Gerald I. Shulman

Last updated
Gerald I. Shulman
NationalityAmerican
Alma mater University of Michigan (BS)
Wayne State University (MD, PhD)
Known forResearch on insulin resistance and type 2 diabetes, MASLD/MASH and mitochondrial metabolism
Awards NAM Member (2005)
NAS Member (2007)
Stanley J. Korsmeyer Award (2008)
AAAS Fellow (2009)
Banting Medal (2018)
American Academy of Arts & Sciences Member (2018)
Manpei Suzuki International Prize for Diabetes Research (2021)
Scientific career
Fields Endocrinology, Metabolism, Physiology
Institutions Yale School of Medicine
Howard Hughes Medical Institute
Website medicine.yale.edu/profile/gerald-shulman

Gerald I. Shulman, MD, PhD, MACP, MACE, FRCP, is an American physician-scientist specializing in endocrinology and metabolism. He is the George R. Cowgill Professor of Medicine (Endocrinology) and Professor of Cellular and Molecular Physiology at the Yale School of Medicine. Shulman also serves as Co-Director of the Yale Diabetes Research Center.

Contents

Education

Shulman earned a Bachelor of Science degree in biophysics from the University of Michigan in 1974, graduating with high honors and distinction. He received both his M.D. and Ph.D. in physiology from Wayne State University in 1979. From 1979 to 1981, he completed his internship and residency training in internal medicine at Duke University Medical Center. He then completed his clinical and research fellowship in endocrinology and metabolism at Massachusetts General Hospital/Harvard Medical School from 1981 to 1984. [1]

Academic career

Shulman began his academic career at Harvard Medical School, serving as an instructor and then as an assistant professor of medicine from 1984 to 1987. In 1987, he joined the faculty at Yale University as an assistant professor of medicine. He was promoted to associate professor in 1989 and became a full professor in both internal medicine and cellular and molecular physiology in 1996. From 1987 to 1993, he concurrently served as a lecturer in Yale's Department of Molecular Biophysics and Biochemistry. [2]

In 2009, he was appointed the inaugural George R. Cowgill Professor of Physiological Chemistry at Yale University, a position he continues to hold. [3]

Shulman served as Associate Director of both the Yale Diabetes Endocrinology Research Center and the Yale Medical Scientist Training Program from 1992 to 2012. In 2012, he became Co-Director of the Yale Diabetes Research Center. [4]

He has served on the editorial boards of journals including the Journal of Clinical Investigation , Cell Metabolism , [5] Science Translational Medicine , [6] and Proceedings of the National Academy of Sciences . [7] He was also an Investigator of the Howard Hughes Medical Institute for 21 years and is now an Investigator Emeritus. [8] [9]

Research

At the Yale School of Medicine, Shulman has investigated the pathophysiology of insulin resistance, metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), type 2 diabetes (T2D), [10] [11] and related cardiometabolic conditions. [12]

His laboratory developed and applied novel 13
C, 31
P, and 1
H NMR techniques to measure intracellular glucose, lipid, and mitochondrial metabolism in vivo. These methods allowed real-time, noninvasive assessment of metabolic fluxes in a tissue-specific manner. Early studies from his group identified defects in insulin-stimulated muscle glycogen synthesis, [13] attributed to reduced glucose transport activity, [14] in individuals with T2D. Later research extended these findings to individuals with prediabetes and obesity and demonstrated that exercise could bypass this defect and reverse muscle insulin resistance. [15]

Using 1
H NMR, Shulman reported that intramyocellular lipid content strongly predicts muscle insulin resistance in both adults and children, [16] [17] and that hepatic lipid content is a strong predictor of hepatic insulin resistance in both humans and rodent models of MASLD. [18] [19] [20]

His team showed that lipid-induced insulin resistance in skeletal muscle stems from impaired glucose transport due to altered insulin signaling, [21] [22] [23] [24] challenging the classical Randle cycle hypothesis.

Shulman proposed that lipid-induced insulin resistance results from the accumulation of sn-1,2-diacylglycerol (DAG) in the plasma membrane, which activates novel protein kinase C (nPKC) isoforms—PKCθ in skeletal muscle and PKCε in liver and white adipose tissue—impairing insulin signaling. [25] [26] [27] [28] [29] [30]

Shulman’s lab explored interventions such as weight loss, thiazolidinediones, adiponectin, leptin, and liver-targeted mitochondrial protonophores to reverse insulin resistance by lowering plasma membrane DAG and inhibiting the nPKC pathway.

He also pioneered 13
C and 31
P NMR methods to measure ATP synthesis and mitochondrial oxidation in vivo. His team identified age-related declines in mitochondrial fat oxidation linked to insulin resistance in elderly individuals, [31] [32] and in insulin-resistant offspring of people with T2D. [33] They showed that chronic AMPK activation drives mitochondrial biogenesis via increased expression of PGC-1α. [34]

Shulman used 13
C NMR to quantify rates of hepatic  glycogenolysis  and  gluconeogenesis , showing that the latter accounts for over half of fasting hepatic glucose production following an overnight fast overturning the Cahill hypothesis that hepatic glycogenolysis accounts for >90% of glucose production in humans following an overnight fast. [35] [36] [37] His group then went on to apply the same technique to assess rates of gluconeogenesis in patients with poorly controlled T2D and demonstrated that virtually all of their increased glucose production can be attributed to increased rates of gluconeogenesis and that metformin lowers hepatic glucose production in these individuals by decreasing the rate of hepatic gluconeogenesis. [38] [39]  He also demonstrated that  metformin suppresses hepatic gluconeogenesis by inhibiting Complex IV and altering the cytosolic redox state.

His lab developed the Positional Isotopomer NMR Tracer Analysis (PINTA) method to measure hepatic mitochondrial fluxes. [40] With this, they showed mechanisms by which caloric restriction reverses diabetes, [41] how leptin maintains gluconeogenesis during fasting, [42] how the glucose-alanine cycle regulates hepatic fat oxidation, [43] and how glucagon stimulates gluconeogenesis via the IP3R1 receptor and CaMKII.

His research has also explored how adiponectin, leptin, and fibroblast growth factors (FGF-1, FGF-19, and FGF-21) regulate hepatic glucose metabolism. Contrary to the prevailing view that insulin acutely suppresses hepatic gluconeogenesis through FoxO1-mediated transcriptional repression, Shulman’s team showed that suppression occurs mainly through inhibition of white adipocyte lipolysis, reducing glycerol and fatty acid flux to the liver. This leads to decreased acetyl-CoA activation of pyruvate carboxylase and lower glycerol-derived glucose production. They further demonstrated that increased hepatic acetyl-CoA and glycerol flux—resulting from white adipose tissue inflammation—are key drivers of elevated gluconeogenesis in rodent models of type 2 diabetes (T2D). [44] [45]

Based on the sn-1,2 DAG–nPKC hypothesis, Shulman’s laboratory developed liver-targeted mitochondrial protonophores that reduce hepatic steatosis, insulin resistance, inflammation, and fibrosis in rodent and nonhuman primate models of MASLD and MASH. [46] [47] [48] These compounds have advanced to clinical evaluation.

Selected honors

References

  1. ↑ "Gerald I Shulman, MD, PhD, MACP, MACE, FRCP". Yale.edu.
  2. ↑ "Gerald I. Shulman, MD, Ph.D. | Global Affairs". University of Connecticut. 23 July 2018.
  3. ↑ "Diabetes expert is appointed inaugural Cowgill Professor". Yale.edu. Archived from the original on 2022-05-20.
  4. ↑ Hathaway, Bill. "Yale's Shulman Honored for Diabetes Research". Yale School of Medicine.
  5. ↑ "Advisory board: Cell Metabolism". Cell.com.
  6. ↑ "Editors and Advisory Boards". Science.org.
  7. ↑ "Editorial Board". PNAS.
  8. ↑ "Gerald I. Shulman, MD, PhD | Investigator Emeriti Profile | 1997-2018". HHMI.
  9. 1 2 "Howard Hughes Investigator Expert In Magnetic Resonance Receives Columbia's Naomi Berrie Award". Columbia University Irving Medical Center. 3 November 2007.
  10. ↑ "How to Manage Your Blood Sugar With Exercise". The New York Times. 2025-05-19.
  11. ↑ "Solving one of the great diabetes mysteries". World Economic Forum.
  12. ↑ "An Epidemic in the Making". Yale School of Medicine.
  13. ↑ Shulman, GI; Rothman, DL; Jue, T; Stein, P; DeFronzo, RA; Shulman, RG (1990). "Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13
    C     nuclear magnetic resonance spectroscopy". The New England Journal of Medicine. 322 (4): 223–228. doi:10.1056/NEJM199001253220403.
  14. ↑ Cline, GW; Petersen, KF; Krssak, M (1999). "Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes". The New England Journal of Medicine. 341 (4): 240–246. doi:10.1056/NEJM199907223410404. PMID   10413736.
  15. ↑ Perseghin, G; Price, TB; Petersen, KF (1996). "Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects". The New England Journal of Medicine. 335 (18): 1357–1362. doi:10.1056/NEJM199610313351804. PMID   8857019.
  16. ↑ Krssak, M; Falk Petersen, K; Dresner, A (1999). "Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1
    H     NMR spectroscopy study". Diabetologia. 42 (1): 113–116. doi:10.1007/s001250051123. PMID   10027589.
  17. ↑ Weiss, R; Dufour, S; Taksali, SE (2003). "Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning". The Lancet. 362 (9388): 951–957. doi:10.1016/S0140-6736(03)14364-4. PMC   2995523 . PMID   14511928.
  18. ↑ Samuel, VT; Liu, ZX; Qu, X (2004). "Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease". The Journal of Biological Chemistry. 279 (31): 32345–32353. doi: 10.1074/jbc.M313478200 . PMID   15166226.
  19. ↑ Petersen, KF; Oral, EA; Dufour, S (2002). "Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy". The Journal of Clinical Investigation. 109 (10): 1345–1350. doi:10.1172/JCI15001. PMC   150981 . PMID   12021250.
  20. ↑ Petersen, KF; Dufour, S; Morino, K (2012). "Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes". Proceedings of the National Academy of Sciences. 109 (21): 8236–8241. Bibcode:2012PNAS..109.8236P. doi: 10.1073/pnas.1205675109 . PMC   3361376 . PMID   22547801.
  21. ↑ Griffin, ME; Marcucci, MJ; Cline, GW (1999). "Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade". Diabetes. 48 (6): 1270–1274. doi:10.2337/diabetes.48.6.1270. PMID   10342815.
  22. ↑ Dresner, A; Laurent, D; Marcucci, M (1999). "Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity". The Journal of Clinical Investigation. 103 (2): 253–259. doi:10.1172/JCI5001. PMC   407880 .
  23. ↑ Yu, C; Chen, Y; Cline, GW (2002). "Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle". The Journal of Biological Chemistry. 277 (52): 50230–50236. doi: 10.1074/jbc.M200958200 . PMID   12006582.
  24. ↑ Roden, M; Price, TB; Perseghin, G (1996). "Mechanism of free fatty acid-induced insulin resistance in humans". The Journal of Clinical Investigation. 97 (12): 2859–2865. doi:10.1172/JCI118742. PMC   507380 . PMID   8675698.
  25. ↑ Shulman, GI (1999). "Cellular mechanisms of insulin resistance in humans". The American Journal of Cardiology. 84 (1A): 3J –10J. doi:10.1016/S0002-9149(99)00350-1. PMID   10418851.
  26. ↑ Shulman, GI (2014). "Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease". The New England Journal of Medicine. 371 (12): 1131–1141. doi:10.1056/NEJMra1011035.
  27. ↑ Song, JD; Alves, TC (2020). "Dissociation of Muscle Insulin Resistance from Alterations in Mitochondrial Substrate Preference". Cell Metabolism. 32 (5): 726–735.e5. doi:10.1016/j.cmet.2020.09.008. PMC   8218871 . PMID   33035493.
  28. ↑ Petersen, MC; Shulman, GI (2018). "Mechanisms of Insulin Action and Insulin Resistance". Physiological Reviews. 98 (4): 2133–2223. doi:10.1152/physrev.00063.2017. PMC   6170977 .
  29. ↑ Lyu, K (2020). "A Membrane-Bound Diacylglycerol Species Induces PKC-Mediated Hepatic Insulin Resistance". Cell Metabolism. 32 (4): 654–664.e5. doi:10.1016/j.cmet.2020.08.001. PMC   7544641 . PMID   32882164.
  30. ↑ Lyu, K (2021). "Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol/PKCε/insulin receptor Thr1160 phosphorylation". JCI Insight. 6 (4). doi:10.1172/jci.insight.139946. PMC   7934919 .
  31. ↑ Petersen, KF (2003). "Mitochondrial dysfunction in the elderly: possible role in insulin resistance". Science. 300 (5622): 1140–1142. Bibcode:2003Sci...300.1140P. doi:10.1126/science.1082889. PMC   3004429 . PMID   12750520.
  32. ↑ Petersen, KF (2015). "Effect of aging on muscle mitochondrial substrate utilization in humans". Proceedings of the National Academy of Sciences. 112 (36): 11330–11334. Bibcode:2015PNAS..11211330P. doi: 10.1073/pnas.1514844112 . PMID   26305973.
  33. ↑ Petersen, KF (2004). "Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes". The New England Journal of Medicine. 350 (7): 664–671. doi:10.1056/NEJMoa031314. PMC   2995502 . PMID   14960743.
  34. ↑ Zong, H (2002). "AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation". Proceedings of the National Academy of Sciences. 99 (25): 15983–15987. Bibcode:2002PNAS...9915983Z. doi: 10.1073/pnas.252625599 .
  35. ↑ Rothman, DL (1991). "Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13
    C     NMR". Science. 254 (5031): 573–576. doi:10.1126/science.1948033. PMID   1948033.
  36. ↑ Petersen, KF (1998). "Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans". The Journal of Clinical Investigation. 101 (6): 1203–1209. doi:10.1172/JCI579. PMC   508673 . PMID   9502760.
  37. ↑ Magnusson, I (1992). "Increased rate of gluconeogenesis in type II diabetes mellitus. A 13
    C     nuclear magnetic resonance study"    . The Journal of Clinical Investigation. 90 (4): 1323–1327. doi:10.1172/JCI115997. PMC   443176 . PMID   1401068.
  38. ↑ Hundal, RS (2000). "Mechanism by which metformin reduces glucose production in type 2 diabetes". Diabetes. 49 (12): 2063–2069. doi:10.2337/diabetes.49.12.2063. PMC   2995498 . PMID   11118008.
  39. ↑ LaMoia, TE (2022). "Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis". Proceedings of the National Academy of Sciences. 119 (10): e2122287119. Bibcode:2022PNAS..11922287L. doi: 10.1073/pnas.2122287119 . PMC   8916010 .{{cite journal}}: CS1 maint: article number as page number (link)
  40. ↑ Perry, RJ (2017). "Non-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA)". Nature Communications. 8 798. Bibcode:2017NatCo...8..798P. doi:10.1038/s41467-017-01143-w. PMC   5630596 . PMID   28986525.
  41. ↑ Perry, RJ (2018). "Mechanisms by which a Very-Low-Calorie Diet Reverses Hyperglycemia in a Rat Model of Type 2 Diabetes". Cell Metabolism. 27 (1): 210–217.e3. doi:10.1016/j.cmet.2017.10.004. PMC   5762419 . PMID   29129786.
  42. ↑ Perry, RJ (2018). "Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation". Cell. 172 (1–2): 234–248.e17. doi:10.1016/j.cell.2017.12.001. PMC   5766366 . PMID   29307489.
  43. ↑ Petersen, KF (2019). "Regulation of hepatic mitochondrial oxidation by glucose-alanine cycling during starvation in humans". The Journal of Clinical Investigation. 129 (11): 4671–4675. doi:10.1172/JCI129913. PMC   6819088 .
  44. ↑ Perry, R.J.; Camporez, J.G.; Kursawe, R.; Tito, R.Y.; Zhang, D.; Jiang, L.; Jiang, G.; Zhang, X.-M.; Kahn, M.; Shulman, G.I. (2015). "Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes". Cell. 160 (4): 745–758. doi:10.1016/j.cell.2015.01.012. PMC   4332677 . PMID   25662011.
  45. ↑ Perry, R.J.; Peng, L.; Cline, G.W.; Petersen, K.F.; Shulman, G.I. (2017). "A Non-invasive Method to Assess Hepatic Acetyl-CoA In Vivo". Cell Metabolism. 25 (3): 749–756. doi:10.1016/j.cmet.2016.12.017. PMC   5337324 . PMID   28178530.
  46. ↑ Perry, R.J.; Kim, T.; Zhang, X.M.; Kusminski, C.M.; Schwarz, J.M.; Zhang, D.; Cline, G.W.; Rangwala, S.M.; Shulman, G.I. (2013). "Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler". Cell Metabolism. 18 (5): 740–748. doi:10.1016/j.cmet.2013.10.004. PMC   3903845 . PMID   24211298.
  47. ↑ Perry, R.J.; Zhang, D.; Zhang, X.M.; Boyer, J.L.; Shulman, G.I. (2015). "Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats". Science. 347 (6227): 1253–1256. Bibcode:2015Sci...347.1253P. doi:10.1126/science.aaa0672. PMC   4491302 . PMID   25745176.
  48. ↑ Goedeke, L.; Peng, L.; Montalvo-Romeral, V.; Bryant, J.D.; Friedline, R.H.; Martínez-Cristóbal, P.; Camporez, J.P.; Zhang, D.; Jiang, G.; Shulman, G.I. (2019). "Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates". Science Translational Medicine. 11 (512). doi:10.1126/scitranslmed.aay0284. PMC   6999954 . PMID   31784412.
  49. ↑ "Gerald I. Shulman, MD, PhD, MACP, MACE, FRCP". The American Society for Clinical Investigation.
  50. ↑ "Outstanding Scientific Achievement Award | American Diabetes Association". professional.diabetes.org. ADA.
  51. ↑ "Directory". Association of American Physicians.
  52. ↑ "Fellows of the Society". ISMRM.
  53. ↑ "Yale's Shulman Honored for Diabetes Research". Yale School of Medicine. Archived from the original on 8 June 2025.
  54. ↑ "NAM Member Listing" (PDF). Archived from the original (PDF) on 2023-08-01.
  55. ↑ "Gerald I. Shulman". National Academy of Sciences.
  56. ↑ Hawley, John (1 February 2008). "The 2008 Stanley J. Korsmeyer Award: Gerald I. Shulman, MD, PhD". The American Society for Clinical Investigation.
  57. ↑ "AAAS Members Elected as Fellows | American Association for the Advancement of Science (AAAS)". AAAS.
  58. ↑ "Past Laureate Award Recipients". Endocrine Society. 28 September 2022.
  59. ↑ "Past Award Winners". Biochemical Society.
  60. ↑ "Past Award and Lectureship Recipients". American Association of Clinical Endocrinology.
  61. ↑ "Announcing our 2016 Harrington Scholar-Innovator Award Recipients | January 13, 2016 | Harrington Discovery Institute at University Hospitals". Harrington Discovery Institute.
  62. ↑ "Fellows of the American Physiological Society, continued" (PDF). p. 240. Archived from the original (PDF) on 2022-06-16.
  63. ↑ "Distinguished Alumni Award Recipients". Development and Alumni Affairs. 10 June 2024.
  64. ↑ "2018 Banting Medal for Scientific Achievement - Gerald I. Shulman, MD, PhD". American Diabetes Association.
  65. ↑ "Gerald I. Shulman". American Academy of Arts and Sciences. 28 April 2025.
  66. ↑ https://medicine.yale.edu/news-article/kudos-july-2019/%5B%5D
  67. ↑ "SAMUEL EICHOLD II MEMORIAL AWARD FOR CONTRIBUTIONS IN DIABETES" (PDF). ACP.
  68. ↑ "Manpei Suzuki Prize for Diabetes Research" (PDF). Manpei Suzuki Diabetes Foundation.
  69. ↑ "AMERICAN COLLEGE OF PHYSICIANS MASTERSHIP RECIPIENTS 1923–present" (PDF). ACP.
  70. ↑ "Register of Fellows". RCP.
  71. ↑ Crawford, Serena. "Shulman Awarded EASD-Lilly Centennial Anniversary Prize". Yale School of Medicine.
  72. ↑ "Bodil M. Schmidt-Nielsen Award Recipients". American Physiological Society.
  73. ↑ "2025 EASD-Novo Nordisk Foundation Diabetes Prize for Excellence Awardee". EASD.
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