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Metabolism

One Week’s Treatment With the Long-Acting Glucagon-Like Peptide 1 Derivative Liraglutide (NN2211) Markedly Improves 24-h Glycemia and α- and β-Cell Function and Reduces Endogenous Glucose Release in Patients with Type 2 Diabetes

  1. Kristine B. Degn1,
  2. Claus B. Juhl1,
  3. Jeppe Sturis2,
  4. Grethe Jakobsen2,
  5. Birgitte Brock1,
  6. Visvanathan Chandramouli3,
  7. Joergen Rungby1,
  8. Bernard R. Landau3 and
  9. Ole Schmitz1
  1. 1Department of Endocrinology (M & C), University Hospital of Aarhus, and Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark
  2. 2Novo Nordisk A/S, Bagsværd, Denmark
  3. 3Case Western Reserve University School of Medicine, Cleveland, Ohio
  1. Address correspondencereprint requests to Ole Schmitz, MD, Department of Medicine M (Endocrinology & Diabetes), University Hospital of Aarhus, AKH, Nørrebrogade 42-44 DK-8000 Aarhus C, Denmark. E-mail: ole.schmitz{at}iekf.au.dk
Diabetes 2004 May; 53(5): 1187-1194. https://doi.org/10.2337/diabetes.53.5.1187
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Abstract

Glucagon-like peptide 1 (GLP-1) is potentially a very attractive agent for treating type 2 diabetes. We explored the effect of short-term (1 week) treatment with a GLP-1 derivative, liraglutide (NN2211), on 24-h dynamics in glycemia and circulating free fatty acids, islet cell hormone profiles, and gastric emptying during meals using acetaminophen. Furthermore, fasting endogenous glucose release and gluconeogenesis (3-3H-glucose infusion and 2H2O ingestion, respectively) were determined, and aspects of pancreatic islet cell function were elucidated on the subsequent day using homeostasis model assessment and first- and second-phase insulin response during a hyperglycemic clamp (plasma glucose ∼16 mmol/l), and, finally, on top of hyperglycemia, an arginine stimulation test was performed. For accomplishing this, 13 patients with type 2 diabetes were examined in a double-blind, placebo-controlled crossover design. Liraglutide (6 μg/kg) was administered subcutaneously once daily. Liraglutide significantly reduced the 24-h area under the curve for glucose (P = 0.01) and glucagon (P = 0.04), whereas the area under the curve for circulating free fatty acids was unaltered. Twenty-four-hour insulin secretion rates as assessed by deconvolution of serum C-peptide concentrations were unchanged, indicating a relative increase. Gastric emptying was not influenced at the dose of liraglutide used. Fasting endogenous glucose release was decreased (P = 0.04) as a result of a reduced glycogenolysis (P = 0.01), whereas gluconeogenesis was unaltered. First-phase insulin response and the insulin response to an arginine stimulation test with the presence of hyperglycemia were markedly increased (P < 0.001), whereas the proinsulin/insulin ratio fell (P = 0.001). The disposition index (peak insulin concentration after intravenous bolus of glucose multiplied by insulin sensitivity as assessed by homeostasis model assessment) almost doubled during liraglutide treatment (P < 0.01). Both during hyperglycemia per se and after arginine exposure, the glucagon responses were reduced during liraglutide administration (P < 0.01 and P = 0.01). Thus, 1 week’s treatment with a single daily dose of the GLP-1 derivative liraglutide, operating through several different mechanisms including an ameliorated pancreatic islet cell function in individuals with type 2 diabetes, improves glycemic control throughout 24 h of daily living, i.e., prandial and nocturnal periods. This study further emphasizes GLP-1 and its derivatives as a promising novel concept for treatment of type 2 diabetes.

  • AUC, area under the curve
  • DPP-IV, dipeptidylpeptidase IV
  • EGR, endogenous glucose release
  • ELISA, enzyme-linked immunosorbent assay
  • FFA, free fatty acid
  • GLP-1, glucagon-like peptide 1
  • GLY, glycogenolysis
  • GNG, gluconeogenesis
  • HMT, hexamethylenetetramine
  • HOMA, homeostasis model assessment
  • ISR, insulin secretion rate
  • OHA, oral hypoglycemic agent
  • tmax, time of occurrence for maximum drug concentration

Footnotes

    • Accepted January 23, 2004.
    • Received October 14, 2003.
  • DIABETES
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May 2004, 53(5)
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One Week’s Treatment With the Long-Acting Glucagon-Like Peptide 1 Derivative Liraglutide (NN2211) Markedly Improves 24-h Glycemia and α- and β-Cell Function and Reduces Endogenous Glucose Release in Patients with Type 2 Diabetes
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One Week’s Treatment With the Long-Acting Glucagon-Like Peptide 1 Derivative Liraglutide (NN2211) Markedly Improves 24-h Glycemia and α- and β-Cell Function and Reduces Endogenous Glucose Release in Patients with Type 2 Diabetes
Kristine B. Degn, Claus B. Juhl, Jeppe Sturis, Grethe Jakobsen, Birgitte Brock, Visvanathan Chandramouli, Joergen Rungby, Bernard R. Landau, Ole Schmitz
Diabetes May 2004, 53 (5) 1187-1194; DOI: 10.2337/diabetes.53.5.1187

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One Week’s Treatment With the Long-Acting Glucagon-Like Peptide 1 Derivative Liraglutide (NN2211) Markedly Improves 24-h Glycemia and α- and β-Cell Function and Reduces Endogenous Glucose Release in Patients with Type 2 Diabetes
Kristine B. Degn, Claus B. Juhl, Jeppe Sturis, Grethe Jakobsen, Birgitte Brock, Visvanathan Chandramouli, Joergen Rungby, Bernard R. Landau, Ole Schmitz
Diabetes May 2004, 53 (5) 1187-1194; DOI: 10.2337/diabetes.53.5.1187
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