Impact of common polymorphisms in candidate genes for insulin resistance and obesity on weight loss of morbidly obese subjects after laparoscopic adjustable gastric banding and hypocaloric diet.

CONTEXT: It is unknown whether genetic factors that play an important role in body weight homeostasis influence the response to laparoscopic adjustable gastric banding (LAGB). OBJECTIVE: We investigated the impact of common polymorphisms in four candidate genes for insulin resistance on weight loss after LAGB. DESIGN: The design was a 6-month follow-up study. SETTING: The study setting was hospitalized care. PATIENTS: A total of 167 unrelated morbidly obese subjects were recruited according to the following criteria: age, 18-66 yr inclusive; and body mass index greater than 40 kg/m2 or greater than 35.0 kg/m2 in the presence of comorbidities. INTERVENTION: LAGB was used as an intervention. MAIN OUTCOME MEASURE: Measure of correlation between weight loss and common polymorphisms in candidate genes for insulin resistance and obesity was the main outcome measure. RESULTS: The following single nucleotide polymorphisms were detected by digestion of PCR products with appropriate restriction enzymes: Gly972Arg of the insulin receptor substrate-1 gene, Pro12Ala of the proliferator-activated receptor-gamma gene, C-174G in the promoter of IL-6 gene, and G-866A in the promoter of uncoupling protein 2 gene. Baseline characteristics including body mass index did not differ between the genotypes. At the 6-month follow-up after LAGB, carriers of G-174G IL-6 genotype had lost more weight than G-174C or C-174C genotype (P = 0.037), and carriers of A-866A uncoupling protein 2 genotype had lost more weight as compared with G-866G (P = 0.018) and G-866A (P = 0.035) genotype, respectively. Weight loss was lower in carriers of Gly972Arg insulin receptor substrate-1 genotype than Gly972Gly carriers, but not statistically significant (P = 0.06). No difference between carriers of Pro12Ala and Pro12Pro proliferator-activated receptor-gamma genotype was observed. CONCLUSIONS: These data demonstrate that genetic factors, which play an important role in the regulation of body weight, may account for differences in the therapeutic response to LAGB.

Chronic hyperglycemia impairs insulin secretion by affecting insulin receptor expression, splicing, and signaling in RIN beta cell line and human islets of Langerhans.

Recent evidence suggests that insulin signaling through the insulin receptor A type (Ex11-), regulates insulin gene transcription. Because chronic hyperglycemia negatively affects insulin receptor function and regulates alternative splicing of the insulin receptor, we inquired whether chronic exposure of pancreatic beta-cells to high glucose results in alterations in insulin signaling due to changes in insulin receptor expression and relative abundance of its spliced isoforms. Our results demonstrate that the insulin receptor is localized in insulin secretory vescicles in human pancreatic beta-cells. Furthermore, we find that alterations in insulin expression and secretion caused by chronic exposure to high glucose are paralleled by decreased insulin receptor expression and increased relative abundance of the Ex11+ isoform in both human islets and RIN beta-cells. PDX-1 and HMGI(Y) transcription factors are down-regulated by high glucose. These changes are associated with defects in insulin signaling involving insulin receptor-associated PI 3-kinase/Akt/PHAS-I pathway in RIN beta-cells. Re-expression in RIN beta-cells chronically exposed to high glucose of the Ex11-, but not the Ex11+, isoform restored insulin mRNA expression. These data suggest that changes in early steps of insulin receptor signaling may play a role in determining beta-cell dysfunction caused by chronic hyperglycemia.

Localization of the human oxytocin receptor in caveolin-1 enriched domains turns the receptor-mediated inhibition of cell growth into a proliferative response.

In this study, we investigated the functional role of the localization of human OTR in caveolin-1 enriched membrane domains. Biochemical fractionation of MDCK cells stably expressing the WT OTR-GFP indicated that only minor quantities of receptor are partitioned in caveolin-1 enriched domains. However, when fused to caveolin-2, the OTR protein proved to be exclusively localized in caveolin-1 enriched fractions, where it bound the agonist with increased affinity and efficiently coupled to Galpha(q/11). Interestingly, the chimeric protein was unable to undergo agonist-induced internalization and remained confined to the plasma membrane even after prolonged agonist exposure (120 min). A striking difference in receptor stimulation was observed when the OT-induced effect on cell proliferation was analysed: stimulation of the human WT OTR inhibited cell growth, whereas the chimeric protein had a proliferative effect. These data indicate that the localization of human OTR in caveolin-1 enriched microdomains radically alters its regulatory effects on cell growth; the fraction of OTR residing in caveolar structures may therefore play a crucial role in regulating cell proliferation.