Liver and Fat in Type 2 Diabetes: New Insights and Clinical Relevance

  • Mukesh Nandave
  • Anup Ramdhave
  • Ramesh K. Goyal
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 9)


Among various organs such as the pancreas, kidney, liver, skeletal muscle, and adipose tissue responsible for control of blood glucose levels, the liver is emerging as one of the principal organs involved in insulin resistance associated with type 2 diabetes mellitus. The liver is involved both short- as well as long-term maintenance of glucose concentrations in the blood. In type 2 diabetes, impaired insulin-mediated suppression of glucose production and diminished glucose uptake ultimately causes an increase in postabsorptive glucose production. Type 2 diabetes associated with liver dysfunction and the vicious circle between liver, adipose tissue, and pancreas leads to various other diseases including nonalcoholic fatty liver disease, cardiovascular complications, and cancer. Despite current advances in pharmacotherapy for diabetes, attaining optimal glycemic control and preventing micro- and macrovascular diabetic complications has remained intangible and daunting. Novel therapeutic targets and their modulators, which include protein tyrosine phosphatase 1B inhibitors, glycogen phosphorylase inhibitors, glucokinase activators, diacylglycerol acyltransferase inhibitors, acetyl-CoA carboxylases inhibitors, and sirtuin activators, show promising results in preclinical and clinical studies. Adding new options with new mechanisms of action to the treatment armamentarium may eventually help to improve outcomes and reduce the burden of type 2 diabetes, which is only possible if we explore and understand the involvement of liver and fats in the pathogenesis of type 2 diabetes.


Liver Fats Adipose tissue Glucose metabolism Insulin resistance Diabetes mellitus 


  1. 1.
    Baudry A, Leroux L, Jackerott M et al (2002) Genetic manipulation of insulin signaling, action and secretion in mice. Insights into glucose homeostasis and pathogenesis of type 2 diabetes. EMBO Rep 3:323–328PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Korenblat KM, Fabbrini E, Mohammed BS et al (2008) Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 134:1369–1375PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Michael MD, Kulkarni RN, Postic C et al (2000) Loss of insulin signalling in hepatocyes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 6:87–97PubMedGoogle Scholar
  4. 4.
    Shimomura I, Matsuda M, Hammer RE et al (2000) Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell 6:77–86PubMedGoogle Scholar
  5. 5.
    Caro JF, Dohm LG, Pories WJ et al (1989) Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and type II diabetes. Diabetes Metab Rev 5:665–689PubMedCrossRefGoogle Scholar
  6. 6.
    Consoli A (1992) Role of liver in pathophysiology of NIDDM. Diabetes Care 15:430–441PubMedCrossRefGoogle Scholar
  7. 7.
    Powers AC, D’Alessio D (2011) Endocrine pancreas and pharmacotherapy of diabetes mellitus and hypoglycaemia. In: Brunton LL (ed) Goodman & Gilman’s the pharmacological basis of therapeutics, 12th edn. McGraw-Hill, New York, pp 1258–1271Google Scholar
  8. 8.
    Huang S, Czech MP (2007) The GLUT4 glucose transporter. Cell Metab 5:237–252PubMedCrossRefGoogle Scholar
  9. 9.
    Postic C, Dentin R, Girard J (2004) Role of the liver in the control of carbohydrate and lipid homeostasis. Diabetes Metab 30:398–408PubMedCrossRefGoogle Scholar
  10. 10.
    Sun Y, Liu S, Ferguson S et al (2002) Phosphoenolpyruvate carboxykinase overexpression selectively attenuates insulin signalling and hepatic insulin sensitivity in transgenic mice. J Biol Chem 277:23301–23307PubMedCrossRefGoogle Scholar
  11. 11.
    Trinh KY, O’Doherty RM, Anderson P et al (1998) Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats. J Biol Chem 273:31615–31620PubMedCrossRefGoogle Scholar
  12. 12.
    Valera A, Pujol A, Pelegrin M et al (1994) Transgenic mice overexpressing phosphoenolpyruvate carboxykinase develop non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A 91:9151–9154PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Massillon D, Barzilai N, Chen W et al (1996) Glucose regulates in vivo glucose-6-phosphatase gene expression in the liver of diabetic rats. J Biol Chem 271:9871–9874PubMedCrossRefGoogle Scholar
  14. 14.
    Mithieux G, Vidal H, Zitoun C et al (1996) Glucose-6-phosphatase mRNA and activity are increased to the same extent in kidney and liver of diabetic rats. Diabetes 45:891–896PubMedCrossRefGoogle Scholar
  15. 15.
    Barzilai N, Rossetti L (1993) Role of glucokinase and glucose-6-phosphatase in the acute and chronic regulation of hepatic glucose fluxes by insulin. J Biol Chem 268:25019–25025PubMedGoogle Scholar
  16. 16.
    Burchell A, Cain DI (1985) Rat hepatic microsomal glucose-6-phosphatase protein levels are increased in streptozotocin-induced diabetes. Diabetologia 28:852–856PubMedCrossRefGoogle Scholar
  17. 17.
    Hanson RW, Reshef L (1997) Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annu Rev Biochem 66:581–611PubMedCrossRefGoogle Scholar
  18. 18.
    Wang X, Sato R, Brown MS et al (1994) SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell 77:53–62PubMedCrossRefGoogle Scholar
  19. 19.
    Kim JB, Spiegelman BM (1996) ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev 10:1096–1107PubMedCrossRefGoogle Scholar
  20. 20.
    McGarry JD (1998) Glucose-fatty acid interactions in health and disease. Am J Clin Nutr 67:500S–504SPubMedGoogle Scholar
  21. 21.
    Shimomura I, Hammer RE, Richardson JA et al (1998) Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12:3182–3194PubMedCrossRefGoogle Scholar
  22. 22.
    Shimomura I, Bashmakov Y, Ikemoto S et al (1999) Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci U S A 96:13656–13661PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Hajer GR, Van Haeften TW, Visseren FL (2008) Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J 29:2959–2971PubMedCrossRefGoogle Scholar
  24. 24.
    Ran J, Hirano T, Fukui T et al (2006) Angiotensin II infusion decreases plasma adiponectin level via its type 1 receptor in rats: an implication for hypertension-related insulin resistance. Metabolism 55:478–488PubMedCrossRefGoogle Scholar
  25. 25.
    Engeli S, Bohnke J, Feldpausch M et al (2005) Activation of the peripheral endocannabinoid system in human obesity. Diabetes 54:2838–2843PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Yamauchi T, Kamon J, Waki H et al (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946PubMedCrossRefGoogle Scholar
  27. 27.
    Chu NF, Spiegelman D, Hotamisligil GS et al (2001) Plasma insulin, leptin, and soluble TNF receptors levels in relation to obesity-related atherogenic and thrombogenic cardiovascular disease risk factors among men. Atherosclerosis 157:495–503PubMedCrossRefGoogle Scholar
  28. 28.
    Wannamethee SG, Lowe GD, Rumley A et al (2007) Adipokines and risk of type 2 diabetes in older men. Diabetes Care 30:1200–1205PubMedCrossRefGoogle Scholar
  29. 29.
    Skurk T, Alberti-Huber C, Herder C et al (2007) Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 92:1023–1033PubMedCrossRefGoogle Scholar
  30. 30.
    Fernandez-Real JM, Pickup JC (2008) Innate immunity, insulin resistance and type 2 diabetes. Trends Endocrinol Metab 19:10–16PubMedCrossRefGoogle Scholar
  31. 31.
    Esteve E, Ricart W, Fernández-Real JM (2009) Adipocytokines and insulin resistance: the possible role of lipocalin-2, retinol binding protein-4, and adiponectin. Diabetes Care 32:S362–S367PubMedCrossRefGoogle Scholar
  32. 32.
    Havel PJ (2001) Peripheral signals conveying metabolic information to the brain: short-term and long- term regulation of food intake and energy homeostasis. Exp Biol Med 226:963–977Google Scholar
  33. 33.
    Havel PJ (2002) Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulating protein, and adiponectin. Curr Opin Lipidol 13:51–59PubMedCrossRefGoogle Scholar
  34. 34.
    Havel PJ (2004) Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism. Diabetes 53:S143–S151PubMedCrossRefGoogle Scholar
  35. 35.
    Cianflone K, Maslowska M, Sniderman AD (1999) Acylation stimulating protein (ASP), an adipocyte autocrine: new directions. Semin Cell Dev Biol 10:31–41PubMedCrossRefGoogle Scholar
  36. 36.
    Cianflone K, Xia Z, Chen LY (2003) Critical review of acylation-stimulating protein physiology in humans and rodents. Biochim Biophys Acta 1609:127–143PubMedCrossRefGoogle Scholar
  37. 37.
    Comuzzie AG, Cianflone K, Martin LJ et al (2001) Serum levels of acylation stimulating protein (ASP) show evidence of a pleiotropic relationship with total cholesterol, LDL, and triglycerides and preliminary evidence of linkage on chromosomes 5 and 17 in Mexican Americans (abstract). Obes Res 9:103SGoogle Scholar
  38. 38.
    Kadowaki T, Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26:439–451PubMedCrossRefGoogle Scholar
  39. 39.
    Danesh FR, Kanwar YS (2004) Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy. FASEB J 18:805–815PubMedCrossRefGoogle Scholar
  40. 40.
    Owen OG (2005) The collaborative atorvastatin diabetes study: preliminary results. Int J Clin Pract 59:121–123PubMedCrossRefGoogle Scholar
  41. 41.
    Russell M, Fleg JL, Galloway WJ et al (2006) Examination of lower targets for low-density lipoprotein cholesterol and blood pressure in diabetes: the Stop Atherosclerosis in Native Diabetics Study (SANDS). Am Heart J 152:867–875PubMedCrossRefGoogle Scholar
  42. 42.
    Hauptman J (2000) Orlistat: selective inhibition of caloric absorption can affect long-term body weight. Endocrine 13:201–206PubMedCrossRefGoogle Scholar
  43. 43.
    Sekar N, Li J, Shechter Y (1996) Vanadium salts as insulin substitutes: mechanism of action, a scientific and therapeutic tool in diabetes mellitus research. Crit Rev Biochem Mol Biol 31:339–359PubMedCrossRefGoogle Scholar
  44. 44.
    Morris DL, Rui L (2009) Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab 297:E1247–E1259PubMedCrossRefGoogle Scholar
  45. 45.
    Johnson TO, Ermolieff J, Jirousek MR (2002) Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat Rev Drug Discov 1:696–709PubMedCrossRefGoogle Scholar
  46. 46.
    Swarbrick MM, Havel PJ, Levin AA et al (2009) Inhibition of protein tyrosine phosphatase-1B with antisense oligonucleotides improves insulin sensitivity and increases adiponectin concentrations in monkeys. Endocrinology 150:1670–1679PubMedCrossRefGoogle Scholar
  47. 47.
    Martin TL, Alquier T, Asakura K et al (2006) Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle. J Biol Chem 281:18933–18941PubMedCrossRefGoogle Scholar
  48. 48.
    Ottanà R, Maccari R, Ciurleo R et al (2009) 5-Arylidene-2-phenylimino-4-thiazolidinediones as PTP1B and LMW-PTP inhibitors. Bioorg Med Chem Lett 17:1928–1937Google Scholar
  49. 49.
    Henke BR, Sparks SM (2006) Glycogen phosphorylase inhibitors. Mini Rev Med Chem 6:845–857PubMedCrossRefGoogle Scholar
  50. 50.
    Martin WH, Hoover DJ, Armento SJ et al (1998) Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo. Proc Natl Acad Sci U S A 95:1776–1781PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Matschinsky FM, Porte D (2010) Glucokinase activators (GKAs) promise a new pharmacotherapy for diabetics. F1000 Med Rep 2:43PubMedCentralPubMedGoogle Scholar
  52. 52.
    Bonadonna RC, Heise T, Arbet-Engels C et al (2010) Piragliatin (RO4389620), a novel glucokinase activator, lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients with type 2 diabetes mellitus: a mechanistic study. J Clin Endocrinol Metab 95:5028–5036PubMedCrossRefGoogle Scholar
  53. 53.
    Kelly RP, Abu-Raddad EJ, Tham LS (2011) Single doses of the glucagon receptor antagonist LY2409021 reduce blood glucose in healthy subjects and patients with Type 2 Diabetes Mellitus (T2DM). American Diabetes Association abstract no. 1004-PGoogle Scholar
  54. 54.
    Petersen KF, Sullivan JT (2001) Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia 44:2018–2024PubMedCrossRefGoogle Scholar
  55. 55.
    Chen HC, Smith SJ, Ladha Z et al (2002) Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerolacyltransferase 1. J Clin Invest 109:1049–1055PubMedCentralPubMedGoogle Scholar
  56. 56.
    Denison H, Nilsson C, Kujacic M et al (2013) Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first-time-in-human single-dose study. Diabetes Obes Metab 15:136–143PubMedCrossRefGoogle Scholar
  57. 57.
    Wakil SJ, Abu-Elheiga LA (2009) Fatty acid metabolism: target for metabolic syndrome. J Lipid Res 50:S138–S143PubMedCrossRefGoogle Scholar
  58. 58.
    Treadway JL, McPherson RK, Petras SF et al (2004) Effect of the acetyl-CoA carboxylase inhibitor CP-640186 on glycemic control in diabetic ob/ob mice. Pfizer Poster PresentationGoogle Scholar
  59. 59.
    Winder WW, Hardie DG (1999) AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol Endocrinol Metab 277:E1–E10Google Scholar
  60. 60.
    Vingtdeux V, Chandakkar P, Zhao HC et al (2011) Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-β peptide degradation. FASEB J 25:219–231PubMedCrossRefGoogle Scholar
  61. 61.
    Lian Z, Li Y, Gao J et al (2011) A novel AMPK activator, WS070117, improves lipid metabolism discords in hamsters and HepG2 cells. Lipids Health Dis 10:67PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Mukesh Nandave
    • 1
  • Anup Ramdhave
    • 1
  • Ramesh K. Goyal
    • 2
  1. 1.SPP School of Pharmacy and Technology ManagementSVKM’s NMIMSMumbaiIndia
  2. 2.Institute of Life ScienceAhmedabad University, Opposite Gujarat UniversityNavrangpuraIndia

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