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Varman Samuel, MD, PhD

Associate Professor of Medicine (Endocrinology); Section Chief, Endocrinology, VA

Contact Information

Varman Samuel, MD, PhD

Mailing Address

  • Internal Medicine

    PO Box 208056, 333 Cedar Street

    New Haven, CT 06520-8056

    United States

Research Summary

Dr. Samuel focuses on the underlying mechanisms by which ectopic lipid accumulation in the liver leads to insulin resistance and increases gluconeogenesis. Dysregulation of insulin signaling and hepatic glucose production account for two of the most common clinical findings in patients with diabetes: impaired glucose tolerance and fasting hyperglycemia. Hepatic insulin resistance arises when an increase in hepatic sn 1,2 diacylglycerol activated protein kinase c epsilon which then impairs hepatic insulin receptor kinase activation. This proximal defect in insulin signaling impacts all downstream pathways tied to insulin signaling. The regulation of gluconeogenesis is more complex. This is an incredibly malleable pathway that is influenced by multiple hormonal signals and substrate inputs. One mechanism that has emerged is the post-translational modification of pyruvate carboxylase. An increase in PC protein content may enhance the capacity for gluconeogenesis and in turn offers the possibility of developing novel therapies.

Coauthors

Research Interests

Diabetes Mellitus, Type 2; Gluconeogenesis; Insulin Resistance; Pyruvate Carboxylase; Non-alcoholic Fatty Liver Disease

Selected Publications

  • Abstract #1184551: Hypertriglyceridemic pancreatitis in a rare case of type A pyruvate carboxylase deficiencyWojeck B, Samuel V. Abstract #1184551: Hypertriglyceridemic pancreatitis in a rare case of type A pyruvate carboxylase deficiency Endocrine Practice 2022, 28: s66-s67. DOI: 10.1016/j.eprac.2022.03.166.
  • 205-OR: Hepatic Protein Kinase C-e Is Necessary and Sufficient in Mediating Lipid-Induced Hepatic Insulin ResistanceLYU K, ZHANG D, KAHN M, RODRIGUES M, HIRABARA S, LUUKKONEN P, LEE S, BHANOT S, RINEHART J, BLUME N, RASCH M, SERLIE M, BOGAN J, CLINE G, SAMUEL V, SHULMAN G. 205-OR: Hepatic Protein Kinase C-e Is Necessary and Sufficient in Mediating Lipid-Induced Hepatic Insulin Resistance Diabetes 2020, 69 DOI: 10.2337/db20-205-or.
  • Non‐alcoholic Fatty Liver Disease and Insulin ResistancePetersen M, Samuel V, Petersen K, Shulman G. Non‐alcoholic Fatty Liver Disease and Insulin Resistance 2020, 455-471. DOI: 10.1002/9781119436812.ch37.
  • 266-OR: Plasma Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin ResistanceLYU K, ZHANG Y, ZHANG D, KAHN M, NOZAKI Y, BHANOT S, BOGAN J, CLINE G, SAMUEL V, SHULMAN G. 266-OR: Plasma Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance Diabetes 2019, 68 DOI: 10.2337/db19-266-or.
  • 1782-P: Mechanism of Lipid-Induced White Adipose Tissue Insulin ResistanceZHANG Y, ZHANG D, LYU K, SONG J, LI X, PERRY R, SAMUEL V, SHULMAN G. 1782-P: Mechanism of Lipid-Induced White Adipose Tissue Insulin Resistance Diabetes 2019, 68 DOI: 10.2337/db19-1782-p.
  • 283-LB: Dissociating Insulin Signaling and SREBP1c Action from the Lipogenic Drive Seen in Human and Murine Hepatic Insulin ResistanceVATNER D, TER HORST K, GOEDEKE L, ZHANG D, SAMUEL V, SERLIE M, SHULMAN G. 283-LB: Dissociating Insulin Signaling and SREBP1c Action from the Lipogenic Drive Seen in Human and Murine Hepatic Insulin Resistance Diabetes 2019, 68 DOI: 10.2337/db19-283-lb.
  • MON-LB024 Episodic Hypoglycemia in Non-Diabetics: Differentiating Distressing from DeadlyWindham M, Siwakoti K, Samuel V. MON-LB024 Episodic Hypoglycemia in Non-Diabetics: Differentiating Distressing from Deadly Journal Of The Endocrine Society 2019, 3: mon-lb024. PMCID: PMC6551052, DOI: 10.1210/js.2019-mon-lb024.
  • Targeting Ketohexokinase (KHK) with a Novel Antisense Oligonucleotide (ASO) Decreases De Novo Lipogenesis and Improves Insulin-Mediated Whole Body Glucose MetabolismLIU D, STERPKA J, VATNER D, BELL M, MURRAY S, BHANOT S, CLINE G, SAMUEL V. Targeting Ketohexokinase (KHK) with a Novel Antisense Oligonucleotide (ASO) Decreases De Novo Lipogenesis and Improves Insulin-Mediated Whole Body Glucose Metabolism Diabetes 2018, 67 DOI: 10.2337/db18-149-or.
  • Evidence against Pathway-Selective Hepatic Insulin Resistance in MiceVATNER D, PETERSEN M, LI X, ROGERS J, CLINE G, SAMUEL V, SHULMAN G. Evidence against Pathway-Selective Hepatic Insulin Resistance in Mice Diabetes 2018, 67 DOI: 10.2337/db18-1766-p.
  • Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance In VivoLYU K, ZHANG D, NOZAKI Y, ZHANG Y, BHANOT S, CLINE G, SAMUEL V, SHULMAN G. Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance In Vivo Diabetes 2018, 67 DOI: 10.2337/db18-243-lb.
  • I'm not Dead Yet: Flies and MiceBirkenfeld A, Samuel V, Shulman G, De Cabo R, Reenan R, Zhu C, Helfand S. I'm not Dead Yet: Flies and Mice Biophysical Journal 2014, 106: 12a. DOI: 10.1016/j.bpj.2013.11.118.
  • Abstract 140: LRP6 Influences Body Fat and Glucose Homeostasis in Mouse by Activating mTOR Pathway and Inhibiting Mitochondrial Energy ExpenditureLiu W, Singh R, Choi C, Young L, Keramati A, Samuel V, Lifton R, Shulman G, Mani A. Abstract 140: LRP6 Influences Body Fat and Glucose Homeostasis in Mouse by Activating mTOR Pathway and Inhibiting Mitochondrial Energy Expenditure Arteriosclerosis Thrombosis And Vascular Biology 2012, 32 DOI: 10.1161/atvb.32.suppl_1.a140.
  • Deletion of the Mammalian INDY Homolog Mimics Aspects of Dietary Restriction and Protects against Adiposity and Insulin Resistance in MiceBirkenfeld A, Lee H, Guebre-Egziabher F, Alves T, Jurczak M, Jornayvaz F, Zhang D, Hsiao J, Martin-Montalvo A, Fischer-Rosinsky A, Spranger J, Pfeiffer A, Jordan J, Fromm M, König J, Lieske S, Carmean C, Frederick D, Weismann D, Knauf F, Irusta P, De Cabo R, Helfand S, Samuel V, Shulman G. Deletion of the Mammalian INDY Homolog Mimics Aspects of Dietary Restriction and Protects against Adiposity and Insulin Resistance in Mice Cell Metabolism 2011, 14: 567. DOI: 10.1016/j.cmet.2011.09.005.
  • Reply to Monetti et al.: Hepatic steatosis and diacylglycerol-mediated hepatic insulin resistance in acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2) transgenic miceJornayvaz F, Jurczak M, Samuel V, Shulman G. Reply to Monetti et al.: Hepatic steatosis and diacylglycerol-mediated hepatic insulin resistance in acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2) transgenic mice Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: e524-e524. PMCID: PMC3161525, DOI: 10.1073/pnas.1109195108.
  • Insulin ResistanceSamuel V, Petersen K, Shulman G. Insulin Resistance 2009, 469-483. DOI: 10.1002/9780470747919.ch31.
  • Insulin Resistance in NAFLD: Potential Mechanisms and TherapiesSamuel V, Shulman G. Insulin Resistance in NAFLD: Potential Mechanisms and Therapies 2004, 38-54. DOI: 10.1002/9780470987438.ch4.