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Exp Clin Endocrinol Diabetes 2004; 112(7): 395-400
DOI: 10.1055/s-2004-821025
Article

J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

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

N. N. Rudovich1 , 2 , M. G. Leyck Dieken3 , H. Rochlitz2 , 1 , A. F. H. Pfeiffer1 , 2
  • 1Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany
  • 2Department of Endocrinology, Diabetes and Nutrition, Campus B. Franklin, Charité University Medicine, Berlin, Germany
  • 3Novo Nordisk Pharma GmbH, Mainz, Germany
Further Information

Publication History

Received: May 23, 2003 First decision: September 10, 2003

Accepted: February 26, 2004

Publication Date:
07 July 2004 (online)

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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

  • 1 Bruttomesso D, Pianta A, Mari A, Valerio A, Marescotti M-C, Avogaro A, Tienego A, Der Parto S. Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetic patients.  Diabetes. 1999;  48 99-105
    CrossrefPubMedGoogle Scholar
  • 2 Chiasson J-L, Hamet P, Verdy M. The effect of Diamicron on the secretion and action of insulin.  Diab Res Clin Pract. 1991;  14 S47-S52
    CrossrefPubMedGoogle Scholar
  • 3 Clark H E, Matthews R. The effect of glimepiride on pancreatic beta-cell function under hyperglycemic clamp and hyperglycemic, euglycemic clamp conditions in non-insulin-dependent diabetes mellitus.  Horm Metab Res. 1996;  28 445-450
    PubMedGoogle Scholar
  • 4 Dabrowski M, Wahl P, Holmes W E, Ashcroft F M. Effect of repaglinide on cloned beta cell, cardiac and smooth muscle types of ATP-sensitive potassium channels.  Diabetologia. 2001;  44 747-756
    CrossrefPubMedGoogle Scholar
  • 5 De Fronzo R A, Tobin J D, Anders R. Glucose clamp technique: a method for quantifying insulin secretion and resistance.  Am J Physiol (Endocrinol Metab). 1971;  273 E214-E223
    PubMedGoogle Scholar
  • 6 De Fronzo R A, Ferrannini E, Simonson D C. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue uptake.  Metabolism. 1989;  38 387-395
    CrossrefPubMedGoogle Scholar
  • 7 De Fronzo R A, Bonadonna R C, Ferrannini E. Pathogenesis of NIDDM.  Diabetes Care. 1992;  15 318-356
    CrossrefPubMedGoogle Scholar
  • 8 Fuhlendorff J, Rorsman P, Kofod H, Brand C L, Rolin B, MacKay P, Shymko R, Carr R D. Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes.  Diabetes. 1998;  47 345-351
    CrossrefPubMedGoogle Scholar
  • 9 Hatorp V, Oliver S, Su C A. Bioavailability of repaglinide, a novel antidiabetic agent, administered orally in tablet or solution form intravenously in healthy meal volunteers.  Int J Clin Pharmacol Ther. 1998;  36 636-641
    PubMedGoogle Scholar
  • 10 Haupt A, Kausch C, Dahl D, Bachmann O, Stumvoll M, Haring H U, Matthaei S. Effect of glimepiride on insulin-stimulated glycogen synthesis in cultured human skeletal muscle cells: a comparison to glibenclamide.  Diabetes Care. 2002;  25 2129-2132
    PubMedGoogle Scholar
  • 11 Johansen K. Efficacy of metformin in the treatment of NIDDM: meta-analysis.  Diabetes Care. 1999;  22 33-37
    PubMedGoogle Scholar
  • 12 Juhl C B, Pørksen N, Hollingdal M, Sturis J, Pincus S, Veldhuis J D, Dejgaard A, Schmitz O. Repaglinide acutely amplifies pulsatile insulin secretion by augmentation of burst mass with no effect on burst frequency.  Diabetes Care. 2000;  23 675-681
    PubMedGoogle Scholar
  • 13 Kahn S E, Montgomery B, Howell W M, Ligueros-Saylan M, Hsu C, Devineni D, McLeod J, Horowitz A D. Nateglinide increases first phase insulin secretion and enhances glucose clearance in type 2 diabetes.  Diabetes. 2000;  49 (Suppl 1) A113
    PubMedGoogle Scholar
  • 14 Malaisse W. Insulinotropic action of meglitinide analogues: modulation by an activator of ATP-sensitive K+ channels and high extracellular K+ concentrations.  Pharmacol Res. 1995;  32 111-114
    CrossrefPubMedGoogle Scholar
  • 15 Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly J, Gerich J. Contribution of abnormal muscle and liver glucose metabolism in postprandial hyperglycemia in NIDDM.  Diabetes. 1990;  39 1381-1390
    PubMedGoogle Scholar
  • 16 Mitrakou A, Kelley D, Mokan M, Veneman T, Reilly J, Gerich J. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance.  N Engl J Med. 1992;  326 22-29
    PubMedGoogle Scholar
  • 17 Moses R, Slobodniuk R, Boyages S, Colagiuri S, Kidson W, Carter J, Donnelly T, Moffitt P, Hopkins H. Effect of repaglinide addition to metformin monotherapy on glycaemic control in patients with type 2 diabetes.  Diabetes Care. 1999;  22 119-124
    CrossrefPubMedGoogle Scholar
  • 18 Owens D R, Luzio S D, Coates P A. Insulin secretion and sensitivity in newly diagnosed NIDDM Caucasians in the UK.  Diabet Med. 1996;  13 S19-S24
    PubMedGoogle Scholar
  • 19 Owens D R, Luzio S D, Ismail I, Bayer T. Increased prandial insulin secretion after administration of a single preprandial oral dose of repaglinide in patients with type 2 diabetes.  Diabetes Care. 2000;  23 518-523
    CrossrefPubMedGoogle Scholar
  • 20 Proks P, Reimann F, Green N, Gribble F, Ashcroft F. Sulfonylurea stimulation of insulin secretion.  Diabetes. 2002;  51 (Suppl 3) S368-376
    CrossrefPubMedGoogle Scholar
  • 21 Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich J E. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus.  N Engl J Med. 1995;  31 550-554
    PubMedGoogle Scholar
  • 22 Turtle J R. Glucose and insulin secretory response pattern following diet and tolazamide therapy in diabetes.  Br Med J. 1970;  3 606-610
    PubMedGoogle Scholar
  • 23 Weyer C, Bogardus C, Mott D M, Pratley R E. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus.  J Clin Invest. 1999;  104 787-794
    CrossrefPubMedGoogle Scholar
  • 24 Whitelaw D C, Clark P M, Smith J M, Nattrass M. Effects of the new oral hypoglycemic agent nateglinide on insulin secretion in Type 2 diabetes mellitus.  Diab Med. 2000;  17 225-229
    CrossrefPubMedGoogle Scholar
  • 25 Yki-Jarvinen H. Glucose toxicity.  Endocr Rev. 1992;  13 415-431
    CrossrefPubMedGoogle Scholar

N. N. Rudovich

German Institute of Human Nutrition, Department of Clinical Nutrition

Arthur-Scheunert-Allee 114 - 116

14558 Nuthetal

Germany

Phone: + 493320088771

Fax: + 49 33 20 08 87 77

Email: afhp@mail.dife.de

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