Type 2 diabetes originated from non-alcoholic fatty liver disease

Abstract

Both non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are highly prevalent metabolic liver diseases. Accumulating epidemiological evidence now indicates that NAFLD and T2DM are strongly associated, yet the causative relationship remains to be elucidated. Liver serves as a hub for nutrient and energy metabolism in the body. Here we demonstrated the pathogenesis linking NAFLD to T2DM through a series of studies and the attenuation of T2DM progression after NALFD improvement in cohort study. We proposed the urgent necessity of NAFLD management and NAFLD drug development, which might be novel therapeutic avenues for T2DM.

Graphical abstract

Keywords

non-alcoholic fatty liver disease / gluconeogenesis / hepatokine / exercise

Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) have become a global epidemic with rapidly increasing prevalence and incidence [1]. Epidemiological studies have established that T2DM and NAFLD are strongly associated, yet the mechanisms underlying the potential causative relationship between these conditions remain unclear.

Epidemiological characteristics of NAFLD and T2DM

NAFLD is the most prevalent chronic liver disease worldwide. It is estimated that NAFLD affects one-third of the general population, and up to 50% overweight and obese people [2]. Over the past decades, NAFLD has been rising in parallel with the prevalence of obesity and T2DM. The prevalence of diabetes among adults is around 10% and much lower than that of NAFLD, which implies that NAFLD occurs prior to diabetes and is associated with diabetes development [3]. A number of cohort studies demonstrate that NAFLD is a risk factor for incident T2DM. Individuals with NALFD have a 2- to 5-fold increase in developing T2DM than those without NAFLD [4]. This increase in risk for T2DM by NAFLD remains after adjustment for body weight, physical activity, family history, and other established metabolic risk factors [5]. Of note, the attenuation or aggravation of NAFLD is also associated with a reduction or an increase in the risk of T2DM [6]. Meanwhile, co-existence of diabetes makes NAFLD patients more likely to progress to severe stages including NASH, liver fibrosis, and end-stage liver disease [7, 8]. NAFLD and diabetes act synergistically and lead to a more severe adverse outcome than either condition alone.

Pathogenesis linking NAFLD to T2DM

Obesity and insulin resistance are key pathogenic factors involved in the development of T2DM. These two pathological conditions are also frequently observed in NAFLD. In the past several decades, our group has been working on elucidating the complex link between NALFD and T2DM. NAFLD is characterized by the over accumulation of triglycerides in the liver. The increase of intrahepatic triglyceride contents can be triggered either way: (i) an increase of lipid synthesis including de novo lipogenesis and hepatic uptake of free fatty acids released from adipose tissues, and (ii) a decrease of hepatic triglyceride clearance including fatty acid β-oxidation and very low-density lipoprotein export [9]. The increase of de novo lipogenesis makes the major contribution to NAFLD development. Sterol regulatory element-binding protein 1c (SREBP-1c) plays a key role in regulating lipogenesis by upregulation of fatty acid synthase, stearoyl-CoA desaturase-1, and acetyl-CoA carboxylase 1/2 gene expressions. SREBP-1c is activated by overnutrition, obesity, inflammation, oxidative stress, endoplasmic reticulum (ER) stress, etc. Our findings demonstrated that farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, could negatively regulate de novo lipogenesis by counteraction against SREBP-1c. FXR expression is markedly reduced in high-fat diet and genetically obese (ob/ob) mice. Deletion of hepatic FXR leads to hepatosteatosis and in contrast, overexpression of FXR in the liver of obese mice greatly ameliorates hepatosteatosis. Our study revealed that Yin Yang 1 suppresses the transcriptional expression of FXR in obese mice [10]. The dysfunction of FXR is also involved in NAFLD development in elderly people and postmenopausal women [11, 12]. Thus, FXR deficiency plays a causal role in the development of NAFLD, and FXR agonist, obeticholic acid, would be a very promising drug against NAFLD.

For years, the potential effect of low-grade inflammation on insulin resistance and T2DM has been investigated [13]. Pre-inflammatory cytokines produced by macrophage in the liver interrupt insulin signaling in the liver, as well as in adipose tissue and skeletal muscle. Hepatic insulin resistance is presented in most NAFLD patient, which results in unsuppressed hepatic glucose production (HGP) and increased blood glucose level.

Insulin resistance of peripheral tissues and pancreatic beta cell dysfunction have long been considered as two major pathophysiological processes of T2DM. The liver is a central player in maintaining glucose homeostasis through regulation of HGP or hepatic glucose utilization depending on blood glucose level. Excessive gluconeogenesis and hepatic glucose output result in fasting hyperglycemia, which is characterized by T2DM. Our previous work revealed that hepatic 17-hydroxyprogesterone (17-OHP) concentrations were increased in NAFLD due to aberrant expression of cytochrome P450 17A1 (CYP17A1). 17-OHP is an intermediate of cortisol biosynthesis, which augments gluconeogenesis in a glucocorticoid receptor-dependent manner and increases glucose production by the liver. Selective inhibitor targeting Cyp17A elicited robust glucose-lowering effect in diabetic mouse models [14]. We also found a chronic low-grade ER stress in the liver of obese NAFLD mice. The sustained ER stress promoted gluconeogenesis through induction of ubiquitin-specific peptidase 14 and therefore stabilization of 3ʹ,5ʹ-cyclic monophosphate-responsive element-binding protein [15]. Together, NAFLD appears to enhance gluconeogenesis through several different mechanisms.

Beyond cell-autonomous mechanisms, several hepatokines have been shown to regulate insulin sensitivity and glucose homeostasis, including fetuin-A. Fetuin-A acts as an endogenous ligand of Toll-like receptor 4 to promote inflammation and insulin resistance in adipose tissue [16]. We found that fetuin-A could be ubiquitinated by F-box and WD repeat domain containing 7 (FBXW7), and subsequently degraded by the proteasomal pathway. Downregulation of hepatic FBXW7 in NAFLD results in accumulation of fetuin-A and systemic insulin resistance [17]. Periostin, another hepatokine that is upregulated in NAFLD, was sufficient to promote hepatic insulin resistance through its activation of c-Jun N-terminal kinase (JNK)/c-Jun signaling pathway and subsequent suppression of fatty acid oxidation [18].

Therapeutic avenues for T2DM targeting hepatic steatosis

Accumulating evidence indicates that NAFLD may precede and exacerbate the development of T2DM. We hypothesized that improvement of NAFLD may reduce the risk of incident T2DM. Currently, there is no approved drugs for the treatment of NAFLD, and lifestyle modification is still the most effective therapy for NAFLD. In a randomized clinical trial conducted by our group, we demonstrated that exercise significantly reduced hepatic lipid content and moderate exercise was equally effective in improving NAFLD as vigorous exercise [19]. The participants were followed up for 10 years to elucidate the incidence of T2DM. Excitedly, we found a 50% reduction of T2DM incidence in both moderate and vigorous exercise groups as compared with the non-exercise control group [20]. In addition, the improvement of hepatic triglyceride content during 1-year exercise intervention is an independent factor for the reduction of the risk for T2DM after adjustment for metabolic confounding factors. Calorie-restricted diet is known to be able to significantly improve NAFLD and also be very effective in delaying the onset of diabetes [21, 22]. Several hypoglycemic agents, including metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors, have been shown to exert beneficial effects on NAFLD [23]. Yet more studies are needed to address whether the glucose-lowering effect of these anti-diabetic drugs was partially mediated by the remission of NAFLD.

Future perspectives

We believe that the pathophysiological connections between NAFLD and T2DM are much more intricated than currently appreciated (Fig. 1). Further research is warranted to fully establish the causal relationship between NAFLD and T2DM. The studies discussed above underscore the necessity for screening, diagnosis, and management of NAFLD. The idea that improvement of NAFLD attenuates T2DM progression might highlight the urgency of NALFD drug development.

References

[1] Younossi ZM, Golabi P, de Avila L et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol 2019; 71: 793–801.

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

[3] Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 2018; 14: 88–98.

[4] Loomba R, Abraham M, Unalp A et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 2012; 56: 943–51.

[5] Mantovani A, Petracca G, Beatrice G et al. Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals. Gut 2021; 70: 962–9.

[6] Yamazaki H, Tsuboya T, Tsuji K et al. Independent association between improvement of nonalcoholic fatty liver disease and reduced incidence of type 2 diabetes. Diabetes Care 2015; 38: 1673–9.

[7] Powell EE, Wong VW, Rinella M. Non-alcoholic fatty liver disease. Lancet 2021; 397: 2212–24.

[8] Jarvis H, Craig D, Barker R et al. Metabolic risk factors and incident advanced liver disease in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of population-based observational studies. PLoS Med 2020; 17: e1003100.

[9] Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 2010; 51: 679–89.

[10] Lu Y, Ma Z, Zhang Z et al. Yin Yang 1 promotes hepatic steatosis through repression of farnesoid X receptor in obese mice. Gut 2014; 63: 170–8.

[11] Xiong X, Wang X, Lu Y et al. Hepatic steatosis exacerbated by endoplasmic reticulum stress-mediated downregulation of FXR in aging mice. J Hepatol 2014; 60: 847–54.

[12] Wang X, Lu Y, Wang E et al. Hepatic estrogen receptor alpha improves hepatosteatosis through upregulation of small heterodimer partner. J Hepatol 2015; 63: 183–90.

[13] Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest 2017; 127: 1–4.

[14] Lu Y, Wang E, Chen Y et al. Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activat glucocorticoid ion of receptor. J Clin Invest 2020; 130: 3791–804.

[15] Liu B, Zhang Z, Hu Y et al. Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14. Proc Natl Acad Sci U S A 2019; 116: 21732–8.

[16] Pal D, Dasgupta S, Kundu R et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 2012; 18: 1279–85.

[17] Zhao J, Xiong X, Li Y et al. Hepatic F-box protein FBXW7 maintains glucose homeostasis through degradation of fetuin-A. Diabetes 2018; 67: 818–30.

[18] Lu Y, Liu X, Jiao Y et al. Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα. J Clin Invest 2014; 124: 3501–13.

[19] Zhang HJ, He J, Pan LL et al. Effects of moderate and vigorous exercise on nonalcoholic fatty liver disease: a randomized clinical trial. JAMA Intern Med 2016; 176: 1074–82.

[20] Chen Y, Chen Z, Pan L et al. Effect of moderate and vigorous aerobic exercise on incident diabetes in obese adults: a 10-year follow-up of a randomized controlled trial. JAMA Intern Med 2023; 183: 272–5.

[21] Holmer M, Lindqvist C, Petersson S et al. Treatment of NAFLD with intermittent calorie restriction or low-carb high-fat diet - a randomised controlled trial. JHEP Rep 2021; 3: 100256.

[22] Goldenberg JZ, Day A, Brinkworth GD et al. Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission: systematic review and meta-analysis of published and unpublished randomized trial data. BMJ 2021; 372: m4743.

[23] Ferguson D, Finck BN. Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus. Nat Rev Endocrinol 2021; 17: 484–95.

RIGHTS & PERMISSIONS

The Author(s) 2023. Published by Oxford University Press on behalf of Higher Education Press.