Varman Samuel, MD, PhD
Research & Publications
Biography
News
Research Summary
Dr. Samuel is broadly interested in investigating the relationships between liver lipid and glucose metabolism and related pathways, such as insulin action and inflammation, that ultimately manifest in common clinical conditions such as type 2 diabetes, alcoholic and non-alcoholic fatty liver disease.
Extensive Research Description
My research focuses on the underlying mechanisms leading to ectopic hepatic lipid accumulation (nonalcoholic fatty liver disease, NAFLD) and the impact on liver insulin action and inflammation. Dysregulation of insulin signaling and hepatic glucose production account for two of the most common clinical findings in patients with type 2 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.
Recently, our lab has been focused on fructose metabolism. We have explored the use of ketohexokinase inhibition using novel antisense oligonucleotides on the development of insulin resistance in rodents fed modest fructose diets that mimic the amounts consumed by humans. Interestingly, this seems to primarily improve white adipose tissue insulin action, suggesting that the primary defect induced by modest amounts of fructose may be at the level of white adipose tissue. The development of hepatic steatosis and hepatic insulin resistance may be secondary to adipose dysfunction. We will explore this hypothesis in rodent and tissue culture models.
In addition, we have used our experience and techniques studying NAFLD to better understanding the pathogenesis of alcohol-associated liver disease (AALD). Together with collaborators, we are applying novel isotopic techniques to quantifying changes in liver mitochondrial flux in acute and chronic models of AALD and assessing the impact of emerging NALFD therapies (i.e. mitochondrial uncouplers and acetyl-CoA carboxylase inhibition). These studies may provide insights into the links between mitochondrial function, lipid accumulation and inflammation
Coauthors
Research Interests
Diabetes Mellitus, Type 2; Fatty Liver, Alcoholic; 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, PMCID: PMC9894197, DOI: 10.1073/pnas.2213628119.
- Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol – PKCε – insulin receptorT1160 phosphorylationLyu K, Zhang D, Song J, Li X, Perry RJ, Samuel VT, Shulman GI. Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol – PKCε – insulin receptorT1160 phosphorylation JCI Insight 2021, 6: e139946. PMID: 33411692, PMCID: PMC7934919, DOI: 10.1172/jci.insight.139946.
- Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice.Abulizi 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: 33455703, DOI: 10.1194/jlr.RA119000586.
- A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin ResistanceLyu K, Zhang Y, Zhang D, Kahn M, Ter Horst KW, Rodrigues MRS, Gaspar RC, Hirabara SM, Luukkonen PK, Lee S, Bhanot S, Rinehart J, Blume N, Rasch MG, Serlie MJ, Bogan JS, Cline GW, Samuel VT, Shulman GI. A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance Cell Metabolism 2020, 32: 654-664.e5. PMID: 32882164, PMCID: PMC7544641, DOI: 10.1016/j.cmet.2020.08.001.
- Metabolic control analysis of hepatic glycogen synthesis in vivoNozaki Y, Petersen MC, Zhang D, Vatner DF, Perry RJ, Abulizi A, Haedersdal S, Zhang XM, Butrico GM, Samuel VT, Mason GF, Cline GW, Petersen KF, Rothman DL, Shulman GI. Metabolic control analysis of hepatic glycogen synthesis in vivo Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 8166-8176. PMID: 32188779, PMCID: PMC7149488, DOI: 10.1073/pnas.1921694117.
- 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.
- Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose ProductionGassaway BM, Cardone RL, Padyana AK, Petersen MC, Judd ET, Hayes S, Tong S, Barber KW, Apostolidi M, Abulizi A, Sheetz JB, Kshitiz, Aerni HR, Gross S, Kung C, Samuel VT, Shulman GI, Kibbey RG, Rinehart J. Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production Cell Reports 2019, 29: 3394-3404.e9. PMID: 31825824, PMCID: PMC6951436, DOI: 10.1016/j.celrep.2019.11.009.
- 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.
- Considering the Links Between Nonalcoholic Fatty Liver Disease and Insulin Resistance: Revisiting the Role of Protein Kinase C εSamuel VT, Petersen MC, Gassaway BM, Vatner DF, Rinehart J, Shulman GI. Considering the Links Between Nonalcoholic Fatty Liver Disease and Insulin Resistance: Revisiting the Role of Protein Kinase C ε Hepatology 2019, 70: 2217-2220. PMID: 31220350, DOI: 10.1002/hep.30829.
- Adipose glucocorticoid action influences whole‐body metabolism via modulation of hepatic insulin actionAbulizi A, Camporez JP, Jurczak MJ, Høyer KF, Zhang D, Cline GW, Samuel VT, Shulman GI, Vatner DF. Adipose glucocorticoid action influences whole‐body metabolism via modulation of hepatic insulin action The FASEB Journal 2019, 33: 8174-8185. PMID: 30922125, PMCID: PMC6593882, DOI: 10.1096/fj.201802706r.
- Ectopic lipid deposition mediates insulin resistance in adipose specific 11β-hydroxysteroid dehydrogenase type 1 transgenic miceAbulizi A, Camporez JP, Zhang D, Samuel VT, Shulman GI, Vatner DF. Ectopic lipid deposition mediates insulin resistance in adipose specific 11β-hydroxysteroid dehydrogenase type 1 transgenic mice Metabolism 2018, 93: 1-9. PMID: 30576689, PMCID: PMC6401251, DOI: 10.1016/j.metabol.2018.12.003.
- PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed RatsBeddow SA, Gattu AK, Vatner DF, Paolella L, Alqarzaee A, Tashkandi N, Popov V, Church C, Rodeheffer M, Cline G, Geisler J, Bhanot S, Samuel VT. PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats Endocrinology 2018, 160: 205-219. PMID: 30445425, PMCID: PMC6307100, DOI: 10.1210/en.2018-00630.
- PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signalingGassaway BM, Petersen MC, Surovtseva YV, Barber KW, Sheetz JB, Aerni HR, Merkel JS, Samuel VT, Shulman GI, Rinehart J. PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: e8996-e9005. PMID: 30181290, PMCID: PMC6156646, DOI: 10.1073/pnas.1804379115.
- 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.
- Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodentsVatner DF, Goedeke L, Camporez JG, Lyu K, Nasiri AR, Zhang D, Bhanot S, Murray SF, Still CD, Gerhard GS, Shulman GI, Samuel VT. Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents Diabetologia 2018, 61: 1435-1446. PMID: 29497783, PMCID: PMC5940564, DOI: 10.1007/s00125-018-4579-1.
- Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic DiseasesSamuel VT, Shulman GI. Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases Cell Metabolism 2017, 27: 22-41. PMID: 28867301, PMCID: PMC5762395, DOI: 10.1016/j.cmet.2017.08.002.
- Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in HumansHorst K, Gilijamse PW, Versteeg RI, Ackermans MT, Nederveen AJ, la Fleur SE, Romijn JA, Nieuwdorp M, Zhang D, Samuel VT, Vatner DF, Petersen KF, Shulman GI, Serlie MJ. Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans Cell Reports 2017, 19: 1997-2004. PMID: 28591572, PMCID: PMC5469939, DOI: 10.1016/j.celrep.2017.05.035.
- Mitochondrial Targeted Catalase Protects Against High-Fat Diet-Induced Muscle Insulin Resistance by Decreasing Intramuscular Lipid AccumulationLee HY, Lee JS, Alves T, Ladiges W, Rabinovitch PS, Jurczak MJ, Choi CS, Shulman GI, Samuel VT. Mitochondrial Targeted Catalase Protects Against High-Fat Diet-Induced Muscle Insulin Resistance by Decreasing Intramuscular Lipid Accumulation Diabetes 2017, 66: db161334. PMID: 28476930, PMCID: PMC5521865, DOI: 10.2337/db16-1334.
- 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.