Etiological investigation of diabetes in young adults presenting with apparent type 2 diabetes.

Objective: Young adults with newly diagnosed apparent type 2 diabetes present the clinician with a wide differential diagnosis of possible etiology, including autoimmune and genetic causes as well as young-onset type 2 diabetes (YT2D). The characteristics of these groups have been described, but it is not known in which subjects investigation for etiology may be beneficial.

Research Design And Methods: A total of 268 unselected U.K. Caucasian subjects diagnosed at ages 18-45 years and not treated with permanent insulin for < or =6 months were studied. All subjects underwent clinical assessment and screening for GAD antibodies (GADA) and tyrosine phosphatase IA-2 antibodies (IA-2A). Screening for a common mutation in the hepatocyte nuclear factor-1 alpha (HNF-1 alpha) gene and the common mitochondrial mutation was performed in the antibody-negative subjects. Subjects without insulin resistance were selected for sequencing of the HNF-1 alpha gene.

Results: A specific etiology was defined in 11.6% of the 268 subjects and in 24.7% of the lean subjects. Twenty-six subjects (9.7%) were positive for a beta-cell antibody, one subject had familial partial lipodystrophy and the lamin A/C mutation R482W, and two subjects had the mitochondrial mutation A3243G. Two of 15 selected subjects had HNF-1 alpha mutations, the novel missense mutation A501T, and the previously reported R583Q.

Conclusions: This unselected series shows that there is considerable heterogeneity in apparent YT2D. beta-Cell autoantibodies should be performed in all those presenting at ages 18-45 years. Genetic investigations can be targeted to phenotypically defined subjects. The finding of a specific etiology will allow individualization of management and give patients valuable information about their condition.