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Aim To evaluate the change in insulin sensitivity, β‐cell function and glucose absorption after 28 days of treatment with high and low doses of SAR425899, a novel dual glucagon‐like peptide‐1 receptor/glucagon receptor agonist, versus placebo. Materials and Methods Thirty‐six overweight to obese subjects with type 2 diabetes were randomized to receive daily subcutaneous administrations of low‐dose SAR425899 (0.03, 0.06 and 0.09 mg) and high‐dose SAR425899 (0.06, 0.12 and 0.18 mg) or placebo for 28 days; dose escalation occurred after days 7 and 14. Mixed meal tolerance tests were conducted before treatment (day −1) and on days 1 and 28. Oral glucose and C‐peptide minimal models were used to quantify metabolic indices of insulin sensitivity, β‐cell responsiveness and glucose absorption. Results With low‐dose SAR425899, high‐dose SAR425899 and placebo, β‐cell function from day −1 to day 28 increased by 163%, 95% and 23%, respectively. The change in area under the curve for the rate of meal glucose appearance between 0 and 120 minutes was −32%, −20% and 8%, respectively. Conclusions After 28 days of treatment, SAR425899 improved postprandial glucose control by significantly enhancing β‐cell function and slowing glucose absorption rate.

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Aims/hypothesisThis study aimed to examine the metabolic health of young apparently healthy non-obese adults to better understand mechanisms of hyperinsulinaemia.MethodsNon-obese (BMI < 30 kg/m2) adults aged 18–35 years (N = 254) underwent a stable isotope-labelled OGTT. Insulin sensitivity, glucose effectiveness and beta cell function were determined using oral minimal models. Individuals were stratified into quartiles based on their insulin response during the OGTT, with quartile 1 having the lowest and quartile 4 the highest responses.ResultsThirteen per cent of individuals had impaired fasting glucose (IFG; n = 14) or impaired glucose tolerance (IGT; n = 19), allowing comparisons across the continuum of insulin responses within the spectrum of normoglycaemia and prediabetes. BMI (~24 kg/m2) was similar across insulin quartiles and in those with IFG and IGT. Despite similar glycaemic excursions, fasting insulin, triacylglycerols and cholesterol were elevated in quartile 4. Insulin sensitivity was lowest in quartile 4, and accompanied by increased insulin secretion and reduced insulin clearance. Individuals with IFG had similar insulin sensitivity and beta cell function to those in quartiles 2 and 3, but were more insulin sensitive than individuals in quartile 4. While individuals with IGT had a similar degree of insulin resistance to quartile 4, they exhibited a more severe defect in beta cell function. Plasma branched-chain amino acids were not elevated in quartile 4, IFG or IGT.Conclusions/interpretationHyperinsulinaemia within normoglycaemic young, non-obese adults manifests due to increased insulin secretion and reduced insulin clearance. Individual phenotypic characterisation revealed that the most hyperinsulinaemic were more similar to individuals with IGT than IFG, suggesting that hyperinsulinaemic individuals may be on the continuum toward IGT. Furthermore, plasma branched-chain amino acids may not be an effective biomarker in identifying hyperinsulinaemia and insulin resistance in young non-obese adults.