Etiological Investigation of Diabetes in Young Adults Presenting With Apparent Type 2 Diabetes

Abstract

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 ≤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-1α (HNF-1α) gene and the common mitochondrial mutation was performed in the antibody-negative subjects. Subjects without insulin resistance were selected for sequencing of the HNF-1α 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 β-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-1α mutations, the novel missense mutation A501T, and the previously reported R583Q. CONCLUSIONS—This unselected series shows that there is considerable heterogeneity in apparent YT2D. β-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.