The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes. Eight obese patients with type 2 diabetes with poor glycaemic control (HbA1c 8.6 ± 1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4 ± 1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0–10 min). The late phase C-peptide response (10–120 min) increased during GIP infusion from 33.0 ± 8.5 to 103.9 ± 24.2 (nmol/l) × (110 min)−1 (p < 0.05) and during GLP-1 infusion from 48.7 ± 11.8 to 126.6 ± 32.5 (nmol/l) × (110 min)−1 (p < 0.05), whereas during saline infusion the late-phase response did not differ before vs after near-normalisation of blood glucose (40.2 ± 11.2 vs 46.5 ± 12.7 [nmol/l] × [110 min]−1). Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three to four. No effect was found on beta cell responsiveness to glucose alone. ClinicalTrials.gov ID no.: NCT 00612950 Funding: This study was supported by The Novo Nordisk Foundation, The Medical Science Research Foundation for Copenhagen.

Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes