R A DeFronzo

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

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Publications (575)3831.46 Total impact

  • C Triplitt · C Solis-Herrera · E Cersosimo · M Abdul-Ghani · Ralph A Defronzo ·
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    ABSTRACT: Introduction: Many patients with type 2 diabetes mellitus (T2DM) fail to achieve the desired A1c goal because the antidiabetic medications used do not correct the underlying pathophysiologic abnormalities and monotherapy is not sufficiently potent to reduce the A1c to the 6.5 - 7.0% range. Insulin resistance and islet (beta and alpha) cell dysfunction are major pathophysiologic abnormalities in T2DM. We examine combination therapy with linagliptin plus empagliflozin as a therapeutic approach for the treatment of inadequately controlled T2DM patients. Areas covered: A literature search of all human diabetes, metabolism and general medicine journals from year 2000 to the present was conducted. Glucagon like peptide-1 (GLP-1) deficiency/resistance contributes to islet cell dysfunction by impairing insulin secretion and increasing glucagon secretion. DPP-4 inhibitors (DPP4i) improve pancreatic islet function by augmenting glucose-dependent insulin secretion and decreasing elevated plasma glucagon levels. Linagliptin, a DPP-4 inhibitor, reduces HbA1c, is weight neutral, has an excellent safety profile and a low risk of hypoglycemia. The expression of sodium-glucose cotransporter-2 (SGLT2) in the proximal renal tubule is upregulated in T2DM, causing excess reabsorption of filtered glucose. The SGLT2 inhibitor (SGLT2i), empagliflozin, improves HbA1c by causing glucosuria and ameliorating glucotoxicity. It also decreases weight and blood pressure, and has a low risk of hypoglycemia. Expert opinion: The once daily oral combination of linagliptin plus empagliflozin does not increase the risk of hypoglycemia and tolerability and discontinuation rates are similar to those with each as monotherapy. At HbA1c values below 8.5% linagliptin/empagliflozin treatment produces an additive effect, whereas above 8.5%, there is a less than additive reduction with combination therapy compared with the effect of each agent alone. Linagliptin/empagliflozin addition is a logical combination in patients with T2DM, especially those with an HbA1c < 8.5%.
    Expert Opinion on Pharmacotherapy 11/2015; DOI:10.1517/14656566.2015.1114098 · 3.53 Impact Factor
  • Mustafa Kanat · Ralph A DeFronzo · Muhammad A Abdul-Ghani ·
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    ABSTRACT: Progression of normal glucose tolerance (NGT) to overt diabetes is mediated by a transition state called impaired glucose tolerance (IGT). Beta cell dysfunction and insulin resistance are the main defects in type 2 diabetes mellitus (type 2 DM) and even normoglycemic IGT patients manifest these defects. Beta cell dysfunction and insulin resistance also contribute to the progression of IGT to type 2 DM. Improving insulin sensitivity and/or preserving functions of beta-cells can be a rational way to normalize the GT and to control transition of IGT to type 2 DM. Loosing weight, for example, improves whole body insulin sensitivity and preserves beta-cell function and its inhibitory effect on progression of IGT to type 2 DM had been proven. But interventions aiming weight loss usually not applicable in real life. Pharmacotherapy is another option to gain better insulin sensitivity and to maintain beta-cell function. In this review, two potential treatment options (lifestyle modification and pharmacologic agents) that limits the IGT-type 2 DM conversion in prediabetic subjects are discussed.
    10/2015; 6(12):1207-22. DOI:10.4239/wjd.v6.i12.1207
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    Muhammad A Abdul-Ghani · Luke Norton · Ralph A DeFronzo ·
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    ABSTRACT: Hyperglycemia is the primary factor responsible for the microvascular, and to lesser extent, macrovascular complications. Despite this well established relationship, approximately half of all type 2 diabetic patients in the US have a HbA1c≥7.0%. In part, this is associated with the side effects, i.e. weight gain and hypoglycemia, of currently available antidiabetic agents and in part by the failure to utilize medications that reverse the basic pathophysiologic defects present in patients with type 2 diabetes. The kidney has been show to play a central role in the development of hyperglycemia by excessive production of glucose throughout the sleeping hours and enhanced reabsorption of filtered glucose by the renal tubules secondary to an increase in the threshold at which glucose spills into the urine. Recently, a new class of antidiabetic agents, the sodium-glucose cotransporter 2 (SGLT2) inhibitors, has been developed and approved for the treatment of patients with type 2 diabetes. In this review, we examine their mechanism of action, efficacy, safety, and place in the therapeutic armamentarium. Since the SGLT2 inhibitors have a unique mode of action that differs from all other oral and injectable antidiabetic agents, they can be used at all stages of the disease and in combination with all other antidiabetic medications.
    AJP Renal Physiology 09/2015; DOI:10.1152/ajprenal.00267.2015 · 3.25 Impact Factor
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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: Weight loss of 5% to 10% can improve type 2 diabetes and related comorbidities. Few safe, effective weight-management drugs are currently available. To investigate efficacy and safety of liraglutide vs placebo for weight management in adults with overweight or obesity and type 2 diabetes. Fifty-six-week randomized (2:1:1), double-blind, placebo-controlled, parallel-group trial with 12-week observational off-drug follow-up period. The study was conducted at 126 sites in 9 countries between June 2011 and January 2013. Of 1361 participants assessed for eligibility, 846 were randomized. Inclusion criteria were body mass index of 27.0 or greater, age 18 years or older, taking 0 to 3 oral hypoglycemic agents (metformin, thiazolidinedione, sulfonylurea) with stable body weight, and glycated hemoglobin level 7.0% to 10.0%. Once-daily, subcutaneous liraglutide (3.0 mg) (n = 423), liraglutide (1.8 mg) (n = 211), or placebo (n = 212), all as adjunct to 500 kcal/d dietary deficit and increased physical activity (≥150 min/wk). Three coprimary end points: relative change in weight, proportion of participants losing 5% or more, or more than 10%, of baseline weight at week 56. Baseline weight was 105.7 kg with liraglutide (3.0-mg dose), 105.8 kg with liraglutide (1.8-mg dose), and 106.5 kg with placebo. Weight loss was 6.0% (6.4 kg) with liraglutide (3.0-mg dose), 4.7% (5.0 kg) with liraglutide (1.8-mg dose), and 2.0% (2.2 kg) with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, -4.00% [95% CI, -5.10% to -2.90%]; liraglutide [1.8 mg] vs placebo, -2.71% [95% CI, -4.00% to -1.42%]; P < .001 for both). Weight loss of 5% or greater occurred in 54.3% with liraglutide (3.0 mg) and 40.4% with liraglutide (1.8 mg) vs 21.4% with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, 32.9% [95% CI, 24.6% to 41.2%]; for liraglutide [1.8 mg] vs placebo, 19.0% [95% CI, 9.1% to 28.8%]; P < .001 for both). Weight loss greater than 10% occurred in 25.2% with liraglutide (3.0 mg) and 15.9% with liraglutide (1.8 mg) vs 6.7% with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, 18.5% [95% CI, 12.7% to 24.4%], P < .001; for liraglutide [1.8 mg] vs placebo, 9.3% [95% CI, 2.7% to 15.8%], P = .006). More gastrointestinal disorders were reported with liraglutide (3.0 mg) vs liraglutide (1.8 mg) and placebo. No pancreatitis was reported. Among overweight and obese participants with type 2 diabetes, use of subcutaneous liraglutide (3.0 mg) daily, compared with placebo, resulted in weight loss over 56 weeks. Further studies are needed to evaluate longer-term efficacy and safety. clinicaltrials.gov Identifier:NCT01272232.
    JAMA The Journal of the American Medical Association 08/2015; 314(7):687-699. DOI:10.1001/jama.2015.9676 · 35.29 Impact Factor
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    ABSTRACT: Delayed-release metformin (Met DR) is formulated to deliver drug to the lower bowel to leverage the gut-based mechanisms of metformin action with lower plasma exposure. Met DR was assessed in two studies. Study 1 compared the bioavailability of single daily doses of Met DR to currently available immediate-release metformin (Met IR) and extended-release metformin (Met XR) in otherwise healthy volunteers. Study 2 assessed glycemic control in subjects with type 2 diabetes (T2DM) over 12 weeks. Study 1 was a Phase 1, randomized, four-period crossover study in 20 subjects. Study 2 was a 12-week, Phase 2, multicenter, placebo-controlled, dose-ranging study in 240 subjects with T2DM randomized to receive Met DR 600, 800, or 1,000 mg administered once daily; blinded placebo; or unblinded Met XR 1,000 or 2,000 mg (reference). The bioavailability of 1,000 mg Met DR bid was ∼50% that of Met IR and Met XR (study 1). In study 2, 600, 800, and 1,000 mg Met DR qd produced statistically significant, clinically relevant, and sustained reductions in fasting plasma glucose (FPG) levels over 12 weeks compared with placebo, with an ∼40% increase in potency compared with Met XR. The placebo-subtracted changes from baseline in HbA1c level at 12 weeks were consistent with changes in FPG levels. All treatments were generally well tolerated, and adverse events were consistent with Glucophage/Glucophage XR prescribing information. Dissociation of the glycemic effect from plasma exposure with gut-restricted Met DR provides strong evidence for a predominantly lower bowel-mediated mechanism of metformin action. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes care 08/2015; DOI:10.2337/dc15-0488 · 8.42 Impact Factor

  • 07/2015; DOI:10.1038/nrdp.2015.19
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    ABSTRACT: Non-human primate (NHP) diabetic models using chemical ablation of β-cells with STZ have been achieved by several research groups. Chemotherapeutic STZ could lead to serious adverse events including nephrotoxicity, hepatotoxicity, and mortality. We implemented a comprehensive therapeutic strategy that included the tether system, permanent indwelling catheter implants, an aggressive hydration protocol, management for pain with IV nubain and anxiety with IV midazolam, moment-by-moment monitoring of glucose levels post-STZ administration, and continuous intravenous insulin therapy. A triphasic response in blood glucose after STZ administration was fully characterized. A dangerous hypoglycemic phase was also detected in all baboons. Other significant findings were hyperglycemia associated with low levels of plasma leptin, insulin and C-peptide concentrations, hyperglucagonemia, and elevated non-esterified fatty acids (NEFA) concentrations. We successfully induced frank diabetes by IV administering a single dose of pharmaceutical-grade STZ safely and without adverse events in conscious tethered baboons. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
    Journal of Medical Primatology 06/2015; 44(4). DOI:10.1111/jmp.12182 · 0.82 Impact Factor
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    ABSTRACT: GLP-1 receptors have been found in the brain, but it currently is unknown whether GLP-1R agonists (GLP-1RA) influence brain glucose metabolism. The study aim was to evaluate the effects of a single injection of the GLP-1RA, exenatide, on cerebral and peripheral glucose metabolism in response to a glucose load.In 15 male subjects with HbA1c=5.7±0.1%, fasting glucose 114±3mg/dl and 2h-glucose 177±11mg/dl, exenatide (5 μg) or placebo were injected in double blind, randomized fashion subcutaneously 30 min before an oral glucose tolerance test (OGTT). Cerebral glucose metabolic rate (CMRglu) was measured by PET following injection of (18)F-FDG before OGTT and rate of glucose absorption (RaO) and disposal were assessed using stable isotope tracers.Exenatide reduced RaO0-60min (4.6±1.4 vs. 13.1±1.7 μmol/min⋅kg) and decreased the rise in mean glucose0-60min (107±6 vs. 138±8 mg/dl) and insulin0-60min (17.3±3.1 vs. 24.7±3.8 mU/l). Exenatide increased CMRglu in areas of the brain related to glucose homeostasis, appetite and food reward, despite lower plasma insulin concentrations, but reduced glucose uptake in the hypothalamus. Decreased RaO0-60min after exenatide was inversely correlated to CMRglu.In conclusion, these results demonstrate, for the first time in man, a major effect of a GLP-1RA on regulation of brain glucose metabolism in the absorptive state. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 06/2015; DOI:10.2337/db14-1718 · 8.10 Impact Factor
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    Ele Ferrannini · Ralph A DeFronzo ·
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    ABSTRACT: Type 2 diabetes mellitus (T2DM) is characterized by multiple pathophysiologic abnormalities. With time, multiple glucose-lowering medications are commonly required to reduce and maintain plasma glucose concentrations within the normal range. Type 2 diabetes mellitus individuals also are at a very high risk for microvascular complications and the incidence of heart attack and stroke is increased two- to three-fold compared with non-diabetic individuals. Therefore, when selecting medications to normalize glucose levels in T2DM patients, it is important that the agent not aggravate, and ideally even improve, cardiovascular risk factors (CVRFs) and reduce cardiovascular morbidity and mortality. In this review, we examine the effect of oral (metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP4 inhibitors, SGLT2 inhibitors, and α-glucosidase inhibitors) and injectable (glucagon-like peptide-1 receptor agonists and insulin) glucose-lowering drugs on established CVRFs and long-term studies of cardiovascular outcomes. Firm evidence that in T2DM cardiovascular disease can be reversed or prevented by improving glycaemic control is still incomplete and must await large, long-term clinical trials in patients at low risk using modern treatment strategies, i.e. drug combinations designed to maximize HbA1c reduction while minimizing hypoglycaemia and excessive weight gain. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
    European Heart Journal 06/2015; 36(34). DOI:10.1093/eurheartj/ehv239 · 15.20 Impact Factor

  • Diabetes care 06/2015; 38(6):1173. DOI:10.2337/dc15-er06a · 8.42 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 04/2015; 10(4):e0119941. DOI:10.1371/journal.pone.0119941 · 3.23 Impact Factor

  • Canadian Journal of Diabetes 04/2015; 39:S35. DOI:10.1016/j.jcjd.2015.01.140 · 2.00 Impact Factor

  • Canadian Journal of Diabetes 04/2015; 39:S36. DOI:10.1016/j.jcjd.2015.01.141 · 2.00 Impact Factor
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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; 290(21). DOI:10.1074/jbc.M114.626077 · 4.57 Impact Factor
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    ABSTRACT: Background: β-Cell dysfunction is a core defect in T2DM, and chronic, sustained hyperglycemia has been implicated in progressive β-cell failure, ie, glucotoxicity. The aim of the present study was to examine the effect of lowering the plasma glucose concentration with dapagliflozin, a glucosuric agent, on β-cell function in T2DM individuals. Research design and methods: Twenty-four subjects with T2DM received dapagliflozin (n = 16) or placebo (n = 8) for 2 weeks, and a 75-g oral glucose tolerance test (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 ± 9 mg/dL, and -60 ± 12 mg/dL · min, respectively, compared to -13 ± 9, -33 ± 13, and -18 ± 9 reductions in placebo-treated subjects (both P < .01). The incremental area under the plasma C-peptide concentration curve tended to increase in dapagliflozin-treated subjects, whereas it did not change in placebo-treated subjects. Thus, ΔC-Pep0-120/ΔG0-120 increased significantly in dapagliflozin-treated subjects, whereas it did not change in placebo-treated subjects (0.019 ± 0.005 vs 0.002 ± 0.006; P < .01). Dapagliflozin significantly improved whole-body insulin sensitivity (insulin clamp). Thus, β-cell function, measured as ΔC-Pep0-120/ ΔG0-120 ÷ insulin resistance, increased by 2-fold (P < .01) in dapagliflozin-treated vs placebo-treated subjects. Conclusion: Lowering the plasma glucose concentration with dapagliflozin markedly improves β-cell function, providing strong support in man for the glucotoxic effect of hyperglycemia on β-cell function.
    Journal of Clinical Endocrinology &amp Metabolism 02/2015; 100(5):jc20143472. DOI:10.1210/jc.2014-3472 · 6.21 Impact Factor
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    ABSTRACT: Objective: To evaluate the efficacy and safety of empagliflozin/linagliptin in subjects with type 2 diabetes. Research design and methods: Subjects not receiving antidiabetes therapy for ≥12 weeks were randomized to empagliflozin 25 mg/linagliptin 5 mg (n = 137), empagliflozin 10 mg/linagliptin 5 mg (n = 136), empagliflozin 25 mg (n = 135), empagliflozin 10 mg (n = 134), or linagliptin 5 mg (n = 135) for 52 weeks. The primary end point was change from baseline in HbA1c at week 24. Results: Mean HbA1c at baseline was 7.99-8.05% (64 mmol/mol). At week 24, adjusted mean (SE) changes from baseline in HbA1c with empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg were -1.08 (0.06)% (-11.8 [0.7] mmol/mol), -1.24 (0.06)% (-13.6 [0.7] mmol/mol), -0.95 (0.06)% (-10.4 [0.7] mmol/mol), -0.83 (0.06)% (-9.1 [0.7] mmol/mol), and -0.67 (0.06)% (-7.3 [0.7] mmol/mol), respectively. Reductions in HbA1c were significantly greater for empagliflozin 25 mg/linagliptin 5 mg compared with linagliptin 5 mg (P < 0.001) but not compared with empagliflozin 25 mg and were significantly greater for empagliflozin 10 mg/linagliptin 5 mg compared with the individual components (P < 0.001 for both). At week 24, 55.4%, 62.3%, 41.5%, 38.8%, and 32.3% of subjects with baseline HbA1c ≥7% (≥53 mmol/mol) reached HbA1c <7% with empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg, respectively. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across groups (68.9-81.5%), with no confirmed hypoglycemic AEs. Conclusions: Reductions from baseline in HbA1c with empagliflozin/linagliptin were significantly different versus linagliptin and empagliflozin 10 mg but not versus empagliflozin 25 mg. Empagliflozin/linagliptin was well tolerated.
    Diabetes Care 01/2015; 38(3). DOI:10.2337/dc14-2365 · 8.42 Impact Factor
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    ABSTRACT: Objective: The objective was to test the clinical utility of Quantose M(Q) to monitor changes in insulin sensitivity after pioglitazone therapy in prediabetic subjects. Quantose M(Q) is derived from fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three nonglucose metabolites shown to correlate with insulin-stimulated glucose disposal. Research design and methods: Participants were 428 of the total of 602 ACT NOW impaired glucose tolerance (IGT) subjects randomized to pioglitazone (45 mg/d) or placebo and followed for 2.4 years. At baseline and study end, fasting plasma metabolites required for determination of Quantose, glycated hemoglobin, and oral glucose tolerance test with frequent plasma insulin and glucose measurements to calculate the Matsuda index of insulin sensitivity were obtained. Results: Pioglitazone treatment lowered IGT conversion to diabetes (hazard ratio = 0.25; 95% confidence interval = 0.13-0.50; P < .0001). Although glycated hemoglobin did not track with insulin sensitivity, Quantose M(Q) increased in pioglitazone-treated subjects (by 1.45 [3.45] mg·min(-1)·kgwbm(-1)) (median [interquartile range]) (P < .001 vs placebo), as did the Matsuda index (by 3.05 [4.77] units; P < .0001). Quantose M(Q) correlated with the Matsuda index at baseline and change in the Matsuda index from baseline (rho, 0.85 and 0.79, respectively; P < .0001) and was progressively higher across closeout glucose tolerance status (diabetes, IGT, normal glucose tolerance). In logistic models including only anthropometric and fasting measurements, Quantose 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 · 6.21 Impact Factor

Publication Stats

57k Citations
3,831.46 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
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
  • 1990-2014
    • University of Texas at San Antonio
      San Antonio, Texas, United States
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
  • 2009
    • Lund University
      • Department of Clinical Sciences, Malmö
      Lund, Skåne, Sweden
  • 1985-2004
    • Università di Pisa
      • Department of Clinical and Experimental Medicine
      Pisa, Tuscany, Italy
  • 2000
    • University of Catania
      Catania, Sicily, Italy
  • 1996
    • University of Padova
      • Department of Information Engineering
      Padua, Veneto, Italy
  • 1995-1996
    • University of Verona
      Verona, Veneto, Italy
  • 1994
    • Second University of Naples
      • Dipartimento di Psicologia
      Caserta, Campania, Italy
    • The University of Tennessee Health Science Center
      • Department of Medicine
      Memphis, TN, United States
  • 1993
    • University of Texas Health Science Center at Tyler
      Tyler, Texas, United States
  • 1989-1993
    • Helsinki University Central Hospital
      • Department of Medicine
      Helsinki, Uusimaa, Finland
  • 1992
    • Albert Einstein Medical Center
      Filadelfia, Pennsylvania, United States
  • 1978-1989
    • Yale-New Haven Hospital
      • Department of Diabetes and Endocrinology
      New Haven, Connecticut, United States
  • 1980-1987
    • Yale University
      • • School of Medicine
      • • Department of Internal Medicine
      • • Department of Molecular Biophysics and Biochemistry
      New Haven, Connecticut, United States
  • 1982-1986
    • University of Lausanne
      • Institute of Pathology
      Lausanne, Vaud, Switzerland
  • 1984
    • Karolinska University Hospital
      • Department of Renal Medicine
      Tukholma, Stockholm, Sweden
  • 1977
    • University of Pennsylvania
      Filadelfia, Pennsylvania, United States
  • 1974
    • National Institute of Child Health and Human Development
      Maryland, United States