R A DeFronzo

University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

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Publications (555)3737.46 Total impact

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    ABSTRACT: Background: In UKPDS stepwise addition of metformin, sulfonylurea, and basal insulin reduced microvascular complications, but A1c rose progressively to > 8.5% and ~ 65% of individuals required insulin therapy aft er 10.5 years. Yet metformin, add SU, add insulin remains the most frequently employed therapeutic recommendation in the US and other countries.
    09/2015; 11(3):80-81. DOI:10.1007/s12467-013-0033-7
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    ABSTRACT: Inflammation and oxidative stress, through the production of reactive oxygen species (ROS), are consistently associated with metabolic syndrome/type 2 diabetes. While the role of Nox2, a major ROS-generating enzyme, is well described in host defense and inflammation, little is known about its potential role in insulin resistance in skeletal muscle. Insulin resistance induced by a high-fat diet (HFD) was mitigated in Nox2-null mice compared with wild-type mice after 3 or 9 months on the diet. High-fat feeding increased Nox2 expression, superoxide production and impaired insulin signaling in skeletal muscle tissue of wild-type mice but not in Nox2-null mice. Exposure of C2C12 cultured myotubes to either high glucose concentration, palmitate or H2O2 decreases insulin-induced Akt phosphorylation and glucose uptake. Pre-treatment with catalase abrogated these effects indicating a key role for H2O2 in mediating insulin resistance. Down-regulation of Nox2 in C2C12 cells by shRNA prevented insulin resistance induced by high glucose or palmitate but not H2O2. These data indicate that increased production of ROS in insulin resistance induced by high glucose in skeletal muscle cells is a consequence of Nox2 activation. This is the first report to show that Nox2 is a key mediator of insulin resistance in skeletal muscle. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 03/2015; DOI:10.1074/jbc.M114.626077 · 4.60 Impact Factor
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    ABSTRACT: Background: Beta cell dysfunction is a core defect in T2DM and chronic, sustained hyperglycemia has been implicated in progressive beta cell failure, i.e. glucotoxicity. The aim of the present study was to examine the effect of lowering the plasma glucose concentration with dapagliflozin, a glucosuric agent, on beta cell function in T2DM individuals. Research Design and Methods: 24 subjects with T2DM received dapagliflozin (n=16) or placebo (n=8) for 2 weeks, and a 75-gram OGTT and insulin clamp were performed before and after treatment. Plasma glucose, insulin, and C-peptide concentrations were measured during the OGTT. Results: Dapagliflozin significantly lowered both the fasting and 2-hour plasma glucose concentrations and the incremental area under the plasma glucose concentration curve (ΔG0-120) during OGTT by -33±5 mg/dl, -73±9mg/dl and -60±12 mg/dl•min, respectively, compared to -13±9, -33±13 and -18±9 reductions in placebo-treated subjects (both p<0.01). The incremental area under the plasma C-peptide concentration curve tended to increase in dapagliflozin-treated subjects, while it did not change in placebo-treated subjects. Thus, ΔC-Pep0-120/ΔG0-120 increased significantly in dapagliflozin-treated subjects, while it did not change in placebo-treated subjects (0.019±0.005 vs 0.002±0.006, p<0.01). Dapagliflozin significantly improved whole body insulin sensitivity (insulin clamp). Thus, beta cell function, measured as ΔC-Pep0-120/ΔG0-120 ÷ insulin resistance, increased by 2-fold (p<0.01) in dapagliflozin-treated versus placebo-treated subjects. Conclusion: Lowering the plasma glucose concentration with dapagliflozin markedly improves beta cell function, providing strong support in man for the glucotoxic effect of hyperglycemia on beta cell function.
    Journal of Clinical Endocrinology &amp Metabolism 02/2015; 100(5):jc20143472. DOI:10.1210/jc.2014-3472 · 6.31 Impact Factor
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    ABSTRACT: Objective: To test the clinical utility of Quantose M(Q) to monitor changes in insulin sensitivity following pioglitazone therapy in prediabetic subjects. M(Q) is derived from fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three non-glucose metabolites shown to correlate with insulin-stimulated glucose disposal., Research design and methods: Participants were 428 of the total of 602 ACT NOW IGT subjects randomized to pioglitazone (45 mg/day) or placebo and followed for, 2.4 years. At baseline and study end fasting plasma metabolites required for determination of Quantose, HbA1c, and OGTT with frequent plasma insulin and glucose measurements to calculate, Matsuda Index of insulin sensitivity were obtained. Results: Pioglitazone treatment lowered IGT conversion to diabetes (HR=0.25, 95%CI = 0.13-0.50, p<0.0001). While HbA1c did not track with insulin sensitivity, M(Q) increased in pioglitazone-treated subjects (by 1.45[3.45] mg(.)min(-1.)kgwbm(-1) (median[interquartile range]), (p<0.001 vs placebo) as did, Matsuda Index (by 3.05[4.77] units, p<0.0001). M(Q) correlated with Matsuda Index at baseline and change in Matsuda Index from baseline (rho's of 0.85 and 0.79, respectively, p<0.0001) and was progressively higher across close-out glucose tolerance status (diabetes, IGT, NGT). In logistic models including only anthropometric and fasting measurements, M(Q) outperformed both Matsuda and fasting insulin in predicting incident diabetes. Conclusions: In IGT subjects, Quantose M(Q) parallels changes in insulin sensitivity and glucose tolerance with pioglitazone therapy. Due to its strong correlation with improved insulin sensitivity and its ease of use, Quantose M(Q) may serve as a useful clinical test to identify and monitor therapy in insulin resistant patients.
    Journal of Clinical Endocrinology &amp Metabolism 01/2015; 100(5):jc20143824. DOI:10.1210/jc.2014-3824 · 6.31 Impact Factor
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    ABSTRACT: Premature infants develop hyperglycemia shortly after birth, increasing their morbidity and death. Surviving infants have increased incidence of diabetes as young adults. Our understanding of the biological basis for the insulin resistance of prematurity and developmental regulation of glucose production remains fragmentary. The objective of this study was to examine maturational differences in insulin sensitivity and the insulin-signaling pathway in skeletal muscle and adipose tissue of 30 neonatal baboons utilizing the euglycemic hyperinsulinemic clamp. Preterm (67% gestation) baboons had reduced peripheral insulin sensitivity shortly after birth (M value 12.5±1.5 vs. 21.8±4.4 mg/kg·min in term baboons) and at 2 weeks of age (M value 12.8±2.6 vs. 16.3±4.2, respectively). Insulin increased Akt phosphorylation, but these responses were significantly lower in preterm baboons during the first week of life (3.2-fold versus 9.8-fold). Preterm baboons had lower GLUT1 protein content throughout the first 2 weeks of life (8-12% of term). In preterm baboons, serum free fatty acids (FFA) did not decrease in response to insulin whereas FFA decreased by >80% in term baboons; the impaired suppression of FFA in preterm animals was paired with decreased GLUT4 protein content in adipose tissue. In conclusion, peripheral insulin resistance and impaired non-insulin dependent glucose uptake play an important role in hyperglycemia of prematurity. Impaired insulin signaling (reduced Akt) contributes to the defect in insulin-stimulated glucose disposal. Counter-regulatory hormones are not major contributors.
    Endocrinology 01/2015; 156(3):en20141757. DOI:10.1210/en.2014-1757 · 4.64 Impact Factor
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    ABSTRACT: Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR ≤ 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR ≤ 10-4) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10-60) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10-9), BMI (5.4 x 10-6), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits.
    PLoS ONE 01/2015; 10(4):e0119941. DOI:10.1371/journal.pone.0119941 · 3.53 Impact Factor
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    ABSTRACT: Abstract Hyperglycemia in patients with and without a prior history of diabetes is an independent marker of morbidity and mortality in critically and noncritically ill patients. Improvement of glycemic control with insulin therapy has been shown to reduce hospital complications in patients with diabetes, but also results in increased rates of hypoglycemia, which have been linked to poor outcomes. Thus, alternative treatment options that can normalize blood glucose levels without undue hypoglycemia are being sought. Incretin-based therapies, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, stimulate insulin secretion in a glucose-dependent fashion, thus not causing hypoglycemia. Alternative points of view exist regarding insulin versus incretin therapy for the care of these patients. We have brought together the authors on the opposite sides of this discussion with the objective of providing a rational synthesis on how to achieve the best possible control of glycemia in the hospital, using both standard insulin approaches and incretin-based therapies to improve patient outcomes. This review examines the benefits of incretin-based therapy in improving glycemic control in hospitalized patients with stress-induced diabetes and in diabetic patients in critical care and non-critical care settings.
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    ABSTRACT: In the liver Wnt-signaling contributes to the metabolic fate of hepatocytes, but the precise role of the TCF7L2 in this process is unknown. We employed a temporal RNA-Seq approach to examine gene expression 3-96 h following Tcf7l2 silencing in rat hepatoma cells, and combined this with ChIP-Seq to investigate mechanisms of target gene regulation by TCF7L2. Silencing Tcf7l2 led to a time-dependent appearance of 406 differentially expressed genes (DEGs), including key regulators of cellular growth and differentiation, and amino acid, lipid and glucose metabolism. Direct regulation of 149 DEGs was suggested by strong proximal TCF7L2 binding (peak proximity score > 10) and early mRNA expression changes (≤18 h). Indirect gene regulation by TCF7L2 likely occurred via alternate transcription factors, including Hnf4a, Foxo1, Cited2, Myc and Lef1, which were differentially expressed following Tcf7l2 knock-down. Tcf7l2-silencing enhanced the expression and chromatin occupancy of HNF4α, and co-siRNA experiments revealed that HNF4α was required for the regulation of a subset of metabolic genes by TCF7L2, particularly those involved in lipid and amino-acid metabolism. Our findings suggest TCF7L2 is an important regulator of the hepatic phenotype, and highlight novel mechanisms of gene regulation by TCF7L2 that involve interplay between multiple hepatic transcriptional pathways. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
    Nucleic Acids Research 12/2014; 42(22):13646-13661. DOI:10.1093/nar/gku1225 · 8.81 Impact Factor
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    ABSTRACT: The molecular mechanisms by which muraglitazar (peroxisome proliferator-activated receptor γ/α agonist) improves insulin sensitivity in Type 2 diabetes mellitus are not fully understood. We hypothesized that muraglitazar would increase expression of 5'-monophosphate-activated protein kinase and genes involved in adiponectin signalling, free fatty acid oxidation and mitochondrial function in skeletal muscle. Sixteen participants with Type 2 diabetes received muraglitazar, 5 mg/day (n = 12) or placebo (n = 4). Before and after 16 weeks, participants had vastus lateralis muscle biopsy followed by 180 min euglycaemic hyperinsulinaemic clamp. Muraglitazar increased plasma adiponectin (9.0 ± 1.1 to 17.8 ± 1.5 μg/ml, P < 0.05), while no significant change was observed with placebo. After 16 weeks with muraglitazar, fasting plasma glucose declined by 31%, fasting plasma insulin decreased by 44%, insulin-stimulated glucose disposal increased by 81%, HbA1c decreased by 21% and plasma triglyceride decreased by 39% (all P < 0.05). Muraglitazar increased mRNA levels of 5'-monophosphate-activated protein kinase, adiponectin receptor 1, adiponectin receptor 2, peroxisome proliferator-activated receptor gamma coactivator-1alpha and multiple genes involved in mitochondrial function and fat oxidation. In the placebo group, there were no significant changes in expression of these genes. Muraglitazar increases plasma adiponectin, stimulates muscle 5'-monophosphate-activated protein kinase expression and increases expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation. These changes represent important cellular mechanisms by which dual peroxisome proliferator-activated receptor agonists improve skeletal muscle insulin sensitivity. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Diabetic Medicine 12/2014; 32(5). DOI:10.1111/dme.12664 · 3.06 Impact Factor
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    ABSTRACT: ADA and EASD recommend lowering HbA1c in T2DM individuals to as close to normal as possible while avoiding hypoglycemia. We hypothesized that initiating therapy with a combination of agents known to improve insulin secretion and insulin sensitivity in subjects with new onset diabetes would produce greater, more durable HbA1c reduction while avoiding hypoglycemia and weight compared to sequential addition of agents that lower plasma glucose but do not correct established pathophysiologic abnormalities. Research Design and Methods Drug naïve, recently diagnosed T2DM subjects were randomized in an open fashion design in a single center study to metformin/pioglitazone/exenatide (Triple Therapy) (n = 106) or escalating dose of metformin followed by sequential addition of sulfonylurea and glargine insulin (Conventional Therapy) (n = 115) to maintain HbA1c < 6.5 for 2 years. Subjects receiving Triple Therapy experienced a significantly greater reduction in HbA1c versus Conventional Therapy (5.95% vs 6.50 %, p < 0.001). Despite lower HbA1c , subjects receiving Triple Therapy experienced 7.5-fold lower rate of hypoglycemia versus subjects receiving Conventional Therapy. Subjects receiving Triple Therapy experienced mean weight loss of 1.2 kg versus mean weight gain of 4.1 kg (p < 0.01) with Conventional Therapy. The results of this exploratory study demonstrate that combination therapy with metformin/pioglitazone/exenatide in newly diagnosed T2DM patients is more effective with less hypoglycemia than sequential add-on therapy with metformin, sulfonylurea, and then basal insulin. This article is protected by copyright. All rights reserved.
    Diabetes Obesity and Metabolism 11/2014; 17(3). DOI:10.1111/dom.12417 · 5.46 Impact Factor
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    ABSTRACT: Background/Objectives Although newer approaches have identified several metabolites associated with obesity, there is paucity of such information in paediatric populations, especially among Mexican–Americans (MAs) who are at high risk of obesity. Therefore, we performed a global serum metabolite screening in MA children to identify biomarkers of childhood obesity.Methods We selected 15 normal-weight, 13 overweight and 14 obese MA children (6–17 years) and performed global serum metabolite screening using ultra-performance liquid chromatography/quadruple orthogonal acceleration time of flight tandem micro mass spectrometer. Metabolite values were analysed to assess mean differences among groups using one-way analysis of variance, to test for linear trend across groups and to examine Pearson's correlations between them and seven cardiometabolic traits (CMTs): body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, homeostasis model of assessment-insulin resistance, triglycerides and high-density lipoprotein cholesterol.ResultsWe identified 14 metabolites exhibiting differences between groups as well as linear trend across groups with nominal statistical significance. After adjustment for multiple testing, mean differences and linear trends across groups remained significant (P < 5.9 × 10−5) for L-thyronine, bradykinin and naringenin. Of the examined metabolite-CMT trait pairs, all metabolites except for 2-methylbutyroylcarnitine were nominally associated with two or more CMTs, some exhibiting significance even after accounting for multiple testing (P < 3.6 × 10−3).Conclusions To our knowledge, this study – albeit pilot in nature – is the first study to identify these metabolites as novel biomarkers of childhood obesity and its correlates. These findings signify the need for future systematic investigations of metabolic pathways underlying childhood obesity.
    Pediatric Obesity 11/2014; DOI:10.1111/ijpo.270 · 2.42 Impact Factor
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    ABSTRACT: In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67-positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67-positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67-positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30-positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a β-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
    American Journal Of Pathology 11/2014; 185(1). DOI:10.1016/j.ajpath.2014.09.009 · 4.60 Impact Factor
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    ABSTRACT: The hyperbolic relationship between insulin secretion and sensitivity has been used to assess in vivo β-cell function (i.e., the disposition index). The disposition index emphasizes the importance of taking into account both skeletal muscle and hepatic insulin resistance to depict insulin secretion. However, we propose that adipose tissue insulin resistance also needs to be accounted for when characterizing glucose-stimulated insulin secretion (GSIS) because elevated plasma free fatty acids (FFAs) impair β-cell function.
    Diabetes Care 08/2014; DOI:10.2337/dc13-3011 · 8.57 Impact Factor
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    ABSTRACT: Introduction: The incidence of type 2 diabetes mellitus (T2DM) has risen to epidemic proportions, and this is associated with enormous cost. T2DM is preceded by ‘prediabetes’, and the diagnosis of impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) provides an opportunity for targeted intervention. Prediabetic subjects manifest both core defects characteristic of T2DM, that is, insulin resistance and β-cell dysfunction. Interventions which improve insulin sensitivity and/or preserve β-cell function are logical strategies to delay the conversion of IGT/IFG to T2DM or revert glucose tolerance to normal.Areas covered: The authors examine pharmacologic agents that have proven to decrease the conversion of IGT to T2DM and represent potential treatment options in prediabetes.Expert opinion: Weight loss improves whole body insulin sensitivity, preserves β-cell function and decreases progression of prediabetes to T2DM. In real life long-term weight loss is the exception and, even if successful, 40 – 50% of IGT individuals still progress to T2DM. Pharmacotherapy provides an alternative strategy to improve insulin sensitivity and preserve β-cell function. Thiazolidinediones (TZDs) are highly effective in T2DM prevention. Long-acting glucagon-like peptide-1 (GLP-1) analogs, because they augment β-cell function and promote weight loss, are effective in preventing IGT progression to T2DM. Metformin is considerably less effective than TZDs or GLP-1 analogs.
    Expert Opinion on Pharmacotherapy 08/2014; 15(14). DOI:10.1517/14656566.2014.944160 · 3.09 Impact Factor
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    ABSTRACT: Aims/Hypothesis: The insulin secretion/insulin resistance (disposition) index (ΔI/ΔG÷IR) commonly is used as a measure of beta cell function (Δ=change from baseline). This relationship is curvilinear and becomes linear when log transformed. ΔI is determined by two variables: insulin secretory rate (ISR) and metabolic clearance of insulin (MCRI). We postulated that the characteristic curvilinear relationship would be lost if Δ plasma C-peptide (instead of Δ plasma insulin) was plotted against insulin sensitivity. Methods: 441 IGT individuals from ACT NOW received an OGTT and were randomized to pioglitazone or placebo for 2.4 years. Results: Pioglitazone reduced IGT conversion to diabetes by 72% (p<0.0001). ΔI/ΔG vs Matsuda Index (MI) of insulin sensitivity showed the characteristic curvilinear relationship. However, when ΔCP/ΔG or ΔISR/ΔG was plotted against MI, the curvilinear relationship was completely lost. This discordance was explained by two distinct physiologic effects that altered plasma insulin response in opposite directions: (i) increased ISR and (ii) augmented MCRI. The net result was a decline in plasma insulin response to hyperglycemia during OGTT. These findings demonstrate a physiologic control mechanism wherein the increase in ISR ensures adequate insulin delivery into portal circulation to suppress HGP while delivering reduced but sufficient amount of insulin to peripheral tissues to maintain the pioglitazone-mediated improvement in insulin sensitivity without excessive hyperinsulinemia. Conclusions: These results demonstrate the validity of disposition index when relating plasma insulin response to insulin sensitivity, but underscore the pitfall of this index when drawing conclusions about beta cell function, since insulin secretion declined despite an increase in plasma insulin response.
    Journal of Clinical Endocrinology &amp Metabolism 06/2014; 99(10):jc20141515. DOI:10.1210/jc.2014-1515 · 6.31 Impact Factor
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    ABSTRACT: Recent work suggests that glucose-stimulated insulin secretion (GSIS) should be adjusted for both skeletal muscle and hepatic insulin resistance to depict β-cell function (i.e. disposition index). However, adipose tissue insulin resistance needs to be accounted for since elevated free fatty acids (FFA) impair β-cell function.PURPOSE: To characterize and validate β-cell function relative to adipose insulin resistance, and test the effects of a 7-day exercise intervention on β-cell function.METHODS: Forty-four subjects (29 F; 59.6±1.3 y; 31.3±0.7 kg/m2), underwent a standard 75g OGTT to determine 1st and 2nd phase GSIS, calculated as area under the curve of insulin divided by glucose during the first 30 and last 60min. [1-14C] palmitate tracer infusions (Ra) were used to assess basal lipolytic rate, and we validated a simplified version of the Ra calculation using plasma as: [1/(FFA*insulin)*GSIS]. Twelve different subjects (11 F; 66.3±1.2 y; 35.1±1.9 kg/m2) underwent 7-days of supervised aerobic exercise (60min/d, ∼85% HRmax) and a 75g OGTT was performed before and after exercise to estimate β-cell function adjusted for skeletal muscle (Matsuda index*GSIS), hepatic ((1/fasting glucose*insulin)*GSIS) and adipose tissue ((1/fastingFFA*insulin)*GSIS) insulin resistance.RESULTS: Plasma FFA and palmitate Ra calculations of 1st and 2nd phase β-cell function were correlated (r=0.86, p<0.001 and r=0.89, p<0.001, respectively) and met hyperbolic criteria. 120min glucose levels were inversely related to 1st and 2nd phase β-cell function (r=-0.86, p<0.0001 and r=-0.90, p<0.001). Exercise had no effect on weight or VO2max, but increased β-cell function relative to changes in skeletal muscle (1st phase Pre: 1.7±0.4 vs. Post: 2.8±0.8, 2nd phase Pre: 1.1±0.1 vs. Post: 1.33±0.2, each p<0.03), but not hepatic (1st phase Pre: 0.23±0.06 vs. Post: 0.30±0.09, 2nd phase Pre: 0.14±0.03 vs. Post: 0.14±0.03, each p<0.87) or adipose insulin resistance (1st phase Pre: 0.13±0.03 vs. Post: 0.13±0.04, 2nd phase Pre: 0.07±0.01 vs. Post: 0.06±0.01, each p<0.61).CONCLUSIONS: Adjusting GSIS for adipose insulin resistance provides an index of β-cell function in obese subjects. Plasma FFA derived calculations may yield additional insight into how exercise influences inter-organ crosstalk for glucose regulation.
    Medicine &amp Science in Sports &amp Exercise 05/2014; 46(5S):157–161. DOI:10.1249/01.mss.0000451129.79793.50 · 4.46 Impact Factor
  • Diabetes Spectrum 05/2014; 27(2):100-112. DOI:10.2337/diaspect.27.2.100
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    ABSTRACT: Binding of insulin receptor substrate proteins 1 and 2 (IRS1/2) to the insulin receptor (IR) is essential for the regulation of insulin sensitivity and energy homeostasis. However, the mechanism of IRS1/2 recruitment to the IR remains elusive. Here, we identify adaptor protein APPL1 as a critical molecule that promotes IRS1/2-IR interaction. APPL1 forms a complex with IRS1/2 under basal conditions, and this complex is then recruited to the IR in response to insulin or adiponectin stimulation. The interaction between APPL1 and IR depends on insulin- or adiponectin-stimulated APPL1 phosphorylation, which is greatly reduced in insulin target tissues in obese mice. appl1 deletion in mice consistently leads to systemic insulin resistance and a significant reduction in insulin-stimulated IRS1/2, but not IR, tyrosine phosphorylation, indicating that APPL1 sensitizes insulin signaling by acting at a site downstream of the IR. Our study uncovers a mechanism regulating insulin signaling and crosstalk between the insulin and adiponectin pathways.
    Cell Reports 05/2014; 7(4). DOI:10.1016/j.celrep.2014.04.006 · 7.21 Impact Factor
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    ABSTRACT: Aim: to examine the relationship between whole body insulin-mediated glucose disposal and the fasting plasma glucose concentration in non-diabetic individuals. Research Design and Methods: 253 non-diabetic subjects with NGT, IFG, IGT and CGI received 75-gram OGTT and euglycemic hyperinsulinemic clamp. Total glucose disposal (TGD) during the insulin clamp was compared in IFG and NGT individuals and was related to fasting and 2-h plasma glucose concentrations in each group. Results: TGD varied considerably between NGT and IFG individuals and displayed a strong inverse relationship with the 2h PG (r=0.40, p<0.0001) but not with the FPG. When IFG and NGT individuals were stratified based upon their 2-h PG concentration, the increase in 2h-PG was associated with a progressive decrease in TGD in both groups, and the TGD was comparable among NGT and IFG individuals. Conclusion: the present results indicate that: (i) as in NGT, insulin-stimulated TGD varies considerably in IFG individuals; ii) the large variability in TGD in IFG and NGT individuals is related to the 2h-PG concentration; (iii) after adjustment for the 2h PG concentration, IFG subjects have comparable TGD to NGT individuals.
    The Journal of Clinical Endocrinology and Metabolism 05/2014; 99(9):jc20132886. DOI:10.1210/jc.2013-2886 · 6.31 Impact Factor
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    ABSTRACT: OBJECTIVE Plasma adiponectin levels are reduced in type 2 diabetes mellitus (T2DM) and other insulin-resistant states. We examined whether plasma adiponectin levels at baseline and after pioglitazone treatment in impaired glucose tolerance (IGT) subjects were associated with improved insulin sensitivity (SI) and glucose tolerance status.RESEARCH DESIGN AND METHODSA total of 602 high-risk IGT subjects in ACT NOW were randomized to receive pioglitazone or placebo with a median follow-up of 2.4 years.RESULTSPioglitazone reduced IGT conversion to diabetes by 72% in association with improved β-cell function by 64% (insulin secretion/insulin resistance index) and increased tissue sensitivity by 88% (Matsuda index). In pioglitazone-treated subjects, plasma adiponectin concentration increased threefold from 13 ± 0.5 to 38 ± 2.5 μg/mL (P < 0.001) and was strongly correlated with the improvement in SI (r = 0.436, P < 0.001) and modestly correlated with glucose area under the curve during oral glucose tolerance test (r = 0.238, P < 0.005) and insulin secretion/insulin resistance index (r = 0.306, P < 0.005). The increase in adiponectin was a strong predictor of reversion to normal glucose tolerance and prevention of T2DM. In the placebo group, plasma adiponectin did not change and was not correlated with changes in glucose levels. There was an inverse association between baseline plasma adiponectin concentration and progression to diabetes in the placebo group but not in the pioglitazone group.CONCLUSIONS Baseline adiponectin does not predict the response to pioglitazone. The increase in plasma adiponectin concentration after pioglitazone therapy in IGT subjects is strongly related to improved glucose tolerance status and enhanced tissue sensitivity to insulin.
    Diabetes care 04/2014; 37(6). DOI:10.2337/dc13-1745 · 8.57 Impact Factor

Publication Stats

50k Citations
3,737.46 Total Impact Points


  • 1988–2015
    • University of Texas Health Science Center at San Antonio
      • • Division of Hospital Medicine
      • • Division of Diabetes
      • • Department of Medicine
      San Antonio, Texas, United States
    • Karolinska Institutet
      • Department of Renal Medicine
      Stockholm, Stockholm, Sweden
  • 2011–2013
    • Southwest Foundation For Biomedical Research
      San Antonio, Texas, United States
  • 2012
    • Central South University
      • Metabolic Syndrome Research Center
      Ch’ang-sha-shih, Hunan, China
  • 2009
    • Lund University
      • Department of Clinical Sciences, Malmö
      Lund, Skåne, Sweden
  • 2007–2008
    • University of Texas Health Science Center at Tyler
      Tyler, Texas, United States
    • University of Dundee
      Dundee, Scotland, United Kingdom
    • Arizona State University
      • School of Life Sciences
      Mesa, AZ, United States
  • 1990–2008
    • University of Texas at San Antonio
      San Antonio, Texas, United States
    • University of Milan
      Milano, Lombardy, Italy
    • Università degli Studi di Genova
      Genova, Liguria, Italy
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
  • 1987–2007
    • Università di Pisa
      • Department of Clinical and Experimental Medicine
      Pisa, Tuscany, Italy
  • 2006
    • University of Texas at Austin
      • Department of Kinesiology and Health Education
      Austin, Texas, United States
  • 1999–2000
    • University of Catania
      Catania, Sicily, Italy
  • 1998
    • Leiden University Medical Centre
      Leyden, South Holland, Netherlands
  • 1995–1998
    • University of Verona
      Verona, Veneto, Italy
    • Second University of Naples
      Caserta, Campania, Italy
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
  • 1996
    • It-Robotics
      Vicenza, Veneto, Italy
  • 1994
    • The University of Tennessee Health Science Center
      • Department of Medicine
      Memphis, TN, United States
  • 1993
    • National Research Council
      • Institute of Clinical Physiology IFC
      Roma, Latium, Italy
  • 1978–1993
    • Yale-New Haven Hospital
      • Department of Diabetes and Endocrinology
      New Haven, Connecticut, United States
  • 1991
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
  • 1980–1991
    • Yale University
      • • Department of Internal Medicine
      • • Department of Psychology
      • • School of Medicine
      New Haven, CT, United States
  • 1988–1989
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
  • 1986–1988
    • University of Lausanne
      • Institute of Pathology
      Lausanne, Vaud, Switzerland
    • Helsinki University Central Hospital
      • Department of Medicine
      Helsinki, Southern Finland Province, Finland
  • 1981
    • Medical College of Wisconsin
      • Department of Medicine
      Milwaukee, WI, United States
  • 1974
    • National Institute of Child Health and Human Development
      Maryland, United States