Treatments and Information on Diabetes

A team of researchers from the Harvard School of Public Health, led by Gökhan Hotamisligil of the Department of Nutrition and collaborators Lufen Chang and Michael Karin from University of California, San Diego, have identified the gene JNK (c-Jun Amino-terminal kinases) as the key component in interfering with insulin sensitivity in the metabolic pathway for obesity, obesity-induced insulin resistance and type 2 diabetes. The discovery identifies a new target for therapeutic drugs for both obesity and diabetes. The research findings appear in the November 21 issue of the journal Nature.

Obesity is closely associated with insulin resistance and is one of the leading risk factors for type 2 diabetes, both affect more than 50 percent of the US population. Little has been known about the molecular mechanisms between these two metabolic diseases. Both are associated with a wide range of inflammatory molecular activity in fatty tissue. These actions activate the JNK that interfere with insulin sensitivity. Type 2 diabetes usually occurs after age 40. People with this type of diabetes do not produce adequate amounts of insulin for the needs of the body and/or cannot use insulin effectively.

To test the role of JNK (also known to researchers as "Junk") in decreasing insulin sensitivity in a variety of obesity models, the team bred mice lacking either form of the gene JNK1or JNK2 and mice possessing the JNK genes and fed both groups a high fat, high calorie diet to induce obesity. A control group of lean mice with identical genotypes was fed a standard diet. JNK activity and protein concentrations were highest in liver, muscle and fat tissue in mice with the JNK1 gene that were on the high fat diet compared to lean control mice and mice fed a high fat diet that lacked the JNK gene. Weight gain rose the sharpest over an eight-week span for the mice on the high fat diet but particularly for those with the JNK genes. In studying total body fat composition, JNK-deficient mice had significantly decreased total body fat accumulation compared to the other groups.

Analyzing blood insulin levels, the researchers found that the obese mice with JNK1 developed mild hyperglycaemia (an excess of glucose in the blood which can lead to diabetic coma if untreated) compared to their lean counterparts. The same group also developed hyperinsulinaemia (insulin is produced but the body is oblivious to it). The obese group lacking JNK1 had significantly lower insulin and blood glucose levels than the obese group with JNK.

"We concluded that the increase in blood glucose and insulin levels in the mice with JNK1, on a high fat diet, were closely linked to obesity-induced insulin resistance, leading to Type 2 diabetes," said Hotamisligal, associate professor of nutrition at HSPH. "The JNK1-deficient group was protected from those dangers. This makes JNK1 an attractive target for new therapeutic drugs to treat the most prevalent metabolic diseases around the world: obesity, insulin resistance and type 2 diabetes." Jiro Hirosumi, and Gürcol Tuncman, Marry K. Iococca Fellow at HSPH were the principal contributors with Cem Z. Görgün, K.Teoman Uysal and Kazuhisha Maeda from the Division of Biological Sciences and the Department of Nutrition at the Harvard School of Public Health. Lufen Chang and Michael Karin were collaborators from the University of California at San Diego.

The study was funded in part by grants from the National Institutes for Health and the Pew Foundation.