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

Abstract

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 β-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 β-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 β-cell decay. Cellular senescence is connected to loss of function in β-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 β-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 β-cell and outlines potential beneficial effects of plantbased nutrients by the example of polyphenols.

The Role of Mitochondria-Derived Peptides in Cardiovascular Diseases and Their Potential as Therapeutic Targets

“…Insulin resistance: Insulin resistance in the metabolic tissues is often associated with a decreased number of mitochondria and available oxidative enzymes, abnormal mitochondria morphology, reduced production of ATP and insulin-dependent glucose disposal [49,50]. Humanin administration was shown to increase insulin sensitivity in muscles and the liver, fatty acid metabolism signalling and insulin-mediated AKT-signalling (Protein kinase B) [51,52].…”

Problems of Pathogenesis and Pathogenetic Therapy of COVID-19 from the Perspective of the General Theory of Pathological Systems (General Pathological Processes)

“…Lipotoxicity linked with a rise in FFA, according to several studies, is the primary cause of type 2 diabetes [ 128 , 129 , 130 ]. Hypoxia, on the other hand, can increase lipotoxicity and pro-inflammatory macrophage activation by saturated FFAs [ 80 ].…”

Preparation of fatty acid solutions exerts significant impact on experimental outcomes in cell culture models of lipotoxicity

“…Preparation of FFA solutions applicable for immortalized or primary cell lines comprises dissolving and complexing FFA. According to our review of over 100 articles about lipotoxic effects on mitochondria in pancreatic β-cells, protocols frequently do not contain essential information on how FFA solutions were prepared [ 15 ]. Since equally concentrated FFA solutions can be composed distinctly differently and thus have significant impact on experimental outcomes, we aim to have a closer look at the respective experimental parameters.…”

“…Frequently used FFA in diabetes research are long-chain fatty acids namely palmitic (PA) and oleic acid (OA) representing the most abundant saturated and unsaturated FFA in T2DM, respectively [ 16 ]. For solubilizing FFA and preparing a high molecular stock solution, most frequently employed protocols include ethanol (26%), saponification (12%), dimethyl sulfoxide (DMSO) (4%), and methanol (3%), while 55% of articles do not specify the substance used [ 15 ]. However, solubility of FFA and respective composition of solutions differ significantly among solvents.…”