Prevention of type 1 diabetes mellitus
- Massimo Pietropaolo, MD
Massimo Pietropaolo, MD
- McNair Type 1 Diabetes Scholar
- Professor of Medicine, Pathology and Immunology
- Baylor College of Medicine
- Section Editors
- Irl B Hirsch, MD
Irl B Hirsch, MD
- Section Editor — Diabetes Mellitus
- Professor of Medicine
- University of Washington School of Medicine
- Joseph I Wolfsdorf, MB, BCh
Joseph I Wolfsdorf, MB, BCh
- Section Editor — Pediatric Endocrinology
- Professor of Pediatrics
- Harvard Medical School
The increase in understanding of the pathogenesis of type 1 diabetes mellitus (formerly known as insulin-dependent diabetes mellitus) has made it possible to consider intervention to slow the autoimmune disease process in an attempt to delay or even prevent the onset of hyperglycemia. This topic will review current and planned efforts to prevent type 1 diabetes. Subjects who are at high risk for type 1 diabetes can be identified using a combination of immune, genetic, and metabolic markers. (See "Prediction of type 1 diabetes mellitus".)
In the current classification of diabetes, immune-mediated type 1 diabetes is called type 1A to distinguish it from less common cases in which an autoimmune etiology cannot be determined (type 1B); the latter are said to be idiopathic . The term type 1 diabetes used here refers to type 1A, or autoimmune diabetes. (See "Classification of diabetes mellitus and genetic diabetic syndromes".)
PREVENTION AND REVERSAL STRATEGIES
Several immunosuppressive and immunomodulatory agents and other drugs have been given either alone or in combination to decrease the immune-mediated destruction of beta cells that occurs in type 1 diabetes . Most of the studies have been performed in recent-onset diabetes, where the majority of beta-cell function has already been lost, and the anticipated outcome is preservation of remaining beta-cell function, usually measured as area under the curve (AUC) insulin secretion in response to stimulation. Many of the studies involve small numbers of patients and are uncontrolled.
Azathioprine — Azathioprine is an immunosuppressive drug that inhibits or prevents T cell responses to antigens. In one randomized, double-blind study of 46 patients treated with azathioprine and glucocorticoids, insulin could be discontinued in 10 of 20 treated patients as compared with 2 of 20 patients in the placebo group . Endogenous insulin secretion (measured as the plasma C-peptide response to a liquid meal) also improved. However, only three treated patients remained in remission at one year. Equally discouraging results were noted in a second study .
Mycophenolate mofetil — Mycophenolate mofetil (MMF) inhibits proliferation of both T- and B-lymphocytes. In a multicenter, randomized trial, 126 patients with type 1 diabetes for less than three months were randomly assigned to MMF, MMF plus daclizumab (an anti-interleukin [IL]-2 receptor monoclonal antibody that selectively binds the IL-2 receptor, inhibiting IL-2-mediated T-lymphocyte proliferation), or placebo . After two years, there was no significant difference in the mean AUC for C-peptide levels during a mixed-meal tolerance test. Thus, neither MMF alone nor in combination with daclizumab slowed progression of beta-cell destruction in recently diagnosed type 1 diabetes.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20:1183.
- Skyler JS. Prediction and prevention of type 1 diabetes: progress, problems, and prospects. Clin Pharmacol Ther 2007; 81:768.
- Silverstein J, Maclaren N, Riley W, et al. Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus. N Engl J Med 1988; 319:599.
- Cook JJ, Hudson I, Harrison LC, et al. Double-blind controlled trial of azathioprine in children with newly diagnosed type I diabetes. Diabetes 1989; 38:779.
- Gottlieb PA, Quinlan S, Krause-Steinrauf H, et al. Failure to preserve beta-cell function with mycophenolate mofetil and daclizumab combined therapy in patients with new- onset type 1 diabetes. Diabetes Care 2010; 33:826.
- Bougnères PF, Landais P, Boisson C, et al. Limited duration of remission of insulin dependency in children with recent overt type I diabetes treated with low-dose cyclosporin. Diabetes 1990; 39:1264.
- Christie MR, Mølvig J, Hawkes CJ, et al. IA-2 antibody-negative status predicts remission and recovery of C-peptide levels in type 1 diabetic patients treated with cyclosporin. Diabetes Care 2002; 25:1192.
- Chatenoud L, Thervet E, Primo J, Bach JF. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci U S A 1994; 91:123.
- Woodle ES, Xu D, Zivin RA, et al. Phase I trial of a humanized, Fc receptor nonbinding OKT3 antibody, huOKT3gamma1(Ala-Ala) in the treatment of acute renal allograft rejection. Transplantation 1999; 68:608.
- Utset TO, Auger JA, Peace D, et al. Modified anti-CD3 therapy in psoriatic arthritis: a phase I/II clinical trial. J Rheumatol 2002; 29:1907.
- Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002; 346:1692.
- Sherry N, Hagopian W, Ludvigsson J, et al. Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet 2011; 378:487.
- Hagopian W, Ferry RJ Jr, Sherry N, et al. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial. Diabetes 2013; 62:3901.
- Herold KC, Gitelman SE, Ehlers MR, et al. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes 2013; 62:3766.
- Keymeulen B, Vandemeulebroucke E, Ziegler AG, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005; 352:2598.
- Keymeulen B, Walter M, Mathieu C, et al. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia 2010; 53:614.
- Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 2009; 361:2143.
- Moran A, Bundy B, Becker DJ, et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet 2013; 381:1905.
- Muir A, Peck A, Clare-Salzler M, et al. Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription. J Clin Invest 1995; 95:628.
- Vlahos WD, Seemayer TA, Yale JF. Diabetes prevention in BB rats by inhibition of endogenous insulin secretion. Metabolism 1991; 40:825.
- Peakman M, Hussain MJ, Millward BA, et al. Effect of initiation of insulin therapy on T-lymphocyte activation in type 1 diabetes. Diabet Med 1990; 7:327.
- Aaen K, Rygaard J, Josefsen K, et al. Dependence of antigen expression on functional state of beta-cells. Diabetes 1990; 39:697.
- Gladstone P, Nepom GT. The prevention of IDDM. Injecting insulin into the cytokine network. Diabetes 1995; 44:859.
- Karounos DG, Bryson JS, Cohen DA. Metabolically inactive insulin analog prevents type I diabetes in prediabetic NOD mice. J Clin Invest 1997; 100:1344.
- Wong FS, Karttunen J, Dumont C, et al. Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library. Nat Med 1999; 5:1026.
- Shah SC, Malone JI, Simpson NE. A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989; 320:550.
- Keller RJ, Eisenbarth GS, Jackson RA. Insulin prophylaxis in individuals at high risk of type I diabetes. Lancet 1993; 341:927.
- Diabetes Prevention Trial--Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002; 346:1685.
- Skyler JS, Krischer JP, Wolfsdorf J, et al. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial--Type 1. Diabetes Care 2005; 28:1068.
- Skyler JS, Type 1 Diabetes TrialNet Study Group. Update on worldwide efforts to prevent type 1 diabetes. Ann N Y Acad Sci 2008; 1150:190.
- Näntö-Salonen K, Kupila A, Simell S, et al. Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Lancet 2008; 372:1746.
- Bonifacio E, Ziegler AG, Klingensmith G, et al. Effects of high-dose oral insulin on immune responses in children at high risk for type 1 diabetes: the Pre-POINT randomized clinical trial. JAMA 2015; 313:1541.
- Boitard C, Timsit J, Assan R, et al. Treatment of type 1 diabetes mellitus with DAB486-IL-2, a toxin conjugate which targets activated T-lymphocytes. Diabetologia 1992; 35:A218.
- Yagi N, Yokono K, Amano K, et al. Expression of intercellular adhesion molecule 1 on pancreatic beta-cells accelerates beta-cell destruction by cytotoxic T-cells in murine autoimmune diabetes. Diabetes 1995; 44:744.
- Tisch R, Liblau RS, Yang XD, et al. Induction of GAD65-specific regulatory T-cells inhibits ongoing autoimmune diabetes in nonobese diabetic mice. Diabetes 1998; 47:894.
- Ludvigsson J, Faresjö M, Hjorth M, et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med 2008; 359:1909.
- Wherrett DK, Bundy B, Becker DJ, et al. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet 2011; 378:319.
- Ludvigsson J, Krisky D, Casas R, et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med 2012; 366:433.
- Orban T, Bundy B, Becker DJ, et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 2011; 378:412.
- Shehadeh N, Calcinaro F, Bradley BJ, et al. Effect of adjuvant therapy on development of diabetes in mouse and man. Lancet 1994; 343:706.
- Pozzilli P. BCG vaccine in insulin-dependent diabetes mellitus. IMDIAB Group. Lancet 1997; 349:1520.
- Gale EA, Bingley PJ, Emmett CL, et al. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet 2004; 363:925.
- Raz I, Elias D, Avron A, et al. Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial. Lancet 2001; 358:1749.
- Ryu S, Kodama S, Ryu K, et al. Reversal of established autoimmune diabetes by restoration of endogenous beta cell function. J Clin Invest 2001; 108:63.
- Kodama S, Kühtreiber W, Fujimura S, et al. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science 2003; 302:1223.
- Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 2004; 429:41.
- Mastrandrea L, Yu J, Behrens T, et al. Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized, placebo-controlled, double-blind study. Diabetes Care 2009; 32:1244.
- Rother KI, Brown RJ, Morales MM, et al. Effect of ingested interferon-alpha on beta-cell function in children with new-onset type 1 diabetes. Diabetes Care 2009; 32:1250.
- LeDoux SP, Hall CR, Forbes PM, et al. Mechanisms of nicotinamide and thymidine protection from alloxan and streptozocin toxicity. Diabetes 1988; 37:1015.
- Yamada K, Nonaka K, Hanafusa T, et al. Preventive and therapeutic effects of large-dose nicotinamide injections on diabetes associated with insulitis. An observation in nonobese diabetic (NOD) mice. Diabetes 1982; 31:749.
- Pozzilli P, Browne PD, Kolb H. Meta-analysis of nicotinamide treatment in patients with recent-onset IDDM. The Nicotinamide Trialists. Diabetes Care 1996; 19:1357.
- Elliott RB, Chase HP. Prevention or delay of type 1 (insulin-dependent) diabetes mellitus in children using nicotinamide. Diabetologia 1991; 34:362.
- Vitamin D supplement in early childhood and risk for Type I (insulin-dependent) diabetes mellitus. The EURODIAB Substudy 2 Study Group. Diabetologia 1999; 42:51.
- Hyppönen E, Läärä E, Reunanen A, et al. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001; 358:1500.
- Mayer-Davis EJ, Dabelea D, Crandell JL, et al. Nutritional factors and preservation of C-peptide in youth with recently diagnosed type 1 diabetes: SEARCH Nutrition Ancillary Study. Diabetes Care 2013; 36:1842.
- Calder PC. Polyunsaturated fatty acids, inflammation, and immunity. Lipids 2001; 36:1007.
- De Caterina R, Madonna R, Massaro M. Effects of omega-3 fatty acids on cytokines and adhesion molecules. Curr Atheroscler Rep 2004; 6:485.
- ClinicalTrials.gov - A service of the US National Institutes of Health http://www.clinicaltrials.gov (Accessed on July 21, 2011).
- Knip M, Virtanen SM, Seppä K, et al. Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med 2010; 363:1900.
- TRIGR Study Group. Study design of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR). Pediatr Diabetes 2007; 8:117.
- Voltarelli JC, Couri CE, Stracieri AB, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2007; 297:1568.
- Couri CE, Oliveira MC, Stracieri AB, et al. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2009; 301:1573.
- PREVENTION AND REVERSAL STRATEGIES
- - Azathioprine
- - Mycophenolate mofetil
- - Cyclosporine
- - Anti-CD3 antibodies
- - Rituximab
- - Interleukin-1 inhibition
- - Thymoglobulin
- - Insulin
- - Immunotherapy DAB486-IL-2
- - GAD65 immunotherapy
- - Costimulation modulation
- - Bacillus Calmette-Guerin (BCG)
- - DiaPep277
- - Donor splenocytes
- - TNF-alpha inhibitors
- - Interferon alpha
- - Nicotinamide
- - Vitamin D supplements
- - Omega-3 polyunsaturated fatty acids
- - Avoidance of cow's milk
- - Hematopoietic stem cell transplant
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS