The GLP-1 Derivative NN2211 Restores β-Cell Sensitivity to Glucose in Type 2 Diabetic Patients After a Single Dose

  1. Annette M. Chang1,
  2. Grethe Jakobsen2,
  3. Jeppe Sturis2,
  4. Marla J. Smith1,
  5. Cathie J. Bloem1,
  6. Bob An3,
  7. Andrzej Galecki4 and
  8. Jeffrey B. Halter1
  1. 1Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
  2. 2Novo Nordisk A/S, Bagsvaerd, Denmark
  3. 3Novo Nordisk Pharmaceuticals, Inc., Princeton, New Jersey
  4. 4Institute of Gerontology, University of Michigan, Ann Arbor, Michigan
  1. Address correspondence and reprint requests to Jeffrey B. Halter, MD, University of Michigan, 1111 CCGC Bldg., 1500 East Medical Center Dr., Ann Arbor, MI 48109-0926. E-mail: jhalter{at}umich.edu

Abstract

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion in a glucose-dependent manner, but its short half-life limits its therapeutic potential. We tested NN2211, a long-acting GLP-1 derivative, in 10 subjects with type 2 diabetes (means ± SD: age 63 ± 8 years, BMI 30.1 ± 4.2 kg/m2, HbA1c 6.5 ± 0.8%) in a randomized, double-blind, placebo-controlled, crossover study. A single injection (7.5 μg/kg) of NN2211 or placebo was administered 9 h before the study. β-cell sensitivity was assessed by a graded glucose infusion protocol, with glucose levels matched over the 5–12 mmol/l range. Insulin secretion rates (ISRs) were estimated by deconvolution of C-peptide levels. Findings were compared with those in 10 nondiabetic volunteers during the same glucose infusion protocol. In type 2 diabetic subjects, NN2211, in comparison with placebo, increased insulin and C-peptide levels, the ISR area under the curve (AUC) (1,130 ± 150 vs. 668 ± 106 pmol/kg; P < 0.001), and the slope of ISR versus plasma glucose (1.26 ± 0.36 vs. 0.54 ± 0.18 pmol · l[min−1 · mmol−1 · kg−1]; P < 0.014), with values similar to those of nondiabetic control subjects (ISR AUC 1,206 ± 99; slope of ISR versus plasma glucose, 1.44 ± 0.18). The long-acting GLP-1 derivative, NN2211, restored β-cell responsiveness to physiological hyperglycemia in type 2 diabetic subjects.

Footnotes

  • G.J., J.S., and B.A. hold stock in Novo Nordisk A/S.

    • Accepted April 8, 2003.
    • Received October 29, 2002.
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