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Nov 7, 2013

Brain-Pancreas Imbalance May Be the Crux of Type 2 Diabetes

  • Insulin, or more precisely insulin-mediated glucose metabolism, may be just half the story of type 2 diabetes. Another system, centered in the brain, also plays a part in regulating glucose levels. In fact, it appears a brain-pancreas balancing act is responsible for blood sugar metabolism—and when the balance is tipped, usually by a failure of the brain-centered system, the insulin-dependent system tries, but ultimately fails, to restore equilibrium.

    By assigning such an important role to brain-centered mechanisms, the scientists investigating brain-pancreas coordination in diabetes are reviving ideas long neglected in diabetes research. The brain was originally thought to play an important role in maintaining normal glucose metabolism. With the discovery of insulin in the 1920s, however, diabetes research began to focus almost exclusively on insulin.

    A new report, published November 6 in Nature, may increase the scope of diabetes research so that it takes more account of insulin-independent mechanisms. This report, entitled “Cooperation between brain and islet in glucose homeostasis and diabetes,” notes that insulin-dependent mechanisms, known collectively as glucose effectiveness, account for roughly 50% of overall glucose disposal. Moreover, the report ventures that reduced glucose effectiveness also contributes importantly to diabetes pathogenesis.

    The report’s authors include scientists from the Diabetes and Obesity Center of Excellence at the University of Washington in Seattle, as well as researchers representing the Universities of Cincinnati, Michigan, and Munich. In the report, lead author Michael W. Schwartz, M.D., director of the Diabetes and Obesity Center, and his colleagues present evidence of a brain-centered glucoregulatory system (BCGS) that can lower blood glucose levels via both insulin-dependent and -independent mechanisms, and propose a model in which complex and highly coordinated interactions between the BCGS and pancreatic islets promote normal glucose homeostasis.

    In addition, the authors reviewed both animal and human studies to develop a model of normal glucose homeostasis. In this model, homeostasis is promoted by complex and highly coordinated interactions between the BCGS and pancreatic islets.

    “Because activation of either regulatory system can compensate for failure of the other, defects in both may be required for diabetes to develop,” write the authors. “Consequently, therapies that target the BCGS in addition to conventional approaches based on enhancing insulin effects may have the potential to induce diabetes remission, whereas targeting just one typically does not.”

    The development of type 2 diabetes appears to involve the failure of both systems, the researchers say. Impairment of the brain-centered system is common, and it places an increased burden on the islet-centered system. For a time, the islet-centered system can compensate, but if it begins to fail, the brain-centered system may decompensate further, causing a vicious cycle that ends in diabetes.

    In their conclusions, the authors call on other researchers to confirm that proper BCGS function is needed to maintain normal glucose effectiveness—and that BCGS dysfunction leads to type 2 diabetes. The authors also propose that considering the brain’s role in diabetes opens new avenues for drug development. They specifically cite the observation that hormones such as FGF19 can act in the brain to improve glucose homeostasis in animal models of diabetes. More to the point, write the authors, a specific FGF receptor subtype, FGFR1c, is widely expressed in the brain, raising the possibility that synthetic agonists of this receptor could prove effective for glucose lowering in patients with diabetes.



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