Issue 211 Item 13 Type 2 Diabetes In Lean Patients Linked to Gene Mutation

Findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans. A missense mutation in the serine/threonine kinase gene (AKT2) has been identified in a family with autosomal dominant inheritance of severe insulin resistance and type 2 diabetes, investigators report in the May 28th issue of Science.

Dr. Stephen O’Rahilly, at the University of Cambridge in the UK, and colleagues had screened genomic DNA from 104 unrelated subjects with severe insulin resistance. . They identified a heterozygous R-to-H substitution at amino acid 274 of AKT1 in a lipodystrophic 34-year old nonobese women who developed diabetes mellitus at age 30.female.

She and three maternal relatives with the same mutated allele were severely hyperinsulinemic. Two of the three relatives had developed diabetes while in their late 30s. The mutation was not found in three other clinically normal first-degree relatives or in 1500 Caucasian control subjects.

An animal model showed that this mutation decreases lipid accumulation in preadipocytes and impairs adipogenesis. Consistent with this observation, the proband, who had severe insulin resistance in both the liver and peripheral tissues, had a 35% lower body fat composition compared with other women of similar BMI.

“These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans,” the authors write, which should lead to “important clues to understanding more common forms” of diabetes. Science 2004;304:1325-1328.
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FACT: In review of NHANES data, it was found that adequate glycemic control is declining among patients with Type 2 diabetes. From 1988-1994 the Nhanes III showed that 44.5% achieved adequate glycemic control, but NHANES from 1990-2000 showed only 35.8% achieved glycemic control.