Sitagliptin Can Slow the Onset of Diabetes

With more than 60 million people in the US with prediabetes and this number growing rapidly, there is a great interest in finding treatments that can reverse prediabetes and prevent someone from becoming diabetic.

Type 2 diabetes is caused by insufficient levels of insulin to keep blood glucose under control. Excessive levels of another hormone, glucagon, can also contribute by causing the liver to flood the body with stored glucose but it doesn’t happen overnight.  Researchers are seeking ways to prevent prediabetes from progressing to diabetes.

In a new study, researchers in the Department of Nutrition at Case Western Reserve University aimed to determine whether a newer diabetes drug, sitagliptin, might be effective in prediabetes. Sitagliptin works by boosting the levels of an intestinal factor known as GLP-1. This factor increases insulin output while also decreasing glucagon output. Researchers used an animal model with prediabetes, the SHROB rat, which was developed at Case Western Reserve University in the 1970’s. These rats are extremely obese and have normal glucose after fasting but high glucose after a meal, similar to pre-diabetic humans. Also like pre-diabetic humans, they have excessive levels of glucagon.

The pre-diabetic rats were divided into three groups and treated with either a placebo, sitagliptin, or another older diabetes medication, glyburide, which boosts the production of insulin by the pancreas. Sitagliptin and glyburide were equally effective in lowering glucose levels after a meal. Surprisingly, only sitagliptin raised the total output of insulin by the pancreas and only sitagliptin lowered glucagon to normal levels.

Neither of the diabetes medications had any effect on body weight, total body fat or food intake. These results match those found in studies on humans, which show no loss or gain of weight from these drugs. But differences appeared when the distribution of body fat was examined. Compared to the older drug glyburide, sitagliptin caused a redistribution of body fat from the abdominal fat deposits to deposits under the skin. Lowering the proportion of fat stored within the abdomen has a number of favorable effects in diabetes and for cardiovascular risk factors. This is the first time that sitagliptin has been found to affect fat distribution, and the cellular basis for this change is an open question.

Paul Ernsberger, Ph.D., group leader, said, “These animal studies suggest that sitagliptin should be tested in the clinic as a possible diabetes-preventing medication. It may act to shore up the function of the pancreas, which deteriorates during the onset of diabetes.”  Co-investigator Richard J. Koletsky, M.D., said, “Sitagliptin’s effects on enhancing post prandial insulin secretion and decreasing glucagon secretion offer new pharmacologic interventions to combat diabetes and potentially delay and even prevent its onset.”

Experimental Biology and Medicine March 2011