Research progress on the mechanism of beta-cell apoptosis in type 2 diabetes mellitus

Abstract

Type 2 diabetes mellitus(T2DM) is regarded as one of the most severe chronic metabolic diseases worldwide, which poses a great threat to human safety and health. The main feature of T2DM is the deterioration of pancreatic beta-cell function. More and more studies have shown that the decline of pancreatic beta-cell function in T2DM can be attributable to beta-cell apoptosis, but the exact mechanisms of beta-cell apoptosis in T2DM are not yet fully clarified. Therefore, in this review, we will focus on the current status and progress of research on the mechanism of pancreatic beta-cell apoptosis in T2DM, to provide new ideas for T2DM treatment strategies.

Keywords: apoptosis; beta-cell; exosomes; glucolipotoxicity; molecular mechanisms; non-coding RNAs; type 2 diabetes.

Figure 1

Molecular mechanisms of beta-cell apoptosis under conditions of IAPP aggregation and glucolipotoxicity. In obesity-associated type 2 diabetes, elevated islet amyloid polypeptide (IAPP), glucotoxicity, lipotoxicity and glucolipotoxicity are the most studied causative factors of beta-cell apoptosis. These factors activate all ER stress pathways in beta-cells, namely the PKR-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) pathways, and subsequently induce ER stress. When ER stress is prolonged or excessive, it may mediate beta-cell dysfunction and apoptosis by increasing the expression of the pro-apoptotic factor CHOP. In the presence of these pathogenic factors, it also leads to mitochondrial dysfunction and increases the production of reactive oxygen species (ROS). The increase of ROS activates the apoptotic pathway mediated by oxidative stress and mitochondrial cytochrome C in beta-cell. Autophagy can degrade damaged or misfolded cellular components and proteins under normal physiological conditions. However, under conditions of glucolipotoxicity and increased IAPP, beta-cells are subjected to sustained metabolic stress that leads to impaired autophagy which ultimately exacerbates beta-cell dysfunction thereby leading to apoptosis. Islet inflammation often occurs during T2D development and is characterized by macrophage recruitment to infiltrating immune cells, which can lead to increased production of cytokines and chemokines such as IL-1β, TNFa, and these pro-inflammatory signals can activate apoptotic mechanisms, including ER stress and oxidative stress in beta-cells. By Figdraw (www.figdraw.com).

Figure 2

ER stress pathways. Exposure of beta-cells to palmitate leads to accumulation of unfolded or misfolded proteins and Ca²⁺depletion, which affects the folding capacity of the endoplasmic reticulum. The reduction in Ca²⁺ reserve is exacerbated by the downregulation of the sarcoendoplasmic reticulum Ca²⁺-ATPase (SERCA) pump under high glucose conditions. The misfolded protein recruits the ER chaperone BiP, leading to its separation from the ER stress sensors PERK, IRE1, and ATF6, triggering its downstream ER stress signal. This in turn upregulates the expression of the pro-apoptotic proteins CHOP, PUMA and DP5, and inhibits the anti-apoptotic members of the Bcl-2 family. These events ultimately lead to mitochondrial permeabilization, cytochrome C release, and apoptosis. By Figdraw (www.figdraw.com).

Figure 3

Oxidative stress pathways. Exposure to high nutrient loads including glucose (Gluc) and free fatty acids (FFA) increases the production of reactive oxygen species (ROS). If not neutralized by antioxidants, elevated ROS levels alter mitochondrial electron transfer efficiency and increase mitochondrial membrane potential (MMP), resulting in electron shedding from the normal mitochondrial electron respiratory chain transfer process. And enhanced mitochondrial metabolism increases cytoplasmic ATP synthesis, which closes ATP-sensitive K⁺ (K⁺-ATP) channels, leading to impaired insulin secretion. In addition, pro-inflammatory NADPH oxidase (NOX) activity can also elevate ROS and impair insulin gene transcription, leading to impaired insulin secretion and beta-cell apoptosis. By Figdraw (www.figdraw.com).

Figure 4

Various non-coding RNAs involved in beta-cell apoptosis. Some non-coding RNAs are involved in glucolipotoxicity and IAPP-mediated beta-cell apoptosis in type 2 diabetes by regulating the expression of beta-cell key factors. Red arrows indicate promoting, upregulation effect; blue arrows indicate inhibiting, downregulation effect. By Figdraw (www.figdraw.com).