Mechanisms for Insulin Resistance in Polycystic Ovary Syndrome with metformin therapy: aminoadipic acid, lysine concentrations, and enrichment (part I)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
TISSUE(S): Blood
DISEASE(S): Polycystic Ovary Syndrome
PROVIDER: ST000947 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description:The polyphenol compound resveratrol (RSV) has attracted attention due to its reputed beneficial effects on insulin sensitivity. Our lab has previously identified protective effects of RSV against the development of type 2 diabetes in rats. These effects occurred in a manner similar to thiazolidinedione's (TZDs), a class of insulin sensitizing drugs. TZDs are commonly prescribed in combination with metformin (MET) and thus we sought to examine the combined effects of RSV and MET in treating insulin resistance. Male C57BL6 mice were fed a low- (LFD; 10% Kcal from fat) or high-fat diet (HFD; 60% Kcal from fat) for 9 weeks to induce glucose and insulin intolerance. HFD mice were then assigned to control (HFD), MET (231.28 ± 12.24 mg/kg/day), RSV (93.68 ± 3.51 mg/kg/day), or combined (COM; MET 232.01 ± 17.12 mg/kg/day and RSV 92.77 ± 6.92 mg/kg/day) treatment groups. Changes in glucose and insulin tolerance and tissue-specific insulin signaling were measured 4 weeks post-treatment. RSV or MET alone did not have beneficial effects on glucose tolerance, although MET significantly improved insulin tolerance compared to HFD Glucose and insulin tolerance were significantly improved in COM compared to HFD and this was mirrored by enhanced insulin-stimulated AKT phosphorylation in triceps muscle and inguinal subcutaneous adipose tissue in COM compared to HFD mice. Improvements with COM treatment were not explained by differences in body weight, adiposity, or markers of adipose tissue inflammation. In summary, this study provides evidence of beneficial effects of combined RSV and MET therapy in treating impairments in glucose homeostasis.
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Project description:Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPARgamma ligands. We characterized 72 human subjects by relating their clinical phenotypes with functional pathway alterations. We transcriptionally profiled 364 biopsies harvested before and after hyperinsulinemic-euglycemic clamp studies, at baseline and after 3-month TZD treatment. We have identified molecular and functional characteristics of insulin resistant subjects and distinctions between TZD treatment responder and nonresponder subjects. Insulin resistant subjects exhibited alterations in skeletal muscle (e.g., glycolytic flux and intramuscular adipocytes) and adipose tissue (e.g., mitochondrial metabolism and inflammation) that improved relative to TZD-induced insulin sensitization. Pre-TZD treatment expression of MLXIP in muscle and HLA-DRB1 in adipose tissue from insulin resistant subjects was linearly predictive of post-TZD insulin sensitization. We have uniquely characterized coordinated cellular and tissue functional pathways that are characteristic of insulin resistance, TZD-induced insulin sensitization, and potential TZD responsiveness.
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Project description:The pathophysiological function of the FOXK family-member FOXK1 remains to be explored. Although tumors classically induce abnormalities in the insulin pathway, clinical trials have failed to establish insulin receptors as potential targets for tumor therapy. Metformin, so far has been identified as an effective treatment in several clinical oncology trials; however, metformin may fail to benefit all patients, and some even suffer from many side effects and drug resistance. Herein, we report that FOXK1 expression correlates with the sensitivity to metformin treatment in a variety of tumors. FOXK1 translocates into the nucleus in response to insulin stimulation and recruits multiple class I HDAC-containing complexes that regulate the expression of genes, such as PER2 and OGT, known to be critically involved in circadian rhythm and insulin resistance. Furthermore, high insulin levels associated with cancer could disturb the subcellular localization and epigenetic regulatory functions of FOXK1. Glycosylation modifications stabilize FOXK1 in the nucleus. Elevated nuclear FOXK1 competes with CLOCK for binding with BMAL1, leading to the deregulation of circadian rhythm, which, in turn, enhanced tumor cell proliferation in vitro and promoted tumor development in vivo. Correspondingly, elevated expression of nuclear FOXK1 was observed during tumor progression and was associated with a poor prognosis. Interestingly, both in vitro and in vivo experiments confirmed that cells with high FOXK1 expression were highly responsive to metformin stimulation. Collectively, these findings revealed that nuclear FOXK1 promotes tumorigenesis by disrupting circadian rhythm under insulin resistance, and its expression may serve as a potential indicator for the adjuvant treatment of tumors using metformin.
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Project description:UnlabelledWhat is already known about this subject Circulating concentrations of branched-chain amino acids (BCAAs) can affect carbohydrate metabolism in skeletal muscle, and therefore may alter insulin sensitivity. BCAAs are elevated in adults with diet-induced obesity, and are associated with their future risk of type 2 diabetes even after accounting for baseline clinical risk factors. What this study adds Increased concentrations of BCAAs are already present in young obese children and their metabolomic profiles are consistent with increased BCAA catabolism. Elevations in BCAAs in children are positively associated with insulin resistance measured 18 months later, independent of their initial body mass index.BackgroundBranched-chain amino acid (BCAA) concentrations are elevated in response to overnutrition, and can affect both insulin sensitivity and secretion. Alterations in their metabolism may therefore play a role in the early pathogenesis of type 2 diabetes in overweight children.ObjectiveTo determine whether paediatric obesity is associated with elevations in fasting circulating concentrations of BCAAs (isoleucine, leucine and valine), and whether these elevations predict future insulin resistance.MethodsSixty-nine healthy subjects, ages 8-18 years, were enrolled as a cross-sectional cohort. A subset of subjects who were pre- or early-pubertal, ages 8-13 years, were enrolled in a prospective longitudinal cohort for 18 months (n = 17 with complete data).ResultsElevations in the concentrations of BCAAs were significantly associated with body mass index (BMI) Z-score (Spearman's Rho 0.27, P = 0.03) in the cross-sectional cohort. In the subset of subjects that followed longitudinally, baseline BCAA concentrations were positively associated with homeostasis model assessment for insulin resistance measured 18 months later after controlling for baseline clinical factors including BMI Z-score, sex and pubertal stage (P = 0.046).ConclusionsElevations in the concentrations of circulating BCAAs are significantly associated with obesity in children and adolescents, and may independently predict future insulin resistance.
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