Jiao P.,Hallett Center for Diabetes and Endocrinology |
Jiao P.,Jilin University |
Ma J.,Jilin University |
Feng B.,Hallett Center for Diabetes and Endocrinology |
And 6 more authors.
Obesity | Year: 2011
Free-fatty acids (FFAs) are well-characterized factor for causing production of inflammatory factors and insulin resistance in adipocytes. Using cultured adipocytes, we demonstrate that FFAs can activate endoplasmic reticulum (ER) stress pathway by examination of ER stress sensor activation and marker gene expression. Chemical chaperone tauroursodeoxycholic acid (TUDCA) can reduce FFA-induced adipocyte inflammation and improve insulin signaling whereas overexpression of spliced X-box protein 1 (XBP-1s) only attenuates FFA-induced inflammation. PKR-like eukaryotic initiation factor 2α kinase (PERK) is one of the three major ER stress sensor proteins and deficiency of PERK alleviates FFA-induced inflammation and insulin resistance. The key downstream target of FFA-induced ER stress is IκB kinase β (IKKβ), a master kinase for regulating expression of inflammatory genes. Deficiency of PERK attenuates FFA-induced activation of IKKβ and deficiency of IKKβ alleviates FFA-induced inflammation and insulin resistance. Consistently, overexpression of IKKβ in 3T3-L1 CAR adipocytes causes inflammation and insulin resistance. In addition, IKKβ overexpression has profound effect on adipocyte lipid metabolism, including inhibition of lipogenesis and promotion of lipolysis. Furthermore, increased endogenous IKKβ expression and activation is also observed in isolated primary adipocytes from mice injected with lipids or fed on high-fat diet (HFD) acutely. These results indicate that ER stress pathway is a key mediator for FFA-induced inflammation and insulin resistance in adipocytes with PERK and IKKβ as the critical signaling components. © 2010 The Obesity Society.
Malandrino N.,Brown University |
Malandrino N.,Catholic University |
Malandrino N.,Hallett Center for Diabetes and Endocrinology |
Wu W.C.,United Medical Systems |
And 10 more authors.
Diabetologia | Year: 2012
Aims/hypothesis Red blood cell distribution width (RDW) has been reported to be a risk marker of morbidity and mortality for cardiovascular disease in various studypopulations. However, no studies have investigated the relationship between RDW and diabetes complications. We therefore evaluated RDW as a marker of macrovascular and microvascular complications in a nationally representative sample of the adult diabetes population in the USA. Methods A cross-sectional study was performed using the nationwide 1988 to 1994 data set from the Third National Health and Nutrition Examination Survey. The association between RDW quartiles and macrovascular and microvascular complications was evaluated in 2,497 non-pregnant adults aged 20 years and older and affected by diabetes. Logistic regression modelling was used to adjust for potential confounding. Results Compared with the lowest RDW quartile, higher RDW values (3rd and 4th quartiles) were associated with increased adjusted odds of any vascular complication (OR 4th quartile 2.06 [95% CI 1.11, 3.83]), myocardial infarction (OR 4th quartile 2.45 [95% CI 1.13, 5.28]), heart failure (OR 4th quartile 4.40 [95% CI 1.99, 9.72]), stroke (OR 4th quartile 2.56 [95% CI 1.21, 5.42]) and nephropathy (OR 4th quartile 2.33 [95% CI 1.42, 3.82]). The odds of developing diabetic retinopathy were not significantly increased across RDW quartiles. Conclusions/interpretation Higher RDW values are associated with increased odds of developing cardiovascular disease nd nephropathy in a nationally representative sample of USA adults with diabetes. RDW may be an important clinical marker of vascular complications in diabetes and one that is independent of traditional risk factors and disease duration. .© 2011 Springer-Verlag.
Nie Y.,Chinese University of Hong Kong |
Nie Y.,Hallett Center for Diabetes and Endocrinology |
Ma R.C.,Chinese University of Hong Kong |
Chan J.C.N.,Chinese University of Hong Kong |
And 2 more authors.
FASEB Journal | Year: 2012
Glucose-dependent insulinotropic peptide (GIP) exerts multiple biological effects via the G-protein-coupled receptor GIPR, including glucose-stimulated insulin production and secretion, cell proliferation, and antiapoptosis in pancreatic β-cells. In an obese state, the circulating level of GIP is elevated. GIPR-knockout mice are resistant to high-fat-diet-induced obesity. The rising evidence suggests a potential role of GIP in adipocyte biology and lipid metabolism. In our study, we overexpressed GIPR in 3T3-L1 CAR adipocytes and demonstrated that GIP impaired the physiological functions of adipocytes as a consequence of increased production of inflammatory cytokines and chemokines and phosphorylation of IkB kinase (IKK)-βthrough activation of the cAMP-PKA pathway. Activation of Jun N-terminal kinase (JNK) pathway was also observed during GIP-induced inflammatory responses in adipocytes. The inhibition of JNK blocked GIP-stimulated secretion of inflammatory cytokines and chemokines, as well as phosphorylation of IKKβ. In addition, GIP-induced inflammatory response increased basal glucose uptake but inhibited insulin-stimulated glucose uptake. Moreover, GIP-induced adipocyte inflammation impaired insulin signaling in adipocytes as demonstrated by a reduction of AKT phosphorylation. Our results suggest that GIP might be one of the stimuli attributable to obesity-induced insulin resistance via the induction of adipocyte inflammation.-Nie, Y., Ma, R. C., Chan, J. C., Xu, H., Xu, G. Glucose-dependent insulinotropic peptide impairs insulin signaling via inducing adipocyte inflammation in glucose-dependent insulinotropic peptide receptor-overexpressing adipocytes. © FASEB.
PubMed | Hallett Center for Diabetes and Endocrinology
Type: | Journal: Diabetes, metabolic syndrome and obesity : targets and therapy | Year: 2011
Obesity constitutes a critical risk factor for the development of many life threatening diseases, particularly insulin resistance and type 2 diabetes. Adipose tissue plays an important role in regulating whole body energy homeostatsis and obesity-related insulin resistance. Inflammation has been commonly linked to insulin resistance. Recent studies demonstrated that adipose tissue is an important source for producing inflammatory molecules in the obese state, primarily due to accumulation of macrophages. Animal models deficient in key inflammatory molecules or with reduced adipose macrophage infiltration are protected from development of obesity-related insulin resistance. Repression of adipose inflammation may be a useful approach to ameliorate obesity-associated metabolic disorders.