Sci. Aging Knowl. Environ., 3 May 2006
In Praise of Insulin Resistance
Immune-cell metabolic defect might hinder atherosclerosis
Insulin resistance, a condition in which body cells quit heeding the hormone, is a stop on the road to type 2 diabetes and a possible heart attack. But a new study of mice indicates that if particular immune cells become unresponsive to insulin, they help fend off one lethal complication of diabetes: atherosclerosis. The work suggests that insulin resistance in these cells curtails inflammation that promotes arterial obstructions.
Most people with diabetes die from heart disease, but researchers don't understand how addled sugar metabolism leads to clogged arteries. An oversupply of blood glucose might damage vessels. But some evidence links a different aspect of the disease, namely, insulin resistance, to atherosclerosis. For instance, people with metabolic syndrome--a condition characterized by obesity and excess blood fats that sometimes segues into diabetes--have normal blood sugar quantities but are insulin resistant, and they are prone to arterial plaques. Mice genetically altered to be insulin resistant also develop the buildup. However, some work indicates that immune cells called macrophages help spur atherosclerosis when they are insulin sensitive, not insulin resistant. Insulin prompts macrophages in the culture dish to pour out inflammation-promoting compounds that foster fatty buildup. To determine whether insulin signaling in macrophages affects atherosclerosis in animals, geneticist Jens Brüning of the University of Cologne in Germany and colleagues disrupted the pathway in genetically altered mice that accumulate large numbers of plaques.
The researchers engineered the animals' macrophages to lack the insulin receptor, on which the hormone docks and relays its message into the cell. The altered rodents amassed smaller plaques in their arteries than did controls, suggesting that insulin resistance in the immune cells limits gunk formation. Next, the researchers set out to bolster this conclusion. First, they severed the insulin-signaling pathway at a different point: They modified another group of atherosclerosis-prone rodents to lack the insulin receptor substrate, the protein inside the cell that's activated when insulin binds to its receptor. These animals developed insulin resistance bodywide and accumulated large plaques. Then the researchers used transfusions to replace the animals' blood with either insulin-responsive or insulin-resistant cells. Mice that received cells with working copies of the insulin-receptor substrate gene sported even bigger plaques than did those that received cells with faulty copies of the gene.
Next, the team wanted to pinpoint the mechanism by which the macrophages influenced plaque formation in the animals. One way macrophages promote atherosclerosis is by amassing cholesterol and bedding down in the arterial lining. But when the scientists tested cultured macrophages that were missing the insulin receptor gene, the cells broke down and released cholesterol normally, which suggests that insulin resistance doesn't disrupt their lipid metabolism. However, they cranked out smaller quantities of two inflammation-spurring molecules. Those findings suggest that in these animals, insulin resistance in macrophages is helpful because it stems inflammation that promotes atherosclerosis, says Brüning. The researchers aren't sure, however, why patients don't seem to gain similar benefits. Macrophages might remain insulin sensitive in people with diabetes; the evidence is equivocal, Brüning says. Another possibility is that the deleterious effects of insulin resistance in other tissues overwhelm the benefits from resistance in immune cells, he says.
The work is intriguing because it supports the view that macrophages' responsiveness to insulin is a factor in atherosclerosis, says endocrinologist Mitchell Lazar of the University of Pennsylvania in Philadelphia. The results don't suggest any new therapies for diabetes, he cautions. But if researchers can work out how insulin resistance hampers atherosclerosis in the mice, the findings might eventually provide new ways to help steer patients away from blocked arteries.
May 3, 2006
Science of Aging Knowledge Environment. ISSN 1539-6150