Young-Mi Kwon ‘15, THURJ Staff

The rise of the chronic disease, Type 2 diabetes, has played a dominant role in modern America and in the world. Affecting over 300 million people world­wide, Type 2 diabetes is becoming increasingly prevalent in younger generations. Its global spread garners atten­tion as one of the biggest public health challenges of the century. Recent advancements in understanding insulin resistance and anti-diabetic treatments have highlighted potential avenues for improving anti-diabetic drugs cur­rently being used.

Bruce Spiegelman’s 1994 discovery of the PPAR gamma nuclear receptor, the so-called “master regulator of fat development,” has led to the use of a class of anti-dia­betic medications called thiazolidinediones (TZD). These include rosiglitazone and pioglitazone, more commonly known by their trade names Avandia and Actos. Although TZD drugs have shown anti-diabetic therapeutic effects, studies have linked these drugs to cardiovascular prob­lems, fluid retention, and loss of bone density.

These TZD drugs act as “full agonists” for PPAR gamma receptors, modulating the action of PPAR gamma and increasing insulin sensitivity. However, partial agonists for PPAR gamma have shown similar anti-diabetic effects despite only weakly activating the receptor.

Dr. Spiegelman’s research has shown that the TZD drugs may not be acting as agonists. Rather, they bind directly to the receptor, blocking the phosphorylation of that receptor by a certain protein kinase, Cdk5. This discovery may explain the effectiveness of partial ago­nists as anti-diabetic drugs. According to Dr. Spiegelman, “people had been going after drugs that bind to the right target, but not the right function.” Creating better ago­nists for PPAR gamma resulted in similar efficacy with the same “benefit to side-effect ratio”. New anti-diabetic drugs could be developed to target this phosphorylation process, ultimately improving this ratio. To that end, Dr. Spiegelman’s lab created drug prototypes that were non-agonist, yet maintained the anti-diabetic action with fewer side effects when tested in obese mice. Although these compounds are not suitable for pharmacology, Professor Spiegelman notes them as a “proof of principle”—a step forward to more specific, potent drugs.

In addition to the research on the PPAR gamma, ongo­ing studies on anti-diabetic action has concentrated on brown fat cell differentiation and their relation to exercise. Brown fat cells possess a high number of mitochondria, through which they dissipate energy as heat. More impor­tantly, Dr. Spiegelman explains that these brown fat cells are the only cell type in the body that has anti-diabetic and anti-obesity effects. Dr. Spiegelman’s laboratory demonstrated the function of PRDM16 as a regulator of brown fat cell differentiation. Further research in this area could enhance our understanding of how manipulation of these mechanisms could increase the amount and action of brown adipose cells, thereby serving as another poten­tial anti-obesity or anti-diabetic treatment. In relation to these studies, researchers have revealed that physical activity is linked with the activation of brown adipose cells. Understanding the biochemical pathways behind the positive health effects of exercise may provide us with yet another avenue for potential treatment in the future.

Future research in the biochemical pathways of PPAR gamma and brown fat differentiation and activation will lead to more effective anti-diabetic therapies. While pre­ventative measures to minimize the risk of obesity and diabetes can be taken through education, appropriate diet, and exercise, for those currently afflicted with diabetes, these new advancements represent another step towards a more effective, less invasive anti-diabetic treatment.

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