A disordered thermostat  pg. 3

Constellation of symptoms

How do the beta cells know when to secrete insulin? Here’s part of the answer: They contain an enzyme called glucokinase, which puts a phosphate group on the glucose molecule. In the process, the enzyme stimulates the beta cell to secrete insulin.

Mark A. Magnuson, M.D., the Earl W. Sutherland Jr. Professor of Molecular Physiology and Biophysics who helped identify the role of glucokinase in insulin secretion, compares it to a “thermostat.” Depending upon whether it is blocked or activated, blood glucose rises or falls.

Maturity-onset Diabetes of the Young or MODY, a rare form of diabetes, can result from mutations in any one of at least six different genes that play a role in the ability of the beta cell to sense the presence of high levels of glucose, including the gene for glucokinase.

“Type 2 diabetes … may actually be a disease of a disordered thermostat,” says Magnuson, who chairs the steering committee of the Beta Cell Biology Consortium, an effort supported by the National Institute of Diabetes and Digestive and Kidney Diseases to improve understanding of the beta cell.

The challenge is to develop drugs or other treatments that can adjust the thermostat without causing serious side effects.

“That’s why (diabetes), despite all the investment of money, intellect and resources, is still getting worse,” says Cherrington, former chairman of the Department of Molecular Physiology and Biophysics at Vanderbilt and past president of the American Diabetes Association. “As yet we don’t understand the complexity of the disease.”

As an example of that complexity, an estimated 17 million Americans have diabetes, but nearly four times that number may have metabolic syndrome, also called insulin resistance, a constellation of symptoms that places them at high risk for developing type 2 diabetes and heart disease.

Symptoms include abdominal obesity, high blood pressure, high blood glucose, high levels of trigylcerides and low levels of high-density lipoproteins (HDL). Trigylcerides are a form of fat that contribute to atherosclerosis, the build-up of fatty deposits in blood vessels, whereas HDL is a type of cholesterol that seems to protect against it.

Fat cells, also called adipocytes, also can build up in the liver and pancreas, affecting their ability to function properly. In addition, recently discovered hormones released by adipose tissue, including leptin, resistin and adiponectin, can influence glucose metabolism in one way or another, some by opposing or complementing the effects of insulin, others by signaling the brain to suppress appetite. So can hormones released the digestive tract, such as ghrelin, PYY and GLP-1.

“You cannot study the beta cell in isolation,” explains Christopher B. Newgard, Ph.D., director of the Sarah W. Stedman Nutrition and Metabolism Center at Duke University. “There is a remarkable interplay and dovetailing of these regulatory circuits.”

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