Part XI Type 1 Diabetes
Introduction Åke Lernmark Epidemiology Type 1 diabetes is increasing worldwide and shows epidemic proportions in several countries or regions [1]. There is evidence to suggest that the annual increase in type 1 diabetes incidence may amount to 2% to 7% dependent on the country or region [1]. In a Swedish countrywide study in 1983 to 1998, it was found that the incidence of type 1 diabetes had not increased but rather shifted to a younger age at diagnosis the 0- to 34-year age group [2]. In a similar study of Belgian patients up to 40 years of age, the rising incidence in children was largely restricted to boys under age 10, where the incidence more than doubled during the 15-year period [3]. At the same time obesity-related hyperglycemia appears to attain epidemic proportion [4]. It is controversial, however, to what extent an increase in body mass index increases the risk for type 1 diabetes [5]. The trend toward a younger age at onset is increasing the risk for ketoacidosis and cerebral edema in conjunction with the clinical onset of hyperglycemia. Genetic Etiology Type 1 diabetes can be diagnosed at any age. The genetic and environmental determinants as well as the clinical course are heterogeneous by age. The common pathway (Fig. XI.1) begins with genetic risk. It is remarkable that about 85% of newly diagnosed type 1 diabetes children or young adults have a first-degree relative (parent or sibling) with the disease [1]. The genetic factors represent primarily human leukocyte antigen (HLA) DR-DQ on chromosome 6 (Table XI.1). The HLA genetic factors may account for about 60% of the genetic risk for type 1 diabetes [4]. The HLA genotypes listed in Table XI.1 would typically account for about 90% of children and young adults developing diabetes. The Å. Lernmark Professor of Experimental Diabetes, Department of Clinical Sciences, Lund University/CRC, University Hospital MAS, Malmö, Sweden T.F. Davies (ed.), A Case-Based Guide to Clinical Endocrinology, C Humana Press, Totowa, NJ 2008 321
322 Å. Lernmark INITIATORS - virus? - diet? PROMOTERS - genes? - virus? - diet? Genetic risk Autoimmunity Diabetes Fig. XI.1 Type 1 diabetes pathophysiology. Children are born with genetic risk primarily conferred by HLA DR-DQ genetic factors on chromosome 6. Initiators are thought to trigger the development of islet autoimmunity, which is marked by autoantibodies against insulin, the 65-kd isoform of glutamic acid decarboxylase (GAD65) or IA-2. Genetic factors, virus infections, or diet may represent promoters of islet autoimmunity eventually resulting in hyperglycemia DR4-DQA1 0301-DQB1 03021/DR3-DQA1 0501-DQB1 0201 genotype (abbreviated DR4-DQ8/DR3-DQ2) is conferring the highest risk for type 1 diabetes in most countries. In North America and in Europe this high-risk genotype may be found among about 30% of the patients compared to 3% to 4% of the controls. The younger the patient, the higher the frequency of this genotype. The second highest risk genotype is DR4-DQA1 0301-DQB1 0302/DR4-DQA1 0301- DQB1 0302 (DR4-DQ8 homozygous), the frequency of which is 25% to 27% compared to about 3% to 4% among controls. These and the other HLA genotypes listed in Table XI.1 are therefore necessary but not sufficient for type 1 diabetes. Table XI.1 Genetic factors affecting the risk of type 1 diabetes Genetic factor Chromosome Contribution to risk Reference HLA DR-DQ genotypes 6p21 Major [5] DR4-DQA1 0301-DQB1 03021/DR3-DQA1 0501-DQB1 0201 DR4-DQA1 0301-DQB1 0302/DR4-DQA1 0301-DQB1 0302 DR4-DQA1 0301-DQB1 03021/DR8-DQA1 0401-DQB1 0402 DR3-DQA1 0501-DQB1 0201/DR3-DQA1 0501-DQB1 0201 DR4-DQA1 0301-DQB1 03021/DR4-DQA1 0301-DQB1 0201 DR4-DQA1 0301-DQB1 03021/DR12-DQA1 0101-DQB1 0501 DR4-DQA1 0301-DQB1 03021/DR13-DQA1 0102-DQB1 0604 DR4-DQA1 0301-DQB1 0302/DR4-DQA1 0301-DQB1 0304 DR4-DQA1 0301-DQB1 03021/DR9-DQA1 0301-DQB1 0303 DR3-DQA1 0501-DQB1 0201/DR9-DQA1 0301-DQB1 0303 Non-HLA genetic factors Minor [5] INS 11p15 CTLA4 2q33 PTPN22 1p13 IL2RA 10p15 IFIH1 2q24 ITPR3 6p Non-HLA genetic regions Minor Unknown 12q Unknown 16p
Part XI Type 1 Diabetes 323 Table XI.2 Virus implicated in the development of islet autoimmunity, type 1 diabetes, or both Virus Type RNA/DNA Coxsackie Enterovirus RNA Echo Enterovirus RNA Rubella Rubivirus RNA Mumps Paroxyvirus RNA Rota Reovirus RNA Cytomegalovirus Herpesvirus DNA Ljungan virus Parechovirus RNA It is speculated that the interaction between these HLA genetic determinants and environmental factors such as certain virus may trigger islet autoimmunity (Fig. XI.1). Islet autoimmunity is marked by the appearance of islet autoantibodies (Table XI.2) to insulin (IAA), GAD65 (GADA) or IA-2 (IA-2A) [5]. The ability to develop these autoantibodies is related to the HLA genotype. Hence, IAA and IA-2A are more common among subjects who are positive for DR4-DQ8, while GADA is more likely to be found among DR3-DQ2 positive subjects. Several non-hla genetic factors (Table XI.1) have been identified either by association in case-control studies or by linkage analyses of affected sib-pairs [4]. The non-hla genetic factors may contribute to age at onset or the presence of islet autoantibodies, increasing the risk of low-risk HLA DR-DQ genotypes. For example, IAA occurs more often in subjects with a high-risk INS genotype [5], while the genetic polymorphism of the PTPN22 gene is increasing the risk for type 1 diabetes in subjects with low-risk HLA genotypes [4]. It will be important to determine to what extent the non-hla genes contribute to islet autoimmunity, as may be the case for the INS gene [4], or represent promoters of the pathogenic process leading to hyperglycemia. Etiologic Factors Virus infection remains the major environmental candidate to trigger islet autoimmunity, onset of hyperglycemia, or both. Several viruses have been implicated (Table XI.2). The association between virus and type 1 diabetes is primarily based on studies carried out at the clinical diagnosis of type 1 diabetes [1]. Several authors are therefore questioning whether virus infections in conjunction with the onset of hyperglycemia rather represent a promoter phenomenon of islet autoimmunity than a trigger of type 1 diabetes. Longitudinal studies of children at genetic risk for type 1 diabetes, such as The Diabetes Autoimmunity Study in the Young (DAISY), The Baby Diabetes study (BABY DIAB), The Diabetes Prevention Project (DIPP), and The Environmental Determinants of Diabetes in the Young (TEDDY) [5], may identify virus infections resulting in islet autoimmunity as marked by the appearance of islet autoantibodies [5].
324 Å. Lernmark Table XI.3 Diagnostic thresholds for diabetes and lesser degrees of glucose dysregulation Category FPG 2-hour PG after OGTT Normal 100 mg/dl (5.6 mmol/l) 140 mg/dl (7.8 mmol/l) IFG 100 125 mg/dl (5.6 6.9 mmol/l) IGT 140 199 mg/dl (7.8 11.0 mmol/l) Diabetes 126 mg/dl (7.0 mmol/l) 200 mg/dl (11.1 mmol/l) Note: When both tests are performed, IFG or IGT should be diagnosed only if diabetes is not diagnosed by the other test. A diagnosis of diabetes needs to be confirmed on a separate day. The table is from [1]. FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test; PG, plasma glucose. Pathogenesis The preclinical beta-cell autoimmunity marked by IAA, GADA, and IA-2A, alone or in combination, may be present for several years before the onset of hyperglycemia. Islet autoantibody-positive subjects have varying degree of betacell dysfunction, particularly in their first-phase insulin response to intravenous glucose [4]. The presence of islet autoantibodies predicts type 1 diabetes by the number of autoantibodies; three autoantibodies that are persistently positive represent the highest risk, higher than any autoantibody alone or characteristics such as isotype, subtype, or epitope-specificity [5]. The islet autoantibodies are standardized, and proficiency tests have been instituted. Islet autoantibodies are used to enroll subjects to immune intervention trials [5]. Islet autoantibodies are the first primary end point in the TEDDY observational cohort study in which newborns who are younger than 4 months and have high-risk HLA genotypes in the general population or are first-degree relatives of patients affected with type 1 diabetes GADA, in particular, may be important to the differential classification of diabetes in adults to distinguish type 2 from type 1 or autoimmune diabetes [5]. Diagnostic Criteria The criteria to diagnose diabetes have remained the same with few modifications since the first recommendations were made in 1979 [1]. The diagnostic thresholds for fasting plasma glucose (FPG) and plasma glucose after a 75-g oral glucose tolerance test (OGTT) are summarized in (Table XI.3). Note also the thresholds for impaired fasting glucose (IFG) as well as impaired glucose tolerance (IGT). It is expected that an increasing number of subjects will be identified with any of the glycemic abnormalities shown in Table XI.3. There is considerable evidence that IFG, IGT, and, of course, diabetes are associated with increased morbidity including cardiovascular disease.
Part XI Type 1 Diabetes 325 Classification of Diabetes Once the diagnosis of hyperglycemia (IFG, IGT, or diabetes) has been made, the classification of disease is next. The classification of diabetes is complicated by the fact that symptoms not defined etiologic, pathogenic, or pathophysiologic criteria are used to classify the disease. In children, type 1 diabetes predominate. Type 1 diabetes is strongly associated with markers of autoimmune phenomena directed against the pancreatic beta-cells [3] and a loss of endogenous insulin production. In contrast to type 2 diabetes, type 1 diabetes is strongly associated with other organ-specific autoimmune disorders [3, 4]. Recent epidemiologic studies indicate that type 2 diabetes is rare among patients under 20 years of age. However, a major advance in molecular diagnosis has made it possible to classify diabetes into maturity-onset diabetes of the young (MODY), a dominantly inherited form of nonketotic diabetes [4]. MODY usually develops in childhood, adolescence, or young adulthood. However, despite the etiology, this disease is characterized by genetic and clinical heterogeneity. Type 2 diabetes genetic markers are beginning to be understood. Interestingly enough, most of the genetic factors identified so far seem to affect the beta-cell function [4]. Type 2 diabetes is strongly associated with obesity and an older age at onset, although current epidemiologic investigations suggest that also younger obese subjects may develop type 2 diabetes. Future Directions Current research efforts are focused on the identification of genetic and environmental determinants of the type 1 diabetes disease process and how they interact. The presentation of diabetes in children and adolescents is heterogeneous. Infants and preschool children, therefore, may be diagnosed at very different pathogenic stages. Children participating in screening studies for type 1 diabetes may be diagnosed by hyperglycemia. Diagnosis without the classic type 1 diabetes symptoms is possible, and ongoing and future studies will be important to establish possible beneficial effects on prognosis. Currently, after initiation of insulin replacement therapy, there is a transient, usually partial, remission. The remission, which is shorter in younger patients, is followed by complete insulin deficiency associated with acute and chronic complications and untimely death. Major research efforts, therefore, are focused on either preventing the development of hyperglycemia in islet autoantibody-positive subjects or intervening with the islet autoimmunity at the time of clinical diagnosis. Acknowledgments Studies in the author s laboratory is supported by the National Institutes of Health (grants DK26190, DK53004, AI42380, DK63861, DK17047), the American Diabetes Association, the Juvenile Diabetes Research Foundation, the Swedish Research Council, the Swedish Diabetes Association, the Skåne County Research and Development Fund, and the University Hospital Malmö Allmänna Sjukhus (UMAS) Fund.
326 Å. Lernmark References 1. Green A, Patterson CC. Trends in the incidence of childhood-onset diabetes in Europe 1989 1998. Diabetologia 2001;44:B3 8. 2. Pundziute-Lycka A, Dahlquist G, Nystrom L, et al. The incidence of Type I diabetes has not increased but shifted to a younger age at diagnosis in the 0 34 years group in Sweden 1983 1998. Diabetologia 2002;45:783 791. Epub 2002 May 2008. 3. Weets I, Rooman R, Coeckelberghs M, et al. The age at diagnosis of type 1 diabetes continues to decrease in Belgian boys but not in girls: a 15-year survey. Diabetes Metab Res Rev 2007;23:637 643. 4. Onengut-Gumuscu S, Concannon P. Recent advances in the immunogenetics of human type 1 diabetes. Curr Opin Immunol 2006;18:634 638. Epub 2006 Aug 2001. 5. Eisenbarth GS. Update in type 1 diabetes. J Clin Endocrinol Metab 2007;92:2403 2407.