R A DeFronzo

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

Are you R A DeFronzo?

Claim your profile

Publications (550)3413.89 Total impact

  • [Show abstract] [Hide abstract]
    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; · 3.24 Impact Factor
  • [Show abstract] [Hide abstract]
    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 & metabolism. 11/2014;
  • [Show abstract] [Hide abstract]
    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; · 2.28 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    The American Journal of Pathology. 11/2014;
  • [Show abstract] [Hide abstract]
    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; · 2.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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; · 7.74 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    The Journal of clinical endocrinology and metabolism. 06/2014;
  • Source
    [Show abstract] [Hide abstract]
    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; · 7.21 Impact Factor
  • [Show abstract] [Hide abstract]
    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; · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    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; · 7.74 Impact Factor
  • Source
    Muhammad A Abdul-Ghani, Ralph A Defronzo
    [Show abstract] [Hide abstract]
    ABSTRACT: Maintaining normoglycaemia not only reduces the risk of diabetic microvascular complications but also corrects the metabolic abnormalities that contribute to the development and progression of hyperglycaemia (i.e. insulin resistance and beta-cell dysfunction). Progressive beta-cell failure, in addition to the multiple side effects associated with many current antihyperglycaemic agents (e.g., hypoglycaemia and weight gain) presents major obstacle to the achievement of the recommended goal of glycaemic control in patients with diabetes mellitus (DM). Thus, novel effective therapies are needed for optimal glucose control in subjects with DM. Recently, specific inhibitors of renal sodium glucose cotransporter 2 (SGLT2) have been developed to produce glucosuria and lower the plasma glucose concentration. Because of their unique mechanism of action (which is independent of the secretion and action of insulin), these agents are effective in lowering the plasma glucose concentration in all stages of DM and can be combined with all other antidiabetic agents. In this review, we summarize the available data concerning the mechanism of action, efficacy and safety of this novel class of antidiabetic agent. This article is protected by copyright. All rights reserved.
    Journal of Internal Medicine 04/2014; · 6.46 Impact Factor
  • Source
    Stanley Schwartz, Ralph A Defronzo
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with hyperglycemia in hospital have increased adverse outcomes compared with patients with normoglycemia, and the pathophysiological causes seem relatively well understood. Thus, a rationale for excellent glycemic control exists. Benefits of control with intensive insulin regimes are highly likely based on multiple published studies. However, hypoglycemia frequency increases and adverse outcomes of hypoglycemia accrue. This has resulted in a 'push' for therapeutic nihilism, accepting higher glycemic levels to avoid hypoglycemia. One would ideally prefer to optimize glycemia, treating hyperglycemia while minimizing or avoiding hypoglycemia. Thus, one would welcome therapies and processes of care to optimize this benefit/ risk ratio. We review the logic and early studies that suggest that incretin therapy use in-hospital can achieve this ideal. We strongly urge randomized prospective controlled studies to test our proposal and we offer a process of care to facilitate this research and their use in our hospitalized patients.
    Current Diabetes Reports 03/2014; 14(3):466. · 3.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Both major forms of diabetes mellitus (DM) involve β-cell destruction and dysfunction. New treatment strategies have focused on replenishing the deficiency of β-cell mass common to both major forms of diabetes by islet transplantation or β-cell regeneration. The pancreas, not the liver, is the ideal organ for islet regeneration, because it is the natural milieu for islets. Since islet mass is known to increase during obesity and pregnancy, the concept of stimulating pancreatic islet regeneration in vivo is both rational and physiologic. This paper proposes a novel approach in which non-viral gene therapy is targeted to pancreatic islets using ultrasound targeted microbubble destruction (UTMD) in a non-human primate model (NHP), the baboon. Treated baboons received a gene cocktail comprised of cyclinD2, CDK, and GLP1, which in rats results in robust and durable islet regeneration with normalization of blood glucose, insulin, and C-peptide levels. We were able to generate important preliminary data indicating that gene therapy by UTMD can achieve in vivo normalization of the intravenous (IV) glucose tolerance test (IVGTT) curves in STZ hyperglycemic-induced conscious tethered baboons. Immunohistochemistry clearly demonstrated evidence of islet regeneration and restoration of β-cell mass.
    Cell Cycle. 02/2014; 13(7).
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Both major forms of diabetes mellitus (DM) involve β-cell destruction and dysfunction. New treatment strategies have focused on replenishing the deficiency of β-cell mass common to both major forms of diabetes by islet transplantation or β-cell regeneration. The pancreas, not the liver, is the ideal organ for islet regeneration, because it is the natural milieu for islets. Since islet mass is known to increase during obesity and pregnancy, the concept of stimulating pancreatic islet regeneration in vivo is both rational and physiologic. This paper proposes a novel approach in which non-viral gene therapy is targeted to pancreatic islets using ultrasound targeted microbubble destruction (UTMD) in a non-human primate model (NHP), the baboon. Treated baboons received a gene cocktail comprised of cyclinD2, CDK, and GLP1, which in rats results in robust and durable islet regeneration with normalization of blood glucose, insulin, and C-peptide levels. We were able to generate important preliminary data indicating that gene therapy by UTMD can achieve in vivo normalization of the intravenous (IV) glucose tolerance test (IVGTT) curves in STZ hyperglycemic-induced conscious tethered baboons. Immunohistochemistry clearly demonstrated evidence of islet regeneration and restoration of β-cell mass.
    Cell cycle (Georgetown, Tex.) 02/2014; 13(7). · 5.24 Impact Factor
  • Stanley Schwartz, Ralph A Defronzo
    Diabetes care 02/2014; 37(2):e42. · 7.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronic hyperglycemia impairs insulin action, resulting in glucotoxicity, which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors. Here, we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 (SGLT2) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes. Eighteen diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks. We measured insulin-mediated whole body glucose uptake and endogenous glucose production (EGP) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique. Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose. Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of dapagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity. Surprisingly, following dapagliflozin treatment, EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration. Together, our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity. However, glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP. These results provide support for the glucotoxicity hypothesis, which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes.
    The Journal of clinical investigation 01/2014; · 15.39 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Insulin resistance and dysregulation of FFA metabolism are core defects in T2DM and obese NGT individuals. Impaired muscle mitochondrial function (reduced ATP synthesis) also has been described in insulin resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with acipimox improved ATP synthesis rate and altered ROS production. 11 NGT obese and 11 T2DM subjects received: (i) OGTT, (ii) euglycemic insulin clamp with muscle biopsy, (iii) (1)H-MRS of tibialis anterior muscle before and after acipimox, 250 mg every 6 hours for 12 days. ATP synthesis rate and ROS generation were measured inmitochondria isolated from muscle tissue ex vivo with chemoluminescence and fluorescence techniques, respectively.Acipimox (i) markedly reduced the fasting plasma FFA concentration and enhanced suppression of plasma FFA during OGTT and insulin clamp in obese NGT and T2DM, and (ii) enhanced insulin-mediated muscle glucose disposal and suppression of hepatic glucose production. The improvement in insulin sensitivity was closely correlated with the decrease in plasma FFA in obese NGT (r = 0.81) and T2DM (r = 0.76)(both p<0.001).Mitochondrial ATP synthesis rate increased by >50% in both obese NGT and T2DM subjects and was strongly correlated with the decrease in plasma FFA and increase in insulin-mediated glucose disposal (both r >0.70, p <0.001). Production of ROS did not change following acipimox.Reduction in plasma FFA in obese NGT and T2DM individuals improves mitochondrial ATP synthesis rate, indicating that the mitochondrial defect in insulin resistant individuals is, at least in part, reversible.
    Diabetes 12/2013; · 7.90 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity is a major public health concern, and complementary research strategies have been directed toward the identification of the underlying causative gene mutations that affect the normal pathways and networks that regulate energy balance. Here, we describe an autosomal-recessive morbid-obesity syndrome and identify the disease-causing gene defect. The average body mass index of affected family members was 48.7 (range = 36.7-61.0), and all had features of the metabolic syndrome. Homozygosity mapping localized the disease locus to a region in 3q29; we designated this region the morbid obesity 1 (MO1) locus. Sequence analysis identified a homozygous nonsense mutation in CEP19, the gene encoding the ciliary protein CEP19, in all affected family members. CEP19 is highly conserved in vertebrates and invertebrates, is expressed in multiple tissues, and localizes to the centrosome and primary cilia. Homozygous Cep19-knockout mice were morbidly obese, hyperphagic, glucose intolerant, and insulin resistant. Thus, loss of the ciliary protein CEP19 in humans and mice causes morbid obesity and defines a target for investigating the molecular pathogenesis of this disease and potential treatments for obesity and malnutrition.
    The American Journal of Human Genetics 11/2013; · 11.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increase in matrix protein content in the kidney is a cardinal feature of diabetic kidney disease. While renal matrix protein content is increased by chronic hyperglycemia, whether it is regulated by acute elevation of glucose and insulin has not been addressed. In this study, we aimed to evaluate if short duration of combined hyperglycemia and hyperinsulinemia, mimicking metabolic environment of pre-diabetes and early type 2 diabetes, induces kidney injury. Normal rats were subjected to either saline infusion (control, n=4) or seven hours of combined hyperglycemic-hyperinsulinemic clamp (HG+HI clamp; n=6). During the clamp, plasma glucose and plasma insulin were maintained at about 350 mg/dl and 16 ng/ml, respectively. HG+HI clamp increased the expression of renal cortical TGFβ and renal matrix proteins, laminin and fibronectin. This was associated with the activation of SMAD3, Akt, mTOR complexes and Erk signaling pathways and their downstream target events in the initiation and elongation phases of mRNA translation, an important step in protein synthesis. Additionally, HG+HI clamp provoked renal inflammation as shown by the activation of toll like receptor 4 (TLR4) and infiltration of CD68 positive monocytes. Urinary F2t isoprostane excretion, an index of renal oxidant stress, was increased in the HG+HI clamp rats. We conclude that even a short duration of hyperglycemia and hyperinsulinemia contributes to activation of pathways that regulate matrix protein synthesis, inflammation and oxidative stress in the kidney. This finding could have implications for the control of short term rises in blood glucose in diabetic individuals at risk of developing kidney disease.
    AJP Cell Physiology 10/2013; · 3.71 Impact Factor
  • Source
    Muhammad A Abdul-Ghani, Ralph A Defronzo, Luke Norton
    [Show abstract] [Hide abstract]
    ABSTRACT: Inhibitors of sodium-glucose cotransporter 2 (SGLT2) are a novel class of antidiabetes drugs, and members of this class are under various stages of clinical development for the management of type 2 diabetes mellitus (T2DM). It is widely accepted that SGLT2 is responsible for >80% of the reabsorption of the renal filtered glucose load. However, maximal doses of SGLT2 inhibitors fail to inhibit >50% of the filtered glucose load. Because the clinical efficacy of this group of drugs is entirely dependent on the amount of glucosuria produced, it is important to understand why SGLT2 inhibitors inhibit <50% of the filtered glucose load. In this Perspective, we provide a novel hypothesis that explains this apparent puzzle and discuss some of the clinical implications inherent in this hypothesis.
    Diabetes 10/2013; 62(10):3324-8. · 7.90 Impact Factor

Publication Stats

35k Citations
3,413.89 Total Impact Points

Institutions

  • 1988–2014
    • University of Texas Health Science Center at San Antonio
      • • Division of Diabetes
      • • Division of Hospital Medicine
      San Antonio, Texas, United States
    • Karolinska Institutet
      • Department of Renal Medicine
      Stockholm, Stockholm, Sweden
  • 2013
    • Louisiana State University
      • Pennington Biomedical Research Center
      Baton Rouge, LA, United States
  • 2011–2013
    • Southwest Foundation For Biomedical Research
      San Antonio, Texas, United States
  • 1993–2013
    • National Research Council
      • • Institute of Clinical Physiology IFC
      • • Laboratory of Stable Isotopes
      Roma, Latium, Italy
  • 1990–2013
    • University of Texas at San Antonio
      San Antonio, Texas, United States
    • Università degli Studi di Genova
      Genova, Liguria, Italy
  • 2012
    • The Second Xiangya Hospital of Central South University
      Ch’ang-sha-shih, Hunan, China
    • Bnai Zion Medical Center, Haifa
      H̱efa, Haifa District, Israel
    • Amgen
      • Department of Medicinal Chemistry
      Thousand Oaks, CA, United States
    • Norwegian School of Sport Sciences (NIH)
      • Department of Physical Performance
      Oslo, Oslo, Norway
  • 2010
    • Medical University of Vienna
      • Universitätsklinik für Innere Medizin I
      Vienna, Vienna, Austria
  • 2007–2009
    • Arizona State University
      • • Center for Metabolic Biology
      • • School of Life Sciences
      Tempe, AZ, United States
  • 1994–2009
    • Texas Tech University Health Sciences Center
      • • Department of Medicine
      • • School of Allied Health Sciences
      Lubbock, TX, United States
    • Karolinska University Hospital
      Tukholma, Stockholm, Sweden
    • The University of Tennessee Health Science Center
      • Department of Medicine
      Memphis, TN, United States
  • 2006
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 1980–2004
    • Università di Pisa
      • Department of Clinical and Experimental Medicine
      Pisa, Tuscany, Italy
  • 1990–2003
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
  • 1999–2000
    • University of Catania
      Catania, Sicily, Italy
    • Wayne State University
      • Department of Obstetrics and Gynecology
      Detroit, MI, United States
  • 1998
    • Leiden University Medical Centre
      Leyden, South Holland, Netherlands
  • 1995–1998
    • University of Verona
      Verona, Veneto, Italy
    • Second University of Naples
      Caserta, Campania, Italy
  • 1997
    • University of Ferrara
      Ferrare, Emilia-Romagna, Italy
  • 1987–1997
    • University of Padova
      • Department of Information Engineering
      Padua, Veneto, Italy
  • 1996
    • Albert Einstein College of Medicine
      • Endocrinology
      New York City, NY, United States
  • 1978–1993
    • Yale-New Haven Hospital
      • • Endocrinology and Diabetes Program
      • • Department of Diabetes and Endocrinology
      New Haven, Connecticut, United States
  • 1989–1992
    • Heinrich-Heine-Universität Düsseldorf
      • Medizinische Fakultät
      Düsseldorf, North Rhine-Westphalia, Germany
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
  • 1986–1992
    • Helsinki University Central Hospital
      • Department of Medicine
      Helsinki, Province of Southern Finland, Finland
  • 1991
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
  • 1979–1991
    • Yale University
      • • Department of Internal Medicine
      • • School of Medicine
      • • Department of Psychology
      New Haven, CT, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1982–1988
    • University of Lausanne
      • Department of Physiology
      Lausanne, VD, Switzerland
  • 1974
    • National Institute of Child Health and Human Development
      Maryland, United States