Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review

Lipotoxicity is a major contributor to type 2 diabetes mainly promoting mitochondrial dysfunction. Lipotoxic stress is mediated by elevated levels of free fatty acids through various mechanisms and pathways. Impaired peroxisome proliferator-activated receptor (PPAR) signaling, enhanced oxidative stress levels, and uncoupling of the respiratory chain result in ATP deficiency, while beta-cell viability can be severely impaired by lipotoxic modulation of PI3K/Akt and mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) pathways. However, fatty acids are physiologically required for an unimpaired beta-cell function. Thus, preparation, concentration, and treatment duration determine whether the outcome is beneficial or detrimental when fatty acids are employed in experimental setups. Further, ageing is a crucial contributor to beta-cell decay. Cellular senescence is connected to loss of function in beta-cells and can further be promoted by lipotoxicity. The potential benefit of nutrients has been broadly investigated, and particularly polyphenols were shown to be protective against both lipotoxicity and cellular senescence, maintaining the physiology of beta-cells. Positive effects on blood glucose regulation, mitigation of oxidative stress by radical scavenging properties or regulation of antioxidative enzymes, and modulation of apoptotic factors were reported. This review summarizes the significance of lipotoxicity and cellular senescence for mitochondrial dysfunction in the pancreatic beta-cell and outlines potential beneficial effects of plant-based nutrients by the example of polyphenols.

Automated summary

Lipotoxicity is a major contributor to the development of type 2 diabetes by promoting mitochondrial dysfunction; it can lead to ATP deficiency, decreased beta-cell viability, but physiologically fatty acids are necessary for beta-cell function under proper conditions; cellular senescence is associated with lipotoxicity, and plant-based nutrients such as polyphenols may have protective effects against lipotoxicity and cellular senescence.