Beneficial Mutation Dissociates Obesity from Diabetes

These animals became severely obese but did not go on to develop type II diabetes. Specifically, reduced function of the Brd2 gene enhanced glucose tolerance; elevated adiponectin; increased the weight of brown adipose tissue; increased heat production and expression of mitochondrial uncoupling proteins in brown adipose tissue; reduced macrophage infiltration in white adipose tissue; and lowered blood glucose, leading to an improved metabolic profile and avoiding eventual type II diabetes.

These findings were published in the November 2, 2009, online edition of The Biochemical Journal (BJ) where the authors also noted that Brd2 was highly expressed in pancreatic beta cells, where it normally inhibits beta-cell mitosis and insulin transcription.

Senior author Dr. Gerald Denis, assistant professor of pharmacology and medicine at the Boston University School of Medicine, said, "Studies have shown that these individuals [obese but free of type II diabetes] have a reduced "inflammatory profile". Inflammation caused by normal immune cells called macrophages leads to insulin resistance and type II diabetes - this inflammation is typically seen in connection with obesity but it is the inflammation that is a trigger for diabetes, not the obesity itself. The mechanisms that explain this protection from diabetes are not well understood. Much like these protected obese humans, the Brd2-deficient mice have reduced inflammation of fat and never develop failure of the beta cells in the pancreas that is associated with type II diabetes."

"The strong influence of Brd2 levels on insulin production and action suggest that Brd2 is likely to be a promising target for diabetes treatment, but also imply that overactive Brd2 might cause diabetes," said Dr. Denis. "The ways in which Brd2 affects the immune system may also play a part in type I diabetes; further studies to determine this are needed."

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Boston University School of Medicine