Diabetes Research Center

UCSD/UCLA/Cedars-Sinai/Salk Supported by NIDDK

Metabolism (Co-Leaders: Richard Bergman and Jerrold Olefsky)

Studies of metabolism encompass a broad range of activities ranging from fundamental basic research in model systems to direct interventional clinical studies at the bedside, and is the largest focus in the DRC. The members in this research base study insulin resistance, the pathophysiology of type 1 and 2 diabetes, obesity, the microbiome, regulatory peptide biology, and understanding of new therapeutics. Highlights include the following.

 

  1. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges, by DRC member Panda and others in Cell Metabolism (2014). Panda and colleagues show that time restricted feeding attenuated metabolic diseases arising from a variety of obesogenic diets, and that benefits were proportional to the fasting duration, and stabilized and reversed the progression of metabolic diseases in mice with preexisting obesity and type 2 diabetes. This manipulation may prevent and treat obesity and metabolic disorders, including type 2 diabetes, hepatic steatosis, and hypercholesterolemia.
  2. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects, by DRC member Saghatelian and others in Cell (2015). Lipidomic analysis of adipose tissue revealed the existence of branched fatty acid esters of hydroxy fatty acids (PAHFAs) that correlate with insulin sensitivity, and are reduced in adipose tissue and serum of insulin-resistant humans. PAHSA administration in mice lowers ambient glycemia and improves glucose tolerance while stimulating GLP-1 and insulin secretion, suggesting that these endogenous lipids have the potential to treat type 2 diabetes.
  3. Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin resistance in obesity, by DRC members Olefsky, Schenk, Quehenberger and others in Nature Medicine (2015). Early in the course of obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia. Genetic or pharmacologic inhibition of these events can prevent or reverse these pathophysiologic events, restoring a state of insulin sensitivity and glucose tolerance.