Type 2 diabetes mellitus (T2DM), Non Alcoholic Fatty Liver Disease (NAFLD), and their associated co- morbidities, are emerging as the most important health care problems in the USA. Recent studies by our group have established a key role for NAFLD in the pathogenesis of hepatic insulin resistance and T2DM in both adults and children. Complementary studies in transgenic and gene knockout mice by our group have elucidated the molecular mechanism for hepatic insulin resistance associated with NAFLD. In this R-24 grant a team of interdisciplinary and independent investigators, who have an established track record of collaboration, will address fundamental questions regarding the relationship between these two increasingly prevalent conditions. Specifically, this team of interdisciplinary scientists will examine the complex and related problems of who develops NAFLD, how does NAFLD cause hepatic insulin resistance, what triggers the increased hepatic gluconeogenesis in T2DM, and how do many of these changes rapidly resolve following Roux-en-Y gastric bypass (RYGB), even before substantial weight loss? Specifically we will examine: 1) The molecular mechanisms of hepatic insulin resistance and increased hepatic gluconeogenesis associated with NAFLD and T2DM. 2) The role of specific gene variants in apolipoprotein C3 in the pathogenesis of NAFLD and hepatic insulin resistance. 3) The cellular and molecular mechanisms responsible for the reversal of insulin resistance and T2DM following Roux-en-Y gastric bypass. This proposal builds on an established track record of interdisciplinary collaboration among the investigators as well as a 25-year history of developing and implementing novel state-of-the-art MRS/MRI and stable isotope methodologies for noninvasively assessing hepatic glucose and lipid metabolism in humans. It is anticipated that the results from the proposed studies will shift the current paradigm in our understanding of the pathogenesis of NAFLD, hepatic insulin resistance and T2DM.

Public Health Relevance

This interdisciplinary team science program will examine the pathogenesis of type 2 diabetes mellitus and non alcoholic fatty liver disease, which are rapidly emerging as the greatest global health challenges of the twenty-first century in both adults and children.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Resource-Related Research Projects (R24)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (O3))
Program Officer
Laughlin, Maren R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
Zip Code
Ter Horst, Kasper W; Gilijamse, Pim W; Versteeg, Ruth I et al. (2017) Hepatic Diacylglycerol-Associated Protein Kinase C? Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans. Cell Rep 19:1997-2004
Camporez, João-Paulo G; Petersen, Max C; Abudukadier, Abulizi et al. (2016) Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice. Proc Natl Acad Sci U S A 113:2212-7
Kursawe, Romy; Dixit, Vishwa D; Scherer, Philipp E et al. (2016) A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents. Diabetes 65:610-8
Samuel, Varman T; Shulman, Gerald I (2016) The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest 126:12-22
Camporez, João Paulo G; Kanda, Shoichi; Petersen, Max C et al. (2015) ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content. J Lipid Res 56:526-36
Perry, Rachel J; Camporez, João-Paulo G; Kursawe, Romy et al. (2015) Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160:745-758
Ziegler, Dan; Strom, Alexander; Strassburger, Klaus et al. (2015) Differential Patterns and Determinants of Cardiac Autonomic Nerve Dysfunction during Endotoxemia and Oral Fat Load in Humans. PLoS One 10:e0124242
Perry, Rachel J; Lee, Sangwon; Ma, Lie et al. (2015) FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic-pituitary-adrenal axis. Nat Commun 6:6980
Lawan, Ahmed; Zhang, Lei; Gatzke, Florian et al. (2015) Hepatic mitogen-activated protein kinase phosphatase 1 selectively regulates glucose metabolism and energy homeostasis. Mol Cell Biol 35:26-40
Vatner, Daniel F; Snikeris, Jaclyn; Popov, Violeta et al. (2015) 3,5 Diiodo-L-Thyronine (T2) Does Not Prevent Hepatic Steatosis or Insulin Resistance in Fat-Fed Sprague Dawley Rats. PLoS One 10:e0140837

Showing the most recent 10 out of 55 publications