Facets of Diabetes and Obesity Research

To further research for predicting, preventing, treating and, ultimately, curing diabetes and obesity, Cedars-Sinai has assembled a team of scientists for the Diabetes and Obesity Research Institute (DORI). Led by Richard N. Bergman, PhD, DORI studies many facets of diabetes and obesity in search of solutions to help curb the growing epidemic of these metabolic diseases.

Earlier in his career, Bergman developed the minimal model of glucose kinetics based on mathematical modeling. His engineering education brought a quantitative approach to a qualitative science, providing the ability to express in quantitative terms the compensatory relationship between insulin resistance and insulin response. The minimal model signaled a breakthrough in understanding the pathogenesis of diabetes, leading to expanded areas of study.

A tool derived from the minimal model, the disposition index, is used to detect when the pancreas begins to fail early in the process and explains who is at risk for diabetes. Measuring insulin resistance as well as measuring the function of pancreatic beta cells led to the discovery that the primary defect in people at risk for diabetes is the inability of the pancreas to adequately compensate for insulin resistance.

The minimal model and disposition index are still used throughout the diabetes research community for epidemiology and genetic studies and have prompted much of DORI’s current research.

• Measuring insulin resistance and identifying it as a risk factor for diabetes has guided studies to learn why insulin resistance is a risk factor. Uncovering the link between adiposity and insulin resistance has led to research to understand why fat is a risk factor for diabetes.
• Another discovery — that insulin works more slowly than initially thought — has led to studies investigating why insulin works slowly and how insulin crosses endothelial cells. DORI researchers are looking at impaired insulin resistance at the cell level to discover when endothelial dysfunction begins.
  
• The minimal model also uncovered the role of the liver and insulin degradation in diabetes. Examining the liver’s role in insulin clearance in both healthy and insulin resistant states may help determine whether therapies targeting the liver to reduce insulin clearance are potentially helpful in treating Type 2 diabetes.
  
• A recently developed lactate metabolism model has enabled an estimation of glucokinase activity to better understand insulin independent of the effects of glucose on metabolism.
  
• Genetic studies continue to search for a specific gene for Type 2 diabetes. Based on observations in twins, diabetes has a strong genetic component. While more than 60 diabetes-related variants have been identified, finding a specific gene has been elusive.
  

Other hypothesis-based research approaches in DORI have been derived from inadvertent discoveries.

• The poisonous saliva of the Gila monster is a glucagon-like peptide-1 (GLP-1) that is resistant to destruction by the enzyme dipeptidyl-peptidase IV, unlike the GLP-1 that is found in the human gut. This knowledge led to the development of important medications currently on the market. DORI studies are focused on understanding and enhancing GLP-1 and the gut-brain communication in order to develop better therapies in regulating blood sugar and body weight.
• Bariatric surgery showed changes in insulin resistance and insulin production in the first week irrespective of weight loss. This finding has DORI scientist looking for the mechanisms leading to remission of Type 2 diabetes after bariatric surgery.
  
• The inverse association between diabetes and obesity in people living in high altitudes has led to DORI studies that examine which attributes related to high altitude are influencing the beneficial effect.
  

In addition to research in the laboratory, Cedars-Sinai favors translational medicine. DORI members include scientists as well as physicians who collaborate on combining relevant science with clinical work. Bergman’s role is to guide the DORI team in performing diabetes and obesity work that has clinical relevance. The goal is to focus on research that leads to the development of drugs and medical devices for treating patients in addition to making new discoveries that could lead to a cure.