"Our findings suggest that, in individuals with diabetes, the ability of insulin to lower blood sugar involves the brain," said senior author of the study, Michael Schwartz of the University of Washington at Seattle. "This effect is not trivial; the brain makes a substantial contribution to insulin response."
The findings in rats suggest that therapies that boost the brain response to insulin in patients with diabetes might improve blood sugar control while lowering the required dose of the hormone, the researchers said. That advance, in turn, might help to reduce side effects of insulin treatment, such as weight gain, they added.
Insulin normally allows body tissues, such as the muscles, to take up the blood sugar glucose, the body's prime energy source. In those with diabetes due to a lack of normal insulin or insulin resistance, blood sugar rises, a condition that can lead to tissue damage.
Scientists once thought that insulin's effects were limited to peripheral body tissues that respond to the hormone by importing glucose. However, more recent studies have revealed that insulin receptors in the brain also play an important role in normal blood sugar control.
To extend those findings to the disease state in the current study, the researchers examined the brain's effect on insulin sensitivity in rats with diabetes due to a lack of so-called pancreatic beta cells, which normally secrete insulin. The rats' condition mimics type I, or juvenile, diabetes, a form of the disease that begins in childhood most often due to autoimmune destruction of cells in the pancreas, which leave the organ unable to produce insulin.
The researchers infused the brains of the diabetic rats with a chemical that limits the function of an enzyme involved in the normal insulin response before injecting the animals with the hormone. Without the normal brain response to insulin, the hormone therapy's efficacy for reducing blood sugar fell by about 35%, Schwartz said. Furthermore, they found that gene therapy interventions designed to increase the brain's insulin response heightened the animals' response to therapy about 2-fold.
Strategies that target the molecules involved in the brain's response to insulin "may therefore prove beneficial in the management of diabetes in humans," the researchers said.
Differences in brain sensitivity to the insulin hormone might also help to explain the often "huge variation in insulin requirement" among otherwise comparable diabetes patients, Schwartz said.
The researchers include Richard W. Gelling of the Harborview Medical Center, University of Washington in Seattle, Washington and Metabolex, Inc. in Hayward, California; Gregory J. Morton and Michael W. Schwartz of the Harborview Medical Center, University of Washington in Seattle, Washington; Christopher D. Morrison of the Harborview Medical Center, University of Washington in Seattle, Washington and Pennington Biomedical Research Center in Baton Rouge, Louisiana; Kevin D. Niswender of the Harborview Medical Center, University of Washington in Seattle, Washington and Vanderbilt University in Nashville, Tennessee; Martin G. Myers Jr. of the University of Michigan in Ann Arbor, Michigan; Christopher J. Rhodes of the Pacific Northwest Research Institute and University of Washington in Seattle, Washington. This work was supported by NIH grants DK52989, DK12829, DK68340, and NS32273 and by the Clinical Nutrition Research Unit of the University of Washington. R.W.G. was supported by a Dick and Julia McAbee Endowed Fellowship from the Diabetes Endocrinology Research Center of the University of Washington.
Gelling et al.: "Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes." Publishing in Cell Metabolism Vol. 3, Issue 1; January 2006, pages 67–73. DOI 10.1016/j.cmet.2005.11.013 www.cellmetabolism.org
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