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Effects of the anti-diabetic imeglimin in hyperglycemic mice with septic shock

Introduction

Shock-related hyperglycemia impairs mitochondrial function and integrity [1], ultimately leading to apoptosis and organ failure [1, 2]. Imeglimin is a new anti-diabetic drug with anti-hyperglycemic and anti-apoptotic properties [3]. Therefore we investigated its effects in hyperglycemic mice with septic shock.

Methods

Immediately after cecal ligation and puncture, mice randomly received s.c. vehicle (n = 9) or imeglimin (n = 10; 100 μg/g). Fifteen hours later animals were anesthetized, mechanically ventilated and instrumented for a consecutive 6-hour observation period. After a second imeglimin bolus, colloid fluid resuscitation and continuous i.v. noradrenaline were titrated to maintain normotensive and hyperdynamic hemodynamics. Then 2 mg/g/hour glucose was infused to induce hyperglycemia. Glucose oxidation and gluconeogenesis were derived from blood 13C6-glucose and mixed expiratory 13CO2/12CO2 isotope enrichment during continuous isotope infusion. Liver mitochondrial activity was assessed using high-resolution respirometry [4, 5], Bax, HO-1 and NF-κB expression by immunoblotting and EMSA. All data are median (quartiles).

Results

Imeglimin decreased blood glucose levels (165 (153; 180) vs. 192 (184; 221) mg/dl, P = 0.007) by increasing whole body glucose oxidation (55 (52; 57) vs. 51 (49; 55)% of infused isotope, P = 0.085), which coincided with partial restoration of gluconeogenesis (0.38 (0.34; 0.41) vs. 0.31 (0.27; 0.33) mg/g/hour, P = 0.032), liver mitochondrial activity (oxidative phosphorylation (136 (134; 160) vs. 116 (97; 122) pmol O2/second/mg tissue, P = 0.003); maximal oxidative capacity (166 (154; 174) vs. 147 (130; 159) pmol O2/second/mg tissue, P = 0.064). Imeglimin increased liver HO-1, reduced liver Bax expression and attenuated NF-κB activation (all P < 0.001).

Conclusion

Imeglimin improved whole body glucose utilization and gluconeogenesis, a well-established marker of liver metabolic capacity [4, 5], and attenuated organ injury, at least in part due to inhibition of the mitochondrial apoptosis pathway.

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Acknowledgements

In memoriam of Xavier Leverve who initiated this project; supported by an unrestricted grant from Poxel.

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Correspondence to F Wagner.

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Wagner, F., Vogt, J., Wachter, U. et al. Effects of the anti-diabetic imeglimin in hyperglycemic mice with septic shock. Crit Care 16, P21 (2012). https://doi.org/10.1186/cc10628

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Keywords

  • Septic Shock
  • Cecal Ligation
  • Mitochondrial Apoptosis Pathway
  • Body Glucose
  • Hyperglycemic Mouse