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Feb 17, 2011

Role of Brain Insulin in Type 2 Diabetes Revealed

Role of Brain Insulin in Type 2 Diabetes Revealed

In particular, impaired hypothalamic insulin action may trigger unrestrained lipolysis, which leads to type 2 diabetes.[V. Yakobchuk/Fotolia.com]

  • Scientists from Mount Sinai School of Medicine have discovered a novel function of brain insulin. They say that impaired brain insulin action may be the cause of the unrestrained lipolysis that initiates and worsens type 2 diabetes.

    The research is published this month in Cell Metabolism in a paper titled “Brain Insulin Controls Adipose Tissue Lipolysis and Lipogenesis.”

    Lipolysis is a process during which triglycerides in fat are broken down and fatty acids are released. White adipose tissue (WAT) dysfunction plays a key role in the pathogenesis of type 2 diabetes. Unrestrained WAT lipolysis results in increased fatty acid release, leading to insulin resistance and lipotoxicity. Additionally, impaired de novo lipogenesis in WAT decreases the synthesis of insulin-sensitizing fatty acid species like palmitoleate.

    Researchers previously believed that insulin’s ability to suppress lipolysis was entirely mediated through insulin receptors expressed on adipocytes. “We knew that insulin has this fundamentally important ability of suppressing lipolysis, but the finding that this is mediated in a large part by the brain is surprising,” says study leader Christoph Buettner, M.D., assistant professor of medicine in the division of endocrinology, diabetes and bone disease.

    Dr. Buettner’s team started by infusing a tiny amount of insulin into the mediobasal hypothalamus (MBH) of Sprague-Dawley rats. They then assessed glucose and lipid metabolism in the whole body of the rats. They found increased WAT lipogenic protein expression, inactivated hormone-sensitive lipase, and suppressed lipolysis.

    Conversely, mice that lack the neuronal insulin receptor exhibited unrestrained lipolysis and decreased de novo lipogenesis in WAT. Thus, brain and, in particular, hypothalamic insulin action play a pivotal role in WAT functionality, the researchers conclude.

    “The major lipolysis-inducing pathway in our bodies is the sympathetic nervous system, and here the studies showed that brain insulin reduces sympathetic nervous system activity in fat tissue,” Dr. Buettner notes. “In patients who are obese or have diabetes, insulin fails to inhibit lipolysis and fatty acid levels are increased. The low-grade inflammation throughout the body’s tissue that is commonly present in these conditions is believed to be mainly a consequence of these increased fatty acid levels.

    “When brain insulin function is impaired, the release of fatty acids is increased,” Dr. Buettner continues. “This induces inflammation, which can further worsen insulin resistance, the core defect in type 2 diabetes.

    “Therefore, impaired brain insulin signaling can start a vicious cycle since inflammation can impair brain insulin signaling,” Dr. Buettner explains. “This cycle is perpetuated and can lead to type 2 diabetes. Our research raises the possibility that enhancing brain insulin signaling could have therapeutic benefits with less danger of the major complication of insulin therapy, which is hypoglycemia.”

    Dr. Buettner’s team plans to further study conditions that lead to diabetes, such as overfeeding, to test if excessive caloric intake impairs brain insulin function. A major second goal will be to find ways of improving brain insulin function that could break the vicious cycle by restraining lipolysis and improving insulin resistance.


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