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

The GLP-1 Derivative NN2211 Restores β-Cell Sensitivity to Glucose in Type 2 Diabetic Patients After a Single Dose Annette M. Chang 1 , Grethe Jakobsen 2 , Jeppe Sturis 2 , Marla J. Smith 1 , Cathie J. Bloem 1 , Bob An 3 , Andrzej Galecki 4 and Jeffrey B. Halter 1 1 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 2 Novo Nordisk A/S, Bagsvaerd, Denmark 3 Novo Nordisk Pharmaceuticals, Inc., Princeton, New Jersey 4 Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 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/m 2 , HbA 1c 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. ADA, American Diabetes Association AUC, area under the curve ELISA, enzyme-linked immunosorbent assay GCRC, General Clinical Research Center GLP-1, glucagon-like peptide 1 ISR, insulin secretion rate Footnotes G.J., J.S., and B.A. hold stock in Novo Nordisk A/S. Accepted April 8, 2003. Received October 29, 2002. DIABETES