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Objective: 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.

Methods: 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.

Results: 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) x (110 min)-1 (p < 0.05) and during GLP-1 infusion from 48.7 /- 11.8 to 126.6 /- 32.5 (nmol/l) x (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] x [110 min]-1).

Conclusions: 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.

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