Monogenic diabetes mellitus in youth. The MODY syndromes.

Maturity onset diabetes of the young is characterized by early onset diabetes inherited in an autosomal dominant pattern. Classic MODY occurs predominantly in Caucasians and presents before age 25, is nonketotic, and is generally not insulin-requiring. Less than 5% of cases of childhood diabetes in Caucasians are caused by MODY. ADM is a subtype of MODY that occurs in approximately 10% of African-Americans with youth onset diabetes. In contrast to MODY in Caucasians, ADM presents clinically as acute onset diabetes often associated with weight loss, ketosis, and even diabetic ketoacidosis. Approximately 50% of patients with ADM are obese. Therefore, based strictly on clinical grounds, at onset, ADM cannot be distinguished from type 1 diabetes. Months to years following diagnosis, a non-insulin-dependent clinical course develops in patients with ADM that is clearly different from type 1 diabetes. Mutations in five genes can cause MODY. These genes encode hepatocyte nuclear factor-4 alpha (HNF-4 alpha, MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1 alpha (HNF-1 alpha, MODY3), insulin promoter factor-1 (IPF-1, MODY4), and hepatocyte nuclear factor-1 beta (HNF-1 beta, MODY5). These monogenic forms of MODY have been used as model systems to investigate the inheritance and pathophysiology of type 2 diabetes. Clinicians, should be able to diagnose MODY. Type 1 diabetes, the most common form of diabetes in Caucasians, is always insulin-requiring for control and survival, whereas patients with MODY do not usually require long-term insulin for survival. Diagnostic confusion can lead to inappropriate management and patient expectations. Primary care physicians must be alert to avoid therapeutic confusion when patients with ADM enter into the non-insulin-dependent stage. An approach to the diagnosis of childhood diabetes is offered in Table 4. The majority of youth onset diabetes remains type 1; however, the frequency of type 2 diabetes is rising in obese children and adolescents and especially in obese minority youth. The diagnosis of MODY can be made through a careful review of the patient's clinical course, severity of hyperglycemia, and family history. The identification of islet autoantibodies is confirmatory evidence of autoimmune (type 1) diabetes. Because testing for MODY mutations is expensive and is performed at a select number of research laboratories only, routine molecular genetic studies to search for the various MODY mutations should be limited to research investigations. In the future, the availability of gene chip technology may allow rapid screening of mitochondrial and MODY mutations.

Non-insulin dependent diabetes mellitus (NIDDM) in minority youth: research priorities and needs.

The prevalence of non-insulin dependent diabetes mellitus (NIDDM) is increasing in Native American and African-American youth, with females more frequently affected than males. This increase is related to increasing rates of obesity and to the greater demand for insulin at adolescence. This review examines the epidemiologic data about NIDDM in minority youth and addresses questions about the type of diabetes minority youth have, the relative contributions of environment and genetics to their diabetes, and whether prevention or control is possible. The heterogeneity of NIDDM in the minority youth population includes: typical NIDDM; atypical diabetes mellitus (ADM), which has been described in a substantial number of African-American youngsters; and a small proportion with a range of defects in the pathway of insulin action. Clinical and experimental evidence that insulin resistance or insulin deficiency is the primary defect in NIDDM are reviewed, as is evidence that fetal undernutrition may be a contributing factor. The numerous reports of linkages, associations, and mutations or polymorphisms in candidate genes account for a very small proportion of non-type 1 diabetes. Environmental and genetic contributors to obesity are also important. Research issues relating to the questions discussed include the need for data comparing various populations and assessing risk factors associated with the epidemic of NIDDM and obesity, costs to the health system and attendant personal and societal costs, clarification of the types of NIDDM in minority populations that will permit appropriate therapy and counseling, and extensive studies of environmental and genetic factors. Genetic studies include a genome wide search and continued analysis for candidate genes for both NIDDM and obesity. Environmental factors for study include the role of fetal and perinatal nutrition and drug exposure. Finally, collaborative multicenter studies are needed of prevention or control of obesity and NIDDM.

Autoimmune diabetes. The role of autoantibody markers in the prediction and prevention of insulin-dependent diabetes mellitus.

In general, reliable and reproducible ICA results are available only from research laboratories that routinely perform ICA testing. Regarding IAA testing, IAA ELISA must be avoided. There are numerous GADA procedures available that definitely have different sensitivities for GADA detection. IA-2A testing is very new and is performed in only a few research laboratories. Islet autoantibody testing should be performed only as part of research protocols. At the present time, we know much more about the prediction of IDDM than its prevention. Once safe and credible methods are available to prevent IDDM, islet autoantibody screening may become as common as childhood immunizations.

Pharmacological approaches to the prevention of autoimmune diabetes.

Insulin-dependent (type I) diabetes mellitus (IDDM) is the consequence of a chronic cell-mediated immune attack upon the insulin-producing beta-cells. Progressive insulinopenia is characteristic of individuals who eventually develop IDDM. Autoimmunity develops because of a failure in self-nonself discrimination. Autoimmunity is usually detected when autoantibodies are present in the patient's serum. However, autoantibodies are not synonymous with disease, as many autoantibody-positive individuals show no evidence of clinical disease. Studies initiated in the early 1980s demonstrated that short term remission from IDDM could be induced or lengthened with immunosuppressive therapy. However, no long term remissions were achieved. Current prevention strategies use a combination of autoantibody marker testing and beta-cell function testing to identify individuals with 'prediabetes'. The most useful autoantibodies for prediabetes screening include islet cell autoantibodies, insulin autoantibodies, glutamic acid decarboxylase autoantibodies and IA-2 autoantibodies. Immunointervention techniques have focused on protecting beta-cells from oxidative damage and developing tolerance to beta-cell autoantigens. Environmental manipulation may also be of benefit but its effectiveness is unproven. The pharmacist of the future may be involved in dispensing autoantigens, cytokines, anti-cytokine antibodies, anti-cytokine receptor antibodies, vaccines or viral vectors for gene therapy in the prevention of IDDM.