Guenther Boden

Temple University, Filadelfia, Pennsylvania, United States

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Publications (106)604.03 Total impact

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    A Singh, G Boden, A K Rao
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    A Singh, G Boden, A K Rao
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    ABSTRACT: Diabetes mellitus (DM) patients have an increased incidence of cardiovascular events. Blood tissue factor-procoagulant activity (TF-PCA), the initiating mechanism for blood coagulation, is elevated in DM. We have shown that hyperglycaemia (HG), hyperinsulinaemia (HI) and combined HG+HI (induced using 24-hour infusion clamps) increases TF-PCA in healthy and type 2 DM (T2DM) subjects, but not in type 1 DM (T1DM) subjects. The mechanisms for this are unknown. DM patients have elevated plasma lipopolysaccharide (LPS), a toll-like receptor (TLR) 4 ligand. We postulated that TLR4 plays a role in modulating TF levels. We studied the effect of HG+HI on TLR4 and TF-PCA in vivo during 24-hour HG+HI infusion clamps in healthy subjects, and T1DM and T2DM subjects, and in vitro in blood. In vivo, in healthy subjects, 24-hour HG + HI infusion increased TLR4 six-fold, which correlated with TF-PCA (r= 0.91, p<0.0001). T2DM patients showed smaller increases in both. In T1DM subjects, TLR4 declined (50%, p<0.05) and correlated with TF-PCA (r=0.55; p<0.05). In vitro, HG (200 mg/dl added glucose) and HI (1-100 nM added insulin) increased TF-PCA in healthy subjects (~2-fold, 2-4 hours). Insulin inhibited by ~30% LPS-induced increase in TF-PCA and high glucose reversed it. TLR4 levels paralleled TF-PCA (r=0.71, p<0.0001); HG and HI increased TLR4 and insulin inhibited LPS-induced TLR4 increase. This is first evidence that even in healthy subjects, HG of short duration increases TLR4 and TF-PCA, key players in inflammation and thrombosis. TLR4-TF interplay is strikingly different in non-diabetic, T1DM and T2DM subjects.
    Thrombosis and Haemostasis 02/2015; 113(4). DOI:10.1160/TH14-10-0884 · 5.76 Impact Factor
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    ABSTRACT: Background Nutrition therapy for gastroparesis focuses on reducing meal size, fiber, fat intake, and increasing liquids intake relative to solid foods. Evidence to support these dietary interventions has been anecdotal. The aim of this study was to determine the effect of fat intake and solid/liquid meal consistency on symptoms in gastroparesis.Methods Twelve patients with gastroparesis were studied on four separate days receiving one of four meals each day in a randomized order: high-fat solid, high-fat liquid, low-fat liquid, and low-fat solid meal. At each visit, eight gastrointestinal symptoms were rated from 0 (none) to 4 (very severe) every 15 min, before and for 4 h after meal ingestion.Key ResultsThere was an increase in the total symptom score in the following order: high-fat solid > low-fat solid > high-fat liquid > low-fat liquid. For the high-fat solid meal, symptoms remained elevated throughout the 4 h postprandial period. Severity of nausea more than doubled after the high-fat solid meal, whereas the low-fat liquid meal caused the least increase in nausea.Conclusions & InferencesA high-fat solid meal significantly increased overall symptoms among individuals with gastroparesis, whereas a low-fat liquid meal had the least effect. With respect to nausea, low-fat meals were better tolerated than high-fat meals, and liquid meals were better tolerated than solid meals. These data provide support for recommendations that low-fat and increased liquid content meals are best tolerated in patients with symptomatic gastroparesis.
    Neurogastroenterology and Motility 01/2015; 146(5). DOI:10.1111/nmo.12519 · 3.42 Impact Factor
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    ABSTRACT: Genome wide association studies have suggested an association of Juxtaposed with another zinc finger gene 1(JAZF1) with type 2 diabetes mellitus (T2DM). As an inhibitor of the TAK1/TR4 signaling pathway, JAZF1 has been shown to be involved in gluconeogenesis, lipid metabolism and insulin sensitivity. However, its role in insulin resistance and atherosclerosis in vivo remains unknown. The present study was designed to investigate in vivo the impact of JAZF1 on insulin resistance-associated dyslipidemia and atherosclerosis. Adenovirus-mediated JAZF1 overexpression was used to characterize the role of JAZF1 in the regulation of lipid metabolism and the development of atherosclerosis in normal chow- or HFD-fed ApoE KO mice. Insulin sensitivity was examined by EHC. Cholesterol de novo synthesis was measured by intraperitoneal [1-14C] acetate injection and atherosclerotic plaques were quantified by histological analysis. A dual-luciferase reporter assay was used to assess the ability of JAZF1 to regulate HMGCR transcriptional activity. JAZF1 overexpression improved HFD-induced hepatic insulin resistance in C57BL/6J mice. In HFD-fed ApoE KO mice, JAZF1 overexpression decreased serum cholesterol levels and hepatic cholesterol synthesis by inhibiting CREB-dependent HMGCR promoter transcriptional activity. Analysis of atherosclerotic lesion showed that JAZF1 overexpression had significantly reduced aortic and aortic sinus en face and cross-sectional plaque areas in HFD-fed ApoE KO mice. These data provide the first evidence for an important role of JAZF1 in increasing hepatic insulin sensitivity and preventing atherosclerosis.
    International Journal of Cardiology 11/2014; 177(1):100–110. DOI:10.1016/j.ijcard.2014.09.007 · 6.18 Impact Factor
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    ABSTRACT: Introduction Diabetes mellitus (DM) is a prothrombotic and proinflammatory state. Hyperglycemia (HG) is encountered even in patients without DM. We have shown that combined HG and hyperinsulinemia (HI) in healthy non-diabetic subjects increased circulating tissue factor (TF) and thrombin generation. To understand the changes in platelet and monocyte pathways induced by combined HG and HI in healthy non-diabetic state, we performed whole genome expression profiling of leukocyte-depleted platelets and monocytes before and after 24 hours of combined HG (glucose ~ 200 mg/dL) and HI by glucose infusion clamp in a healthy non-diabetic subject. Results We defined time-dependent differential mRNA expression (24 versus 0 hour fold change (FC) ≥ 2) common to platelets and monocytes. Ingenuity Pathways Analysis revealed alterations in canonical insulin receptor signaling and coagulation pathways. A preliminary group of 9 differentially expressed genes was selected for qRT-PCR confirmation. Platelet 24 hour sample was compared to the 0 hour sample plus 4 controls. Five transcripts in platelets and 6 in monocytes were confirmed. Platelet GSK3B and PTPN1 were upregulated, and STXBP4 was downregulated in insulin signaling, and F3 and TFPI were upregulated in coagulation pathways. Monocyte, PIK3C3, PTPN11 and TFPI were downregulated. Platelet GSKβ3 and PTPN11 protein and TF antigen in platelets and monocytes was increased. Conclusions Even in non-diabetic state, HG + HI for 24 hours induces changes in platelets and monocytes. They suggest downregulation of insulin signaling and upregulation of TF. Further studies are needed to elucidate cellular alterations leading to the prothrombotic and proinflammatory state in DM.
    Thrombosis Research 09/2014; 134(3). DOI:10.1016/j.thromres.2014.06.029 · 2.43 Impact Factor
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    ABSTRACT: We have recently shown that insulin increased ER stress in human adipose tissue. The effect of insulin resistance on ER stress is not known. It could be decreased, unchanged or increased, depending on whether insulin regulates ER stress via the metabolic/phosphoinositide 3-kinase (PI3K) or alternate signaling pathways.To address this question, we have examined effects of lipid induced insulin resistance on insulin stimulation of ER stress.mRNAs of several ER stress markers were determined in fat biopsies obtained before and after 8 hour hyperglycemic-hyperinsulinemic clamping in 13 normal subjects and in 6 chronically insulin resistant patients with type 2 diabetes (T2DM).In normal subjects, hyperglycemia-hyperinsulinemia increased post/pre mRNA ratios of several ER stress markers (determined by ER stress pathway array and by individual RT-PCR). Lipid infusion was associated with inhibition of the PI3K insulin signaling pathway and with a decrease of hyperinsulinemia induced ER stress responses. In chronically insulin resistant patients with T2DM, hyperglycemic-hyperinsulinemia was unable to increase ER stress response marker mRNAs.In summary, insulin resistance, either produced by lipid infusions in normal subjects or chronically present in T2DM patients, was associated with decreased hyperinsulinemia induced ER stress responses. This suggested, but did not prove, that these 2 phenomena were causally related.
    Diabetes 04/2014; 63(9). DOI:10.2337/db14-0055 · 8.47 Impact Factor
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    Diabetes 04/2014; 63(4):e2. DOI:10.2337/db13-1906 · 8.47 Impact Factor
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    ABSTRACT: Insulin resistance is a metabolic disorder associated with type 2 diabetes. Recent reports have shown that fibroblast growth factor-21 (FGF-21) plays an important role in the progression of insulin resistance. However, the biochemical and molecular mechanisms, by which changes in FGF-21 activation result in changes in the rates of hepatic gluconeogenesis and glycogenolysis, remain to be elucidated. In this study, we developed adenovirus-mediated short hairpin RNAs (shRNAs) against FGF-21 to inhibit FGF-21 expression in ApoE KO mice. Using this mouse model, we determined the effects of FGF-21 knockdown in vivo on hepatic glucose production, on gluconeogenesis and glycogenolysis, and their relationship with the STAT3/SOCS3 signal pathways. We show that liver-specific knockdown of FGF-21 in high fat diet (HFD)-fed ApoE KO mice produced a 39% increase in glycogenolysis and a 75% increase in gluconeogenesis, which were accompanied by increased hepatic expression of G6Pase and PEPCK. Furthermore, FGF-21 knockdown decreased phosphorylation of STAT3 and SOCS3 expression in HFD-fed mice. Our data suggest that hepatic FGF-21 knockdown increases gluconeogenesis and glycogenolysis by activation of G6Pase and PEPCK via the STAT3-SOCS3 pathway, which ultimately leads to the exacerbation of hepatic insulin resistance.
    FEBS Journal 03/2014; DOI:10.1111/febs.12767 · 3.99 Impact Factor
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    ABSTRACT: Aldose reductase inhibitors (ARIs) can block the metabolism of the polyol pathway, and have been used to slow or reverse the progression of diabetic cardiovascular autonomic neuropathy (DCAN). The purpose of this study was to review the effectiveness and safety of ARIs in the treatment of DCAN as determined by five cardiac autonomic neuropathy function tests. CENTRAL, MEDLINE, EMBASE, Scopus databases (inception to May 2012) were searched to identify randomized controlled trials (RCTs) and non-randomized controlled trials (non-RCTs) investigating ARIs for the treatment of DCAN with an English-language restriction. The data were analyzed using RevMan 5.0, and the heterogeneity between the trials was evaluated using the Cochrane's Q-test as well as the I(2) test. The type of model (random or fixed) used for analysis was based on heterogeneity. Weighted mean differences (WMD) with 95% confidence intervals (CI) were computed for the five cardiac automatic neuropathy function tests to evaluate the effects. Ten articles met the prerequisites for this review. Analysis of the results showed that ARIs significantly improved function in at least three of the five automatic neuropathy tests, including the resting heart rate variation coefficients (WMD = 0.25, 95%CI 0.02 to 0.48, P = 0.040); the 30∶15 ratio (WMD = 0.06, 95%CI 0.01 to 0.10, P = 0.010) and the postural systolic blood pressure change (WMD = -5.94, 95%CI -7.31 to -4.57, P = 0.001). The expiration/inspiration ratio showed a marginally significant benefit (WMD = 0.05, 95%CI 0.00 to 0.09, P = 0.040). Glycaemic control was not significantly affected by ARIs. Adverse effects of ARIs except for Tolerestat were minimal. Based on these results, we conclude that ARIs could ameliorate cardiac automatic neuropathy especially mild or asymptomatic DCAN but need further investigation.
    PLoS ONE 02/2014; 9(2):e87096. DOI:10.1371/journal.pone.0087096 · 3.53 Impact Factor
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    ABSTRACT: Nesfatin-1, an 82 amino acid neuropeptide, has recently been characterized as a potent metabolic regulator. However, the metabolic mechanisms and signaling steps directly associated with the action of nesfatin-1 have not been well delineated. We established a loss-of-function model of hypothalamic nesfatin-1/NUCB2 signaling in rats using an adenoviral-mediated RNAi. Using this model, we found that inhibition of central nesfatin-1/NUCB2 activity markedly increased food intake and hepatic glucose flux, and decreased glucose uptake in peripheral tissue in both normal chow diet (NCD)- and high fat diet (HFD)-fed rats. The change of hepatic glucose fluxes in the hypothalamic nesfatin-1/NUCB2 knockdown rats was accompanied by increased hepatic levels of G-6-Pase and PEPCK and decreased insulin receptor (InsR), insulin receptor substrate 1 (IRS-1), and AKT kinase (AKT) phosphorylation. Furthermore, knockdown of hypothalamic nesfatin-1 led to decreased phosphorylation of mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), and the subsequent suppressor of cytokine signaling 3 (SOCS3) levels. These results demonstrated that hypothalamic nesfatin-1/NUCB2 plays an important role in glucose homeostasis and hepatic insulin sensitivity, which at least in part, is associated with the activation of the mTOR-STAT3 signaling pathway.
    Diabetes 01/2014; 63(4). DOI:10.2337/db13-0899 · 8.47 Impact Factor
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    ABSTRACT: Endoplasmic reticulum (ER) stress is increased in obesity and is postulated to be a major contributor to many obesity related pathologies. Little is known about what causes ER stress in obese people. Here, we show that insulin upregulated the unfolded protein response (UPR), an adaptive reaction to ER stress, in vitro in 3T3-L1 adipocytes and in vivo, in subcutaneous (sc) adipose tissue of non-diabetic subjects, where it increased the UPR dose dependently over the entire physiologic insulin range (from ∼ 35 to ∼ 1450 pmol/l). The insulin induced UPR was not due to increased glucose uptake/metabolism and oxidative stress. It was associated, however, with increased protein synthesis, with accumulation of ubiquitination associated proteins, and with multiple post-translational protein modifications (acetylations, methylations, nitrosylations, succinylation, ubiquitinations), some of which are potential causes for ER stress. These results reveal a new physiologic role of insulin and provide a putative mechanism for the development of ER stress in obesity. They may also have clinical and therapeutical implications, for instance in diabetic patients treated with high doses of insulin.
    Diabetes 10/2013; 63(3). DOI:10.2337/db13-0906 · 8.47 Impact Factor
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    ABSTRACT: The stimulatory effects of insulin on de novo lipogenesis (DNL) in the liver, where it is an important contributor to non-alcoholic fatty liver disease (NAFLD), hepatic and systemic insulin resistance, is strong and well established. In contrast, insulin plays only a minor role in DNL in adipose tissue. The reason why insulin stimulates DNL more in liver than in fat is not known but may be due to differential regulation of the transcription and post-translational activation of sterol regulatory element binding proteins (SREBPs). To test this hypothesis, we have examined effects of insulin on activation of SREBP-1c in liver of rats and in adipose tissue of rats and human subjects. Liver and epidydimal fat were obtained from alert rats and subcutaneous adipose tissue from human subjects in response to 4 h euglycemic-hyperinsulinemic clamps. Here we show that acutely raising plasma insulin levels in rats and humans increased SREBP-1 mRNA comparably 3-4 fold in rat liver and rat and human adipose tissue, but increased post-translational activation of SREBP-1c only in rat liver, while decreasing it in adipose tissue. These differential effects of insulin on SREBP-1c activation in liver and adipose tissue were associated with robust changes in the opposite direction of INSIG-1 and to a lesser extent of INSIG-2 mRNA and proteins. We conclude that these findings support the hypothesis that insulin stimulated activation of SREBP-1c in the liver, at least in part, by suppressing INSIG-1 and -2, whereas in adipose tissue, an increase in INSIG-1 and -2 prevented SREBP-1c activation.
    Obesity 06/2013; 21(6):1208-14. DOI:10.1002/oby.20134 · 4.39 Impact Factor
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    Guenther Boden, Sajad Salehi
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    ABSTRACT: Insulin resistance and inflammation are recognized as important links between obesity and cardiovascular disease (CVD). Plasma free fatty acids (FFA), either released from the abnormally enlarged adipose tissue or as part of the excessive nutrient intake, produce insulin resistance and inflammation. Both insulin resistance and inflammation are tightly linked to several independent CVD risk factors such as type 2 diabetes (T2DM), hypertension, dyslipidemia and disorders of blood coagulation. Several hypotheses have been proposed to explain how increased plasma FFA levels can cause insulin resistance including a) the lipid metabolite hypothesis, b) the inflammation hypothesis, c) the hyperinsulinemia hypothesis and d) the endoplasmic reticulum (ER) stress hypothesis. The latter does not require presence of elevated plasma FFA levels and thus provides a mechanism to explain the development of insulin resistance and inflammation in all obese individuals, i.e., those with and without elevated plasma FFA levels.
    Current pharmaceutical design 02/2013; DOI:10.2174/1381612811319320003 · 3.29 Impact Factor
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    ABSTRACT: To assess the efficacy and safety of hyperbaric oxygenation (HBO) therapy as adjunctive treatment for diabetic foot ulcers with a systematic review and meta-analysis of the literature. MEDLINE, EMBASE, and the Cochrane Library were searched to find relevant articles published up to April 20, 2012, without restriction as to language or publication status. All controlled trials that evaluated adjunctive treatment with HBO therapy compared with treatment without HBO for chronic diabetic foot ulcers were selected. A meta-analysis was performed to assess the efficacy and safety of hyperbaric oxygen in managing foot ulcers. Thirteen trials (a total of 624 patients), including 7 prospective randomized trials, performed between January 1, 1966, and April 20, 2012, were identified as eligible for inclusion in the study. Pooling analysis revealed that, compared with treatment without HBO, adjunctive treatment with HBO resulted in a significantly higher proportion of healed diabetic ulcers (relative risk, 2.33; 95% CI, 1.51-3.60). The analysis also revealed that treatment with HBO was associated with a significant reduction in the risk of major amputations (relative risk, 0.29; 95% CI, 0.19-0.44); however, the rate of minor amputations was not affected (P=.30). Adverse events associated with HBO treatment were rare and reversible and not more frequent than those occurring without HBO treatment (P=.37). This meta-analysis reveals that treatment with HBO improved the rate of healing and reduced the risk of major amputations in patients with diabetic foot ulcers. On the basis of these effects, we believe that quality of life could be improved in selected patients treated with HBO.
    Mayo Clinic Proceedings 02/2013; 88(2):166-75. DOI:10.1016/j.mayocp.2012.10.021 · 5.81 Impact Factor
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    ABSTRACT: BACKGROUND & AIMS: Liraglutide, a Glucagon-like peptide-1(GLP-1) analogue with 97% sequence identity to human GLP-1, increases insulin secretion and insulin sensitivity. Its effect on non-alcoholic fatty liver disease (NAFLD) remains poorly understood. In this study, we examined whether liraglutide can protect against inflammatory stress by inhibiting activation of c-Jun N-terminal protein kinase (JNK). METHODS: ApoE KO and adiponectin (Acrp30) knockdown mice fed a high-fat diet (HFD) were treated with liraglutide (1 mg/kg, twice daily) for 8 weeks. Liver tissue was procured for histological examination, real-time RT-PCR and Western blot analysis. RESULTS: The results showed that the combination of HFD, Acrp30 knockdown and ApoE deficiency had additive effects on the development of insulin resistance (IR) and NAFLD. Administration of liraglutide prevented the development of HFD and hypoadiponectinaemia-induced IR and NAFLD in this model. Liraglutide also attenuated the expression of proinflammatory cytokines or transcription factor, including TNF-α and NF-κB(65) , and the expression of two lipogenesis-related genes, Acetyl-CoA Carboxylase (ACC) and fatty acid synthase (FAS). These changes were accompanied by elevated plasma of Acrp30, increased Acrp30 mRNA, AMP Kinase phosphorylation, and decreased mitogen-activated protein kinase 4 (MKK4) mRNA expression and JNK phosphorylation. CONCLUSIONS: Our study also showed potent inhibitory effects of liraglutide on MKK4/JNK signalling which may be a mechanism for the observed improved insulin sensitivity and inflammatory stress induced by HFD and hypoadiponectinaemia.
    Liver international: official journal of the International Association for the Study of the Liver 01/2013; 33(5). DOI:10.1111/liv.12120 · 4.41 Impact Factor
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    ABSTRACT: OBJECTIVE Zinc-α(2)-glycoprotein (ZAG) has been proposed to play a role in the pathogenesis of insulin resistance. Previous studies in humans and in rodents have produced conflicting results regarding the link between ZAG and insulin resistance. The objective of this study was to examine the relationships between ZAG and insulin resistance in cross-sectional and interventional studies.RESEARCH DESIGN AND METHODS Serum ZAG (determined with ELISA) was compared with various parameters related to insulin resistance in subjects with normal glucose tolerance, impaired glucose tolerance (IGT), and newly diagnosed type 2 diabetes mellitus (T2DM), and in women with or without polycystic ovary syndrome (PCOS). Euglycemic-hyperinsulinemic clamps were performed in healthy and PCOS women. Real-time RT-PCR and Western blotting were used to assess mRNA and protein expression of ZAG. The effect of a glucagon-like peptide-1 agonist on ZAG was studied in a 12-week liraglutide treatment trial.RESULTSCirculating ZAG was lower in patients with IGT and newly diagnosed T2DM than in controls. Circulating ZAG correlated positively with HDL cholesterol and adiponectin, and correlated inversely with BMI, waist-to-hip ratio, body fat percentage, triglycerides, fasting blood glucose, fasting insulin, HbA(1c), and homeostasis model assessment of insulin resistance (HOMA-IR). On multivariate analysis, ZAG was independently associated with BMI, HOMA-IR, and adiponectin. ZAG mRNA and protein were decreased in adipose tissue of T2DM patients. Moreover, circulating ZAG levels were lower in women with PCOS than in women with high insulin sensitivity. Liraglutide treatment for 12 weeks significantly increased circulating ZAG levels.CONCLUSIONS We conclude that ZAG may be an adipokine associated with insulin resistance.
    Diabetes care 12/2012; 36(5). DOI:10.2337/dc12-0940 · 8.57 Impact Factor
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    ABSTRACT: BACKGROUND: Liraglutide is a glucagon-like peptide-1 analogue that stimulates insulin secretion and improves β-cell function. However, it is not clear whether liraglutide achieves its glucose lowering effect only by its known effects or whether other as yet unknown mechanisms are involved. The aim of this study was to examine the effects of liraglutide on Fibroblast growth factor-21 (FGF-21) activity in High-fat diet (HFD) fed ApoE(-/-) mice with adiponectin (Acrp30) knockdown. METHOD: HFD-fed ApoE(-/-) mice were treated with adenovirus vectors expressing shAcrp30 to produce insulin resistance. Hyperinsulinemic-euglycemic clamp studies were performed to evaluate insulin sensitivity of the mouse model. QRT-PCR and Western blot were used to measure the mRNA and protein expression of the target genes. RESULTS: The combination of HFD, ApoE deficiency, and hypoadiponectinemia resulted in an additive effect on insulin resistance. FGF-21 mRNA expressions in both liver and adipose tissues were significantly increased while FGF-21 receptor 1 (FGFR-1) and β-Klotho mRNA levels in adipose tissue, as well as FGFR-1-3 and β-Klotho mRNA levels in liver were significantly decreased in this model. Liraglutide treatment markedly improved insulin resistance and increased FGF-21 expression in liver and FGFR-3 in adipose tissue, restored β-Klotho mRNA expression in adipose tissue as well as FGFR-1-3, β-Klotho levels and phosphorylation of FGFR1 up to the levels observed in control mice in liver. Liraglutide treatment also further increased FGF-21 proteins in liver and plasma. In addition, as shown by hyperinsulinemic-euglycemic clamp, liraglutide treatment also markedly improved glucose metabolism and insulin sensitivity in these animals. CONCLUSION: These findings demonstrate an additive effect of HFD, ApoE deficiency, and adiponectin knockdown on insulin resistance and unveil that the regulation of glucose metabolism and insulin sensitivity by liraglutide may be partly mediated via increased FGF-21 and its receptors action.
    PLoS ONE 11/2012; 7(11):e48392. DOI:10.1371/journal.pone.0048392 · 3.53 Impact Factor
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    ABSTRACT: In 2010, the American Diabetes Association revised its criteria for the diagnosis of diabetes to include A1C ≥ 6.5%; however, this has remained controversial, particularly for African Americans. The objective of this pilot study was to examine the usefulness of a single A1C determination in comparison with a same day 2-hour oral glucose tolerance test to diagnose type 2 diabetes in African Americans. In sum, 195 oral glucose tolerance tests and A1Cs were obtained on the same day from 77 overweight and obese African American women and 6 men over a period of 15 months. A1C ≥ 6.5% was present in 31 of 195 patients, with 15 of these having type 2 diabetes by oral glucose tolerance test, another 12 having impaired glucose tolerance, and 4 having normal glucose tolerance. This gives a sensitivity of 50% and a specificity of 90%, with a positive predictive value of 48% and a negative predictive value of 91%. A1C ≤ 5.6%, proposed by the American Diabetes Association to indicate normal glucose tolerance, was present in only 28 patients, 10 (35.7%) of whom had normal glucose tolerance, whereas 18 (64.3%) had either impaired glucose tolerance (15 patients) or type 2 diabetes (3 patients). Fasting plasma glucose ≥ 126 mg/dL was present in 5 of 29 patients with type 2 diabetes (sensitivity, 17.2%; specificity, 100%). First, A1C ≥ 6.5% was a good "rule in" value to identify impaired glucose tolerance and type 2 diabetes (ie, patients at high risk for micro- and macrovascular complications). Second, A1C ≤ 5.6% did not rule out impaired glucose tolerance or type 2 diabetes. Last, fasting plasma glucose ≥ 126 mg/dL detected less than 1 in 5 cases with type 2 diabetes.
    10/2012; 3(4):235-238. DOI:10.1177/2150131911435526
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    ABSTRACT: Nesfatin-1, derived from nucleobindin 2, was recently identified as an anorexigenic signal peptide. However, its neural role in glucose homeostasis and insulin sensitivity is unknown. To evaluate the metabolic impact and underlying mechanisms of central nesfatin-1 signaling, we infused nesfatin-1 in the third cerebral ventricle of high-fat diet (HFD)-fed rats. The effects of central nesfatin-1 on glucose metabolism and changes in transcription factors and signaling pathways were assessed during euglycemic-hyperinsulinemic clamping. The infusion of nesfatin-1 into the third cerebral ventricle markedly inhibited hepatic glucose production (HGP), promoted muscle glucose uptake, and was accompanied by decreases in hepatic mRNA and protein expression and enzymatic activity of PEPCK in both standard diet- and HFD-fed rats. In addition, central nesfatin-1 increased insulin receptor (InsR)/insulin receptor substrate-1 (IRS-1)/AMP-dependent protein kinase (AMPK)/Akt kinase (Akt)/target of rapamycin complex (TORC) 2 phosphorylation and resulted in an increase in Fos immunoreactivity in the hypothalamic nuclei that mediate glucose homeostasis. Taken together, these results reveal what we believe to be a novel site of action of nesfatin-1 on HGP and the PEPCK/InsR/IRS-1/AMPK/Akt/TORC2 pathway and suggest that hypothalamic nesfatin-1 action through a neural-mediated pathway can contribute to increased peripheral and hepatic insulin sensitivity by decreasing gluconeogenesis and promoting peripheral glucose uptake in vivo.
    Diabetes 06/2012; 61(8):1959-68. DOI:10.2337/db11-1755 · 8.47 Impact Factor
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    ABSTRACT: High-fat diet (HFD) is associated with insulin resistance, hyperinsulinemia, elevated plasma free fatty acid (FFA), and increased risk for atherosclerotic vascular disease. However, the mechanisms underlying the HFD-induced insulin resistance have not been fully clarified. The aim of present study is to evaluate the effects of long-term HFD on the regulation of the insulin-sensitizing fibroblast growth factor-21 (FGF-21) and visfatin in ApoE(-/-) mice. A total of twenty male ApoE(-/-) mice were randomly divided into normal chow diet (NC) or HFD (HF) group for 16 weeks. Euglycemic-hyperinsulinemic clamp was performed to evaluate insulin sensitivity in this animal model. Both mRNA and protein contents of FGF-21 and visfatin were assayed by Quantitative real-time PCR and Western blot. Long-term HFD resulted in the marked abnormality of glucose and lipid metabolism as well as a large decrease in whole-body insulin sensitivity. Accompanied by abnormal glucose-lipid metabolism and aggravated insulin resistance, FGF-21, β-klotho, FGFR1, FGFR3 and FGFR4 mRNA expressions were markedly up-regulated, whereas visfatin mRNA expression was markedly down-regulated in liver and/or adipose tissue of HFD-fed mice. In addition, Western blotting also revealed both up-regulation of the FGF-21 protein and down-regulation of visfatin protein in liver, adipose tissue and plasma of HFD-fed mice. Both FGF-21 and visfatin expression and secretion are regulated by a potent regulator, long-term HFD. And these adipokines are associated with glucose-lipid metabolism and insulin resistance.
    Cytokine 04/2012; 59(1):131-7. DOI:10.1016/j.cyto.2012.03.030 · 2.87 Impact Factor

Publication Stats

4k Citations
604.03 Total Impact Points

Institutions

  • 1993–2014
    • Temple University
      • Section of Endocrinology, Diabetes and Metabolism
      Filadelfia, Pennsylvania, United States
  • 2008–2010
    • Chongqing Medical University
      • Department of Surgery
      Ch’ung-ch’ing-shih, Chongqing Shi, China
  • 2009
    • West Chester University
      • Department of Sports Medicine
      West Chester, Pennsylvania, United States
  • 2006
    • Boston University
      Boston, Massachusetts, United States
  • 2005
    • Drexel University
      Philadelphia, Pennsylvania, United States
  • 2004
    • University of Kuopio
      Kuopio, Northern Savo, Finland