ABSTRACT
AIMS: Although metformin is widely used for treatment of type 2 diabetes (T2D), its glucose-lowering mechanisms remains unclear. Using the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) antagonist exendin(9-39)NH2, we tested the hypothesis that postprandial GLP-1-mediated effects contribute to the glucose-lowering potential of metformin in T2D. METHODS: In a randomised, placebo-controlled, double-blind, crossover study, 15 individuals with T2D (median HbA1c 50 mmol/mol (6.7%), BMI 30.1 kg/m2, age 71 years) underwent, in randomised order, 14 days of metformin and placebo treatment, respectively. Each treatment period was preceded by 14 days without any glucose-lowering medicine and concluded by two 4-hour mixed meal tests performed in randomised order and separated by >24 hours with either continuous intravenous exendin(9-39)NH2 or saline infusion. RESULTS: Compared to placebo, metformin treatment lowered fasting plasma glucose (mean of differences (MD) 1.4 mmol/l×min (95% CI 0.8-2.0)) as well as postprandial plasma glucose excursions during both saline infusion (MD 186 mmol/l×min (95% CI 64-307)) and exendin(9-39)NH2 infusion (MD 268 mmol/l×min (95% CI 108-427)). The metformin-induced improvement in postprandial glucose tolerance was unaffected by GLP-1R antagonization (MD 82 mmol/l×min (95% CI -6,564-170)). Metformin treatment increased fasting plasma GLP-1 (MD 1.7 pmol/l×min (95% CI 0.39-2.9)) but did not affect postprandial GLP-1 responses (MD 820 pmol/l×min (95% CI -1,750-111)). CONCLUSIONS: Using GLP-1R antagonization, we could not detect GLP-1-mediated postprandial glucose-lowering effect of metformin in individuals with T2D. We show that two weeks of metformin treatment increases fasting plasma GLP-1, which may contribute to metformin's beneficial effect on fasting plasma glucose in T2D. TRIAL REGISTRATION: Clinicaltrials.gov NCT03246451.
ABSTRACT
Impaired mitochondrial oxidative phosphorylation (OXPHOS) in liver tissue has been hypothesised to contribute to the development of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease (NAFLD). It is unknown whether OXPHOS capacities in human visceral (VAT) and subcutaneous adipose tissue (SAT) associate with NAFLD severity and how hepatic OXPHOS responds to improvement in NAFLD. In biopsies sampled from 62 patients with obesity undergoing bariatric surgery and nine control subjects without obesity we demonstrate that OXPHOS is reduced in VAT and SAT while increased in the liver in patients with obesity when compared with control subjects without obesity, but this was independent of NAFLD severity. In repeat liver biopsy sampling in 21 patients with obesity 12 months after bariatric surgery we found increased hepatic OXPHOS capacity and mitochondrial DNA/nuclear DNA content compared with baseline. In this work we show that obesity has an opposing association with mitochondrial respiration in adipose- and liver tissue with no overall association with NAFLD severity, however, bariatric surgery increases hepatic OXPHOS and mitochondrial biogenesis.
