Classification and Diagnosis
Type 1 diabetes has traditionally been diagnosed based on clinical catabolic symptoms suggestive of insulin deficiency: polyuria, polydipsia, weight loss, and marked hyperglycemia that is nonresponsive to oral agents. It is classified as an autoimmune disease with progressive β-cell destruction, resulting in a physiological dependence on exogenous insulin. Recent studies have broadened our understanding of the disease, but have made diagnosis more complex.
There is tremendous variability in the initial presentation of type 1 diabetes in both youth and adults. Children often present acutely, with severe symptoms of polyuria, polydipsia, and ketonemia. However, in adults, type 1 diabetes presents with a more gradual onset, with a clinical presentation that may initially appear consistent with type 2 diabetes. Distinguishing between type 1 and type 2 diabetes presents diagnostic challenges. Traditionally, progressive β-cell destruction has been the hallmark of type 1 diabetes, but residual C-peptide (a surrogate marker for insulin secretion) may be detected over 40 years after initial diagnosis, regardless of whether the initial diagnosis was made in childhood or in adulthood.
Much of the diagnosis will depend on clinical clues, but the rising incidence of overweight/obesity has also confounded the diagnosis of type 1 diabetes. A lean individual presenting with clinical symptoms without a first-degree relative with diabetes (but often with a history of distant relatives with type 1 diabetes or other autoimmune disease) is generally suggestive of type 1 diabetes. An overweight individual (of any age) with metabolic syndrome and a strong family history of type 2 diabetes may be assessed only for the development of type 2 diabetes, even though type 1 diabetes is on the differential diagnosis. Obesity does not preclude that autoimmunity and hyperglycemia will occur even amid the relatively higher levels of endogenous insulin secretion observed in obesity. In young patients aged 10–17 years with phenotypic type 2 diabetes, 10% have evidence of islet autoimmunity suggesting that type 1 diabetes was the likely diagnosis. Thus, although leaner individuals are more likely to be diagnosed as having type 1 diabetes, the potential for type 1 diabetes exists in those who phenotypically appear to have type 2 diabetes. If hyperglycemia persists after treatment with noninsulin agents, which is unusual in the treatment of newly diagnosed type 2 diabetes, then type 1 diabetes should be considered.
Pancreatic autoantibodies are characteristic of type 1 diabetes. Highly sensitive laboratory measurements capture ~98% of individuals with autoantibodies at diagnosis. Unfortunately, most commercial laboratories do not have reliably sensitive or specific assays that measure all five autoantibodies: GADA, islet cell antibodies (ICA), insulin autoantibodies (IAA), protein tyrosine phosphatase antibodies (ICA512 or IA2A), and zinc transporter protein (ZnT8). Thus, it may be inappropriate to report a patient as autoantibody negative. Another cause of "false-negative" autoantibodies is testing far out from diagnosis as antibody titers diminish over time (Fig. 1). It appears that there is an increased incidence of type 1 diabetes in ethnic populations where autoantibody markers may be of variable utility, such as in Asians where autoantibodies are often negative.[11–15]
The percentage of antibody-positive subjects is affected by the duration of type 1 diabetes for GADA (A) and IA2A (B). Given an increase in the scatter (due to lower numbers of subjects), the x-axis is truncated at a duration of 30 years. Reproduced with permission from Tridgell et al..16
Type 1 diabetes has a genetic predilection and, in some cases, can be predicted in family members. The overall prevalence of type 1 diabetes in the U.S. is ~0.3%, but if a first-degree relative has diabetes, the empiric risk of being affected is ~5%,[17,18] representing a 15-fold increase among family members. Studies evaluating children at risk for developing type 1 diabetes have shown that the presence of more than two autoantibodies was associated with a nearly 70% risk for disease development within 10 years and 84% within 15 years. Evaluating at-risk individuals in the clinical setting is not yet recommended due to limited clinical interventions; however, ongoing research studies are identifying at-risk individuals through genetic testing in both the lower-risk general population and in the higher-risk population of relatives of people with type 1 diabetes.
The American Diabetes Association's (ADA's) diagnostic criteria for type 1 and type 2 diabetes are the same (Table 1). (A)
Consider measurement of pancreatic autoantibodies to confirm the diagnosis of type 1 diabetes. (B)
Identification of At-Risk Relatives:
Inform type 1 diabetic patients of the opportunity to have their relatives tested for type 1 diabetes risk in the setting of a clinical research study. (B)
Diabetes Care. 2014;37(7):2034-2054. © 2014 American Diabetes Association, Inc.