ADA 2008: Hepatic steatosis new worry in type 2 diabetes

Clinicians and type 2 diabetes patients have a new worry: hepatic steatosis, or nonalcoholic fatty liver disease. Liver disease is a less-obvious problem than kidney disease but may have equally grave consequences.

"Fatty liver is a growing complication of diabetes," said Kenneth Cusi, MD, University of Texas Health Science Center, San Antonio, TX. "Fatty liver is being recognized as a direct complication of diabetes as well as a contributor to vascular disease."

A recent study in Dallas found that about one-third of cardiovascular patients with diabetes also have fatty livers. The incidence is somewhat lower in African-Americans, said Jay Horton, MD, University of Texas Southwest Medical Center, Dallas, apparently due to unknown genetic protective factors.

Liver triglycerides come from four sources, Dr. Horton said. The fatty liver may over-synthesize triglycerides, excretion of triglycerides may be blocked, the uptake of free fatty acids may be increased, and mitochronical dysfunction may lead to a build-up of fatty acids.

Studies suggest that free fatty acids account for about 50% of the fatty acid burden in hepatic steatosis, Dr. Horton said. Fatty acid synthesis accounts for another 26% of the liver fat burden.

The synthesis of fatty acids is mediated by sterol regulatory element binding protein (SREBP), which is affected by insulin and glucose levels. Insulin resistance upregulates SREBP, which increases the synthesis of fatty acids in the liver. Dr. Horton and his research team found that blocking SREBP in insulin-resistant mice reduced fatty acid synthesis and reduced total liver triglycerides by about 50%.

A second pathway, mediated by carbohydrate response element binding protein (ChREBP), also leads to increased fatty acid synthesis. ChREBP is activated by hyperglycemia. Blocking these two pathways in diabetic hamsters reduces fatty acid synthesis to normal levels even on a high carbohydrate diet, he reported.

"There is accumulating evidence in humans that lipogenesis is as important in the development of fatty liver disease as it is in mice," he said. "If we can find a way to reduce fat synthesis in humans the way we can in mice and hamsters, we will have a very beneficial effect."