title: Population pharmacodynamic modeling of hyperglycemic clamp and meal tolerance tests in patients with type 2 diabetes mellitus.
abstract: In this study, glucose and insulin concentration-time profiles in subjects with type 2 diabetes mellitus (T2DM) under meal tolerance test (MTT) and hyperglycemic clamp (HGC) conditions were co-modeled simultaneously. Blood glucose and insulin concentrations were obtained from 20 subjects enrolled in a double-blind, placebo-controlled, randomized, two-way crossover study. Patients were treated with palosuran or placebo twice daily for 4 weeks and then switched to the alternative treatment after a 4-week washout period. The MTT and HGC tests were performed 1 h after drug administration on days 28 and 29 of each treatment period. Population data analysis was performed using NONMEM. The HGC model incorporates insulin-dependent glucose clearance and glucose-induced insulin secretion. This model was extended for the MTT, in which glucose absorption was described using a transit compartment with a mean transit time of 62.5 min. The incretin effect (insulin secretion triggered by oral glucose intake) was also included, but palosuran did not influence insulin secretion or sensitivity. Glucose clearance was 0.164 L/min with intersubject and interoccasion variability of 9.57% and 31.8%. Insulin-dependent glucose clearance for the HGC was about 3-fold greater than for the MTT (0.0111 vs. 0.00425 L/min/[mU/L]). The maximal incretin effect was estimated to enhance insulin secretion 2-fold. The lack of palosuran effect coupled with a population-based analysis provided quantitative insights into the variability of glucose and insulin regulation in patients with T2DM following multiple glucose tolerance tests. Application of these models may also prove useful in antihyperglycemic drug development and assessing glucose-insulin homeostasis.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, SUNY, 431 Kapoor Hall, Buffalo, New York, 14214, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hong
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
authors.forename: Patricia
authors.initials: P
authors.lastname: Sidharta
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis; D004311:Double-Blind Method; D005215:Fasting / Q000097:blood*; D005260:Female; D015309:Glucose Clamp Technique / Q000379:methods*; D006801:Humans; D006943:Hyperglycemia / Q000097:blood* / Q000175:diagnosis; D008297:Male; D008875:Middle Aged; D008954:Models, Biological
chemical_list: D001786:Blood Glucose
references.citation: Diabetes. 2004 May;53(5):1201-7
references.pmid: 15111487
references.citation: Clin Pharmacol Ther. 2006 Sep;80(3):246-56
references.pmid: 16952491
references.citation: Am J Physiol Endocrinol Metab. 2006 Jan;290(1):E169-E176
references.pmid: 16144811
references.citation: Diabetes. 2002 Feb;51 Suppl 1:S109-16
references.pmid: 11815468
references.citation: J Pharmacol Exp Ther. 2006 Mar;316(3):1115-21
references.pmid: 16267137
references.citation: Lancet. 2006 Nov 11;368(9548):1696-705
references.pmid: 17098089
references.citation: Am J Physiol. 1979 Sep;237(3):E214-23
references.pmid: 382871
references.citation: Diabetologia. 2003 Jul;46(7):972-6
references.pmid: 12830381
references.citation: Br J Clin Pharmacol. 2009 Oct;68(4):502-10
references.pmid: 19843053
references.citation: J Pharmacokinet Biopharm. 1993 Dec;21(6):735-50
references.pmid: 8138894
references.citation: Diabetes Care. 1996 Mar;19(3):278-86
references.pmid: 8742583
references.citation: Expert Opin Investig Drugs. 2005 Jun;14(6):705-27
references.pmid: 16004598
references.citation: J Pharmacokinet Pharmacodyn. 2007 Oct;34(5):711-26
references.pmid: 17653836
references.citation: J Clin Pharmacol. 2009 Oct;49(10):1168-75
references.pmid: 19625629
references.citation: J Clin Pharmacol. 2007 Sep;47(9):1159-71
references.pmid: 17766701
references.citation: J Gerontol A Biol Sci Med Sci. 2012 Dec;67(12):1307-12
references.pmid: 22219517
references.citation: Am J Physiol. 1987 Dec;253(6 Pt 1):E595-602
references.pmid: 2892414
references.citation: Diabetes. 1997 Jul;46(7):1167-71
references.pmid: 9200652
references.citation: J Pharmacol Exp Ther. 2004 Oct;311(1):204-12
references.pmid: 15146030
references.citation: Diabetes. 1994 Jul;43(7):890-6
references.pmid: 8013753
references.citation: J Clin Pharmacol. 2007 Oct;47(10):1244-55
references.pmid: 17906159
references.citation: J Clin Pharmacol. 2011 Jul;51(7):1015-24
references.pmid: 20940337
references.citation: Am J Physiol. 1979 Jun;236(6):E667-77
references.pmid: 443421
references.citation: Am J Med. 1985 Aug 23;79(2B):6-12
references.pmid: 2863979
references.citation: Horm Res. 2005;64 Suppl 3:8-15
references.pmid: 16439839
references.citation: Diabetes Care. 2004 Jun;27(6):1487-95
references.pmid: 15161807
references.citation: J Pharmacol Exp Ther. 2004 Nov;311(2):830-5
references.pmid: 15199095