Improved Glycemic Control Enhances the Incretin Effect in Patients With Type 2 Diabetes

Background and Aims: Impairment of the incretin effect is one of the hallmarks of type 2 diabetes mellitus (T2DM). However, it is unknown whether this abnormality is specific to incretin-stimulated insulin secretion or a manifestation of generalized beta-cell dysfunction. The aim of this study was to determine whether improved glycemic control restores the incretin effect. Methods: Fifteen T2DM subjects were studied before and after 8 weeks of intensified treatment with insulin. The incretin effect was determined by comparing plasma insulin and C-peptide levels at clamped hyperglycemia from iv glucose, and iv glucose plus glucose ingestion. Results: Long-acting insulin, titrated to reduce fasting glucose to 7 mM, lowered hemoglobin A1c from 8.6% +/- 0.2% to 7.1% +/- 0.2% over 8 weeks. The incremental C-peptide responses and insulin secretion rates to iv glucose did not differ before and after insulin treatment (5.6 +/- 1.0 and 6.0 +/- 0.9 nmol/L.min and 0.75 +/- 0.10 and 0.76 +/- 0.11 pmol/min), but the C-peptide response to glucose ingestion was greater after treatment than before (10.9 +/- 2.2 and 7.1 +/- 0.9 nmol/L.min; P = .03) as were the insulin secretion rates (1.11 +/- 0.22 and 0.67 +/- 0.07 pmol/min; P = .04). The incretin effect computed from plasma C-peptide was 21.8% +/- 6.5% before insulin treatment and increased 40.9% +/- 3.9% after insulin treatment (P < .02). Conclusion: Intensified insulin treatment to improve glycemic control led to a disproportionate improvement of insulin secretion in response to oral compared with iv glucose stimulation in patients with type 2 diabetes. This suggests that in T2DM the impaired incretin effect is independent of abnormal glucose-stimulated insulin secretion.