Lipotoxicity: A New Perspective in Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes mellitus is a non-communicable metabolic disorder characterized by insulin resistance (IR) associated with defects in insulin production and secretion. Recent studies have shown that lipotoxicity, which is characterized by the abnormal accumulation of lipids in non-adipose tissues, leads to bodily dysfunction and metabolic disorders, thereby promoting the progression of T2DM. This process is mediated by the induction of endoplasmic reticulum (ER) stress, oxidative stress (OS), mitochondrial dysfunction, and inflammatory responses in pancreatic β-cells, ultimately leading to the activation of apoptosis pathways, which results in β-cell dysfunction and cell death. Furthermore, lipotoxicity interferes with insulin signaling pathways, which worsens IR. Current clinical approaches aimed at mitigating lipotoxicity-induced IR and β-cell dysfunction include the use of metformin, glucagon-like peptide-1 analogs, thiazolidinediones, and molecular chaperones, in addition to interventions such as caloric restriction and physical activity, which reduce fat accumulation in the pancreas and enhance β-cell function. Investigating the interplay between lipotoxicity and T2DM is essential for understanding the underlying disease mechanisms and providing new insights into prevention and therapeutic strategies. This review offers a comprehensive analysis of the mechanisms underlying lipotoxicity in T2DM, highlighting how these insights may drive future research and inform the development of novel treatment approaches.

Keywords: adipose tissue; insulin resistance; lipotoxicity; type 2 diabetes mellitus.

Graphical abstract

Figure 1

SREBP mediate hepatic de novo lipogenesis. When cholesterol levels exceed a certain threshold concentration, the SCAP/SREBP complex binds to the insulin-inducible gene Insigs and remains in the ER. Conversely, when cholesterol levels fall below this threshold, the SCAP/SREBP complex is released from Insigs and translocates from the ER to the Golgi apparatus. There, SREBP is sequentially cleaved by the proteases S1P and S2P, resulting in the release of nSREBPs, which are then translocated into the nucleus to interact with target gene promoters and enhancers. The SREs of the subunit bind to initiate transcription and translation. SREBP-1c primarily regulates the expression of fatty acid synthesis genes, while SREBP-2 mainly governs the expression of cholesterol synthesis genes. Created in BioRender. Wu, Y (2024) https://BioRender.com/o54q509.

Figure 2

FFA affects endoplasmic reticulum stress (By Figdraw: ISAWRaa0a5). FFA accumulation influences the expression of protein arginine methyltransferase (PRMT1), which promotes the phosphorylation of PERK and the subsequent dissociation of ATF6. Following its dissociation from the heavy chain binding protein BiP, PERK undergoes dimerization and activation, leading to the phosphorylation of eukaryotic translation initiation factor α (eIF2α). This phosphorylation of eIF2α selectively activates the translation of downstream transcription factor 4 (ATF4) and its target gene, CHOP. CHOP, in turn, upregulates the expression of GADD34, which binds to protein phosphatase 1 (PP1c) and facilitates the dephosphorylation of eIF2α, thereby establishing a negative feedback loop. ATF4 also induces the expression of genes involved in the anti-oxidative stress response, contributing to insulin resistance and pancreatic β-cell failure. Furthermore, FFA accumulation promotes the dissociation of IRE1α from BiP and its phosphorylation. IRE1α is capable of cleaving the mRNA of the transcription factor X-box DNA binding protein 1 (XBP1), thus regulating lipolysis and exacerbating lipotoxicity. Additionally, IRE1α interacts with tumor necrosis factor receptor-associated factor 2 (TRAF2) and activates apoptosis signal-regulated kinase 1 (ASK1), which triggers the JNK-mediated pro-apoptotic pathway, leading to pancreatic β-cell apoptosis. In the resting state, the C-terminus of ATF6 is situated in the ER lumen, while its N-terminus extends into the cytoplasm. When unfolded or misfolded proteins accumulate in the ER membrane, the C-terminal CD1 domain senses this stress, resulting in the release of transcription factor 6α (ATF6α) from BiP and its transport to the Golgi compartment, where it undergoes regulated cleavage by the proteases S1P and S2P. The cleaved ATF6α then forms a complex with SRE-bound SREBP2 N to inhibit lipogenesis, thereby mitigating lipotoxic damage.

Figure 3

Lipotoxicity activates OS and mitochondrial dysfunction in pancreatic β-cells. The accumulation of FFAs leads to increased beta oxidation, resulting in the production of excess acetyl-CoA, which subsequently enters the tricarboxylic acid (TCA) cycle. This cycle becomes overloaded, generating elevated levels of NADH and FADH₂, which enhance the activity of the electron transport chain. This heightened activity results in the overproduction of ROS, contributing to oxidative stress and mitochondrial dysfunction. The excessive generation of ROS adversely affects insulin signaling by activating stress kinases, including c-Jun N-terminal kinase (JNK), IκB kinase beta (IKKβ), p38 MAPK, and protein kinase C (PKC). Consequently, the phosphorylation of insulin receptor substrate (IRS) at serine residues inhibits insulin signaling and induces insulin resistance. Created in BioRender. Wu, Y (2024) https://BioRender.com/l04l119.