Metformin increases endogenous glucose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes

  • Lars C. Gormsen
  • Esben Søndergaard
  • Nana L. Christensen
  • Kim Brøsen
  • Niels JessenEmail author
  • Søren Nielsen
Short Communication



Metformin is the endorsed first-line glucose-lowering drug for treating patients with type 2 diabetes but despite more than 50 years of use, no consensus has been reached on its mechanisms of action. In this study, we investigated the glucose-lowering effects of metformin in individuals with type 2 diabetes and non-diabetic individuals.


We performed a randomised, placebo-controlled trial in 24 individuals with recent-onset type 2 diabetes (diabetes duration 50 [48] months) who had good glycaemic control (HbA1c 48 mmol/mmol [6.5%]). The studies were conducted at Aarhus University Hospital between 2013 and 2016. Participants were randomised to receive either metformin (2000 mg/day, n = 12, MET group) or placebo (n = 12, PLA group) for 90 days, using block randomisation set up by an unblinded pharmacist. Two participants withdrew from the study prior to completion and were replaced with two new participants receiving the same treatment. In addition, we recruited a group of non-diabetic individuals with similar age and BMI (n = 12, CONT group), who were all treated with 2000 mg metformin daily. Before and after treatment all individuals underwent studies of whole-body glucose metabolism by non-steady-state [3-3H]glucose kinetics, hyperinsulinaemic–euglycaemic clamping, indirect calorimetry, metabolomics, dual x-ray absorptiometry and muscle biopsies. The primary study endpoint was the effect of metformin treatment on lipid kinetics as well as glucose rate of disappearance (Rd) and endogenous glucose production (EGP).


One participant from the CONT group withdrew due to intolerable gastrointestinal side-effects and was excluded from analysis. As expected, metformin treatment lowered fasting plasma glucose (FPG) in the MET group (~1.5 mmol/l, p < 0.01), whereas no effect was observed in the PLA and CONT groups. Body weight and composition did not change in any of the groups. In both of the metformin-treated groups (MET and CONT), basal glucose Rd, EGP and glucagon levels increased by ~30% (p < 0.05) whereas this was not the case in the PLA group.


Ninety days of metformin treatment resulted in similar increases in EGP and glucose Rd in individuals with recent-onset type 2 diabetes and in non-diabetic control individuals. These results challenge the existing paradigm that metformin primarily acts in the liver by inhibiting EGP, at least in individuals with type 2 diabetes of short duration and who have discretely affected glycaemic status. Whether metformin increases basal glucose Rd by facilitating glucose uptake in other tissues such as the intestines remains to be further clarified.

Trial registration NCT01729156


This study was supported by grants from The Danish Council for Independent Research | Medical Sciences, Aase Danielsen Fund, the Novo Nordisk Foundation, the Danish Diabetes Association and the Danish Diabetes Academy supported by the Novo Nordisk Foundation.


Clinical trial Glucose kinetics Metformin Type 2 diabetes 



Non-diabetic individuals given metformin 1000 mg twice daily


Endogenous glucose production


Fasting plasma glucose


Participants with type 2 diabetes given metformin 1000 mg twice daily


Non-oxidative glucose disposal


Organic cation transporter-1


Participants with type 2 diabetes given placebo


Rate of disappearance



The authors would like to thank L. Kvist and S. Sørensen (Medical Research Laboratories, Aarhus University Hospital) for excellent technical help during the studies.

Contribution statement

All authors conceptualised the study, wrote the protocol, researched the data and contributed to discussion. LCG wrote the manuscript and ES, NLC, KB, NJ and SN reviewed and edited the manuscript. LCG, NJ and SN are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the final version of the manuscript.


The study was supported by grants from The Danish Council for Independent Research | Medical Sciences, Aase Danielsen Fund, the Novo Nordisk Foundation, the Danish Diabetes Association and the Danish Diabetes Academy supported by the Novo Nordisk Foundation.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2019_4872_MOESM1_ESM.pdf (2.4 mb)
ESM 1 (PDF 2497 kb)
125_2019_4872_MOESM2_ESM.pdf (277 kb)
Table 2 (PDF 277 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Nuclear Medicine & PET CentreAarhus University HospitalAarhusDenmark
  2. 2.Department of EndocrinologyAarhus University HospitalAarhusDenmark
  3. 3.Danish Diabetes AcademyOdense University HospitalOdenseDenmark
  4. 4.Department of PharmacologyOdense University HospitalOdenseDenmark
  5. 5.Department of Clinical PharmacologyAarhus University HospitalAarhusDenmark
  6. 6.Department of BiomedicineAarhus UniversityAarhusDenmark
  7. 7.Steno Diabetes Center AarhusAarhus University HospitalAarhusDenmark

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