A Clinical Trial to Prevent New Onset Diabetes After Transplantation

Summary

Principal Investigator: Akinlolu O Ojo
Abstract: DESCRIPTION (provided by applicant): Immediately following allogeneic kidney transplantation, the pancreatic beta-cell mass is relentlessly punished by four counterregulatory metabolic factors namely: (1) gluconeogenic surgery-related stress;(2) exogenous glucocortocoid-induced peripheral insulin resistance and hepatic gluconeogenesis;(3) direct beta-cell injury by the calcineurin inhibitor (cyclosporine or tacrolimus) and;(4) increased dietary caloric load secondary to the abrogation of chronic uremia-related anorexia. Consequent to this metabolic engagement, 45-80% of new kidney transplant recipients (KTRs) will manifest persistent reversible hyperglycemia, 30% will maintain chronic impaired glucose intolerance and 15-20% will succumb to new onset diabetes after transplantation (NODAT) by the end of the first post transplant year. NODAT is a form type 2 diabetes mellitus that afflicts up to 30% of kidney transplant recipients who survive through the third post transplant year. NODAT is associated with increased risk for post transplant cardiovascular events, higher health care utilization and dramatically inferior kidney graft and patient survival. The offending determinants of NODAT are largely unavoidable because calcineurin inhibitors are the mainstay immunosuppressive drug for kidney transplantation, 70-80% of KTRs are treated initially high dose corticosteroid followed by low dose maintenance therapy and improved dietary intake is a desired benefit of kidney transplantation. Evidence shows that the state of glucotoxicity induced by persistent hyperglycemia causes continuous decline in pancreatic beta-cell function during the early period of development of type 2 diabetes mellitus. More recently, protection of beta-cells by aggressive lowering of hyperglycemia with early initiation of insulin therapy has shown promise in inducing remission of newly diagnosed type 2 diabetes mellitus in the general population. We posit that early use of insulin therapy in previously non-diabetic KTRs who exhibit abnormal glucose metabolism immediately after kidney transplantation will enable the discontinuation of anti-diabetic therapy during the subsequent follow-up and will result in a reduced incidence of NODAT. We have completed a proof-of-concept clinical trial, using basal insulin during the immediate post-transplant period in 50 KTRs. The prevalence of NODAT at 12 months was reduced by 65%. We now propose to conduct a safety and efficacy open-label, block-randomized clinical trial in a diverse population of KTRs to test the primary hypothesis that an early NPH insulin regimen will reduce the incidence of NODAT from 15% to 10% without a significant difference in the risk of detectable hypoglycemia between the experimental and the control arms of the study. A sample size of 180 KTRs has a 90% power to detect a 30% risk reduction for NODAT at one-year post transplantation after protecting one interim analysis with the O'Brien-Fleming method. The study would be conducted at the University of Michigan Health System (n=90) and the Medical University of Vienna 'General Hospital'(n=90). Participants will be enrolled over a 24 months period with a minimum follow-up of 24 months post randomization.
Funding Period: 2011-09-09 - 2015-05-30
more information: NIH RePORT

Top Publications

  1. pmc Metabolic syndrome, vitamin D deficiency and hypoadiponectinemia among nondiabetic patients early after kidney transplantation
    Satyarth Kulshrestha
    Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
    Am J Nephrol 37:399-404. 2013

Research Grants

  1. Metabolic Determinants of Cardiovascular Dysfunction in Obesity
    David W Stepp; Fiscal Year: 2013
  2. Cellular Mechanisms for Increased Gluconeogenesis in Type 2 Diabetes
    Varman T Samuel; Fiscal Year: 2013
  3. Neural Functioning of Feeding Centers in Obese Youth
    ROBERT STANLEY SHERWIN; Fiscal Year: 2013
  4. PANCREAS AND ISLET TRANSPLANTATION IN HUMANS
    RODERICK PAUL ROBERTSON; Fiscal Year: 2013
  5. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  6. MOLECULAR GENETICS OF COAGULATION DISORDERS
    David Ginsburg; Fiscal Year: 2013
  7. The effect of bariatric surgery on carbohydrate metabolism
    Adrian Vella; Fiscal Year: 2013
  8. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013

Detail Information

Publications1

  1. pmc Metabolic syndrome, vitamin D deficiency and hypoadiponectinemia among nondiabetic patients early after kidney transplantation
    Satyarth Kulshrestha
    Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
    Am J Nephrol 37:399-404. 2013
    ..Metabolic syndrome (MetS) is common among kidney transplant patients. We studied the relationship between MetS, vitamin D deficiency/insufficiency and hypoadiponectinemia early posttransplantation and their impact on clinical outcomes...

Research Grants30

  1. Metabolic Determinants of Cardiovascular Dysfunction in Obesity
    David W Stepp; Fiscal Year: 2013
    ..Successful completion of these aims may identify new targets to aid in the treatment of the most common clinical outcomes of obesity. ..
  2. Cellular Mechanisms for Increased Gluconeogenesis in Type 2 Diabetes
    Varman T Samuel; Fiscal Year: 2013
    ....
  3. Neural Functioning of Feeding Centers in Obese Youth
    ROBERT STANLEY SHERWIN; Fiscal Year: 2013
    ....
  4. PANCREAS AND ISLET TRANSPLANTATION IN HUMANS
    RODERICK PAUL ROBERTSON; Fiscal Year: 2013
    ..We envision the results will provide novel insights that will pertain not only to improving outcomes in TP/AIT recipients but also insights that will improve outcomes in alloislet transplantation for type 1 diabetic patients. ..
  5. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  6. MOLECULAR GENETICS OF COAGULATION DISORDERS
    David Ginsburg; Fiscal Year: 2013
    ..This Project will identify key genes in this system that should provide valuable new diagnostic tools as well as suggest novel approaches to treatment. ..
  7. The effect of bariatric surgery on carbohydrate metabolism
    Adrian Vella; Fiscal Year: 2013
    ..Understanding the effect of these interventions on glucose metabolism and GLP-1 secretion (amongst other gut hormones) will immeasurably increase our ability to develop new treatment strategies in individuals affected with diabetes. ..
  8. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013
    ..abstract_text> ..