Hepatic Insulin Resistance Produces Features of Metabolic Syndrome

Dr. Sudha B. Biddinger from the Joslin Diabetes Center, Harvard Medical School in Boston states that, "There is a metabolic syndrome, and a single pathophysiological event can produce all the symptoms and increase the cardiovascular disease risk."

Dr. Biddinger and colleagues used the liver insulin receptor knockout (LIRKO) mouse model to investigate the effects of hepatic insulin resistance on the development of dyslipidemia and atherosclerosis.

Hepatic insulin resistance alone produced atherogenic changes in lipoprotein metabolism, the authors report, including 50% reductions in HDL cholesterol and 3-fold increases in VLDL cholesterol.

Several transcription factors were dysregulated in the livers of LIRKO mice, the report indicates, and there was an uncoupling of cholesterol and triglyceride secretion such that only triglyceride secretion was impaired, resulting in cholesterol-rich VLDL particles.

LIRKO mice proved unable to maintain cholesterol homeostasis in the presence of excess dietary fat and cholesterol, the investigators say, and, unlike control mice, they developed severe hypercholesterolemia and atherosclerosis after 12 weeks on an atherogenic diet.

"Therefore," the authors conclude, "hepatic insulin resistance alone is sufficient for the development of dyslipidemia and, when coupled with a permissive diet, the development of atherosclerosis."

In ongoing animal studies, Dr. Biddinger said, the research team hopes to identify how insulin alters the synthesis and clearance of HDL and to find the exact target that leads to its decrease. They plan to systematically go through the nodes of insulin action to see which one controls cholesterol and glucose.

"As we can identify and reverse causes, we can have a real treatment for the trigger of the metabolic syndrome," Dr. Biddinger said. "This represents a paradigm shift: Insulin is more important than simply glucose control."

Cell Metabolism 2008;7:1-10.

================================

FACT:
Sanofi to start this quarter phase III with GLP-1 analog:Zealand Pharma reported that Sanofi-Aventis will begin the Phase III program for the GLP-1 agonist AVE0010/ZP10 licensed from Zealand Pharma A/S in the first quarter of 2008.

The program will include over 3,000 diabetic patients and will evaluate a once-a-day injection of AVE0010/ZP10 in combination with the principal existing treatments (metformin, sulfonylurea, insulin), as well as a comparison with exenatide and a monotherapy study. Filing for approval is expected in 2010. A prolonged release formulation is currently being evaluated in Phase I. AVE0010/ZP10 is a glucagon-like peptide 1, or "GLP-1", receptor agonist developed for subcutaneous injection treatment of Type 2 Diabetes and incorporates Zealand Pharma's "SIP" technology