Sci. Aging Knowl. Environ., 21 July 2004
Wising Up to Diabetes
Insulin activity in brain and liver collaborate to prevent the metabolic disease
Slide over, fat. Move back, muscle. The brain and liver mastermind the regulation of blood sugar, according to new work. The study shows that stimulating the insulin receptor only in these organs spares mice from diabetes, a finding that could help researchers devise new drugs to rein in blood sugar.
Insulin prods a protein called the insulin receptor, causing cells to sop up glucose. But many people's cells ignore the hormone, a condition known as insulin resistance that often presages diabetes. Researchers aren't sure how insulin resistance develops, but they have long suspected that the hormone response goes awry in muscle and fat. Cells there require insulin in order to imbibe glucose. The hormone also hinders the liver from releasing sugar into the bloodstream. But researchers didn't think organs such as the liver and brain contributed to insulin resistance because they absorb sugar without the hormone. Recent studies suggest otherwise. Losing the protein bodywide swiftly kills mice. But animals that lack the receptor in muscle or fat cells survive and avoid diabetes (see "Lasting Without Fasting"). Domenico Accili, a diabetes researcher at Columbia University in New York City, and colleagues wanted to pin down which tissues must respond to insulin to fend off diabetes.
They created three lines of genetically altered mice. One carried insulin receptors only in the brain, liver, and pancreas. The other two produced the protein exclusively in the liver and pancreas. The mice in the second and third lines became diabetic, and all of them died before the age of 8 months. Their blood carried about four times the normal amount of glucose. Blood sugar in the first line was about 50% above normal, but the rodents had a normal life span of 2 years, and only about 35% of them developed diabetes. Using other mice, the researchers activated the receptor only in the pancreas. The animals died shortly after birth, faring no better than rodents lacking the receptor. A different group of mice, with the receptor only in the brain, developed diabetes and rarely lived more than 2 months. The results suggest that insulin must work in the brain and liver to save mice from diabetes, Accili says: "We have overestimated how important insulin is in muscle and fat and underestimated its importance in other tissues." The antidiabetic drug metformin blocks the liver from releasing glucose, and according to Accili, insulin might goad the brain into exuding compounds that have the same effect. If so, drugs that mimic insulin's impact on the brain might provide another way to moderate blood glucose, he says.
The study shows that the mice can "live quite well" even if their muscle and fat tissues don't help regulate blood sugar, says molecular biologist H. Joseph Goren of the University of Calgary in Canada. Now researchers should turn on the receptor in fat, muscle, and other tissues individually and in combination to gauge each one's contribution to regulating blood sugar, says biochemist Scott Summers of the University of Utah School of Medicine in Salt Lake City. That work might settle the question of which tissue is in charge.
July 21, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150