Pathophysiological Relationship between Type 2 Diabetes Mellitus and Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Therapeutic Approaches

Abstract

Type 2 diabetes mellitus (T2DM), often featuring hyperglycemia or insulin resistance, is a global health concern that is increasing in prevalence in the United States and worldwide. A common complication is metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of metabolic syndrome that is also rapidly increasing in prevalence. The majority of patients with T2DM will experience MASLD, and likewise, individuals with MASLD are at an increased risk for developing T2DM. These two disorders may act synergistically, in part due to increased lipotoxicity and inflammation within the liver, among other causes. However, the pathophysiological mechanisms by which this occurs are unclear, as is how the improvement of one disorder can ameliorate the other. This review aims to discuss the pathogenic interactions between T2D and MASLD, and will highlight novel therapeutic targets and ongoing clinical trials for the treatment of these diseases.

Keywords: MASLD; hyperglycemia; liver disease; metabolic disease; steatosis.

Figure 1

Spectrum of MASLD progression. Due to obesity, lifestyle or other factors, a healthy liver may become steatotic (TG present in >5% of hepatocytes). Steatohepatitis can develop from steatosis with the addition of inflammatory insults. Both MASLD and MASH are often reversible, while cirrhosis may partially regress with treatment. Otherwise, this can lead to hepatocellular carcinoma and may ultimately require liver transplantation [9,10].

Figure 2

Inflammation, lipotoxicity and fibrosis contribute to the pathophysiological relationships between T2DM and MASLD. β-cell dysfunction causes IR in T2DM, followed by organ-specific pathology. (A) A chronic high-fat diet (HFD) can lead to IR, with increased glucose and insulin but blunted downstream receptor signaling, resulting in sustained elevated blood glucose. Glucose and insulin promote de novo lipogenesis through the activation of ChREBP and SREBP1c, respectively, to produce free fatty acids (FFAs). (B) Increased hepatic FFA causes mitochondrial dysfunction and ER stress followed by the rise of reactive oxygen species (ROS) and inflammatory mediators. The activation of JNK signaling by these mediators can cause hepatic cell damage and lead to inflammation; JNK signaling also decreases insulin sensitivity. (C) The development of IR is also related to alterations in adipokines secreted from adipose tissue. Decreased adiponectin induces lipotoxicity by increasing FFA, while increased inflammatory TNF-α drives hepatic satellite cell activation, leading to hepatic fibrosis due to excess collagen deposition. (D) Finally, chronic HFD affects the gut microbiota. Increased gut permeability and bacterial cellular lipopolysaccharide (LPS) or ethanol production due to dysbiosis leads to an increase in hepatic toll-like receptor 4 activation and subsequent inflammation and fibrogenesis in the liver. Red: hepatic pathways; green: adipocyte pathways; purple: intestinal pathways.

Figure 3

Novel treatment approaches common to T2DM and MASLD. PPAR agonists and THR agonists act to reduce hepatic free fatty acids and subsequent lipogenesis. AMPK activation is targeted via direct agonists or indirectly through THR agonists and GPR119 agonists to reduce lipogenesis. Mitochondrial targeting increases thermogenesis and reduces gluconeogenesis to ultimately reduce lipogenesis and steatosis in the liver. In the pancreas, PPAR and THR agonists act to increase insulin secretion and reduce hepatic lipogenesis. In the distal small intestine, GRP119 agonists as well as incretin mimetics potently stimulate insulin release and promote weight loss.

Figure 4

Bile-acid-based treatments for MASLD. Bile acids are synthesized from cholesterol and are released into the duodenum post-prandially to aid in nutrient and fat digestion. Bile acids also activate the receptors FXR and TGR5 to regulate metabolism. In enterocytes, the activation of FXR by bile acids or agonists induces FGF19 release which suppresses bile acid synthesis and has been shown to reduce steatosis. In hepatocytes, the activation of FXR suppresses bile acid synthesis and promotes glucose homeostasis and β-oxidation. Also in the liver, FGF21 promotes insulin sensitivity and reduces lipogenesis. In intestinal L-cells, the activation of TGR5 promotes insulin sensitivity through the release of GLP-1.