New Discovery In Diabetes Patients May Suggest Underlying Disorder

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KineMed and Daiichi Sankyo announced that researchers have discovered a key difference in bile acid metabolism in people with type 2 diabetes which may suggest a newly identified underlying disorder.

It has long been known that bile acids help the body absorb fat and cholesterol. In the last decade, we learned that bile acids are important signaling molecules that regulate the metabolism of glucose, fat, and energy. And until now, there has been only preliminary data suggesting alterations in bile acid metabolism in people with type 2 diabetes. Now new data highlight crucial alterations in bile acid metabolism in this population. Researchers reported results from the first controlled study addressing this issue, which they hope will lead to a better understanding of how bile acid metabolism is impacted in people with type 2 diabetes.

The study found that the most important bile acid, cholic acid (CA), had a significantly higher synthesis rate in people with type 2 diabetes than in patients with normal glucose levels. Researchers also learned that the rate at which deoxycholic acid (DCA) was recycled back into the liver (i.e. DCA input rate) was almost twice as great in those with type 2 diabetes as in the healthy subjects. In addition, the total amount of bile acid synthesized by the liver was elevated, although not statistically significantly, in people who have type 2 diabetes as compared to the healthy control group.

KineMed, Inc., a pathway-based drug discovery and development company, initiated the research which used their proprietary translational medicine technology, KineMarker. The results from the study were presented at the American Diabetes Association's 68th Scientific Sessions. The research was funded with an investigator-initiated grant from Daiichi Sankyo, Inc.

"We expect that physicians and other researchers will eagerly watch as this evolves," said Elizabeth Murphy, M.D., DPhil, Chief, Endocrinology and Metabolism, San Francisco General Hospital, consultant to KineMed and lead study investigator. "We've long wanted to know the relationship between type 2 diabetes and bile acid metabolism, and the unique insights provided by KineMed's technology have now answered some of our questions. In the second phase of our study, we are investigating whether treatment with the bile acid sequestrant colesevelam HCl may improve an underlying disorder in bile acid metabolism in patients with type 2 diabetes. We're heading down a fascinating path that may lead to a new approach to fighting this disease, which strikes some 21 million people in the U.S. and 246 million worldwide." Colesevelam HCl is marketed in the U.S. as Welchol.

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"Daiichi Sankyo is very excited about these findings and what they might mean for diabetes research and therapy going into the future," said Sukumar Nagendran, M.D., Senior Director, Diabetes and Metabolism, Daiichi Sankyo, Inc.

"KineMed is grateful to have collaborated with Daiichi Sankyo and leveraged its insights into pathway kinetics to identify this new inflection point for the treatment of type 2 diabetes," said David Fineman, President and CEO of KineMed.

Study Details

The study investigators hypothesized that bile acid metabolism is altered in patients with type 2 diabetes which may contribute to the observed metabolic behavior, and further, that treatment with a bile acid sequestrant (BAS) might normalize these alterations. In order to test this hypothesis, as a first step, a baseline understanding of bile acid kinetics in people with type 2 diabetes needed further illumination.

The study compared the levels and metabolism of bile acids in healthy men to that of men with type 2 diabetes. Before administering any interventions, researchers recorded baseline values of bile acids in nine men with type 2 diabetes and in 12 healthy men. The men ranged in age from 42 to 56 years old and were also matched for body mass index. From study outset, those subjects with type 2 diabetes had significantly higher blood glucose levels, as measured by A1C (A1C gives a reading of the average blood glucose levels for the past two to three months). The men with type 2 diabetes also had significantly higher fasting glucose as well as triglyceride levels.

In the study, bile acid tracers were given to the men after they had eaten their evening meal. The researchers then recorded blood samples at 13, 17.5, 24, 37, 46, 63, 70 and 91 hours after the bile acid tracers were administered. No differences between the two groups were observed for cholic acid (CA) or the chenodeoxycholic acid (CDCA) pool sizes, CDCA synthesis rate, or bile acid fractional turnover rates.

However, compared to the healthy cohort (HC), the men with type 2 diabetes showed a significantly higher CA synthesis rate (15.9 plus or minus 3.1 vs. HC 9.5 plus or minus 3.2 micro mol/kg/d; p<0.01), DCA input rate (9.0 plus or minus 1.5 vs. HC 4.9 plus or minus 2.4 micro mol/kg/d; p<0.01), DCA pool size (21.4 plus or minus 6.5 vs. HC 13.7 plus or minus 6.3 micro mol/kg; p<0.05) and total bile acid synthesis (28.1 plus or minus 6.7 vs. HC 18.5 plus or minus 6.4 micro mol/kg; p<0.05). The researchers concluded that these changes in bile acid metabolism may contribute to altered glucose, fat, and energy metabolism in patients with type 2 diabetes.

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