August Krogh Seminar

The pathogenesis of insulin resistance: Integrating signaling pathways and substrate flux

v/ Professor Gerald I. Shulman, M.D., Ph.D., George R. Cowgill Professor of Medicine and Cellular & Molecular Physiology. Investigator, Howard Hughes Medical Institute, Yale University School of Medicine. Director, Metabolic Imaging and Liver Metabolism, Novo Nordisk Foundation Center for Basic Metabolic Research

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major factor in the pathogenesis of type 2 diabetes (T2D) and nonalcoholic steatohepatitis (NASH). This presentation will focus on the cellular mechanisms of liver and muscle insulin resistance in humans and the role of dysregulated intracellular lipid metabolism in its pathogenesis. Specifically this talk will review recent studies that have implicated increases in ectopic lipid content in causing insulin resistance in these organs as well as recent studies that have implicated diacylglycerol, as the molecular trigger for lipid-induced insulin resistance through its activation of PKC-epsilon in liver and PKC-theta in skeletal muscle leading to inhibition of insulin signaling and the identification of Thr1160 phosphorylation on the insulin receptor as a mediator of lipid-induced hepatic insulin resistance. This talk will also review recent studies that identify the link between white adipose tissue inflammation and increased rates of hepatic gluconeogenesis and fasting hyperglycemia in patients with type 2 diabetes due to increased rates of lipolysis leading to increased hepatic acetyl CoA content and allosteric activation of pyruvate carboxylase. Finally I will discuss our recent studies demonstrating the potential utility of promoting mild liver-targeted hepatic mitochondrial inefficiency as a novel therapeutic approach to treat NASH and T2D.

Relevant papers

Role of ectopic fat in insulin resistance, dyslipidemia and cardiometabolic disease. N Engl J Med. 2014;371(12)1131-1141. Shulman, GI.

Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science. 2015;347(6227)1253-56. Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI.

Reversal of hypertriglyceridemia, fatty liver disease and insulin resistance by a liver-targeted mitochondrial uncoupler. Cell Metabolism. 2013;(18):740-48. Perry RJ, Kim T, Zhang XM, Lee HY, Pesta D, Popov VB, Zhang, D, Rahimi Y, Jurczak MJ, Cline GW, Spiegel DA, Shulman GI

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest, 2016;126(1)12-22. Samuel VT, Shulman GI.

Research profile

Dr. Shulman is the George R. Cowgill Professor of Medicine, Cellular & Molecular Physiology and Physiological Chemistry at Yale University, where he serves as Co-Director of the Yale Diabetes Research Center and Prof (Hon) at the University of Copenhagen where he is Director of Metabolic Imaging and Liver Metabolism at the Novo Nordisk Center for Basic Metabolic Research. He is also an Investigator of the Howard Hughes Medical Institute.

Dr. Shulman has pioneered the use of magnetic resonance spectroscopy to non-invasively examine intracellular glucose and fat metabolism in humans for the first time. Using this approach he has conducted ground breaking basic and clinical investigative studies on the cellular mechanisms of liver and muscle insulin resistance that have led to several paradigm shifts in our understanding of type 2 diabetes.

Dr. Shulman has authored and co-authored over 400 peer-reviewed publications, and he has also trained more than 60 postdoctoral fellows and graduate students, many of whom now direct their own independent laboratories around the world.

Dr. Shulman is a Master of the American College of Endocrinologists, Fellow of the American Association for the Advancement of Science and he has been elected to the American Society for Clinical Investigation, the Association of American Physicians, the National Academy of Medicine and the National Academy of Sciences.

Time

5 December 2016

14:00-15:00: Seminar and discussion
15:00-15:30: Post seminar servings and socializing

Venue

Auditorium 1, August Krogh Building, Universitetsparken 13, DK-2100 Copenhagen

Registration

Participation is free, but please register here.

For PhD students

PhD students participating in August Krogh seminars receive 0,2 ECTS per seminar

Contact

Christian Frøsig, CFrosig@nexs.ku.dk, mobile +45 2875 1617

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