Skip to Main Content
DownloadHi-Res Photo

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

  • Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Ceramides.Samuel VT, Shulman GI. Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Ceramides. The New England Journal Of Medicine 2019, 381: 1866-1869. PMID: 31693811, DOI: 10.1056/NEJMcibr1910023.
  • The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis.Herman MA, Samuel VT. The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis. Trends In Endocrinology And Metabolism: TEM 2016, 27: 719-730. PMID: 27387598, PMCID: PMC5035631, DOI: 10.1016/j.tem.2016.06.005.
  • Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance.Petersen 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. The Journal Of Clinical Investigation 2016, 126: 4361-4371. PMID: 27760050, PMCID: PMC5096902, DOI: 10.1172/JCI86013.
  • Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids.Vatner 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: 1143-8. PMID: 25564660, PMCID: PMC4313795, DOI: 10.1073/pnas.1423952112.
  • The emerging role of oestrogen-related receptor γ as a regulator of energy metabolism.Samuel VT. The emerging role of oestrogen-related receptor γ as a regulator of energy metabolism. Diabetologia 2014, 57: 2440-3. 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 rats.Cantley 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. American Journal Of Physiology. Endocrinology And Metabolism 2014, 307: E773-83. PMID: 25159329, PMCID: PMC4216948, DOI: 10.1152/ajpendo.00148.2014.
  • Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways.Vatner 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. American Journal Of Physiology. Endocrinology And Metabolism 2013, 305: E89-100. PMID: 23651850, PMCID: PMC3725564, DOI: 10.1152/ajpendo.00573.2012.
  • Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance.Kumashiro 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: 2183-94. PMID: 23423574, PMCID: PMC3712050, DOI: 10.2337/db12-1311.
  • Mechanisms for insulin resistance: common threads and missing links.Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell 2012, 148: 852-71. PMID: 22385956, PMCID: PMC3294420, DOI: 10.1016/j.cell.2012.02.017.
  • Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease.Kumashiro 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: 16381-5. PMID: 21930939, PMCID: PMC3182681, DOI: 10.1073/pnas.1113359108.
  • Deletion of the alpha-arrestin protein Txnip in mice promotes adiposity and adipogenesis while preserving insulin sensitivity.Chutkow 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 alpha-arrestin protein Txnip in mice promotes adiposity and adipogenesis while preserving insulin sensitivity. Diabetes 2010, 59: 1424-34. PMID: 20299477, PMCID: PMC2874703, DOI: 10.2337/db09-1212.
  • Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 Diabetes.Samuel 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: 12121-6. PMID: 19587243, PMCID: PMC2707270, DOI: 10.1073/pnas.0812547106.
  • Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease.Samuel VT, Liu ZX, Wang A, Beddow SA, Geisler JG, Kahn M, Zhang XM, Monia BP, Bhanot S, Shulman GI. Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. The Journal Of Clinical Investigation 2007, 117: 739-45. PMID: 17318260, PMCID: PMC1797607, DOI: 10.1172/JCI30400.
  • 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. The Journal Of Biological Chemistry 2004, 279: 32345-53. PMID: 15166226, DOI: 10.1074/jbc.M313478200.
Edit Profile