Studies on the mechanisms of glucolipotoxicity in human beta cells in the context of type 2 diabetes mellitus
Final Report Abstract
As diabetes mellitus is the most expensive widespread disease worldwide, affecting more than 500 million people, understanding the underlying pathomechanisms is essential for the development of improved preventive and therapeutic approaches. Type 2 diabetes accounts for 90% of all cases. One of the main elements associated with the development of type 2 diabetes is increased concentrations of free fatty acids (FFAs) in the blood plasma and their damaging effect on pancreatic beta cells, also known as lipotoxicity. Using structure-activity relationships of FFAs, I was able to demonstrate that it is primarily the long-chain (C16-C18) and very longchain (C19-C22) saturated and monounsaturated FFAs that lead to the death of murine and human insulin-producing pancreatic beta cells, and thus may contribute to insulin resistance with subsequent hyperglycaemia. Besides lipids, glucose is one of the major sources of energy in mammals. Excess sugar can be converted to fatty acids, particularly palmitic acid, when the stores and metabolic capacitiy are exhausted. The interaction of FFA and sugar overloading (glucolipotoxicity) has been studied in murine and human beta cell lines. It has become clear that the fatty acid component is of decisive importance in the context of glucolipotoxicity. The potentiation of the effect by glucose depends on the structure of the FFA. Only the long-chain saturated stearic acid (C18:0) and very long-chain saturated FFAs exhibited an additive toxic effect in combination with elevated glucose concentrations. Interestingly, the enzyme stearoyl-CoA desaturase (SCD) plays an important role in this scenario. SCD converts long-chain saturated FFAs (C16:0, C18:0) into monounsaturated FFAs (C16:1, C18:1), thereby shifting the ratio in favour of long-chain unsaturated FFAs within the cell. The conversion of C16:0 to C16:1 by SCD is significantly increased at elevated glucose concentrations, whereas the conversion is reduced with longer-chain saturated FFAs. This provides an explanation for the occurrence of glucolipotoxicity from a chain length of C18:0, as an increased concentration ratio of saturated FFAs to unsaturated FFAs in conjunction with elevated glucose concentrations results in increased beta cell toxicity. The effects of glucolipotoxicity are due to an increase in ER stress and mitochondrial damage. In conlusion, the data indicate that the structural features of FFAs play an important role in the occurrence of glucolipotoxicity in human beta cells. This is confirmed by the chain lengthdependent interaction with the SCD in combination with elevated glucose concentrations.
Publications
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Sphingosine-1 Phosphate Lyase Regulates Sensitivity of Pancreatic Beta-Cells to Lipotoxicity. International Journal of Molecular Sciences, 22(19), 10893.
Tang, Yadi; Plötz, Thomas; Gräler, Markus H. & Gurgul-Convey, Ewa
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Differential effects of saturated and unsaturated free fatty acids on ferroptosis in rat β-cells. The Journal of Nutritional Biochemistry, 106, 109013.
Krümmel, Bastian; von Hanstein, Anna-Sophie; Plötz, Thomas; Lenzen, Sigurd & Mehmeti, Ilir
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Bedeutung der humanen Stearoyl-CoA-Desaturasen für die zellschädigende Lipotoxizität in murinen und humanen pankreatischen Betazellen. Diabetologie und Stoffwechsel, 18(S 01), S20-S21.
Plötz, Thomas; von Hanstein, Anna-Sophie; Tsikas, Dimitrios; Lenzen, Sigurd & Jörns, Anne
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Oxidative and ER stress by elevated insulin biosynthesis and palmitic acid in insulin-producing cells. Journal of Molecular Endocrinology, 72(2).
Vidrio-Huerta, Brenda; Plötz, Thomas & Lortz, Stephan
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Potentiation of Lipotoxicity in Human EndoC‐βH1 β‐Cells by Glucose is Dependent on the Structure of Free Fatty Acids. Molecular Nutrition & Food Research, 67(5).
von Hanstein, Anna‐Sophie; Tsikas, Dimitrios; Lenzen, Sigurd; Jörns, Anne & Plötz, Thomas
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Mechanisms of lipotoxicity‐induced dysfunction and death of human pancreatic beta cells under obesity and type 2 diabetes conditions. Obesity Reviews, 25(5).
Plötz, Thomas & Lenzen, Sigurd
