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DIABETES RESEARCH Brain Found to Play Unexpected Role in Type II DiabetesFindings Could Change Theory and Treatment of the Disease Adult onset diabetes mows a wide swath through the body, robbing the liver, pancreas, muscles and fat of their ability to respond sufficiently to the vital hormone insulin. Until recently, the brain was thought to be largely spared by the disease's deadly scythe. A report appearing in the Sept. 22 Science suggests that defects in the brain's ability to respond to insulin could contribute to some of the central symptoms of adult, or Type II, diabetes, including obesity and lowered fertility.
Defects in insulin signaling in the brain may help to bring about increased appetite and obesity and lowered fertility in diabetics, according to Ronald Kahn and his colleagues. Photo by Graham Ramsay Until now, the brain was assumed to be a side player in diabetes. "For the most part, diabetes researchers have not been looking at the brain," said C. Ronald Kahn, the Mary K. Iacocca professor of medicine and president of Joslin Diabetes Center. The findings, made in mice, cast doubt on that assumption. More importantly, if confirmed in humans, the discovery could call into question a longstanding dogma about how insulin resistance, the hallmark of diabetes, paves its ruinous course through the body. Indeed, the new findings, along with others reported in the past two years by Kahn and his colleagues, are already pointing to an alternative view of the disease which, if confirmed, could lead to new diabetes treatments. A Fatter, Less Fertile MouseTo explore the possible role of insulin resistance in the brain, Kahn and his colleagues genetically deprived a strain of mice of most of the insulin receptors in their brains. The mice ate more, had higher fat stores, and were more likely to become obese when fed the same high-fat diet as their normal counterparts. They also had higher levels of triglycerides, creating a metabolic profile that closely parallels that found in human diabetics.In addition, the mutants were found to be nearly 50 percent less successful at breeding than those equipped with all their brain insulin receptors. "We were hoping to be surprised but the surprise turned out to be even greater than we envisioned," said Kahn. Most researchers assumed that the tendency of people with Type II diabetes to become obese was a secondary effect, the consequence of changes in fat metabolism brought about by the body's inability to respond properly to insulin. Few considered the possibility that obesity might be a direct consequence of an insulin-signaling defect in the brain. Even more unexpected were the defects in fertility. "We anticipated something about feeding behavior and obesity. We did not anticipate such a strong phenotype with regard to reproductive potency," he said. The Reproductive NudgeThough it is not clear how the brain's lack of insulin receptors is causing the mice's poor reproductive showing, Kahn and his colleagues think it may affect how the hypothalamus, a knot of neurons in the brain, plays its part in controlling reproduction.To get reproduction going, the hypothalamus produces a substance that nudges the pituitary gland to produce luteinizing hormone, which helps to drive the ovaries and testes. Kahn and his colleagues believe that the receptor-deprived mutants' hypothalamus may be producing less of the pituitary-stimulating hormone. "What's missing is that endogenous push," he said. As for the relevance of all this for humans, while infertility is not often associated with Type II diabetes, which usually develops past reproductive age, it is strongly associated with another insulin resistant condition, polycystic ovarian disease (PCOD). Young women suffering from this disease often find it very hard to conceive. Researchers have attributed this lower fertility to insulin resistance at the level of the ovaries, but it is possible that these women may also have some degree of insulin resistance affecting the brain or pituitary. In fact, Kahn and his colleagues hope to look at the hormonal patterns of these women, and also of younger people with diabetes, to see if they mirror those found in the mice. Their findings, if positive, could lead to new approaches to treating infertility in PCOD women. But the more immediate impact of the research coming out of Kahn's lab will be on diabetes research. "It's forcing us to reevaluate the way we were thinking about the pathophysiology of diabetes, what the genetics might be, and ultimately where the therapeutic targets might be," said Kahn. Turning Theory Inside OutFor years, researchers have labored under the notion that the amount of glucose flowing through the bloodstream is the result of how much glucose the liver makes and how much of it fat and muscle use—with insulin controlling each side of the equation. Diabetes was thought to disturb this balance by a kind of reverse ripple effect. The disease was thought to start at the periphery, with fat and muscle cells, followed by liver cells, losing their ability to respond to insulin.To overcome this insulin resistance, the pancreas—the body's insulin factory—would put out more and more insulin. Eventually, the beleaguered pancreas would fail to keep up with demand, at which point the hyperglycemia and symptoms characteristic of diabetes, such as the drive to eat and drink more, would develop. In an effort to explore this outside-in hypothesis, Kahn and his colleagues used a genetic method, the Cre-loxP system, to selectively remove the insulin receptor from individual tissues of mice, starting with muscle. "We thought we would reproduce the earliest pathophysiological defect in Type II diabetes, and we would watch as the animal aged, got obese, and developed Type II diabetes," he said. "That's not what we found." While the muscle mutants displayed several diabetic symptoms—they were fatter and had higher levels of triglycerides and fatty acids—the mice appeared to be maintaining their glucose metabolism relatively well. As it turned out, the glucose normally taken up by muscle was taken up by fat cells. When they knocked out the insulin receptor from the liver of mice, they found more serious symptoms such as hyperglycemia and abnormal glucose metabolism. But, as reported in the August Molecular Cell, the symptoms appeared to lessen, rather than worsen, as the animals got older. In another round of experiments, the researchers knocked out the insulin receptor from the insulin-producing beta cells of the pancreas, even though the pancreas was not thought to be insulin-resistant in diabetes. To their surprise, they reproduced their most significant defect yet. The beta cells lost their ability to respond normally to glucose. "What is important about the combination is that the earliest defect in diabetes is the loss of glucose-stimulated insulin secretion while retaining the ability to respond to other stimulants," said Kahn. The pancreas findings, along with the most recent findings—that symptoms such as obesity and lowered fertility may be a direct consequence of insulin resistance in the brain, rather than a secondary or ripple effect—support a new view of the origins of diabetes, said Kahn. In the traditional view, the failure of the pancreas to produce enough insulin, and the development of symptoms such as obesity, were viewed as reactions to an initial insulin resistance in muscle, fat, and liver. According to the "unified" view proposed by Kahn and his colleagues, these are not secondary effects but part of the same initial disease process. Not just the liver, muscles, and fat but also the brain and the pancreas become insulin resistant in Type II diabetes, and they may do so at a very early stage of the disease. If the theory bears up to scrutiny, it will be of more than theoretical interest. "By better understanding the real pathophysiology of the disease, our hope would be to find new targets for therapeutic intervention," said Kahn. "Before, the most important site of insulin resistance was the muscle. We thought if we could control insulin resistance in muscle, that would lead to improved diabetes control. Maybe that isn't true. Maybe it's more important in the liver or the beta cells or even the brain. So maybe the drugs we're using don't really get to all these target tissues." —Misia Landau |
