A relatively rare genetic variant in the CCND2 gene halves the risk of type 2 diabetes by improving insulin secretion and sensitivity, but it does not appear to impact insulin processing, new data suggest.

In an effort to replicate earlier work that identified a low-frequency variant at CCND2 associated with lower risk of type 2 diabetes, enhanced insulin response to a glucose challenge, higher height and, paradoxically, higher body mass index, researchers examined associations between the variant and type 2 diabetes in 29,956 European individuals, finding a 51% lower incidence of type 2 diabetes among carriers of the allele, which ranged in frequency from 1.51% to 2.14%, according to a paper published online March 24 in Diabetes.

Individuals with the variant had significantly improved insulin secretion in response to a glucose challenge test, a higher disposition index of beta-cell function, as well as being significantly taller and of slightly greater BMI than controls (Diabetes 2015 [ doi:10.2337/db14-1456 ]).

“The associations with improved disposition index and insulinogenic index but smaller effects with the Matsuda index, in up to 13,181 individuals, show that the protective diabetes effect operates primarily through a mechanism of relatively favorable insulin secretory response to a glucose challenge and to lower blood sugar more effectively than noncarriers,” wrote Dr. Hanieh Yaghootkar of the University of Exeter (England) and coauthors.

“Our best estimate of the effect of the variant on BMI suggests that the effect is smaller than reported in the original publication due to index event bias. Further studies are needed to establish the size of the BMI association. Our data, together with the original finding, show a mechanism through improved insulin secretion which results in lower fasting glucose levels, lower 2-hour OGTT glucose levels, and a lower risk of type 2 diabetes. Combining all data including 19,586 type 2 diabetes cases and 83,554 controls from the original study and our study provides evidence that carrying this variant reduces the risk of type 2 diabetes by approximately 50% relative to noncarriers,” the investigators wrote.

The study was supported by European Research Council, the Wellcome Trust, the University of Exeter Medical School, Novo Nordisk, and various government agencies, universities, and nonprofit organizations. There were no conflicts of interest declared.