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

Abstract

Aims/hypothesis 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 glucoselowering effects of metformin in individuals with type 2 diabetes and non-diabetic individuals. Methods 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 (HbA 1c 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 [3-3 H]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 (R d ) and endogenous glucose production (EGP). Results 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 R d , EGP and glucagon levels increased bỹ 30% (p < 0.05) whereas this was not the case in the PLA group. Conclusions/interpretation Ninety days of metformin treatment resulted in similar increases in EGP and glucose R d 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 R d by facilitating glucose uptake in other tissues such as the intestines remains to be further clarified. Trial registration ClinicalTrials.gov NCT01729156Søren Nielsen and Niels Jessen contributed equally to this work.

Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals

“…In keeping with this, they show an increase in their fasting EGP, which may be due to glucagon-induced glycogenolysis or gluconeogenesis. This finding is consistent with the data presented by Gormsen et al [6].…”

“…It is, therefore, with great interest that we read the article recently published in Diabetologia entitled 'Metformin increases endogenous glucose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes' [6]. In the article, using studies of whole-body glucose metabolism, including non-steady state glucose tracer kinetics and hyperinsulinaemic-euglycaemic clamping, Gormsen et al report that metformin treatment is associated with an increase in the glucose rate of disappearance (R d ), glucagon levels and EGP both in healthy control individuals and in individuals with recent-onset type 2 diabetes with good glycaemic control.…”

The Metformin Mechanism on Gluconeogenesis and AMPK Activation: The Metabolite Perspective

“…Type 2 diabetes is commonly associated with nutrient excess which predicts compromised intracellular homeostasis. Recent studies have reported lack of efficacy of metformin in healthy non-diabetic people as well as in newly diagnosed well-controlled type 2 diabetes [116,117]. Although several factors may interact with the efficacy of metformin on endogenous glucose production, further work on the metformin mechanism should focus on cell and animal models with compromised intracellular metabolite homeostasis that more closely simulate the dysregulation in poorly controlled type 2 diabetes, to determine whether AMPK-independent repression of G6pc by metformin predominates in the compromised metabolic state.…”

Understanding glycaemic control and current approaches for screening antidiabetic natural products from evidence-based medicinal plants

“…To date, metabolomics-based approaches have become increasingly applied to all aspects of diabetes research. Recent literature shows that metabolomics has been applied to biomarker and drug discovery, drug assessment [259, 260], toxicology [261, 262], and clinical biochemistry with a particular focus on gestational diabetes mellitus (GDM) [263–270]. Some of the recent metabolomics-aided discoveries in antidiabetic plant research are summarised below.…”

“…For instance, a metabolomics-based study found that 90 days of treatment with metformin increased endogenous glucose production in newly diagnosed T2DM patients. This challenges the widely accepted paradigm that the antihyperglycaemic effects of metformin is primarily due to inhibition of endogenous glucose production in the liver [260]. This illustrates the importance of establishing the metabolic effects of drugs and determining whether the same drug may differ in their mechanisms of action within different stages of a disease.…”