Although type 1 and type 2 diabetes represent the vast majority of affected individuals with the disease, not all cases of diabetes fit neatly into these categories. A smaller in magnitude, but clinically significant, subset of patients may develop diabetes from a different pathophysiology. These forms may occur at any stage of life and be acquired environmentally, iatrogenically, as a result of a genetic mutation that predisposes to type 1, type 2, or a combined form of diabetes, or in other metabolic disorders where hyperglycemia is more likely to develop.
Congenital viral infections, predominantly rubella and cytomegalovirus (CMV), have historically been linked to diabetes. Although they are presently not observed often in the United States, rubella continues to represent a potential important etiology given fluctuation in vaccination rates. Multiple other viruses have been implicated as potential pathogens in triggering the autoimmune response or through direct infection of the pancreas.
Cystic fibrosis-related diabetes (CFRD) affects 12% of children with cystic fibrosis and 33% of adults with cystic fibrosis. CFRD is an important comorbidity to diagnose and treat, as patients with CFRD are at increased risk for mortality and treatment with insulin improves clinical outcomes.
Pancreatitis-related diabetes may account for 0.5%–1% of all new cases of diabetes in the general population. Some of these individuals will seek elective pancreatectomy due to persistence of pain associated with pancreatitis flares and poor quality of life. Islet autotransplantation continues to develop as a procedure to prevent diabetes in these patients.
Hemochromatosis, a disorder of iron metabolism, is present in 0.5%–1% of the population in the United States. Within this population, 7%–40% will eventually develop diabetes. These patients have evidence for both increased insulin resistance and insulin deficiency, which can lead to clinical diabetes.
Drugs associated with diabetes represent perhaps one of the most important other types of diabetes given the sheer numbers of pharmacologic agents implicated and the numbers of patients treated. Glucocorticoids are the most commonly encountered and most frequently identified agents that result in diabetes. In addition, other immunosuppressive agents used in transplant medicine, pharmacologic agents used in cardiovascular disease prevention, some antimicrobial and antiviral agents, hormone replacement therapies, and environmental pollutants have all been linked to development of diabetes.
Diabetes can also be part of an immune-mediated syndrome or underlying endocrinopathy. These forms may occur in disorders with a single gene defect (e.g., APS-1 or IPEX syndrome) and highlight the importance of screening for other endocrinopathies. Increased secretion of several hormones, including cortisol, growth hormone, thyroid hormone, aldosterone, epinephrine, and gut hormones, can also result in diabetes. Thus, patients with hypersecretion syndromes should be screened for diabetes as a comorbid condition.
Several relatively common genetic syndromes are associated with an increased risk for either type 1 or type 2 diabetes. Diabetes can be particularly challenging in populations with these syndromes, which are often associated with developmental delays, making prevention efforts paramount. Screening and treatment should be part of routine management in those syndromes where diabetes has been most strongly linked.
Other unique associations have emerged representing the last grouping of other diabetes forms. Diabetes occurs in up to 25% of transplant recipients. Risk is predominantly modified by the type of agent used posttransplant and inversely correlated with length of time from transplant. Infants with a history of intrauterine growth retardation are more likely to have characteristics of type 2 diabetes later in life, illustrating the importance of in utero nutrition and fetal programming. Similarly, children and adults with severe malnutrition may also develop diabetes that is distinct from other forms. Mutations in mitochondrial DNA can result in another form of maternally inherited diabetes, either as part of a distinct neurologic syndrome or on its own.