Cellular & Molecular Physiology

The pathologic changes that underlie type 1 and type 2 diabetes begin years before these diseases actually develop. Researchers in the Section on Cellular and Molecular Physiology are especially interested in identifying early genetic, epigenetic, molecular and cellular changes that presage and promote the development of diabetes and associated complications. Their expectation is that breakthroughs in understanding the early natural history of these diseases will lead to new and improved methods for intervention. 

Members of the section work on different aspects of the diabetes problem, with primary interests including genetics and epigenetics, beta-cell development and growth, insulin resistance, immunology and inflammation and the regulation of metabolic homeostasis. Although their approaches differ and they tackle problems from different directions, section investigators share a strong desire to translate discoveries from bench to bedside and back to bench again in an effort to extend their basic findings to patient care.

The triple whammy of weight gain, poor diet and lack of exercise—seen all too often in Americans and increasingly worldwide—leads to multiple health problems, including type 2 diabetes, high blood pressure, elevated lipid levels and heart disease. Researchers in the section have found that inflammation, an immune system response that normally fights infection and promotes healing, plays a major role in the development of insulin resistance and type 2 diabetes. These researchers were the first to show that a major trigger of inflammation—the transcription factor NF-kB—is activated in obese tissues and perhaps provides the “missing link” between obesity and diabetes.
  
In a bench-to-bedside victory, researchers built on these discoveries by conducting small trials in patients with diabetes, testing anti-inflammatory salicylates, which inhibit NF-kB, as insulin sensitizers. In these patients, blood glucose and lipid levels substantially decreased, glucose uptake and utilization improved and liver glucose production increased. Over the next several years, researchers will conduct much larger, multicenter trials to compare the effects of anti-inflammatory salicylates to current standards of therapy in patients with diabetes and cardiovascular disease.

Risk factors for type 2 diabetes include family history, obesity, sedentary lifestyle, poor fetal nutrition and low birth weight. Section researchers are interested in learning how these different risk factors converge at the genetic level to predispose to diabetes. One approach is the use of gene chip technology to simultaneously measure the activities of more than 7,000 genes. 

In a seminal discovery, section investigators found that the expression of a group of genes is impaired in people with type 2 diabetes and pre-diabetes. The identified genes help regulate the function of mitochondria, the small power plants in cells that convert fuel into energy. Due to the faulty genes, the cells have trouble burning fat and other fuels, which may allow the fats to accumulate and thus impair responses to insulin. In these studies as well as those in the area of fetal malnutrition, section researchers are hoping to identify new avenues for intervention, with drugs as well as through nutrition, to improve the lives of patients with diabetes. 

Healthy beta cells respond to the increasing demands of insulin resistance by producing more insulin. Diabetes occurs only when the beta cells fail to produce sufficient insulin to meet metabolic demands. The underlying vulnerabilities that predispose people to the beta-cell dysfunction in type 2 diabetes may be genetic or acquired. Given that beta cells produce insulin, it may seem counterintuitive that they also respond to insulin and may even develop insulin resistance, but this appears to be the case.  Researchers in the section are leading the way in this new area of discovery, looking at new roles for insulin and insulin-like growth factor 1, and even the fat-cell-derived hormone leptin, in beta-cell development, replication, glucose sensing and insulin production. These studies will potentially impact type 1 as well as type 2 diabetes, as researchers in this area consider new methods for beta-cell regeneration and replenishment.