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Issue 93 Item 12 New Protein Identified in Liver Might Lead to Type 2 Diabetes C

Feb 15, 2002

Researchers at the Medical College of Ohio have identified a protein in the liver that helps clear insulin from blood. This discovery could eventually lead to a cure for type 2 diabetes. It has been a common belief among scientists that type 2 diabetes is initiated when the body’s muscles, fat tissues, and liver stop responding to insulin. Insulin brings sugar from blood into muscle and fat tissues to be stored as fuel and stops the liver from making its own sugar. Lack of response to insulin in type 2 diabetes leads to increased sugar levels in blood.

Sonia M. Najjar Ph.D., associate professor of pharmacology and therapeutics, contends that type 2 diabetes may actually begin a step before the body starts resisting insulin. Using genetically modified mice, Najjar has found when there is increased fat in the body, the liver’s ability to clear insulin is impaired. This, in turn, can lead to insulin resistance in the liver and other tissues, thus resulting in type 2 diabetes.


This discovery coupled with the identification of CEACAM1, a liver protein that controls insulin clearance, may play a major role in the battle against type 2 diabetes.

"I can easily envision a drug that enhances the function of this protein and leads to a cure for type 2 diabetes," said Najjar.

A paper from Najjar’s laboratory about the function of the CEACAM1 protein in insulin clearance will be published in the prestigious journal, Nature Genetics in March 2002 and can be read online now on its Website. Najjar’s research is currently sponsored by the National Institute of Diabetes, Digestive and Kidney Diseases and the American Diabetes Association. The Medical College of Ohio Foundation sponsored the initial phase of her studies

We hypothesized that insulin stimulates phosphorylation of CEACAM1 which in turn leads to upregulation of receptor-mediated insulin endocytosis and degradation in the hepatocyte. We have generated transgenic mice over-expressing in liver a dominant-negative, phosphorylation-defective S503A-CEACAM1 mutant. Supporting our hypothesis, we found that S503A-CEACAM1 transgenic mice developed hyperinsulinemia resulting from impaired insulin clearance. The hyperinsulinemia caused secondary insulin resistance with impaired glucose tolerance and random, but not fasting, hyperglycemia. Transgenic mice developed visceral adiposity with increased amounts of plasma free fatty acids and plasma and hepatic triglycerides. These findings suggest a mechanism through which insulin signaling regulates insulin sensitivity by modulating hepatic insulin clearance.