419-P: Glucose-Induced Cellular Resistance to Methylglyoxal Is Lost in Patients with Diabetes Complications and Further Deteriorated after Caloric Restriction

Abstract

Aim: Glucose stress can be protective against dicarbonyl-mediated toxicity. This study aimed to investigate cellular resistance against methylglyoxal (MG) after glucose stress in healthy humans (CON), patients with (T2D+) and without diabetes complications (T2D-) and whether this is affected by caloric restriction. Fibroblast growth factor 21 (FGF21) and β- hydroxybutyrate (β-HB) were analyzed as marker for metabolic adaptation to stress response and ketogenesis. Methods: Peripheral blood mononuclear cells were isolated before and 2h after oGTT and incubated at each time-point with increasing MG-levels for 24hrs. Cell viability was measured with CellTiter-Glo to determine changes of MG-resistance at 2h after oGTT (ΔEC50). Experiments were repeated after a 5-day fasting-mimicking diet (FMD). FGF21 and β-HB were measured in venous blood. Results: Thirty participants (18m/12f, age 64.6 [62.2, 67.0] y, BMI 28.6 [27.2, 30.0] kg/m2) were included. HbA1c was higher in T2D+ (7.4 [6.9, 7.9] %) and T2D- (7.0 [6.2, 7.7] %) compared to CON (5.5 [5.1, 5.8] %, p<0.001), age and BMI were comparable. ΔEC50 of MG increased in CON before and after FMD (12.9% vs. 12.6%), was unaffected in T2D- (1.8% vs. -1.7%) and decreased in T2D+ after FMD (-3.9% vs. -19.0%, p<0.01) and when compared to T2D- and CON (p<0.05). ΔFGF21 increased in CON after FMD (7.7% vs. 115.0%, p<0.05) and tended to be higher compared to T2D- and T2D+ (115.0% vs. 69.3% vs. 47.5%, p=0.5). ΔFGF21 correlated with β-HB (r = 0.48, p<0.01), with strongest correlation for T2D+. Conclusion: Acute glucose stress induces cellular resistance to MG in healthy humans, a response which is lost in T2D with diabetic complications and aggravates after caloric restriction. Our data suggest for an association between loss of capacity for handling dicarbonyl stress and the presence of diabetic complications. FGF21 might play an important role in the metabolic adaptation to dicarbonyl stress and ketosis. Disclosure E.V.Rauchhaupt: None. C.Rodemer: None. E.Kliemank: None. S.Kopf: Advisory Panel; Novo Nordisk, Bayer Inc., Recordati Rare Disease, Speaker's Bureau; Novo Nordisk, Boehringer-Ingelheim. S.Herzig: Consultant; Novo Nordisk, Actimed, Research Support; Novo Nordisk, Boehringer-Ingelheim, Almac. P.Nawroth: None. J.Szendroedi: None. J.Zemva: None. A.Sulaj: None. Funding DFG; German Research Foundation (236360313-SFB, 1118DZD); German Center for Diabetes Research (82DZD07C2G)