The Chicken or the Egg: The Relationship Between Nonalcoholic Fatty Liver Disease and Type 2 Diabetes

July 30, 2022

Class Act Clinical Questions 4 min read

By Mahip Grewal

Peer Reviewed

Nonalcoholic fatty liver disease (NAFLD) is estimated to affect 25% of the world’s population.1 NAFLD is a spectrum of disease ranging from nonalcoholic fatty liver (NAFL), which is generally nonprogressive isolated steatosis, to nonalcoholic steatohepatitis (NASH), which is characterized by hepatocyte ballooning, lobular inflammation, and fibrosis, and can precipitate cirrhosis and hepatocellular carcinoma (HCC). The broad schema is that excess lipid deposition in the liver constitutes the initial insult, and various genetic susceptibilities, risk factors, and environmental influences interact to differentially activate inflammatory pathways. 2

NAFLD is now a leading indication for liver transplantation in the US, and its rapidly rising incidence coincides with the ongoing obesity epidemic. It is often identified as the liver manifestation of metabolic syndrome, which encompasses a combination of abnormalities including abdominal obesity, insulin resistance/hyperglycemia, hypertension, hypertriglyceridemia, and dyslipidemia. 3 Moreover, NAFLD patients have a 2- to 3-fold increased risk of developing type 2 diabetes mellitus (T2DM). At the same time, NAFLD patients with T2DM exhibit a higher rate of progression to NASH.4  Furthermore, just as cardiovascular disease is the driver of mortality among T2DM patients, most NAFLD patients who do not receive liver transplants die due to their coexisting cardiometabolic disease rather than from complications of their liver disease.5

Such findings fuel ongoing research into the liver-pancreas axis and its dysfunction in these diseases. Considering the propensity for T2DM among NAFLD patients, Godoy-Matos and colleagues describe how free fatty acid (FFA) deposition in adipose tissue and muscles leads to insulin resistance (IR), which “facilitates lipolysis and increases the flux of FFAs to the liver, inducing hepatic IR and enhancing glucose production.”3 In response to IR, the pancreas upregulates insulin production; however, persistent IR, often in conjunction with lipotoxicity arising from FFA deposition in the pancreas, can impair beta-cell function. More recent evidence suggests that FFA deposition in the liver can also drive hepatic glucagon resistance, disrupting metabolism of amino acids, with the resulting increased levels of amino acids further promoting glucagon production.6

Viewed from the opposite direction, peripheral IR in T2DM leads to increased FFA flux to the liver, associated with “mitochondrial dysfunction, increased oxidative stress and uncoupled oxidative phosphorylation, activating a fibrogenic response in hepatic stellate cells,” which can drive progression to NASH, cirrhosis, and HCC. Additionally, glucotoxicity promotes de novo lipogenesis, through mechanisms including increased citric acid cycle activity and activation of the carbohydrate response element binding protein (ChREBP) transcription factor, along with pancreatic beta-cell damage, oxidative stress, and production of reactive oxygen species.7

Already the leading liver disease globally, NAFLD is continuing to rise in prevalence, but there are unfortunately no pharmacological agents specifically approved for its treatment. However, an international consensus panel recently proposed revised nomenclature, “metabolic associated fatty liver disease” (MAFLD), which is diagnosed when hepatic steatosis coexists with at least one of the following: established T2DM, overweight/obesity, or metabolic dysregulation.8 Unlike NAFLD, MAFLD does not necessitate the exclusion of other contributing etiologies such as alcohol consumption, and it more holistically appraises the growing pathophysiological understanding. It is important to note that there remains significant heterogeneity in fatty liver disease presentation. “Lean NAFLD,” for instance, describes a subset of patients who have normal body-mass index but exhibit steatosis.9 Thus, further exploration of NAFLD risk factors and corresponding disease mechanisms is warranted to guide more nuanced patient stratification and therapeutic options.

Notwithstanding, with the growing shift towards the MAFLD framework, efforts to investigate the utility of T2DM pharmacologic agents for the treatment of NAFLD are underway. While metformin was not found to be effective for NASH patients, there are promising results for glucagon-like peptide 1(GLP-1) receptor agonists, thiazolidinediones, and sodium-glucose cotransporter 2 (SGLT-2) inhibitors.5 For example, a double-blind, randomized phase II trial showed that, compared to placebo, the GLP-1 agonist liraglutide was associated with histological resolution of NASH and reductions in weight and HbA1c among overweight NASH patients with or without diabetes. 10 Trials of SLGT-2 inhibitors have shown, in addition to glucose control, improvements in liver enzyme levels, lipid content, and stiffness. In fact, canagliflozin and dapagliflozin have been found to reduce liver enzyme levels, independent of weight loss and HbA1c-lowering.5 Along with trialing existing therapies, various groups are studying agents targeting other modulators of metabolic pathways, such as inhibitors of acetyl CoA carboxylases (ACCs) implicated in de novo lipogenesis, and quantifying hepatic benefits associated with weight loss modalities, such as bariatric surgery.5,3 

Altogether, elucidation of the pathophysiological pathways coalescing and branching into subtypes of NAFLD/MAFLD, T2DM, and metabolic syndrome represents a promising avenue for pinpointing effective, multitarget prevention and treatment options.

Mahip Grewal is a 3rd year student at NYU Grossman School of Medicine

Reviewed by Michael Tanner, MD, associate editor, Clinical Correlations

Image courtesy Wikimedia Commons, source: https://www.flickr.com/photos/38854364@N00
File:Chicken or Egg.jpg|Chicken_or_Egg

References

  1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. doi:10.1002/hep.28431 https://pubmed.ncbi.nlm.nih.gov/26707365/
  2. Parthasarathy G, Revelo X, Malhi H. Pathogenesis of nonalcoholic steatohepatitis: an overview. Hepatol Commun. 2020;4(4):478-492. doi:10.1002/hep4.1479
  3. Godoy-Matos AF, Silva Júnior WS, Valerio CM. NAFLD as a continuum: from obesity to metabolic syndrome and diabetes. Diabetol Metab Syndr. 2020;12:60. doi:10.1186/s13098-020-00570-y  https://pubmed.ncbi.nlm.nih.gov/32684985/
  4. Tomah S, Alkhouri N, Hamdy O. Nonalcoholic fatty liver disease and type 2 diabetes: where do Diabetologists stand? Clin Diabetes Endocrinol. 2020;6:9. Published 2020 Jun 5. doi:10.1186/s40842-020-00097-1
  5. Ferguson D, Finck BN. Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus. Nat Rev Endocrinol. 2021;17(8):484-495. doi:10.1038/s41574-021-00507-z  https://pubmed.ncbi.nlm.nih.gov/34131333/
  6. Holst JJ, Wewer Albrechtsen NJ, Pedersen J, Knop FK. Glucagon and amino acids are linked in a mutual feedback cycle: the liver-α-cell axis. Diabetes. 2017;66(2):235-240. doi:10.2337/db16-0994  https://pubmed.ncbi.nlm.nih.gov/28108603/
  7. Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options. JHEP Rep. 2019;1(4):312-328. doi:10.1016/j.jhepr.2019.07.002  https://pubmed.ncbi.nlm.nih.gov/32039382/
  8. Eslam M, Sanyal AJ, George J; International Consensus Panel. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology. 2020;158(7):1999-2014.e1. doi:10.1053/j.gastro.2019.11.312
  9. Chrysavgis L, Ztriva E, Protopapas A, Tziomalos K, Cholongitas E. Nonalcoholic fatty liver disease in lean subjects: Prognosis, outcomes and management. World J Gastroenterol. 2020;26(42):6514-6528. doi:10.3748/wjg.v26.i42.6514
  10. Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679-690. doi:10.1016/S0140-6736(15)00803-X https://pubmed.ncbi.nlm.nih.gov/26608256/