58th EASD Annual Meeting of the European Association for the Study of Diabetes : Stockholm, Sweden, 19 - 23 September 2022

Background and aims: Elevated saturated fatty acid deposition in the heart results in insulin resistance, stress kinase activation, and increased cardiovascular risk in humans. The viability of human cardiac progenitor cells (CPC) is essential for myocardium homeostasis. This study investigates the ability of palmitate, a saturated fatty acid, to impair insulin signaling in human CPC, and the potential protective effects of oleate, a mono-unsaturated fatty acid, on palmitate-induced abnormalities. Materials and methods: Human CPC were obtained from non-diabetic and non-obese subjects undergoing cardiac surgery for coronary artery bypass grafting and/or valve surgery. Human CPC were exposed to 0.25 mMpalmitate and/or 0.1mMoleate for 24 h, and then exposed to 100 nM insulin for the last 15 minutes. Expression of insulin receptor (IR) isoforms, A (IR-A) and B (IR-B), was evaluated by quantitative real-time PCR. IR and Akt protein levels, as well asAkt (S473), p38MAPK (T180/Y182), and c-Jun (S63) phosphorylation levels were assessed by immunoblotting. P38 MAPK and JNK inhibition was achieved using 15 μM SB202190 and 20 μM SP600125 for 1 h, respectively. Results: Human CPC were found to express both IR-A and IR-B, with higher IR-A:IR-B ratio. Exposure of human CPC to insulin induced Akt (S473) phosphorylation (p<0.05). Treatment with palmitate, but not with oleate, resulted in impaired insulin-induced Akt phosphorylation (p<0.05), with no effect on total Akt protein levels, and in downregulation of IR protein levels (p<0.05), increased expression of total IRmRNA, IRA, IR-B, and increased IR-A/IR-B ratio (p<0.05). Palmitate, but not oleate, also induced p38MAPK (T180/Y182) and c-Jun (S63) phosphorylation (p<0.05). Pretreatment with SB202190 or with SP600125 significantly inhibited the ability of palmitate to impair insulin-induced Akt phosphorylation (p<0.05), but not downregulation of IR protein levels. Interestingly, co-incubation of palmitate with oleate abolished the palmitate-induced p38 MAPK (p<0.05) and c-Jun phosphorylation (p<0.05), and inhibition of insulin-induced Akt phosphorylation (p<0.05). Co-incubation with oleate also prevented the palmitate-induced changes in IR (p<0.05). Conclusion: Oleate prevents the palmitate-induced abnormalities in insulin signaling in human CPC, largely by counteracting p38 MAPK and JNK activation. Hence, oleate supplementation might limit lipotoxicity in cardiac progenitor cells, thus contributing to cardiac protection.