Skip to main content

Advertisement

SpringerLink
Log in

A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue?

  • Review Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

Evidence suggests a close relationship between nonalcoholic fatty liver disease (NAFLD) and type two diabetes (T2D). On the grounds of prevalence of disease, both conditions account for a significant financial cost for health care systems and individuals. Aim of this review article is to explore the epidemiological basis and the putative molecular mechanisms underlying the association of NAFLD with T2D. Epidemiological studies have shown that NAFLD is associated to the development of incident T2D and either reversal or improvement of NAFLD will result into decreased risk of developing incident T2D. On the other side of the coin data have shown that T2D will worsen the course of NAFLD doubling the risk of disease progression (i.e. evolution from simple steatosis to advanced fibrosis, cirrhosis, hepatocellular carcinoma, liver transplant and death). Conversely, NAFLD will contribute to metabolic decompensation of T2D. The pathogenesis of T2D in NAFLD patients may be mediated by several hepatokines impairing metabolic control. Among these, Fetuin-B, which causes glucose intolerance and is increased in patients with T2D and NAFLD with fibrosis is one of the most promising. T2D may affect the progression of NAFLD by acting at different levels of the pathogenic cascade involving gut microbiota and expanded, inflamed, dysfunctional adipose tissue. In conclusion, T2D and NAFLD are mutually, closely and bi-directionally associated. An improved understanding of molecular pathogenesis underlying this bi-directional association may allow us to be able to prevent the development of T2D by halting the progression of NAFLD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

ALT:

Alanine transaminase

AST:

Aspartate transaminase

BMI:

Body mass index

CI:

Confidence interval

DAG:

Diacylglycerol

HCC:

Hepatocellular carcinoma

HDL:

High density lipoproteins

HOMA-IR:

Homeostasis model assessment of insulin resistance

HR:

Hazard ratio

IKKβ/NfκB pathway:

IκB-kinase/nuclear factor κB pathway

IR:

Insulin resistance

IL:

Interleukin

LOXL2:

Lysil oxidase 2

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

NFS:

NAFLD fibrosis score

PDGFA:

Platelet-derived growth factor A

PK:

Protein kinase

RPG:

Random plasma glucose

TNF:

Tumor necrosis factor

T2D:

Type 2 diabetes

WC:

Waist circumference

References

  1. Italian Association for the Study of the Liver (AISF) (2017) AISF position paper on nonalcoholic fatty liver disease (NAFLD): updates and future directions. Dig Liver Dis 49:471–483

    Article  Google Scholar 

  2. Sayiner M, Koenig A, Henry L (2016) Epidemiology of nonalcoholic fatty liver disease and nonalcoholic Steatohepatitis in the United States and the Rest of the World. Clin Liver Dis 20:205–214

    Article  PubMed  Google Scholar 

  3. Nascimbeni F, Ballestri S, Machado MV et al (2018) Clinical relevance of liver histopathology and different histological classifications of NASH in adults. Expert Rev Gastroenterol Hepatol 12:351–367

    Article  PubMed  CAS  Google Scholar 

  4. Angulo P, Hui JM, Marchesini G et al (2007) The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 45:846–854

    Article  PubMed  CAS  Google Scholar 

  5. Inzucchi SE (2012) Clinical practice. Diagnosis of diabetes. N Engl J Med 367:542–550

    Article  PubMed  CAS  Google Scholar 

  6. Juliana CN, Chan V, Weiping J et al (2009) Diabetes in Asia: epidemiology. Risk Factors Pathophysiol JAMA 301:2129–2140

    Google Scholar 

  7. Haw JS, Galaviz KI, Straus AN et al (2017) Long-term sustainability of diabetes prevention approaches: a systematic review and meta-analysis of randomized clinical trials. JAMA Intern Med 177:1808–1817

    Article  PubMed  PubMed Central  Google Scholar 

  8. Stratton IM, Adler AI, Neil HA et al (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321:405–412

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Dluhy RG, McMahon GT (2008) Intensive glycemic control in the ACCORD and ADVANCE trials. N Engl J Med 358:2630–2633

    Article  PubMed  CAS  Google Scholar 

  10. Ballestri S, Zona S, Targher G et al (2016) Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol 31:936–944

    Article  PubMed  CAS  Google Scholar 

  11. Hjellvik V, Sakshaug S, Strøm H (2012) Body mass index, triglycerides, glucose, and blood pressure as predictors of type 2 diabetes in a middle-aged Norwegian cohort of men and women. Clin Epidemiol 4:213–224

    Article  PubMed  PubMed Central  Google Scholar 

  12. Mamtani M, Kulkarni H, Dyer TD et al (2013) Waist circumference independently associates with the risk of insulin resistance and type 2 diabetes in mexican american families. PLoS One 8(3):e59153

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Kim SS, Cho HJ, Kim HJ et al (2018) Nonalcoholic fatty liver disease as a sentinel marker for the development of diabetes mellitus in non-obese subjects. Dig Liver Dis 50:370–377

    Article  PubMed  Google Scholar 

  14. Sung KC, Lee MY, Kim YH et al (2018) Obesity and incidence of diabetes: effect of absence of metabolic syndrome, insulin resistance, inflammation and fatty liver. Atherosclerosis 275:50–57

    Article  PubMed  CAS  Google Scholar 

  15. Lonardo A, Ballestri S, Guaraldi G et al (2016) Fatty liver is associated with an increased risk of diabetes and cardiovascular disease—evidence from three different disease models: NAFLD, HCV and HIV. World J Gastroenterol 22:9674–9693

    Article  PubMed  PubMed Central  Google Scholar 

  16. Meisinger C, Thorand B, Schneider A et al (2002) Sex differences in risk factors for incident type 2 diabetes mellitus: the MONICA Augsburg cohort study. Arch Intern Med 162:82–89

    Article  PubMed  Google Scholar 

  17. Ballestri S, Nascimbeni F, Romagnoli D et al (2016) The independent predictors of non-alcoholic steatohepatitis and its individual histological features.: Insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment. Hepatol Res 46:1074–1087

    Article  PubMed  CAS  Google Scholar 

  18. Mantovani A, Byrne CD, Bonora E et al (2018) Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis. Diabetes Care 41:372–382

    Article  PubMed  CAS  Google Scholar 

  19. Enooku K, Kondo M, Fujiwara N et al (2018) Hepatic IRS1 and ß-catenin expression is associated with histological progression and overt diabetes emergence in NAFLD patients. J Gastroenterol. https://doi.org/10.1007/s00535-018-1472-0

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sung KC, Wild SH, Byrne CD (2013) Resolution of fatty liver and risk of incident diabetes. J Clin Endocrinol Metab 98:3637–3643

    Article  PubMed  CAS  Google Scholar 

  21. Yamazaki H, Tsuboya T, Tsuji K et al (2015) Independent association between improvement of nonalcoholic fatty liver disease and reduced incidence of type 2 diabetes. Diabetes Care 38:1673–1679

    Article  PubMed  CAS  Google Scholar 

  22. Fukuda T, Hamaguchi M, Kojima T et al (2016) Transient remission of nonalcoholic fatty liver disease decreases the risk of incident type 2 diabetes mellitus in Japanese men. Eur J Gastroenterol Hepatol 28:1443–1449

    Article  PubMed  CAS  Google Scholar 

  23. Bae JC, Kim SK, Han JM et al (2017) Additive effect of non-alcoholic fatty liver disease on the development of diabetes in individuals with metabolic syndrome. Diabetes Res Clin Pract 129:136–143

    Article  PubMed  CAS  Google Scholar 

  24. Ballestri S, Nascimbeni F, Romagnoli D et al (2016) The role of nuclear receptors in the pathophysiology, natural course, and drug treatment of NAFLD in humans. Adv Ther 33(3):291–319

    Article  PubMed  CAS  Google Scholar 

  25. , Lonardo A, Bellentani S, Argo CK et al. Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups. Dig Liver Dis. 2015;47:997–1006

    Article  PubMed  Google Scholar 

  26. Dai W, Ye L, Liu A et al (2017) Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a meta-analysis. Medicine (Baltimore) 96:e8179

    Article  Google Scholar 

  27. Simeone JC, Bae JP, Hoogwerf BJ et al (2017) Clinical course of nonalcoholic fatty liver disease: an assessment of severity, progression, and outcomes. Clin Epidemiol 9:679–688

    Article  PubMed  PubMed Central  Google Scholar 

  28. Pang Y, Kartsonaki C, Turnbull I et al (2018) Diabetes, plasma glucose and incidence of fatty liver, cirrhosis and liver cancer: a prospective study of 0.5 million people. Hepatology https://doi.org/10.1002/hep.30083

    Article  PubMed Central  PubMed  Google Scholar 

  29. Roulot D, Costes JL, Buyck JF et al (2011) Transient elastography as a screening tool for liver fibrosis and cirrhosis in a community-based population aged over 45 years. Gut 60:977–984

    Article  PubMed  CAS  Google Scholar 

  30. Koehler EM, Plompen EP, Schouten JN et al (2016) Presence of diabetes mellitus and steatosis is associated with liver stiffness in a general population: the Rotterdam study. Hepatology 63:138–147

    Article  PubMed  CAS  Google Scholar 

  31. Pelusi S, Petta S, Rosso C et al (2016) Renin-angiotensin system inhibitors, type 2 diabetes and fibrosis progression: an observational study in patients with nonalcoholic fatty liver disease. PLoS One 11(9):e0163069

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Caballería L, Pera G, Arteaga I et al (2018) High prevalence of liver fibrosis among European adults with unknown liver disease: a population-based study. Clin Gastroenterol Hepatol 16:1138–1145.e5

    Article  PubMed  Google Scholar 

  33. Wild SH, Walker JJ, Morling JR et al (2018) Cardiovascular disease, cancer, and mortality among people with type 2 diabetes and alcoholic or nonalcoholic fatty liver disease hospital admission. Diabetes Care 41:341–347

    Article  PubMed  Google Scholar 

  34. Zoppini G, Fedeli U, Gennaro N et al (2014) Mortality from chronic liver diseases in diabetes. Am J Gastroenterol 109:1020–1025

    Article  PubMed  Google Scholar 

  35. Ryysy L, Häkkinen AM, Goto T et al (2000) Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49:749–758

    Article  PubMed  CAS  Google Scholar 

  36. Cusi K, Sanyal AJ, Zhang S et al (2017) Non-alcoholic fatty liver disease (NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes and type 2 diabetes. Diabetes Obes Metab 19:1630–1634.

    Article  PubMed  CAS  Google Scholar 

  37. Patel PJ, Hossain F, Horsfall LU et al (2018) Controlled attenuation parameter in NAFLD identifies risk of suboptimal glycaemic and metabolic control. J Diabetes Complications. https://doi.org/10.1016/j.jdiacomp.2018.05.008

    Article  PubMed  Google Scholar 

  38. Ertunc ME, Hotamisligil GS (2016) Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment. J Lipid Res 57:2099–2114

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Lonardo A, Targher G (2018) From a fatty liver to a sugary blood. Dig Liver Dis 50(4):378–380

    Article  PubMed  Google Scholar 

  40. Lonardo A, Nascimbeni F, Mantovani A et al (2018) Hypertension, diabetes, atherosclerosis and NASH: cause or consequence? J Hepatol 68:335–352

    Article  PubMed  Google Scholar 

  41. Petersen MC, Madiraju AK, Gassaway BM et al (2016) Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance. J Clin Invest 126:4361–4371

    Article  PubMed  PubMed Central  Google Scholar 

  42. Goedeke L, Bates J, Vatner DF et al (2018) Acetyl-CoA carboxylase inhibition reverses NAFLD and hepatic insulin resistance but promotes hypertriglyceridemia in rodents. Hepatology. https://doi.org/10.1002/hep.30097

    Article  PubMed  Google Scholar 

  43. Petersen MC, Shulman GI (2017) Roles of diacylglycerols and ceramides in hepatic insulin resistance. Trends Pharmacol Sci 38:649–665

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Abderrahmani A, Yengo L, Caiazzo R et al (2018) Increased hepatic PDGF-AA signaling mediates liver insulin resistance in obesity-associated type 2 diabetes. Diabetes 67:1310–1321

    Article  PubMed  Google Scholar 

  45. Meex RCR, Watt MJ (2017) Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol 13:509–520

    Article  PubMed  CAS  Google Scholar 

  46. Wang J, Yang W, Chen Z et al (2018) Long noncoding RNA lncSHGL recruits hnRNPA1 to suppress hepatic gluconeogenesis and lipogenesis. Diabetes 67:581–593

    Article  PubMed  CAS  Google Scholar 

  47. Sohail MU, Althani A, Anwar H et al (2017) Role of the gastrointestinal tract microbiome in the pathophysiology of diabetes mellitus. J Diabetes Res 2017:9631435

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Brunkwall L, Orho-Melander M (2017) The gut microbiome as a target for prevention and treatment of hyperglycaemia in type 2 diabetes: from current human evidence to future possibilities. Diabetologia 60:943–951

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Kim JK, Kim YJ, Fillmore JJ et al (2001) Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 108:437–446

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Hundal RS, Petersen KF, Mayerson AB et al (2002) Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest 109:1321–1326

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445

    Article  PubMed  CAS  Google Scholar 

  52. Lee BC, Lee J (2014) Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta 1842:446–462

    Article  PubMed  CAS  Google Scholar 

  53. Dongiovanni P, Meroni M, Baselli GA et al (2017) Insulin resistance promotes lysyl oxidase like 2 induction and fibrosis accumulation in non-alcoholic fatty liver disease. Clin Sci (Lond) 131:1301–1315

    Article  CAS  Google Scholar 

  54. Barry-Hamilton V, Spangler R et al (2010) Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 16:1009–1017

    Article  PubMed  CAS  Google Scholar 

  55. Meissner EG, McLaughlin M, Matthews L et al (2016) Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial. Liver Int 36:1783–1792

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Gerbes A, Zoulim F, Tilg H et al (2018) Gut roundtable meeting paper: selected recent advances in hepatocellular carcinoma. Gut 67:380–388

    Article  PubMed  CAS  Google Scholar 

  57. Tao R, Wang C, Stöhr O et al (2018) Inactivating hepatic follistatin alleviates hyperglycemia. Nat Med 24:1058–1069

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Meex RC, Hoy AJ, Morris A et al (2015) Fetuin B is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism. Cell Metab 22:1078–1089

    Article  PubMed  CAS  Google Scholar 

  59. Haasch D, Berg C, Clampit JE et al (2006) PKC theta is a key player in the development of insulin resistance. Biochem Biophys Res Commun 343:361–368

    Article  PubMed  CAS  Google Scholar 

  60. Smith AC, Mullen KL, Junkin KA et al (2007) Metformin and exercise reduce muscle FAT/CD36 and lipid accumulation and blunt the progression of high-fat diet-induced hyperglycemia. Am J Physiol Endocrinol Metab 293:E172–E181

    Article  PubMed  CAS  Google Scholar 

  61. Zabielski P, Hady HR, Chacinska M et al (2018) The effect of high fat diet and metformin treatment on liver lipids accumulation and their impact on insulin action. Sci Rep 8:7249

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Inoue T, Kobayashi K, Inoguchi T et al (2011) Reduced expression of adipose triglyceride lipase enhances tumor necrosis factor alpha-induced intercellular adhesion molecule-1 expression in human aortic endothelial cells via protein kinase C-dependent activation of nuclear factor-kappa B. J Biol Chem 286:32045–32053

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Gonzalo T, Beljaars L, van de Bovenkamp M et al (2007) Local inhibition of liver fibrosis by specific delivery of a platelet-derived growth factor kinase inhibitor to hepatic stellate cells. J Pharmacol Exp Ther 321:856–865

    Article  PubMed  CAS  Google Scholar 

  64. Perumpail BJ, Cholankeril R, Yoo ER et al (2017) An overview of dietary interventions and strategies to optimize the management of non-alcoholic fatty liver disease. Diseases 5:4

    Article  CAS  Google Scholar 

  65. Sung KC, Ryu S, Lee JY et al (2016) Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver. J Hepatol 65:791–797

    Article  PubMed  CAS  Google Scholar 

  66. Snyder HS, Sakaan SA, March KL et al (2018) Non-alcoholic fatty liver disease: a review of anti-diabetic pharmacologic therapies. J Clin Transl Hepatol 6:168–174

    PubMed  PubMed Central  Google Scholar 

  67. Targher G, Lonardo A, Byrne CD (2018) Nonalcoholic fatty liver disease and chronic vascular complications of diabetes mellitus. Nat Rev Endocrinol 14:99–114

    Article  PubMed  CAS  Google Scholar 

  68. Lonardo A, Bellentani S, Ratziu V et al (2011) Insulin resistance in nonalcoholic steatohepatitis: necessary but not sufficient - death of a dogma from analysis of therapeutic studies? Expert Rev Gastroenterol Hepatol 5:279–289

    Article  PubMed  Google Scholar 

  69. Townsend SA, Newsome PN (2017) Review article: new treatments in non-alcoholic fatty liver disease. Aliment Pharmacol Ther 46:494–507

    Article  PubMed  CAS  Google Scholar 

  70. Caldwell S (2017) NASH Therapy: omega 3 supplementation, vitamin E, insulin sensitizers and statin drugs. Clin Mol Hepatol 23:103–108

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Simonetta Lugari, Stefano Ballestri and Fabio Nascimbeni contributed equally.

Authors and Affiliations

  1. Azienda Ospedaliero-Universitaria Modena, UO di Medicina Metabolica, Ospedale Civile di Baggiovara, Via Giardini 1135, 41125, Modena, Italy

    Amedeo Lonardo, Fabio Nascimbeni & Mauro Maurantonio

  2. Università di Modena e Reggio Emilia, via del Pozzo, 71, 41124, Modena, Italy

    Simonetta Lugari & Enrica Baldelli

  3. Azienda USL di Modena, Ospedale Di Pavullo, UO di Medicina, Pavullo (Mo), Italy

    Stefano Ballestri

Authors
  1. Amedeo Lonardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simonetta Lugari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefano Ballestri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fabio Nascimbeni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Enrica Baldelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mauro Maurantonio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amedeo Lonardo.

Ethics declarations

Conflict of interest

None of the authors has any conflict of interest to disclose.

Human and animal rights statement

This article does not contain any studies with human or animal subjects performed by any of the authors.

Informed consent

For this type of study formal consent is not required.

Additional information

Managed by Massimo Porta.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lonardo, A., Lugari, S., Ballestri, S. et al. A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue?. Acta Diabetol 56, 385–396 (2019). https://doi.org/10.1007/s00592-018-1266-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-018-1266-0

Keywords

Search

Navigation