Certain human leukocyte antigen (HLA)-DR/DQ gene polymorphisms, particularly HLA-DR and HLA-DQ alleles, increase susceptibility to, or provide protection from, the disease. In susceptible individuals, environmental factors may trigger the immune-mediated destruction of pancreatic beta cells. Although the geographic variation in disease prevalence and increasing worldwide incidence of type 1 diabetes argue for a major environmental contribution to pathogenesis, the specific factors involved remain unknown. Among viruses, the strongest associations have been found with human enteroviruses. Among dietary factors, supplementation with vitamin D may be protective. Further research is required to determine the effect of cow's milk, early introduction of cereals, or maternal vitamin D ingestion on type 1 diabetes risk. Celiac disease shares the HLA-DQ2 genotype with type 1 diabetes, and is more common among those with type 1 diabetes. The incidence of type 1 diabetes may also be higher among those with celiac disease, although a causal relationship is not suggested.
Type 1 diabetes usually develops as a result of autoimmune pancreatic beta-cell destruction in genetically susceptible individuals. Up to 90% of patients will have autoantibodies to at least one of three antigens: glutamic acid decarboxylase; insulin; and a tyrosine-phosphatase-like molecule, islet autoantigen-2 (IA-2). Over 25% of individuals without one of these or islet cytoplasmic autoantibodies will have positive antibodies to ZnT8, a pancreatic beta-cell-specific zinc transporter. In addition, 10% of adults who have been classified as having type 2 diabetes may have circulating islet cell antibodies or antibodies to glutamic acid decarboxylase, indicating autoimmune destruction of beta cells.
Beta-cell destruction proceeds subclinically for months to years as insulitis (inflammation of the beta cell). When 80% to 90% of beta cells have been destroyed, hyperglycemia develops. Insulin resistance has no role in the pathophysiology of type 1 diabetes. However, with increasing prevalence of obesity, some patients with type 1 diabetes may be insulin resistant in addition to being insulin deficient.
Patients with insulin deficiency are unable to utilize glucose in peripheral muscle and adipose tissues. This stimulates the secretion of counter-regulatory hormones such as glucagon, epinephrine, cortisol, and growth hormone. These counter-regulatory hormones, especially glucagon, promote gluconeogenesis, glycogenolysis, and ketogenesis in the liver. As a result, patients present with hyperglycemia and anion gap metabolic acidosis.
Long-term hyperglycemia leads to vascular complications due to a combination of factors that include glycosylation of proteins in tissue and serum, production of sorbitol, and free radical damage. Microvascular complications include retinopathy, neuropathy, and nephropathy. Macrovascular complications include cardiovascular, cerebrovascular, and peripheral vascular disease. Hyperglycemia is known to induce oxidative stress and inflammation. Oxidative stress can cause endothelial dysfunction by neutralizing nitric oxide. Dysfunctional endothelium allows entry of low-density lipoprotein into the vessel wall, which induces a slow inflammatory process and leads to atheroma formation.
Types of type 1 diabetes
Characterized by absolute insulin deficiency and the presence of antibodies to pancreatic beta cells.
Uncommon form that is characterized by absence of antibodies.
Increased likelihood in patients of African or Asian ancestry and has a strong genetic component.
Presentation of idiopathic type 1 diabetes does not differ from that of autoimmune type 1 diabetes.
Staging of type 1 diabetes
The American Diabetes Association has produced a staging system for type 1 diabetes based on clinical features, glycemic levels, and the presence of autoantibodies. The persistent presence of two or more autoantibodies is an almost certain predictor of clinical hyperglycemia and diabetes, and the rate of progression is dependent on the age at first detection of antibody, the number of antibodies, the antibody specificity, and the antibody titer. Glucose and glycosylated hemoglobin (HbA1c) levels rise well before the clinical onset of diabetes, making early diagnosis possible. This staging can serve as a framework for future research and screening.
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