derangements were associated with a marked loss of cortical filamentous actin (F-actin) that is essential for GLUT4 regulation and known to be compromised by increases in membrane cholesterol. Both the withdrawal of the HF diet and two subcutaneous injections of the cholesterol-lowering agent methyl-β-cyclodextrin at 3 and 6 days during the 1-wk HF feeding intervention completely mitigated cholesterol accumulation, cortical F-actin loss, and GLUT4 dysregulation. Moreover, these beneficial membrane/cytoskeletal changes occurred concomitant with a full restoration of metabolic responses. These results identify skeletal muscle membrane cholesterol accumulation as an early, reversible, feature of insulin resistance and suggest cortical F-actin loss as an early derangement of skeletal muscle insulin resistance.