Quantification of the Incretin Effect in Healthy Subjects and Patients With Type 2 Diabetes

Incretin Effect Clinical Trial

Official title:

Quantification of the Incretin Effect in Healthy Subjects and Patients With Type 2 Diabetes Using Increasing Amounts of Oral Glucose Challenges

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00529048
• Other study ID #: INK-GLUKOSE1
• Status: Completed
• Phase: N/A
• First received: September 12, 2007
• Last updated: October 19, 2009
• Start date: October 2007
• Est. completion date: September 2009

Study information

• Verified date: October 2009
• Source: Herlev Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Patients with T2DM lac a sufficient incretin response after oral glucose intake. It has only been tested using 50g of glucose. We don't know if patients with T2DM are capable of regulating the incretin effect like healthy people in responds to different amounts of glucose intake.

The aim of the present study is to quantify the incretin effect in healthy subjects and in patients with T2DM during increasing amounts of oral glucose challenges. The proposed studies will answer important questions on the mechanisms underlying T2DM and be of importance in relation to future preventive- and treatment strategies.

Description:

The impaired incretin effect in patients with type 2 diabetes mellitus (T2DM) has previously only been evaluated using a glucose load of 50 g, and it is uncertain whether patients with T2DM are capable of regulating their incretin effect equivalent to healthy subjects. Furthermore, it is of great interest to quantify the secretion of GIP and GLP-1 during increasing glucose loads in both patients with T2DM and in healthy subjects in order to evaluate whether an increased secretion of one or both of the two incretin hormones contributes to the regulation of the incretin effect.

The aim of the present study is to quantify the incretin effect in healthy subjects and in patients with T2DM during increasing amounts of oral glucose challenges and corresponding isoglycemic iv glucose challenges. The proposed studies will answer important questions on the pathophysiology underlying T2DM and be of importance in relation to future preventive- and treatment strategies.

Eight patients with T2DM and 8 matched healthy subjects will be evaluated with oral glucose tolerance tests (OGTT) using increasing glucose loads (25, 50 and 100 g glucose) and isoglycemic iv glucose tolerance tests imitating the glucose concentrations as obtained during the oral glucose loads. The results will describe the regulation of the incretin effect in patients with T2DM and, thereby, contribute to the clarification of the pathophysiology of the postprandial hyperglycemia characterizing these patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: September 2009
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria: Cases

• Caucasians with T2DM according to WHO's criteria

• Normal Hemoglobin

• Agree to participate (orally and in writing)

• HbA1c: 6.5-9 %

• BMI: 23-35 kg/m2

Exclusion Criteria:Cases

• Liver disease (ALAT > 2 x normal level)

• Diabetic nephropathy (s-creatinin > 130 µM or albuminuria)

• Diabetic neuropathy (anamnestic)

• Proliferative diabetic retinopathy (anamnestic)

• Medical treatment witch cannot be stopped for 12 hours

• Pregnancy or breastfeed

• Treatment with Insulin or glitazones

Inclusion Criteria: Control group

• Caucasians

• Normal oral glucose tolerance according to WHO's criteria

• Normal Hemoglobin

• Agree to participate (orally and in writing)

• BMI: 23-35 kg/m2

Exclusion Criteria: Control group

• Liver disease (ALAT > 2 x normal level)

• Impaired function of the kidney (s-creatinin > 130 µM or albuminuria)

• Directly related til to someone suffering from diabetes mellitus

• Medical treatment witch cannot be stopped for 12 hours

• Pregnancy or breastfeed

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Incretin Effect

Intervention

Other:
• Oral Glucose Tolerance Test
The test is preformed 3 times with 3 different amounts of glucose (25g, 75g and 125g) deluded in 300ml of water.
• Isoglycemic clamp
I.v. glucose infusion initiating the glucose responds curves from the OGTT
• Gastric emptying rate
Paracetamol absorption test. Intake of 1,5g of paracetamol followed by measuring the absorption curve

Locations

Country	Name	City	State
Denmark	Endokrinologisk afd. J, Herlev Hospital	Herlev	Region Hovedstaden

Sponsors (5)

Lead Sponsor	Collaborator
Herlev Hospital	Diabetesforeningen, Forskningsrådet, Merck Sharp & Dohme Corp., University of Copenhagen

Country where clinical trial is conducted

Denmark, 

References & Publications (13)

Edwards CM, Todd JF, Mahmoudi M, Wang Z, Wang RM, Ghatei MA, Bloom SR. Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. Diabetes. 1999 Jan;48(1):86-93. — View Citation

Gault VA, O'Harte FP, Harriott P, Mooney MH, Green BD, Flatt PR. Effects of the novel (Pro3)GIP antagonist and exendin(9-39)amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: evidence that GIP is the major physiological incretin. Diabetologia. 2003 Feb;46(2):222-30. Epub 2003 Feb 12. — View Citation

Habener JF. The incretin notion and its relevance to diabetes. Endocrinol Metab Clin North Am. 1993 Dec;22(4):775-94. Review. — View Citation

Kjems LL, Holst JJ, Vølund A, Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes. 2003 Feb;52(2):380-6. — View Citation

Kolligs F, Fehmann HC, Göke R, Göke B. Reduction of the incretin effect in rats by the glucagon-like peptide 1 receptor antagonist exendin (9-39) amide. Diabetes. 1995 Jan;44(1):16-9. — View Citation

Miyawaki K, Yamada Y, Yano H, Niwa H, Ban N, Ihara Y, Kubota A, Fujimoto S, Kajikawa M, Kuroe A, Tsuda K, Hashimoto H, Yamashita T, Jomori T, Tashiro F, Miyazaki J, Seino Y. Glucose intolerance caused by a defect in the entero-insular axis: a study in gastric inhibitory polypeptide receptor knockout mice. Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14843-7. — View Citation

Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986 Jan;29(1):46-52. — View Citation

Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986 Aug;63(2):492-8. — View Citation

Scrocchi LA, Brown TJ, MaClusky N, Brubaker PL, Auerbach AB, Joyner AL, Drucker DJ. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med. 1996 Nov;2(11):1254-8. — View Citation

Tseng CC, Zhang XY, Wolfe MM. Effect of GIP and GLP-1 antagonists on insulin release in the rat. Am J Physiol. 1999 Jun;276(6 Pt 1):E1049-54. — View Citation

Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept. 2003 Jul 15;114(2-3):115-21. — View Citation

Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia. 2002 Aug;45(8):1111-9. Epub 2002 Jul 4. — View Citation

Wang Z, Wang RM, Owji AA, Smith DM, Ghatei MA, Bloom SR. Glucagon-like peptide-1 is a physiological incretin in rat. J Clin Invest. 1995 Jan;95(1):417-21. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progress in Incretin effect in patients with T2DM compared with healthy subjects		4 hours
Secondary	GIP and GLP-1 responscurvs		4 hours