Abstract
Aims/hypothesis
Oral glucose elicits a higher insulin secretory response than intravenous glucose at matched glucose concentrations. This potentiation, known as the incretin effect, is typically expressed as the difference between the total insulin response to oral vs intravenous glucose. This approach does not describe the dynamics of insulin secretion potentiation. We developed a model for the simultaneous analysis of oral and isoglycaemic intravenous glucose responses to dissect the impact of hyperglycaemia and incretin effect on insulin secretion and beta cell function.
Methods
Fifty individuals (23 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT] and ten with type 2 diabetes) received an OGTT and an isoglycaemic test with measurement of plasma glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Our model featured an incretin potentiation factor (PINCR) for the dose–response function relating insulin secretion to glucose concentration, and an effect on early secretion (rate sensitivity).
Results
In NGT, PINCR rapidly increased and remained sustained during the whole OGTT (mean PINCR > 1, p < 0.009). The increase was transient in IGT and virtually absent in diabetes. Mean PINCR was significantly but loosely correlated with GLP-1 AUC (r = 0.49, p < 0.006), while the relationship was not significant for GIP. An incretin effect on rate sensitivity was present in all groups (p < 0.002).
Conclusions/interpretation
The onset of the incretin effect is rapid and sustained in NGT, transient in IGT and virtually absent in diabetes. The profiles of the incretin effect are poorly related to those of the incretin hormones.
This is a preview of subscription content, log in via an institution to check access.
Abbreviations
- DDMoRe:
-
Drug Disease Model Resources
- GIP:
-
Glucose-dependent insulinotropic polypeptide
- GLP-1:
-
Glucagon-like peptide-1
- IGT:
-
Impaired glucose tolerance
- IIGI:
-
Isoglycaemic intravenous glucose infusion test
- NGT:
-
Normal glucose tolerance
- PINCR :
-
Incretin potentiation factor
References
Vilsbøll T, Holst JJ (2004) Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia 47:357–366
Nauck MA, Homberger E, Siegel EG et al (1986) Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 63:492–498
Muscelli E, Mari A, Casolaro A et al (2008) Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes 57:1340–1348
Muscelli E, Mari A, Natali A et al (2006) Impact of incretin hormones on beta-cell function in subjects with normal or impaired glucose tolerance. Am J Physiol Endocrinol Metab 291:E1144–E1150
Campioni M, Toffolo G, Shuster LT, Service FJ, Rizza RA, Cobelli C (2007) Incretin effect potentiates beta-cell responsivity to glucose as well as to its rate of change: OGTT and matched intravenous study. Am J Physiol Endocrinol Metab 292:E54–E60
Burattini R, Morettini M (2012) Identification of an integrated mathematical model of standard oral glucose tolerance test for characterization of insulin potentiation in health. Comput Methods Prog Biomed 107:248–261
Jauslin PM, Silber HE, Frey N et al (2007) An integrated glucose-insulin model to describe oral glucose tolerance test data in type 2 diabetics. J Clin Pharmacol 47:1244–1255
Silber HE, Frey N, Karlsson MO (2010) An integrated glucose-insulin model to describe oral glucose tolerance test data in healthy volunteers. J Clin Pharmacol 50:246–256
Brubaker PL, Ohayon EL, D'Alessandro LM, Norwich KH (2007) A mathematical model of the oral glucose tolerance test illustrating the effects of the incretins. Ann Biomed Eng 35:1286–1300
Dalla Man C, Micheletto F, Sathananthan A, Rizza RA, Vella A, Cobelli C (2010) A model of GLP-1 action on insulin secretion in nondiabetic subjects. Am J Physiol Endocrinol Metab 298:E1115–E1121
Salinari S, Bertuzzi A, Mingrone G (2011) Intestinal transit of a glucose bolus and incretin kinetics: a mathematical model with application to the oral glucose tolerance test. Am J Physiol Endocrinol Metab 300:E955–E965
Mari A, Tura A, Gastaldelli A, Ferrannini E (2002) Assessing insulin secretion by modeling in multiple-meal tests: role of potentiation. Diabetes 51(Suppl 1):S221–S226
Mari A, Schmitz O, Gastaldelli A, Oestergaard T, Nyholm B, Ferrannini E (2002) Meal and oral glucose tests for assessment of beta-cell function: modeling analysis in normal subjects. Am J Physiol Endocrinol Metab 283:E1159–E1166
American Diabetes Association (1997) Report of the Expert Committee on Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183–1197
Vardarli I, Arndt E, Deacon CF, Holst JJ, Nauck MA (2013) Effects of sitagliptin and metformin treatment on incretin hormone and insulin secretory responses to oral and ‘isoglycemic’ intravenous glucose. Diabetes 63:663–674
Nauck MA, Vardarli I, Deacon CF, Holst JJ, Meier JJ (2011) Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 54:10–18
Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA (2005) Beta-cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J Clin Endocrinol Metab 90:493–500
Mari A, Bagger JI, Ferrannini E, Holst JJ, Knop FK, Vilsbøll T (2013) Mechanisms of the incretin effect in subjects with normal glucose tolerance and patients with type 2 diabetes. PLoS One 8:e73154
Mari A, Ferrannini E (2008) Beta-cell function assessment from modelling of oral tests: an effective approach. Diabetes Obes Metab 10(Suppl 4):77–87
Funding
The collection of the original data was supported by a European Foundation for the Study of Diabetes and Novo Nordisk Type 2 Programme Focused Research Grant, and by funds from the Italian Ministry of University and Scientific Research (protocol 2001065883-001). The research leading to the results of this study has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115156 (Drug Disease Model Resources, [DDMoRe] project), the resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations companies’ in kind contribution. The DDMoRe project is also supported by financial contribution from academic, and Small and Medium Enterprise partners. This work does not necessarily represent the view of all DDMoRe partners.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
Contribution statement
EM, AG and EF were in charge of the acquisition of the experimental data. AT and AM developed the mathematical model, and made the data analysis and interpretation. AT also wrote the manuscript. All other authors critically revised the manuscript. AM was responsible for the integrity of the work as a whole. All authors approved the final version.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM Methods
(PDF 135 kb)
ESM Fig. 1
(PDF 18 kb)
ESM Fig. 2
(PDF 60.4 kb)
ESM Fig. 3
(PDF 31.2 kb)
Rights and permissions
About this article
Cite this article
Tura, A., Muscelli, E., Gastaldelli, A. et al. Altered pattern of the incretin effect as assessed by modelling in individuals with glucose tolerance ranging from normal to diabetic. Diabetologia 57, 1199–1203 (2014). https://doi.org/10.1007/s00125-014-3219-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00125-014-3219-7