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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

  • Deletion of Jazf1 gene causes early growth retardation and insulin resistance in miceLee H, Jang H, Li H, Samuel V, Dudek K, Osipovich A, Magnuson M, Sklar J, Shulman G. Deletion of Jazf1 gene causes early growth retardation and insulin resistance in mice Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2213628119. PMID: 36442127, DOI: 10.1073/pnas.2213628119.
  • 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.
  • Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout miceAbulizi A, Vatner DF, Ye Z, Wang Y, Camporez JP, Zhang D, Kahn M, Lyu K, Sirwi A, Cline GW, Hussain MM, Aspichueta P, Samuel VT, Shulman GI. Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice Journal Of Lipid Research 2020, 61: 1565-1576. PMID: 32907986, PMCID: PMC7707176, DOI: 10.1194/jlr.ra119000586.
  • 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.
  • Nonalcoholic Fatty Liver Disease, Insulin Resistance, and CeramidesSamuel VT, Shulman GI. Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Ceramides New England Journal Of Medicine 2019, 381: 1866-1869. PMID: 31693811, DOI: 10.1056/nejmcibr1910023.
  • 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.
  • Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistancePetersen MC, Madiraju AK, Gassaway BM, Marcel M, Nasiri AR, Butrico G, Marcucci MJ, Zhang D, Abulizi 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 Journal Of Clinical Investigation 2016, 126: 4361-4371. PMID: 27760050, PMCID: PMC5096902, DOI: 10.1172/jci86013.
  • The Sweet Path to Metabolic Demise: Fructose and Lipid SynthesisHerman MA, Samuel VT. The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis Trends In Endocrinology And Metabolism 2016, 27: 719-730. PMID: 27387598, PMCID: PMC5035631, DOI: 10.1016/j.tem.2016.06.005.
  • Insulin-independent regulation of hepatic triglyceride synthesis by fatty acidsVatner DF, Majumdar SK, Kumashiro N, Petersen MC, Rahimi Y, Gattu AK, Bears M, Camporez JP, Cline GW, Jurczak MJ, Samuel VT, Shulman GI. Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 1143-1148. PMID: 25564660, PMCID: PMC4313795, DOI: 10.1073/pnas.1423952112.
  • The emerging role of oestrogen-related receptor γ as a regulator of energy metabolismSamuel VT. The emerging role of oestrogen-related receptor γ as a regulator of energy metabolism Diabetologia 2014, 57: 2440-2443. PMID: 25257097, PMCID: PMC4488899, DOI: 10.1007/s00125-014-3377-7.
  • Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male ratsCantley JL, Vatner DF, Galbo T, Madiraju A, Petersen M, Perry RJ, Kumashiro N, Guebre-Egziabher F, Gattu AK, Stacy MR, Dione DP, Sinusas AJ, Ragolia L, Hall CE, Manchem VP, Bhanot S, Bogan JS, Samuel VT. Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats AJP Endocrinology And Metabolism 2014, 307: e773-e783. PMID: 25159329, PMCID: PMC4216948, DOI: 10.1152/ajpendo.00148.2014.
  • 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.
  • Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin ResistanceKumashiro N, Beddow SA, Vatner DF, Majumdar SK, Cantley JL, Guebre-Egziabher F, Fat I, Guigni B, Jurczak MJ, Birkenfeld AL, Kahn M, Perler BK, Puchowicz MA, Manchem VP, Bhanot S, Still CD, Gerhard GS, Petersen KF, Cline GW, Shulman GI, Samuel VT. Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance Diabetes 2013, 62: 2183-2194. PMID: 23423574, PMCID: PMC3712050, DOI: 10.2337/db12-1311.
  • Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathwaysVatner DF, Weismann D, Beddow SA, Kumashiro N, Erion DM, Liao XH, Grover GJ, Webb P, Phillips KJ, Weiss RE, Bogan JS, Baxter J, Shulman GI, Samuel VT. Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways AJP Endocrinology And Metabolism 2013, 305: e89-e100. PMID: 23651850, PMCID: PMC3725564, DOI: 10.1152/ajpendo.00573.2012.
  • 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.
  • Mechanisms for Insulin Resistance: Common Threads and Missing LinksSamuel VT, Shulman GI. Mechanisms for Insulin Resistance: Common Threads and Missing Links Cell 2012, 148: 852-871. PMID: 22385956, PMCID: PMC3294420, DOI: 10.1016/j.cell.2012.02.017.
  • 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.
  • Cellular mechanism of insulin resistance in nonalcoholic fatty liver diseaseKumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, Still CD, Gerhard GS, Han X, Dziura J, Petersen KF, Samuel VT, Shulman GI. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 16381-16385. PMID: 21930939, PMCID: PMC3182681, DOI: 10.1073/pnas.1113359108.
  • 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.
  • Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in miceAyala JE, Consortium F, Samuel V, Morton G, Obici S, Croniger C, Shulman G, Wasserman D, McGuinness O. Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice Disease Models & Mechanisms 2010, 3: 525-534. PMID: 20713647, PMCID: PMC2938392, DOI: 10.1242/dmm.006239.
  • Deletion of the α-Arrestin Protein Txnip in Mice Promotes Adiposity and Adipogenesis While Preserving Insulin SensitivityChutkow WA, Birkenfeld AL, Brown JD, Lee HY, Frederick DW, Yoshioka J, Patwari P, Kursawe R, Cushman SW, Plutzky J, Shulman GI, Samuel VT, Lee RT. Deletion of the α-Arrestin Protein Txnip in Mice Promotes Adiposity and Adipogenesis While Preserving Insulin Sensitivity Diabetes 2010, 59: 1424-1434. PMID: 20299477, PMCID: PMC2874703, DOI: 10.2337/db09-1212.
  • Insulin ResistanceSamuel V, Petersen K, Shulman G. Insulin Resistance 2009, 469-483. DOI: 10.1002/9780470747919.ch31.
  • Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 DiabetesSamuel VT, Beddow SA, Iwasaki T, Zhang XM, Chu X, Still CD, Gerhard GS, Shulman GI. Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 Diabetes Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 12121-12126. PMID: 19587243, PMCID: PMC2707270, DOI: 10.1073/pnas.0812547106.
  • Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver diseaseSamuel VT, Liu ZX, Wang A, Beddow SA, Geisler JG, Kahn M, Zhang XM, Monia BP, Bhanot S, Shulman GI. Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease Journal Of Clinical Investigation 2007, 117: 739-745. PMID: 17318260, PMCID: PMC1797607, DOI: 10.1172/jci30400.
  • 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.
  • Mechanism of Hepatic Insulin Resistance in Non-alcoholic Fatty Liver Disease*Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI. Mechanism of Hepatic Insulin Resistance in Non-alcoholic Fatty Liver Disease* Journal Of Biological Chemistry 2004, 279: 32345-32353. PMID: 15166226, DOI: 10.1074/jbc.m313478200.
  • Disruption of Sur2-containing KATP channels enhances insulin-stimulated glucose uptake in skeletal muscleChutkow W, Samuel V, Hansen P, Pu J, Valdivia C, Makielski J, Burant C. Disruption of Sur2-containing KATP channels enhances insulin-stimulated glucose uptake in skeletal muscle Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 11760-11764. PMID: 11562480, PMCID: PMC58803, DOI: 10.1073/pnas.201390398.
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