Metformin Gastrointestinal Intolerance: Measurement of Mitochondrial Complex I

Summary

Metformin is associated with a high degree of gastrointestinal intolerance, which limits the effective use of the medication. It is proposed to be an inhibitor of liver mitochondrial glycerophosphate dehydrogenase which results in partial blockade of mitochondrial complex 1 and inhibition of metabolism of lactate to pyruvate. There is also evidence that it is accumulated in gastrointestinal cells, and that there are certain genotypes associated with inclusion or lack of exclusion of the metformin from these cells. To validate this hypothesis investigators propose to give metformin after a standard meal test to see if there is the accumulation of lactic acid in those with gastrointestinal intolerance to metformin, compared to those without intolerance, and to determine if these elevations of lactic acid and GI symptoms are associated with genetic predispositions. Aims: 1. To determine if the GI intolerance to metformin is associated with post meal elevations of lactic acid. a. The test will measure the inhibition of mitochondrial complex 1 levels of lactate to pyruvate compared with non- intolerant subjects. 2. To determine if individuals with gastrointestinal symptoms and elevated lactate/pyruvate ratios have genetic variation in the organic cation transporters.

Timeline

Start

2018-10-15

Primary completion

2020-10-27

Completion

2020-10-27

Publications

• Background Ferrannini E. The target of metformin in type 2 diabetes. N Engl J Med. 2014 Oct 16;371(16):1547-8. doi: 10.1056/NEJMcibr1409796. No abstract available.
• Background Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak MJ, Camporez JP, Lee HY, Cline GW, Samuel VT, Kibbey RG, Shulman GI. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014 Jun 26;510(7506):542-6. doi: 10.1038/nature13270. Epub 2014 May 21.
• Background Bailey CJ, Wilcock C, Scarpello JH. Metformin and the intestine. Diabetologia. 2008 Aug;51(8):1552-3. doi: 10.1007/s00125-008-1053-5. Epub 2008 Jun 5. No abstract available.
• Background Bailey CJ, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol. 1992 Apr;105(4):1009-13. doi: 10.1111/j.1476-5381.1992.tb09093.x.
• Background Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, Baron A, Fineman M. The Primary Glucose-Lowering Effect of Metformin Resides in the Gut, Not the Circulation: Results From Short-term Pharmacokinetic and 12-Week Dose-Ranging Studies. Diabetes Care. 2016 Feb;39(2):198-205. doi: 10.2337/dc15-0488. Epub 2015 Aug 18.
• Background Tarasova L, Kalnina I, Geldnere K, Bumbure A, Ritenberga R, Nikitina-Zake L, Fridmanis D, Vaivade I, Pirags V, Klovins J. Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients. Pharmacogenet Genomics. 2012 Sep;22(9):659-66. doi: 10.1097/FPC.0b013e3283561666.
• Background Pawlyk AC, Giacomini KM, McKeon C, Shuldiner AR, Florez JC. Metformin pharmacogenomics: current status and future directions. Diabetes. 2014 Aug;63(8):2590-9. doi: 10.2337/db13-1367.
• Background Wang L, Weinshilboum R. Metformin pharmacogenomics: biomarkers to mechanisms. Diabetes. 2014 Aug;63(8):2609-10. doi: 10.2337/db14-0609. No abstract available.
• Background Davidson J, Howlett H. New prolonged-release metformin improves gastrointestinal tolerability. British Journal of Diabetes & Vascular Disease 2004; 4: 273.
• Background Blonde L, Dailey GE, Jabbour SA, Reasner CA, Mills DJ. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin. 2004 Apr;20(4):565-72. doi: 10.1185/030079904125003278.

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