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Ghrelin Involved in Development of Diabetes

Ghrelin, a hormone long considered a key player in obesity, may instead take a major role in maintaining the balance between insulin and glucose and the development of diabetes.

“Everybody has been pushing the connection between obesity and ghrelin,” said Dr. Roy G. Smith, director of the BCM Huffington Center on Aging, “Companies have been developing ghrelin antagonists as anti-obesity drugs. Now these drugs may have a value in treating diabetes.” The downside is that the drugs may not forestall obesity.

In studies in his laboratory, mice bred to be deficient in both ghrelin (which stimulates appetite) and leptin (associated with controlling obesity) could be expected to be thin or of normal body weight, said Smith, also a professor of Molecular and Cellular Biology at BCM. That was a surprise, said the paper’s first author, Dr. Yuxiang Sun, a BCM instructor in the center.

“They were just as fat as the mice bred to lack only leptin,” said Smith.

However, their glucose levels were lower than in leptin-deficient mice. When Sun did a glucose tolerance test on the mice, she found much lower levels in the animals that did not produce either ghrelin or leptin.

“They were more resistant to glucose because they secreted more insulin in response to the glucose challenge,” said Smith.

When Sun and Smith investigated further, they found lower levels of uncoupling protein-2 (Ucp2) in cells called pancreatic islets (where insulin is made). Reducing Ucp2 improves the cell’s ability to make ATP, the cell’s energy molecule, thereby increasing the sensitivity of the pancreatic beta cell (the cell in the pancreas which produces insulin) to glucose-induced insulin release. Further tests in animals lacking ghrelin, showed that besides increased insulin secretion, their sensitivity to insulin was increased, said Sun. “That means glucose was cleared more efficiently.”

While Smith sees a role for drugs that block ghrelin in treatment of type 2 diabetes (which usually occurs in adulthood and is often associated with obesity), he sounds a cautionary note.

“If through this process, you increase ATP production by the beta cell, you may in the long-term get oxidative stress which could eventually destroy the beta cell,” he said. He said he does not yet have data to determine whether that is true or not.

In an accompanying analysis, Dr. Rexford S. Ahima of the University of Pennsylvania School of Medicine, wrote, “Overall, the studies provide compelling evidence that ghrelin has unique dual effects on glucose homeostasis (the balance between glucose and insulin), at least in a genetic model. Ghrelin antagonism (or blocking) may be a new approach for treating type 2 diabetes by improving insulin secretion in response to glucose and enhancing peripheral insulin action. The challenge is to ascertain if these results in rodents can be translated to patients.”

journal Cell Metabolism, May 2006

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DID YOU KNOW: A decreasing incidence of diabetes complications, in the type 1 diabetes population around the world over the past 15–20 years. Mortality rates have also been decreasing, most likely reflecting better management and the declining morbidity. Improved metabolic control, facilitated by the advent of self-monitoring of blood glucose and HbA1c (A1C) testing and stimulated by the results of the Diabetes Control and Complications Trial, along with better blood pressure management are likely to be major contributors. However, Rossing et al. were unable to show decreasing rates for diabetic nephropathy and retinopathy after 15 years in a hospital-based cohort, whereas Brown et al., using a historical comparison of type 2 diabetic patients, demonstrated an unchanged prevalence of proliferative diabetic retinopathy, despite improved levels of glycemia and blood pressure. Diabetes. 2006;55(5):1463-1469.