Diabetes and the liver

Abstract

Type 2 diabetes mellitus (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed non-alcoholic fatty liver disease (NAFLD), are increasingly prevalent conditions that are closely associated. The shared pathophysiology of insulin resistance, chronic inflammation and increased lipid deposition means that there is a bidirectional relationship between the two conditions. MASLD is now a leading cause of cirrhosis and hepatocellular carcinoma (HCC) and has a high prevalence in patients with T2D. This review explores the synergy between MASLD and T2D, while also outlining the diagnostic approach and management of T2D in the context of MASLD. Management involves lifestyle intervention, optimisation of cardiometabolic risk factors and multidisciplinary team involvement. We evaluate the use of antidiabetic medication such as SGLT-2 inhibitors and GLP-1 receptor agonists. Early identification of MASLD can help guide treatment and reduce the risk of progression to liver cirrhosis in high-risk patients.

Keywords: Diabetes; Liver; MASLD; Metabolic; Obesity.

Fig. 1

Schematic diagram illustrating the connection between insulin resistance, lipid metabolism and glucose metabolism. ^aT1D is characterised by autoimmune destruction of pancreatic beta-cells. ^bIn T2D, obesity and metabolic syndrome, insulin has a reduced effect on sensitive tissues and there is reduced glucose uptake from peripheral tissues. There is a compensatory hyperinsulinaemia. In both circumstances, there is insufficient insulin action. ^cInsulin is required to suppress lipolysis. Without sufficient insulin, there is reduced lipolysis inhibition via reduced stimulation of LPL and reduced inhibition of HSL as well as ^dreduced suppression of HGP. ^eIncreased lipolysis causes a higher hepatic output of lipids (vLDL, TG), progression to steatohepatitis (MASH/MASLD) and fibrosis and increased HGP. ^fUltimately, insulin resistance and hyperinsulinaemia result in hyperlipidaemia, adipose hypertrophy and hepatic de novo lipogenesis as well as hyperglycaemia. ^gChronic hyperlipidaemia impairs pancreatic beta-cell function and subsequently causes a progression of T2D. Abbreviations: FFA, free fatty acids; HGP, hepatic glucose production; HSL, hormone sensitive lipase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; MASLD, metabolic dysfunction-associated steatotic liver disease; MASH, metabolic dysfunction-associated steatohepatitis; TG, triglycerides; T1D, type 1 diabetes mellitus; T2D, type 2 diabetes mellitus; TNF-α, tumour necrosis factor alpha; VLDL, very low-density lipoprotein.

Fig. 2

Flowchart illustrating the progression of MASLD. MASLD encompasses a spectrum of conditions and there is typically, but not always, a sequential nature of liver injury. Hepatic triglyceride accumulation (fat in >5% of hepatocytes) without a secondary cause would be defined as the first benign presentation of MASL (hepatic steatosis). Progression to MASH occurs through further inflammation from adipokines. Ongoing cellular injury, fibrogenesis and architectural destruction leads to cirrhosis. Regression is possible with effective management until the cirrhotic stage. At this point, only liver transplantation would be able to treat liver cirrhosis. Chronic metabolic dysfunction and fibrosis carries a high risk of neoplastic transformation into the malignant HCC.