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. Whether metformin increases basal glucose R d by facilitating glucose uptake in other tissues such as the intestines remains to be further clarified. 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. 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. In both of the metformin-treated groups (MET and CONT), basal glucose R d, EGP and glucagon levels increased by ~30% ( p < 0.05) whereas this was not the case in the PLA group. Body weight and composition did not change in any of the groups. 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. One participant from the CONT group withdrew due to intolerable gastrointestinal side-effects and was excluded from analysis. 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). Before and after treatment all individuals underwent studies of whole-body glucose metabolism by non-steady-state glucose kinetics, hyperinsulinaemic–euglycaemic clamping, indirect calorimetry, metabolomics, dual x-ray absorptiometry and muscle biopsies. 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. Two participants withdrew from the study prior to completion and were replaced with two new participants receiving the same treatment. 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.
The studies were conducted at Aarhus University Hospital between 20. We performed a randomised, placebo-controlled trial in 24 individuals with recent-onset type 2 diabetes (diabetes duration 50 months) who had good glycaemic control (HbA 1c 48 mmol/mmol ). In this study, we investigated the glucose-lowering effects of metformin in individuals with type 2 diabetes and non-diabetic individuals.
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.
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