Vitamin D, Inflammation, and Relations to Insulin Resistance in Morbidly Obese Pre-Menopausal Women.

摘要

Obesity is associated with low-grade inflammation, insulin resistance and low vitamin D status. Vitamin D has traditionally been known to involve in calcium homeostasis and prevent rickets; however, recently it has been recognized to inversely associate with many non-skeletal diseases and conditions including obesity and type 2 diabetes (T2DM). In vitro studies have demonstrated that vitamin D possesses anti-inflammatory properties. It remains unknown if the effect of vitamin D on insulin sensitivity is mediated by suppressing inflammation in human adipose tissues.;The original main objective of this study was to assess the association between vitamin D and insulin sensitivity and inflammation in morbidly obese pre-menopausal women. Obese women (n=76) were recruited from the University of Illinois at Chicago (UIC) Nutrition and Wellness Center and the UIC medical center bariatric surgery clinics. Insulin sensitivity/resistance was assessed by (1) Oral glucose insulin sensitivity (OGIS) index, derived from dynamic oral glucose tolerance test (OGTT), and (2) Homeostasis model of insulin resistance (HOMA-IR), calculated from fasting steady-state glucose and insulin. Also, to better understand the potential mechanism and the role circulating vitamin D (25OHD) plays in adipose tissue inflammation, we assessed messenger ribonucleic acid (mRNA) expression of vitamin D receptor (VDR), marker of macrophage infiltration (CD68), marker of fibrosis development (Collagen VI) and various inflammatory genes in visceral (VAT) and subcutaneous adipose tissues (SAT) of obese women that underwent a restrictive bariatric procedure. To further explore features of metabolic health the original study was expanded to include evaluation of their lipid status (n=57) and constituents of the interleukin 6 (IL6) system (n=26, matched for age and race with healthy lean controls: n=14) (i.e. serum IL6, soluble IL6 receptor (sIL6R) and soluble glycoprotein 130 (sgp130)).;Based on a 2-hour blood glucose level of an OGTT, approximately 82% of the subjects were normal glucose tolerance. Nearly 90% of our subjects were vitamin D adequate (Mean ± SD: 89.90 ± 39.93 nmol/l). There was no association between serum 25OHD and insulin sensitivity, markers of insulin resistance (adiponectin (APN)) or markers of inflammation (Creactive protein (CRP) and IL6). When analysis was restricted to subjects with elevated CRP (>=5.2 ìg/ml) a significant negative association between 25OHD and CRP (r=-0.33, p=0.04) was found. There was no association between serum 25OHD and adipose tissue VDR mRNA expression in both VAT and SAT. Serum 25OHD negatively correlated with TNFα mRNA expression in VAT (r= -0.83, p=0.04) only in subjects who were vitamin D inadequate. There were significant positive correlations between logVDR mRNA expression and mRNA expression of log Collagen VI (VAT: r=0.75, p<0.0001; SAT: r=0.66, p=<0.0001), log IL1β (VAT: r=0.89, p=<0.0001; SAT: r=0.95, p<0.0001), log TNFα (VAT: r=0.75, p<0.0001; SAT: r=0.82, p<0.0001) in both adipose depots. LogVDR mRNA expression significantly and positively predicted logHOMA-IR among non-African American (β=1.67, p=0.05, R2=0.16).;Lipid analysis showed that our subjects had lower or similar LDL cholesterol, lower total- and HDL cholesterol but higher triglyceride than other morbidly insulin sensitive obese individuals. Their triglyceride levels (126.12 ± 79.86 mg/dl) were similar to those observed in NHANES 2005-2006 non diabetic obese women (n=74, 123.5± 60.92 mg/dl) and well below the cutoff of 150mg/dl used to categorize it as a risk factor of metabolic syndrome. Analysis on the IL6 system (26 obese, 14 lean) revealed that logIL6 positively correlated with BMI (r=0.69, p<0.0001). However, logsIL6R and logsgp130 had no correlation with BMI. Similarly, logleptin (r= 0.50, p=0.001) and CRP (r=0.69, p<0.0001) correlated significantly and positively with logIL6, but not with logsIL6R and logsgp130. In the obese (n=26) leptin surprisingly inversely correlated with sIL6R (r=-0.49, p=0.01).;In conclusion, we found that there are women displaying remarkably healthy metabolic profiles and sufficient vitamin D levels despite their morbid obesity. Our study supports the concept of threshold optimal 25OHD levels above which negligible effect on metabolic outcome is observed. Whether there are different optimal levels for different health outcomes remains to be explored. We found that VDR does not relate to circulating levels of vitamin D in vitamin D sufficient individuals and does not possess protective effect in adipose tissues as in other tissues. Further investigations in individuals with a broader spectrum of vitamin D levels are warranted. Our findings suggest the role of other components of the IL6 system, sIL6R and sgp130, in inducing inflammation and insulin resistance and down-regulation of sIL6R as a potential mechanism in metabolically healthy obesity. Future studies are needed to confirm this hypothesis.