Research & Publications
Insulin resistance is a major factor responsible for the pathogenesis of type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD)/ nonalcoholic steatohepatitis (NASH), obesity associated cancers and neurodegenerative disease. Over the last three decades my laboratory has pioneered the development and application of nuclear magnetic resonance spectroscopy combined with stable isotopes and GC-MS, LC-MS/MS analyses to assess tissue specific flux rates of glucose and fat metabolism in vivo in both humans and awake transgenic rodent models of insulin resistance in order to elucidate the molecular basis of insulin resistance. These studies have in turn provided paradigm-shifting insights into the cellular and molecular mechanisms of lipid-induced insulin resistance in liver and skeletal muscle which my group has established in both humans and rodent models of NAFLD and type 2 diabetes. Based on these studies, my group has now developed novel liver-targeted mitochondrial protonophores that reverse hyperlipidemia, insulin resistance, diabetes, NAFLD, NASH and liver fibrosis in rodent models of type 2 diabetes and NASH, which are now in clinical development. During my tenure at Yale, I have had the pleasure of mentoring well over 100 trainees, and more than three dozen of these trainees have gone on to direct their own research laboratories around the world.
Extensive Research Description
Mitochondria play an essential role in energy conversion and nearly all of the different components of food pass through the mitochondria for the generation of energy yet surprisingly little is known regarding the regulation of these anaplerotic and cataplerotic mitochondrial fluxes in vivo and the potential role they have in causing rare and common metabolic diseases such as type 2 diabetes and related cardiometabolic diseases.
The Shulman Lab is interested in: 1) Understanding the hormonal regulation of mitochondrial fluxes in vivo using novel NMR and LC-MS/MS methods (e.g. PINTA, Q-Flux) which we have recently developed to measure mitochondrial oxidative and anaplerotic fluxes in an organ (e.g. liver, muscle, renal cortex, brain) specific manner for the first time 2) Understanding the role of dysregulated mitochondrial fluxes in the pathogenesis of type 2 diabetes, lipodystrophy, polycystic kidney disease as well as other rare inherited metabolic diseases, 3) Development of novel agents to promote: a) liver-targeted mitochondrial uncoupling, b) alterations of intracellular NAD+ metabolism, c) alterations of intracellular CoA formation, for the treatment of, diabetes, atherosclerosis, aging and inherited diseases of lipid metabolism, 4) Assess the impact of SGLT2 inhibitors on myocardial and atrial mitochondrial metabolism and elucidate the mechanism for their cardioprotective effects, 5) Understand the role of cytosolic and mitochondrial Ca++ in the regulation of hepatic mitochondrial oxidation and gluconeogenesis and 6) Development of additional novel NMR, LC/MS/MS and GC/MS methodology to assess in vivo intracellular flux rates of glucose, amino acid and fatty acid metabolism and their applications to humans and transgenic/gene knockout rodent models of metabolic diseases.
• Shulman, GI. Role of ectopic fat in insulin resistance, dyslipidemia and cardiometabolic disease. N Engl J Med. 2014;371(12)1131-1141.
• Perry RJ, Camporez JP, Kursawe R, Titchenell PM, Zhang D, Perry CJ, Jurczak MJ, Abudukadier A, Han MS, Zhang XM Ruan HB, Yang, X, Caprio, S, Kaech, SM, Sul, HS, Birnbaum MJ, Davis RJ, Cline GW, Petersen KF, Shulman GI. Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell. 2015;(160)745-58.
• Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak, M, Camporez JP, Lee HY, Cline GW, Samuel VT, Kibbey RG, Shulman GI. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510:542-546
• Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science. 2015;347(6227)1253-56.
• Petersen KF, Befroy DE, Dufour S, Rothman DL, Shulman GI. Direct assessment of hepatic mitochondrial oxidation and pyruvate cycling in nonalcoholic fatty liver disease by 13C magnetic resonance spectroscopy. Cell Metab. 2016;24(1)167-71,
• Petersen MC, Madiraju AK, Gassaway BM, Marcel M, Nasiri AR, Butrico G, Marcucci MJ, Zhang D, Abudukadier A, Zhang XM, Philbrick W, Hubbard SR, Jurczak MJ, Samuel VT, Rinehart J, Shulman GI. Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance. J Clin Invest, 2016;1-11.
• Perry RJ, Peng L, Abudukadier A, Kennedy L, Cline GW, Shulman GI. Mechanism for leptin’s acute insulin-independent effect to reverse diabetic ketoacidosis. J Clin Invest. 2017;127(2)657-669.
• Perry RJ, Wang Y, Cline GW, Rabin-Court A, Song JD, Dufour S, Zhang XM, Petersen KF, Shulman GI. Leptin mediates a glucose-fatty acid cycle to maintain glucose homeostasis in starvation. Cell. 2018; 172 (1-2) 234-248.
• Roden M, Shulman GI. The Integrative Biology of Type-2 Diabetes. Nature. 576 (7785): 51-60.
• Petersen KF, Dufour S, Cline GW, Shulman GI. Regulation of Hepatic Mitochondrial Oxidation by Glucose-Alanine Cycling During Starvation in Humans. J Clin Invest. 2019; 129 (11): 4671-467.
• Goedeke L, Peng L, Montalvo-Romeral V, Butrico G, Dufour S, Zhang XM, Perry RJ, Cline GW, Kievit P, Chng K, Petersen KF, Shulman GI. Controlled-release Mitochondrial Protonophore (CRMP) Reverses Dyslipidemia and Hepatic Steatosis in Dysmetabolic Nonhuman Primates. Science Translational Medicine. 2019; 11 (512)
• Perry RJ, Zhang D, Guerra MT, Brill AL, Goedeke L, Nasiri AR, Rabin-Court A, Wang Y, Peng L, Dufour S, Zhang Y, Zhang XM, Butrico G, Toussaint K, Nozaki Y, Cline GW, Petersen KF, Nathanson MH, Ehrlich BE, Shulman GI. Glucagon Stimulates Gluconeogenesis by InsP3R-I Mediated Hepatic Lipolysis. Nature. 2020; 579(7798):279-283.
• Hubbard BT, LaMoia TE, Goedeke L, Gaspar RC, Galsgaard KD, Kahn M, Mason GF, Shulman GI. Q-Flux: A Novel Method to Assess Rates of Hepatic Mitochondrial Succinate Dehydrogenase, Methylmalonyl-CoA Mutase, and Glutaminase Fluxes in vivo. Cell Metabolism. 2023; 35 (1): 212-226. PMID: 36516861.
Endocrine System Diseases; Insulin Resistance; Molecular Biology; Physiology; Non-alcoholic Fatty Liver Disease; Chemicals and Drugs; Analytical, Diagnostic and Therapeutic Techniques and Equipment
Public Health Interests
Cardiovascular Diseases; Metabolism; Nutrition; Obesity