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Stanford BIO 230 - Type One Diabetes Mellitus

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MOUNT SINAI JOURNAL OF MEDICINE 75:385–397, 2008 385Type 1 Diabetes Mellitus: Primary,Secondary, and Tertiary PreventionJennifer Bollyky, MD,1Srinath Sanda, MD,1,2and Carla J. Greenbaum, MD11Diabetes Program, Benaroya Research Institute, Seattle, WA2Department of Pediatrics, Seattle Children’s Hospital, Seattle, WAABSTRACTWe have entered the era of clinical trials to preventtype 1 diabetes mellitus (T1DM). Before 1922, wheninsulin was first given to a patient with diabetes, adiagnosis of T1DM was considered a death sentence.Advances in treatment for subjects with diabetes arenot yet sufficient to prevent the deleterious impactof diabetes on both day-to-day activities and theearly morbidity and mortality still associated with thedisease. We now understand a great deal about bloodglucose regulation and potential health complicationsassociated with long-term T1DM, but the mystery ofwhy, or the pathogenesis of this devastating disease,remains elusive. Great strides toward unraveling thismystery have been made over the past severaldecades. Even without definitive answers, we aremoving from the period of discovery and animalresearch to the era of clinical trials. In this review,we wish to convey the palpable excitement in thefield. It is time to determine if we can safely changethe course of T1DM. Mt Sinai J Med 75:385–397,2008.  2008 Mount Sinai School of MedicineKey Words: Type 1 diabetes, clinical trial, autoim-munity, prevention.Although diabetes was known in ancient times,it was not until 1889 that Von Mering and Minkowskiat the University of Strasbourg were able todemonstrate that the removal of the pancreas indogs caused diabetes.1It then took 33 years beforethis discovery translated into therapy when BantingAddress Correspondence to:Carla J. Greenbaum, MDDiabetes ProgramBenaroya Research InstituteSeattle, WAEmail: [email protected] Best identified, isolated, purified, and treatedthe first subject with insulin. It was not until the1970s that evidence convincingly demonstrated thatinsulin-dependent diabetes was an immune-mediateddisease. The evidence included measurements ofautoantibodies to islet cells2,3(and subsequentlyinsulin4and others5–7), pathology reports describinginsulitis in pancreatic specimens,8,9and associationsof the disease with genes that encode cell-surfaceantigen-presenting proteins [the human leukocyteantigen (HLA) system or HLA type].10 – 12In the 1980s,reports of islet cell and insulin antibodies togetherwith deficiency of insulin secretion were noted inpatients prior to the onset of clinical disease.13TheEisenbarth model of disease, describing a preclinicalperiod of autoimmune beta cell destruction followedby overt disease, was widely accepted.14,15During thesame era, advances in immunotherapy, reports andthen standardization of measurements of additionalautoantibodies, and the ability to change the courseof disease in the 2 animal models (nonobese diabeticmouse and biobreeding rat) led to the developmentof clinical trials to do the same. As illustrated inFigure 1, increased understanding of the naturalhistory of the T1DM disease process expanded theconcept of prevention to include primary prevention,in which the goal is to stop the initiation ofautoimmunity; secondary prevention, in which thegoal is to stop the progression of immune-mediatedbeta cell destruction and prevent clinical disease;and tertiary prevention, with the aim of easingday-to-day management of diabetes and diminishingcomplications.NATURAL HISTORY OF DISEASEThe incidence of T1DM in the general Caucasianpopulation is about 0.3%. In contrast, the over-all risk among family members is about 15 timesgreater. Thus, although the majority of individualswho develop T1DM have no family members withPublished online in Wiley InterScience (www.interscience.wiley.com).DOI:10.1002/msj.20054 2008 Mount Sinai School of Medicine386 J. BOLLYKY ET AL:PREVENTION OF TYPE 1DIABETES MELLITUSFig 1. Stages of Type 1 Diabetes Prevention. [Color figure can be viewed in the onlineissue, which is available at www.interscience.wiley.com.].disease, the majority of the data about the natu-ral history of disease come from studies of familymembers. A large amount of such data has con-firmed that a small percentage of individuals atgenetic risk develop autoimmunity. This autoimmu-nity is detected first by the presence of autoanti-bodies and second by the loss of beta cell functionassessed by impaired insulin secretion and subse-quently abnormal glucose tolerance. Overt clinicaldiabetes occurs only after the remaining beta cellfunction is insufficient to prevent hyperglycemia.At clinical onset, beta cell function is further tran-siently depressed. For many individuals, a temporaryimprovement in glucose tolerance is seen withinthe first few months of diagnosis–the honeymoonperiod. The honeymoon period is characterizedclinically as requiring decreased exogenous insulinand metabolically by improvements in both insulinaction and secretion. Whether the honeymoon periodis due to the resolution of the acute effects ofmetabolic decompensation on beta cells and res-olution of insulin-sensitive tissues or the immune-mediated cytokine impairment of beta cell functionis unknown. Post-diagnosis, immune-mediated betacell dysfunction and destruction continue, as mea-sured by decreased responses to beta cell insulinsecretagogues.This overall description of the T1DM diseaseprocess masks the heterogeneity evident in clin-ical practice. Some individuals progress to clini-cal T1DM in infancy; others do so during lateadulthood. Whether this is because the diseaseprocess is more rapid in younger children orthey start with less islet reserve is unknown.Post–clinical diagnosis, about 15% of individu-als still have measurable beta cell function even5 years later,16 – 18and recent data suggest thatsmall amounts of insulin secretion may persistfor decades in selected patients. Overall, however,although the vast majority of patients present withsignificant amounts of beta cell function at diag-nosis, this is gradually and inevitably lost overtime.Although our current knowledge about thenatural history of the disease allows for the selectionof subjects for clinical trials, further understandingof the causes of the disease will need to takeinto account emerging information. For example,the incidence of T1DM is increasing worldwide.The increase is particularly evident in the veryyoung.19 – 23Such an increase


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Stanford BIO 230 - Type One Diabetes Mellitus

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