Enhancement of Early- and Late-Phase Insulin Secretion and Insulin Sensitivity by the Combination of Repaglinide and Metformin in Type 2 Diabetes Mellitus

Abstract

The effects of a combination of repaglinide and metformin on the insulin secretion pattern and insulin sensitivity were studied in a fixed-dose, open-label, placebo-controlled cross-over study. Eleven patients with T2 DM were allocated in random order to treatment with placebo or repaglinide (1 mg pre-meal 3 ×/day) in combination with metformin (2550 mg/day) for one-week periods of each. At the end of each period a hyperglycaemic (HC) and a euglycaemic clamp (EC) were performed. Both early (0 - 10 min) and late (25 - 180 min) phases of insulin secretion were significantly increased during HC with repaglinide compared to placebo (263.3 ± 133.1 vs. 443.6 ± 138.5 pmol/l/10 min, p = 0.008 and 18 750.9 ± 5936.4 vs. 34 508.65 ± 9234.0 pmol/l/25 - 180 min; p = 0.008). The C-peptide concentrations under steady-state conditions were lower in EC with placebo than with repaglinide (p = 0.014). When euglycaemia was achieved in EC, the C-peptide concentrations decreased from hyperglycaemic to normoglycaemic values in the presence of repaglinide but remained higher than after placebo. The insulin sensitivity index (ISI) was increased by 35 % after 1 week of combination therapy with repaglinide plus metformin (1.11 ± 0.03 × 10² vs. 0.83 ± 0.21 × 10² mg × kg^-1 body weight × min^-1 × pmol^-1 × l, respectively; p = 0.033).

Repaglinide increased early and late phases of insulin responses in HC, without markedly enhancing insulin secretion in euglycaemia. Repaglinide in combination with metformin produced a significant enhancement of ISI, suggesting a synergistic effect on insulin sensitivity.

Key words

Englycaemic clamp, hyperglycaemic clamp - repaglinide - metformin - insulin secretion - insulin sensitivity - type 2 diabetes mellitus

References

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