LADA and CARDS: a prospective study of clinical outcome in established adult-onset autoimmune diabetes.

OBJECTIVE: Diabetes-associated autoantibodies can be detected in adult-onset diabetes, even when initially non-insulin requiring, i.e., with latent autoimmune diabetes. We aimed to identify adult-onset autoimmune diabetes in patients with established "type 2 diabetes" participating in the Collaborative Atorvastatin Diabetes Study (CARDS) to characterize their phenotype and clinical outcome. RESEARCH DESIGN AND METHODS: We prospectively studied 2,425 European patients with presumed type 2 diabetes (mean age 62 years, diabetes duration 7.9 years) for outcomes at 3.9 years after randomization to either atorvastatin or placebo. Subjects were screened for autoantibodies to GAD (GADA), insulinoma-associated antigen-2 (IA-2A), and zinc-transporter 8 (ZnT8A). RESULTS: A total of 173 patients (7.1%) had GADA, of whom 11 (0.5%) and 5 (0.2%) were also positive for IA-2A and ZnT8A, respectively. At baseline, 44% of GADA-positive patients were not on insulin. Fewer autoantibody-positive than autoantibody-negative patients had metabolic syndrome (64 vs. 80%), and more were on insulin (56 vs. 17%) (P < 0.0001 for each) without lower HbA1c (69 mmol/mol [8.5%] vs. 62 mmol/mol [7.8%]). The frequency of microvascular and macrovascular events was similar in both cohorts, independent of atorvastatin. CONCLUSIONS: Adult-onset autoimmune diabetes was prevalent, even in patients with established diabetes presumed to have type 2 diabetes. After 11.8 years' diabetes duration, nearly half the patients with autoimmune diabetes were not on insulin treatment and almost two-thirds had metabolic syndrome. The type of diabetes, whether autoimmune diabetes or type 2 diabetes, did not impact the risk of microvascular disease.

Impact of genetic and non-genetic factors in type 1 diabetes.

Type 1 insulin-dependent diabetes is due to destruction of the insulin secreting cells of the islets of Langerhans. The disease is caused by non-genetic, probably environmental, factors operating in a genetically susceptible host to initiate a destructive immune process. These unknown environmental factors may operate over a limited period either in early or later and to a variable degree, playing a particularly substantial role in adults. The environment then induces an immune process associated with destruction of the islet beta cell that can be detected in early life and persists up to disease onset. Apart from an association with the insulin gene there is no evidence that genes associated with type 1 diabetes, including HLA and CTLA4 influence the targeting of the immune response to the insulin-secreting cells. The critical period of immune activation is probably short and the process leading to diabetes probably has a long prodrome but of variable duration that determines the age at presentation with clinical disease. The amplification both of this immune response and the destructive process is in part genetically determined, involving HLA genes. The clinical spectrum of the disease process associated with type 1 diabetes is wide, encompassing insulin-dependence, non-insulin dependence and even transient impaired glucose tolerance. Type 1 diabetes presenting in adults, in contrast to children, is predominantly determined by non-genetic factors with a reduced role for protective and susceptibility HLA alleles. Thus, the evidence is that genes involved in genetic susceptibility to type 1 diabetes operate predominantly in children not adults and in both amplify the immune response and the rate of disease progression.