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Yang S.,University of Pittsburgh | Yang S.,Chongqing Medical University | Xu H.,Hallett Center for Diabetes and Endocrinology | Yu S.,University of Pittsburgh | And 7 more authors.
Journal of Biological Chemistry | Year: 2011

In this study, we determined the molecular mechanisms whereby forkhead transcription factor Foxo1, a key downstream signaling molecule of insulin-like growth factor 1 (IGF1)/insulin actions, regulates Runx2 activity and expression of the mouse osteocalcin gene 2 (Bglap2) in osteoblasts in vitro. We showed that Foxo1 inhibited Runx2-dependent transcriptional activity and osteocalcin mRNA expression and Bglap2 promoter activity in MC-4 preosteoblasts. Co-immunoprecipitation assay showed that Foxo1 physically interacted with Runx2 via its C-terminal region in osteoblasts or when co-expressed in COS-7 cells. Electrophoretic mobility shift assay demonstrated that Foxo1 suppressed Runx2 binding to its cognate site within the Bglap2 promoter. IGF1 and insulin prevented Foxo1 from inhibiting Runx2 activity by promoting Foxo1 phosphorylation and nuclear exclusion. In contrast, a neutralizing anti-IGF1 antibody decreased Runx2 activity and osteocalcin expression in osteoblasts. Chromatin immunoprecipitation assay revealed that IGF1 increased Runx2 interaction with a chromatin fragment of the proximal Bglap2 promoter in a PI3K/AKT-dependent manner. Conversely, knockdown of Foxo1 increased Runx2 interaction with the promoter. This study establishes that Foxo1 is a novel negative regulator of osteoblast-specific transcription factor Runx2 and modulates IGF1/insulin-dependent regulation of osteocalcin expression in osteoblasts. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. Source


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. Source


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. Source


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. Source


Wu Z.,Novartis | Jiao P.,Hallett Center for Diabetes and Endocrinology | Huang X.,Novartis | Feng B.,Hallett Center for Diabetes and Endocrinology | And 7 more authors.
Journal of Clinical Investigation | Year: 2010

Insulin resistance results in dysregulated hepatic gluconeogenesis that contributes to obesity-related hyperglycemia and progression of type 2 diabetes mellitus (T2DM). Recent studies show that MAPK phosphatase-3 (MKP-3) promotes gluconeogenic gene transcription in hepatoma cells, but little is known about the physiological role of MKP-3 in vivo. Here, we have shown that expression of MKP-3 is markedly increased in the liver of diet-induced obese mice. Consistent with this, adenovirus-mediated MKP-3 overexpression in lean mice promoted gluconeogenesis and increased fasting blood glucose levels. Conversely, shRNA knockdown of MKP-3 in both lean and obese mice resulted in decreased fasting blood glucose levels. In vitro experiments identified forkhead box O1 (FOXO1) as a substrate for MKP-3. MKP-3-mediated dephosphorylation of FOXO1 at Ser256 promoted its nuclear translocation and subsequent recruitment to the promoters of key gluconeogenic genes. In addition, we showed that PPARγ coactivator-1α (PGC-1α) acted downstream of FOXO1 to mediate MKP-3-induced gluconeogenesis. These data indicate that MKP-3 is an important regulator of hepatic gluconeogenesis in vivo and suggest that inhibition of MKP-3 activity may provide new therapies for T2DM. Source

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