R A DeFronzo

University of Texas at San Antonio, San Antonio, Texas, United States

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Publications (605)3938.3 Total impact

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    ABSTRACT: Aim: To investigate the effect of lowering the plasma glucose and free fatty acid concentrations with dapagliflozin and acipimox, respectively, on insulin sensitivity and insulin secretion in T2DM individuals. Methods: 14 male T2DM patients received an OGTT and euglycemic hyperinsulinemic clamp at baseline and were treated for three weeks with dapagliflozin (10 mg per day). During week 3, acipimox (250 mg four times per day) treatment was added to dapagliflozin. The OGTT and insulin clamp were repeated at the end of weeks 2 and 3. Results: Dapagliflozin cause glucosuria and significantly lowered the plasma glucose concentration (by 35 mg/dl, P<0.01) while the fasting plasma FFA concentration was unaffected. Acipimox caused a further decrease in the fasting plasma glucose concentration (by 20 mg/dl, P<0.01) and a significant decrease in the fasting plasma FFA concentration. Compared to baseline, insulin-mediated glucose disposal increased significantly at week 2 (from 4.48±0.50 to 5.30±0.50 mg/kgmin, p<0.05). However, insulin-mediated glucose disposal at week 3 (after the addition of acipimox) did not differ significantly from that at week 2. Glucose-stimulated insulin secretion at week 2 increased significantly compared to baseline and it increased further and significantly at week 3 compared to week 2. Conclusion: Lowering the plasma glucose concentration with dapagliflozin improves both insulin sensitivity and beta cell function, while lowering plasma FFA concentration by addition of acipimox to dapagliflozin improves beta cell function without significantly affecting insulin sensitivity.
    No preview · Article · Jan 2016 · The Journal of Clinical Endocrinology and Metabolism
  • Robert EJ Ryder · Ralph A Defronzo

    No preview · Article · Nov 2015 · The British Journal of Diabetes & Vascular Disease
  • 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%.
    No preview · Article · Nov 2015 · Expert Opinion on Pharmacotherapy
  • 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.
    No preview · Article · Oct 2015
  • Ralph A. DeFronzo

    No preview · Article · Oct 2015 · Journal of diabetes and its complications
  • Ralph A. DeFronzo · John McMurray

    No preview · Article · Oct 2015 · Journal of diabetes and its complications
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    ABSTRACT: Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of lactic acidosis. Metformin, along with other drugs in the biguanide class, increase plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma metformin concentrations (as occurs in individuals with renal impairment) and a secondary event or condition that further disrupts lactate production or clearance (e.g., cirrhosis, sepsis, or hypoperfusion), are typically necessary to cause metformin-associated lactic acidosis (MALA). As these secondary events may be unpredictable and the mortality rate for MALA approaches 50%, metformin has been contraindicated since its FDA approval in patients with normal renal function or mild renal insufficiency to minimize the potential for toxic metformin levels and MALA. However, the reported incidence of lactic acidosis in clinical practice has proved to be very low (<10 cases per 100,000 patient-years). Several groups have suggested that current renal function cutoffs for metformin are too conservative, thus depriving a substantial number of type 2 diabetes patients from the potential benefit of metformin therapy. On the other hand, the success of metformin as the first-line diabetes therapy may be a direct consequence of conservative labeling, the absence of which could have led to excess patient risk and eventual withdrawal from the market, as happened with earlier biguanide therapies. An investigational delayed-release metformin currently under development could potentially provide a treatment option for patients with renal impairment pending the results of future studies. This literature-based review provides an update on the impact of renal function and other conditions on metformin plasma levels and the risk of MALA in patients with type 2 diabetes.
    Preview · Article · Oct 2015 · Metabolism
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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.
    Full-text · Article · Sep 2015 · AJP Renal Physiology
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    Full-text · Dataset · Sep 2015
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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.
    No preview · Article · Sep 2015
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    Full-text · Dataset · Aug 2015
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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.
    Full-text · Article · Aug 2015 · JAMA The Journal of the American Medical Association
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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.
    No preview · Article · Aug 2015 · Diabetes care

  • No preview · Article · Jul 2015
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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.
    Full-text · Article · Jun 2015 · Journal of Medical Primatology
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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.
    No preview · Article · Jun 2015 · Diabetes
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    Robert EJ Ryder · Ralph A Defronzo

    Preview · Article · Jun 2015 · The British Journal of Diabetes & Vascular Disease
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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.
    Preview · Article · Jun 2015 · European Heart Journal

  • No preview · Article · Jun 2015 · Diabetes care
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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.
    Full-text · Article · Apr 2015 · PLoS ONE

Publication Stats

62k Citations
3,938.30 Total Impact Points

Institutions

  • 1990-2015
    • University of Texas at San Antonio
      San Antonio, Texas, United States
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
  • 1988-2015
    • University of Texas Health Science Center at San Antonio
      • • Department of Medicine
      • • Division of Diabetes
      • • Division of Hospital Medicine
      San Antonio, Texas, United States
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
  • 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
  • 1994-1997
    • Second University of Naples
      • Dipartimento di Psicologia
      Caserta, Campania, Italy
    • University of Tennessee
      • Department of Medicine
      Knoxville, Tennessee, United States
  • 1995-1996
    • University of Verona
      Verona, Veneto, Italy
    • University of Padova
      • Department of Information Engineering
      Padua, Veneto, Italy
  • 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
  • 1980-1988
    • 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