The National Institute of Diabetes & Digestive & Kidney Diseases

1983 BS (Caltech)

1984 MA (Princeton)

1988 PhD (Princeton)

1988-1991 Research Physicist, Institute for Theoretical Physics, University of California, Santa Barbara

1991-1993 Member, The Institute for Advanced Study, Princeton

1993-2001 Assistant Professor, Physics Department, Princeton University, Princeton

Quantitative Estimation of Sensitivity of Lipolysis to Insulin

Insulin resistance is a primary risk factor for several common diseases, including diabetes, cardiovascular disease, hypertension and some forms of cancer. The mechanisms underlying insulin resistance are not completely understood. One important gap in our understanding relates to defects in insulin_s ability to regulate lipolysis, leading to relative elevations of plasma free fatty acids (FFA). Elevated FFA have been implicated in the modification of insulin action in various tissues as well as altering intermediates in the insulin signaling pathway and mitochondrial enzymes. Therefore, methods to quantify insulin effects on lipolysis and plasma FFA levels in various conditions of insulin resistance would be useful. As insulin is a critical modulator of FFA levels in vivo, our goal is to find a simple mathematical model that could reproduce the time course of serum FFA levels in response to insulin and to use this model as the basis of an index of FFA sensitivity to insulin that described insulin_s acute effect (minutes to hours) on plasma FFA levels.

Model of Reactive Oxygen Species in Mitochondria

Reactive oxygen species (ROS) have been shown to have tissue-damaging effects that underlie many disease complications, including those associated with diabetes, Parkinson's, Alzheimer's, and atherosclerosis (Brownlee, 2005). This oxidative stress is thought to result from an organism's inability to detoxify and repair damage at the same rate that ROS are produced. On the other hand, it should be noted that ROS signaling is important in cellular functioning. In mitochondria, where ROS (e.g., superoxide) are produced through a process that is very sensitive to the proton motive force, oxidative stress is prevented by scavenging enzymes (SC; e.g., MnSOD) and uncoupling proteins (UCP; e.g., UCP2). Details of this regulation in mitochondria are still being established. The interplay between nutrient sensing and ROS signaling is complex and the goal of our research is to mathematically model the relevant pathways to understand the deleterious aspects of this interplay as it relates to the metabolic syndrome and obesity.

Adipocyte development and Insulin Resistance

Our overall goal is to understand how adipose tissue dynamics is related to insulin resistance and diabetes. Adipose tissue grows by two mechanisms: hyperplasia (cell number increase) and hypertrophy (cell size increase). How do genetics and diet affect the relative contributions of these two mechanisms to the growth of adipose tissue in obesity? We are particularly interested in investigating the role played by insulin sensitizing agents such as thiazoledinediones in altering the development of adipocytes. We chose to investigate this dynamic behavior by mathematically modeling the changes in cell size distributions in adipose tissue over time under several conditions since this provides a global view of cell size dynamics as adipocytes accumulate lipid and move from small sizes to maturity.

1. Patterns in food intake correlate with body mass index.

Periwal V, Chow CC. Am J Physiol Endocrinol Metab. 2006 Nov;291(5):E929-36.

2. Evaluation of quantitative models of the effect of insulin on lipolysis and glucose disposal.

Periwal V, Chow CC, Bergman RN, Ricks M, Vega GL, Sumner AE. Am J Physiol Regul Integr Comp Physiol. 2008 Oct;295(4):R1089-96.

3. Hypertrophy and/or Hyperplasia: Dynamics of Adipose Tissue Growth.

Jo J, Gavrilova O, Pack S, Jou W, Mullen S, Sumner AE, Cushman SW, Periwal V. PLoS Comput Biol. 2009 Mar;5(3):e1000324.

4. A model of liver regeneration.

Furchtgott LA, Chow CC, Periwal V. Biophys J. 2009 May 20;96(10):3926-35.

5. Islet formation during the neonatal development in mice.

Miller K, Kim A, Kilimnik G, Jo J, Moka U, Periwal V, Hara M. PLoS One. 2009 Nov 6;4(11):e7739.

6. Differential effects of thiazolidinediones on adipocyte growth and recruitment in Zucker fatty rats.

MacKellar J, Cushman SW, Periwal V. PLoS One. 2009 Dec 24;4(12):e8196.

7. Cdk4 regulates recruitment of quiescent beta-cells and ductal epithelial progenitors to reconstitute beta-cell mass.

Lee JH, Jo J, Hardikar AA, Periwal V, Rane SG. PLoS One. 2010 Jan 13;5(1):e8653.

8. Waves of adipose tissue growth in the genetically obese Zucker fatty rat.

MacKellar J, Cushman SW, Periwal V. PLoS One. 2010 Jan 22;5(1):e8197.

9. Expression in aneuploid Drosophila S2 cells.

Zhang Y, Malone JH, Powell SK, Periwal V, Spana E, Macalpine DM, Oliver B. PLoS Biol. 2010 Feb 23;8(2):e1000320.

10. Autoregulation of free radicals via uncoupling protein control in pancreatic beta-cell mitochondria.

Heuett WJ, Periwal V. Biophys J. 2010 Jan 20;98(2):207-17.