Effects of 18-months metformin versus placebo in combination with three insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes: A post-hoc analysis of a randomized clinical trial

Emil List Larsen*, Laura K. Kjær, Louise Lundby-Christensen, Trine W. Boesgaard, Leif Breum, Christian Gluud, Christoffer Hedetoft, Thure Krarup, Søren S. Lund, Elisabeth R. Mathiesen, Hans Perrild, Simone B. Sneppen, Lise Tarnow, Birger Thorsteinsson, Henrik Vestergaard, Henrik E. Poulsen, Sten Madsbad, Thomas P. Almdal

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Abstract

Formation of reactive oxygen species has been linked to the development of diabetes complications. Treatment with metformin has been associated with a lower risk of developing diabetes complications, including when used in combination with insulin. Metformin inhibits Complex 1 in isolated mitochondria and thereby decreases the formation of reactive oxygen species. Thus, we post-hoc investigated the effect of metformin in combination with different insulin regimens on RNA and DNA oxidation in individuals with type 2 diabetes. Four hundred and fifteen individuals with type 2 diabetes were randomized (1:1) to blinded treatment with metformin (1,000 mg twice daily) versus placebo and to (1:1:1) open-label biphasic insulin, basal-bolus insulin, or basal insulin therapy in a 2 × 3 factorial design. RNA and DNA oxidation were determined at baseline and after 18 months measured as urinary excretions of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), respectively. Urinary excretion of 8-oxoGuo changed by +7.1% (95% CI: 0.5% to 14.0%, P = 0.03) following metformin versus placebo, whereas changes in 8-oxodG were comparable between intervention groups. Biphasic insulin decreased urinary excretion of 8-oxoGuo (within-group: −9.6% (95% CI: −14.4% to −4.4%)) more than basal-bolus insulin (within-group: 5.2% (95% CI: −0.5% to 11.2%)), P = 0.0002 between groups, and basal insulin (within-group: 3.7% (95% CI: −2.0% to 9.7%)), P = 0.0007 between groups. Urinary excretion of 8-oxodG decreased more in the biphasic insulin group (within-group: −9.9% (95% CI: −14.4% to −5.2%)) than basal-bolus insulin (within group effect: −1.2% (95% CI: −6.1% to 3.9%)), P = 0.01 between groups, whereas no difference was observed compared with basal insulin. In conclusion, eighteen months of metformin treatment in addition to different insulin regimens increased RNA oxidation, but not DNA oxidation. Biphasic insulin decreased both RNA and DNA oxidation compared with other insulin regimens.

OriginalsprogEngelsk
TidsskriftFree Radical Biology and Medicine
Vol/bind178
Sider (fra-til)18-25
ISSN0891-5849
DOI
StatusUdgivet - jan. 2022

Bibliografisk note

Funding Information:
The trial was funded by an unrestricted research grant from Novo Nordisk A/S. Novo Nordisk A/S did not decide trial design and was not involved in clinical conduction, data analyses, interpretation, or writing of manuscript. Novo Nordisk A/S was allowed to comment on the protocol.

Funding Information:
We thank all, who contributed with conduction of the trial. We thank chemist Trine Henriksen, PhD and laboratory technician Katja R. Christensen for their analysis of urine 8-oxoGuo, 8-oxodG, and creatinine. We thank Kristian Karstoft for critical reviewing the manuscript and valuable discussion regarding interpretation of the results. E.L.L. has received a research grant from the Copenhagen University Hospital – Bispebjerg and Frederiksberg ("Bispebjerg Frederiksbergs Forskningsfond") for completion of this study in relation to his Ph.D. thesis. At last, but foremost, we thank the participants for making this study possible.

Funding Information:
The trial was funded by an unrestricted research grant from Novo Nordisk A/S. Novo Nordisk A/S did not decide trial design and was not involved in clinical conduction, data analyses, interpretation, or writing of manuscript. Novo Nordisk A/S was allowed to comment on the protocol.We thank all, who contributed with conduction of the trial. We thank chemist Trine Henriksen, PhD and laboratory technician Katja R. Christensen for their analysis of urine 8-oxoGuo, 8-oxodG, and creatinine. We thank Kristian Karstoft for critical reviewing the manuscript and valuable discussion regarding interpretation of the results. E.L.L. has received a research grant from the Copenhagen University Hospital ? Bispebjerg and Frederiksberg (?Bispebjerg Frederiksbergs Forskningsfond?) for completion of this study in relation to his Ph.D. thesis. At last, but foremost, we thank the participants for making this study possible.

Publisher Copyright:
© 2021

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