Dual glucagon-like peptide-1 receptor/glucagon receptor agonist SAR425899 improves beta-cell function in type 2 diabetes.
beta-cell function
disposition index
dual agonist
glucagon
glucagon-like peptide 1
insulin sensitivity
oral minimal model
Journal
Diabetes, obesity & metabolism
ISSN: 1463-1326
Titre abrégé: Diabetes Obes Metab
Pays: England
ID NLM: 100883645
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
04
09
2019
revised:
02
12
2019
accepted:
02
12
2019
pubmed:
7
12
2019
medline:
25
6
2021
entrez:
7
12
2019
Statut:
ppublish
Résumé
To evaluate the change in insulin sensitivity, β-cell function and glucose absorption after 28 days of treatment with high and low doses of SAR425899, a novel dual glucagon-like peptide-1 receptor/glucagon receptor agonist, versus placebo. Thirty-six overweight to obese subjects with type 2 diabetes were randomized to receive daily subcutaneous administrations of low-dose SAR425899 (0.03, 0.06 and 0.09 mg) and high-dose SAR425899 (0.06, 0.12 and 0.18 mg) or placebo for 28 days; dose escalation occurred after days 7 and 14. Mixed meal tolerance tests were conducted before treatment (day -1) and on days 1 and 28. Oral glucose and C-peptide minimal models were used to quantify metabolic indices of insulin sensitivity, β-cell responsiveness and glucose absorption. With low-dose SAR425899, high-dose SAR425899 and placebo, β-cell function from day -1 to day 28 increased by 163%, 95% and 23%, respectively. The change in area under the curve for the rate of meal glucose appearance between 0 and 120 minutes was -32%, -20% and 8%, respectively. After 28 days of treatment, SAR425899 improved postprandial glucose control by significantly enhancing β-cell function and slowing glucose absorption rate.
Substances chimiques
Blood Glucose
0
C-Peptide
0
Glucagon-Like Peptide-1 Receptor
0
Hypoglycemic Agents
0
Insulin
0
Receptors, Glucagon
0
Banques de données
ClinicalTrials.gov
['NCT02411825']
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
640-647Subventions
Organisme : CARIPARO
Pays : International
Informations de copyright
© 2019 John Wiley & Sons Ltd.
Références
Holt RIG, Cockram CS, Flyvbjerg A, Goldstein BJ. Textbook of Diabetes. 4th ed. Oxford, UK: Blackwell Publishing Ltd; 2010.
Ma R, Chan J. Metabolic complications of obesity. In: Williams G, Fruhbeck G, eds. Obesity: Science to Practice. Chichester, UK: John Wiley & Sons Ltd; 2009:235-270.
Finan B, Clemmensen C, Muller TD. Emerging opportunities for the treatment of metabolic diseases: glucagon-like peptide-1 based multi-agonists. Mol Cell Endocrinol. 2015;418:42-54.
Tschop MH, Finan B, Clemmensen C, et al. Unimolecular polypharmacy for treatment of diabetes and obesity. Cell Metab. 2016;24:51-62.
Heppner KM, Perez-Tilve D. GLP-1 based therapeutics: simultaneously combating T2DM and obesity. Front Neurosci. 2015;9:92.
Habegger KM, Heppner KM, Geary N, Bartness TJ, DiMarchi R, Tschop MH. The metabolic actions of glucagon revisited. Nat Rev Endocrinol. 2010;6:689-697.
Salem V, Izzi-Engbeaya C, Coello C, et al. Glucagon increases energy expenditure independently of brown adipose tissue activation in humans. Diabetes Obes Metab. 2016;18:72-81.
Tan TM, Field BC, McCullough KA, et al. Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes. 2013;62:1131-1138.
Wynne K, Park AJ, Small CJ, et al. Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int J Obes (Lond). 2006;30:1729-1736.
Ambery P, Parker VE, Stumvoll M, et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet. 2018;391:2607-2618.
Sanchez-Garrido MA, Brandt SJ, Clemmensen C, Muller TD, DiMarchi RD, Tschop MH. GLP-1/glucagon receptor co-agonism for treatment of obesity. Diabetologia. 2017;60:1851-1861.
Tillner J, Posch MG, Wagner F, et al. A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: results of randomized, placebo- controlled first-in-human and first-in-patient trials. Diabetes Obes Metab. 2019;21:120-128.
Basu R, Dalla Man C, Campioni M, et al. Effects of age and sex on postprandial glucose metabolism differences in glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction. Diabetes. 2006;55:2001-2014.
Basu A, Dalla Man C, Basu R, Toffolo G, Cobelli C, Rizza RA. Effects of type 2 diabetes on insulin secretion, insulin action, glucose effectiveness, and postprandial glucose metabolism. Diabetes Care. 2009;32:866-872.
Bock G, Dalla Man C, Campioni M, et al. Pathogenesis of pre-diabetes: mechanisms of fasting and postprandial hyperglycemia in people with impaired fasting glucose and/or impaired glucose tolerance. Diabetes. 2006;55:3536-3549.
Sathananthan A, Dalla Man C, Zinsmeister AR, et al. A concerted decline in insulin secretion and action occurs across the spectrum of fasting and postchallenge glucose concentrations. Clin Endocrinol (Oxf). 2012;76:212-219.
Nair KS, Rizza RA, O'Brien P, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med. 2006;355:1647-1659.
Dalla Man C, Bock G, Giesler PD, et al. Dipeptidyl peptidase-4 inhibition by vildagliptin and the effect on insulin secretion and action in response to meal ingestion in type 2 Diabetes. Diabetes Care. 2009;32:14-18.
Dalla Man C, Micheletto F, Sathananthan A, Rizza RA, Vella A, Cobelli C. A model of GLP-1 action on insulin secretion in nondiabetic subjects. Am J Physiol Endocrinol Metab. 2010;298:E1115-E1121.
Smushkin G, Sathananthan M, Piccinini F, et al. The effect of a bile acid sequestrant on glucose metabolism in subjects with type 2 diabetes. Diabetes. 2013;62:1094-1101.
Cobelli C, Dalla Man C, Toffolo G, Basu R, Vella A, Rizza R. The oral minimal model method. Diabetes. 2014;63:1203-1213.
Dalla Man C, Caumo A, Basu R, Rizza R, Toffolo G, Cobelli C. Minimal model estimation of glucose absorption and insulin sensitivity from oral test: validation with a tracer method. Am J Physiol Endocrinol Metab. 2004;287:E637-E643.
Dalla Man C, Yarasheski KE, Caumo A, et al. Insulin sensitivity by oral glucose minimal models: validation against clamp. Am J Physiol Endocrinol Metab. 2005;289:E954-E959.
Toffolo G, De Grandi F, Cobelli C. Estimation of b-cell sensitivity from IVGTT C-peptide data. Knowledge of the kinetics avoids errors in modeling the secretion. Diabetes. 1995;44:845-854.
Toffolo G, Cefalu W. Cobelli C. B-cell function during insulin modified IVGTT successfully assessed by the C-peptide minimal model. Metabolism. 1999;48:1162-1166.
Dalla Man C, Caumo A, Cobelli C. The oral glucose minimal model: estimation of insulin sensitivity from a meal test. IEEE Trans Biomed Eng. 2002;49:419-429.
Toffolo G, Campioni M, Basu R, Rizza RA, Cobelli C. A minimal model of insulin secretion and kinetics to assess hepatic insulin extraction. Am J Physiol Endocrinol Metab. 2006;290:E169-E176.
Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest. 1981;68:1456-1467.
Cobelli C, Toffolo GM, Dalla Man C, et al. Assessment of beta-cell function in humans, simultaneously with insulin sensitivity and hepatic extraction, from intravenous and oral glucose tests. Am J Physiol Endocrinol Metab. 2007;293:E1-E15.
Visentin R, Klabunde T, Dalla Man C, Cobelli C. 2015 Diabetes Technology Meeting Abstracts. Modeling the effect of liraglutide in type 2 diabetes mellitus with the type 2 diabetes mellitus simulator: a paradigm for in silico trials. J Diabetes Sci Technol. 2016:10;476-611 (abstract A110).
Kapitza C, Forst T, Coester H-V, Poitiers F, Ruus P, Hincelin-Mery A. Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. Diabetes Obes Metab. 2013;15:642-649.