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Post-mortem analysis of lactate concentration in diabetics and metformin poisonings

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Abstract

Lactate is produced in carbohydrate metabolism under anaerobic conditions. Lactic acidosis occurs when the production of lactate exceeds its removal. In post-mortem (PM) context, the lactic acidosis is difficult to interpret due to unknown pathophysiological factors prior to death and PM changes that may affect the lactate levels. We evaluated 1865 medico-legal autopsy cases where the quantitation of glucose, lactate, and ketone bodies was performed as a part of the cause of death (CoD) investigation. Lactate was shown to ascend in a logarithmic manner as the PM interval increased until a plateau was achieved approximately after 8–10 days PM, and the elevation was caused mainly by PM changes. The lactate level was higher than the mean in cases where the CoD was diabetes mellitus type 2 (DM2) or metformin poisoning. Although there was a correlation between metformin and lactate levels, our findings suggest the DM2 and its complications were the cause for elevated lactate levels rather than metformin, since the lactate levels were similar in DM2-associated deaths where no metformin was detected. Elevated lactate levels in PM samples rather referred to metabolic disturbances often caused by DM2. An assay to detect D-lactate in PM samples was described.

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References

  1. Luft D, Deichsel G, Schmulling RM, Stein W, Eggstein M (1983) Definition of clinically relevant lactic acidosis in patients with internal diseases. Am J Clin Pathol 80(4):484–489

    CAS  PubMed  Google Scholar 

  2. Boulagnon C, Garnotel R, Fornes P, Gillery P (2011) Post-mortem biochemistry of vitreous humor and glucose metabolism: an update. Clin Chem Lab Med 49(8):1265–1270. doi:10.1515/CCLM.2011.638

    Article  CAS  PubMed  Google Scholar 

  3. Hess C, Musshoff F, Madea B (2011) Disorders of glucose metabolism-post mortem analyses in forensic cases: part I. Int J Legal Med 125(2):163–170. doi:10.1007/s00414-010-0509-6

    Article  PubMed  Google Scholar 

  4. Sippel H, Mottonen M (1982) Combined glucose and lactate values in vitreous humour for postmortem diagnosis of diabetes mellitus. Forensic Sci Int 19(3):217–222

    Article  CAS  PubMed  Google Scholar 

  5. Traub F (1969) Method for the detection of lethal glucose metabolism disorders in the corpse (diabetes mellitus and hypoglycemia). Zentralbl Allg Pathol 112(4):390–399

    CAS  PubMed  Google Scholar 

  6. Hess C, Wollner K, Musshoff F, Madea B (2013) Detection of diabetic metabolism disorders post-mortem--forensic case reports on cause of death hyperglycaemia. Drug Test Anal 5(9–10):795–801. doi:10.1002/dta.1479

    Article  CAS  PubMed  Google Scholar 

  7. Palmiere C, Sporkert F, Vaucher P, Werner D, Bardy D, Rey F, Lardi C, Brunel C, Augsburger M, Mangin P (2012) Is the formula of Traub still up to date in antemortem blood glucose level estimation? Int J Legal Med 126(3):407–413. doi:10.1007/s00414-011-0659-1

    Article  PubMed  Google Scholar 

  8. Zilg B, Alkass K, Berg S, Druid H (2009) Postmortem identification of hyperglycemia. Forensic Sci Int 185(1–3):89–95. doi:10.1016/j.forsciint.2008.12.017

    Article  CAS  PubMed  Google Scholar 

  9. Brinkmann B, Fechner G, Karger B, DuChesne A (1998) Ketoacidosis and lactic acidosis--frequent causes of death in chronic alcoholics? Int J Legal Med 111(3):115–119

    Article  CAS  PubMed  Google Scholar 

  10. Keltanen T, Sajantila A, Palo JU, Partanen T, Valonen T, Lindroos K (2013) Assessment of Traub formula and ketone bodies in cause of death investigations. Int J Legal Med 127(6):1131–1137. doi:10.1007/s00414-013-0917-5

    Article  PubMed  Google Scholar 

  11. Vivero G, Vivero-Salmeron G, Perez Carceles MD, Bedate A, Luna A, Osuna E (2008) Combined determination of glucose and fructosamine in vitreous humor as a post-mortem tool to identify antemortem hyperglycemia. Rev Diabet Stud 5(4):220–224

    Article  PubMed Central  PubMed  Google Scholar 

  12. Fall PJ, Szerlip HM (2005) Lactic acidosis: from sour milk to septic shock. J Intensive Care Med 20(5):255–271. doi:10.1177/0885066605278644

    Article  PubMed  Google Scholar 

  13. De Letter EA, Piette MH (1998) Can routinely combined analysis of glucose and lactate in vitreous humour be useful in current forensic practice? Am J Forensic Med Pathol 19(4):335–342

    Article  PubMed  Google Scholar 

  14. Bailey CJ, Turner RC (1996) Metformin. N Engl J Med 334(9):574–579

    Article  CAS  PubMed  Google Scholar 

  15. Lalau JD (2010) Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf : Int J Med Toxicol Drug Experience 33(9):727–740. doi:10.2165/11536790-000000000-00000

    Article  CAS  Google Scholar 

  16. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE (2010) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 4, CD002967. doi:10.1002/14651858.CD002967.pub4

    PubMed  Google Scholar 

  17. Scale T, Harvey JN (2011) Diabetes, metformin and lactic acidosis. Clin Endocrinol (Oxf) 74(2):191–196. doi:10.1111/j.1365-2265.2010.03891.x

    Article  CAS  Google Scholar 

  18. Stades AME, Heikens JT, Erkelens DW, Holleman F, Hoekstra JBL (2004) Metformin and lactic acidosis: cause or coincidence? A review of case reports. J Intern Med 255(2):179–187. doi:10.1046/j.1365-2796.2003.01271.x

    Article  CAS  PubMed  Google Scholar 

  19. Uribarri J, Oh MS, Carroll HJ (1998) D-lactic acidosis. A review of clinical presentation, biochemical features, and pathophysiologic mechanisms. Medicine 77(2):73–82

    Article  CAS  PubMed  Google Scholar 

  20. Felby S, Nielsen E (1994) Determination of Ketone-Bodies in Postmortem Blood by Headspace Gas-Chromatography. Forensic Sci Int 64(2–3):83–88

    Article  CAS  PubMed  Google Scholar 

  21. Felby S, Nielsen E, Thomsen JL (2008) The postmortem distribution of ketone bodies between blood, vitreous humor, spinal fluid, and urine. Forensic Sci Med Pathol 4(2):100–107. doi:10.1007/s12024-007-9018-4

    Article  PubMed  Google Scholar 

  22. Thomsen JL, Felby S, Theilade P, Nielsen E (1995) Alcoholic ketoacidosis as a cause of death in forensic cases. Forensic Sci Int 75(2–3):163–171

    Article  CAS  PubMed  Google Scholar 

  23. Laffel L (1999) Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 15(6):412–426. doi:10.1002/(sici)1520-7560(199911/12)15:6<412::aid-dmrr72>3.0.co;2-8

    Article  CAS  PubMed  Google Scholar 

  24. Gergov M, Nenonen T, Ojanpera I, Ketola RA (2015) Compensation of matrix effects in a standard addition method for metformin in postmortem blood using liquid chromatography-electrospray-tandem mass spectrometry. J Anal Toxicol. doi:10.1093/jat/bkv020

    PubMed  Google Scholar 

  25. Harper DR (1989) A comparative study of the microbiological contamination of postmortem blood and vitreous humour samples taken for ethanol determination. Forensic Sci Int 43(1):37–44

    Article  CAS  PubMed  Google Scholar 

  26. Lalau JD, Arnouts P, Sharif A, De Broe ME (2015) Metformin and other antidiabetic agents in renal failure patients. Kidney Int 87(2):308–322. doi:10.1038/ki.2014.19

    Article  CAS  PubMed  Google Scholar 

  27. Cox K, Cocchi MN, Salciccioli JD, Carney E, Howell M, Donnino MW (2012) Prevalence and significance of lactic acidosis in diabetic ketoacidosis. J Crit Care 27(2):132–137. doi:10.1016/j.jcrc.2011.07.071

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Kraut JA, Madias NE (2007) Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol 2(1):162–174. doi:10.2215/CJN.03020906

    Article  CAS  PubMed  Google Scholar 

  29. Lu J, Zello GA, Randell E, Adeli K, Krahn J, Meng QH (2011) Closing the anion gap: contribution of D-lactate to diabetic ketoacidosis. Clin Chim Acta 412(3–4):286–291. doi:10.1016/j.cca.2010.10.020

    Article  CAS  PubMed  Google Scholar 

  30. Sheikh-Ali M, Karon BS, Basu A, Kudva YC, Muller LA, Xu J, Schwenk WF, Miles JM (2008) Can serum beta-hydroxybutyrate be used to diagnose diabetic ketoacidosis? Diabetes Care 31(4):643–647. doi:10.2337/dc07-1683

    Article  CAS  PubMed  Google Scholar 

  31. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN (2009) Hyperglycemic crises in adult patients with diabetes. Diabetes Care 32(7):1335–1343. doi:10.2337/dc09-9032

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Bonsignore A, Pozzi F, Fraternali Orcioni G, Ventura F, Palmiere C (2013) Fatal metformin overdose: case report and postmortem biochemistry contribution. Int J Legal Med. doi:10.1007/s00414-013-0927-3

    PubMed  Google Scholar 

  33. Tolman KG, Fonseca V, Dalpiaz A, Tan MH (2007) Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care 30(3):734–743. doi:10.2337/dc06-1539

    Article  CAS  PubMed  Google Scholar 

  34. Suzuki T, Shinjo S, Arai T, Kanai M, Goda N (2014) Hypoxia and fatty liver. World J Gastroenterol 20(41):15087–15097. doi:10.3748/wjg.v20.i41.15087

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Weidemann A, Johnson RS (2008) Biology of HIF-1alpha. Cell Death Differ 15(4):621–627. doi:10.1038/cdd.2008.12

    Article  CAS  PubMed  Google Scholar 

  36. Xiao H, Gu Z, Wang G, Zhao T (2013) The possible mechanisms underlying the impairment of HIF-1alpha pathway signaling in hyperglycemia and the beneficial effects of certain therapies. Int J Med Sci 10(10):1412–1421. doi:10.7150/ijms.5630

    Article  PubMed Central  PubMed  Google Scholar 

  37. Pawlyk AC, Giacomini KM, McKeon C, Shuldiner AR, Florez JC (2014) Metformin pharmacogenomics: current status and future directions. Diabetes 63(8):2590–2599. doi:10.2337/db13-1367

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Talasniemi JP, Pennanen S, Savolainen H, Niskanen L, Liesivuori J (2008) Analytical investigation: assay of D-lactate in diabetic plasma and urine. Clin Biochem 41(13):1099–1103. doi:10.1016/j.clinbiochem.2008.06.011

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Financial support for TK was provided by the Doctoral Programme in Population Health (DocPop), University of Helsinki.

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Authors and Affiliations

  1. Department of Forensic Medicine, University of Helsinki, P.O.Box 40, 00014, Helsinki, Finland

    T. Keltanen, T. Nenonen, R. A. Ketola, I. Ojanperä, A. Sajantila & K. Lindroos

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  1. T. Keltanen
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  2. T. Nenonen
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  3. R. A. Ketola
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Correspondence to T. Keltanen.

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Keltanen, T., Nenonen, T., Ketola, R.A. et al. Post-mortem analysis of lactate concentration in diabetics and metformin poisonings. Int J Legal Med 129, 1225–1231 (2015). https://doi.org/10.1007/s00414-015-1256-5

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