GIP, GLP-1 and GLP-2 in Type 2 Diabetic Hyperglucagonemia - Full Text View

Sponsor:	Herlev Hospital
Collaborators:	University of Copenhagen The Danish Medical Research Council The Danish Diabetes Association
Information provided by:	Herlev Hospital
ClinicalTrials.gov Identifier:	NCT00716170

Purpose

In order to investigate the mechanisms underlying the hyperglucagonemia characterizing patients with type 2 diabetes mellitus (T2DM) we wish to test the following hypothesis: Do pancreatic alpha-cells exhibit inappropriate glucagon responses to substances released from the small intestine (GIP, GLP-2 and GLP-2) in patients with T2DM?

Condition	Intervention
Type 2 Diabetes Mellitus	Biological: Glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2)

Study Type:	Observational
Study Design:	Observational Model: Case-Only Time Perspective: Cross-Sectional
Official Title:	The Role of GIP, GLP-1 and GLP-2 in Type 2 Diabetic Hyperglucagonemia

Resource links provided by NLM:

Genetics Home Reference related topics: 6q24-related transient neonatal diabetes mellitus

MedlinePlus related topics: Diabetes Diabetes Medicines Diabetes Type 2

Drug Information available for: Dextrose Glucagon Glucagon-like peptide 1

U.S. FDA Resources

Further study details as provided by Herlev Hospital:

Primary Outcome Measures:

Plasma glucagon responses [ Time Frame: 3 hours ] [ Designated as safety issue: No ]

Biospecimen Retention: Samples With DNA

Blood plasma and leucocytes

Estimated Enrollment:	10
Study Start Date:	July 2008
Study Completion Date:	July 2009
Primary Completion Date:	July 2009 (Final data collection date for primary outcome measure)

Groups/Cohorts	Assigned Interventions
A: Patients with type 2 diabetes mellitus	Biological: Glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) Day A: Oral glucose tolerance test (50g glucose) Day B: Isoglycemic intravenous (iv) glucose infusion Day C: Isoglycemic iv glucose infusion + iv GIP infusion (0-20 min: 4 pmol/kg body weight/min; 20-50 min: 2 pmol/kg body weight/min) Day D: Isoglycemic iv glucose infusion + iv GLP-1 infusion (0-20 min: 0,6 pmol/kg body weight/min; 20-50 min: 0,3 pmol/kg body weight/min) Day E: Isoglycemic iv glucose infusion + iv GLP-2 infusion (0-20 min: 1 pmol/kg body weight/min; 20-50 min: 0,5 pmol/kg body wight/min) Day F: Isoglycemic iv glucose infusion + iv infusion of GIP, GLP-1 and GLP-2 in doses as Day C, D and E. Other Names: Human GIP (glucose-dependent insulinotropic polypeptide) Human GLP-1 (glucagon-like peptide-1) Human GLP-2 (glucagon-like peptide-2)

Groups/Cohorts

Assigned Interventions

A:

Patients with type 2 diabetes mellitus

Biological: Glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2)

Day A: Oral glucose tolerance test (50g glucose)

Day B: Isoglycemic intravenous (iv) glucose infusion

Day C: Isoglycemic iv glucose infusion + iv GIP infusion (0-20 min: 4 pmol/kg body weight/min; 20-50 min: 2 pmol/kg body weight/min)

Day D: Isoglycemic iv glucose infusion + iv GLP-1 infusion (0-20 min: 0,6 pmol/kg body weight/min; 20-50 min: 0,3 pmol/kg body weight/min)

Day E: Isoglycemic iv glucose infusion + iv GLP-2 infusion (0-20 min: 1 pmol/kg body weight/min; 20-50 min: 0,5 pmol/kg body wight/min)

Day F: Isoglycemic iv glucose infusion + iv infusion of GIP, GLP-1 and GLP-2 in doses as Day C, D and E.

Other Names:

Human GIP (glucose-dependent insulinotropic polypeptide)
Human GLP-1 (glucagon-like peptide-1)
Human GLP-2 (glucagon-like peptide-2)

Detailed Description:

Patients with T2DM are not able to suppress their secretion of glucagon after a meal or after oral ingestion of glucose. Patients actually respond with pathological high plasmaglucagon concentrations to these stimuli. Previous studies have shown that postprandial hyperglucagonemia results in increased hepatic glucose production and therefore contributes significantly to the hyperglycemia characterizing these patients.

Recently we have shown that patients with T2DM exhibit a normal suppression of glucagon secretion following an adjustable intravenous (iv) glucose challenge mimicking the glucose excursion following a 50-g oral glucose tolerance test (OGTT) with the latter resulting in lack of glucagon suppression. Why this difference? A possible explanation could be that the oral administration stimulates intestinal factors resulting in a differentially glucagon response to the two similar glucose excursions. We wish to establish whether GIP, GLP-1 and/or GLP-2 are responsible for the inappropriate glucagon suppression following OGTT and meals in patients with T2DM.

Eligibility

Ages Eligible for Study:	35 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

The patients will be recruted from the outpatient clinic of Department of Endocrinology, Herlev Hospital.

Criteria

Inclusion Criteria:

Caucasians with diet and/or tablet treated T2DM of at least 3 months duration (diagnosed according to the criterias of the World Health Organization (WHO))
Normal Hemoglobin
Prior Informed Consent

Exclusion Criteria:

Liver disease (ALAT/ASAT > 2 x upper normal value)
Diabetic nephropathy (se-creatinin > 130 um and/or albuminuria
Treatment with drugs that cannot be discontinued for 12 hours

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00716170

Locations

Denmark
Department of Endocrinology J, Herlev Hospital
Herlev, Denmark, 2730

Sponsors and Collaborators

Herlev Hospital

University of Copenhagen

The Danish Medical Research Council

The Danish Diabetes Association

Investigators

Study Chair:	Tina Vilsbøll, MD DMSc	Herlev Hospital
Study Director:	Filip K Knop, MD PhD	Gentofte Hospital

More Information

Publications:

Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003 Jan;26 Suppl 1:S5-20. No abstract available.

Unger RH, Orci L. Glucagon and the A cell: physiology and pathophysiology (first two parts). N Engl J Med. 1981 Jun 18;304(25):1518-24. No abstract available.

Unger RH, Orci L. Glucagon and the A cell: physiology and pathophysiology (second of two parts). N Engl J Med. 1981 Jun 25;304(26):1575-80. No abstract available.

Shah P, Vella A, Basu A, Basu R, Schwenk WF, Rizza RA. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2000 Nov;85(11):4053-9.

Knop FK, Vilsbøll T, Madsbad S, Holst JJ, Krarup T. Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus. Diabetologia. 2007 Apr;50(4):797-805. Epub 2007 Jan 16.

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.

Knop FK, Vilsbøll T, Højberg PV, Larsen S, Madsbad S, Vølund A, Holst JJ, Krarup T. Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state? Diabetes. 2007 Aug;56(8):1951-9. Epub 2007 May 18.

Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993 Aug;36(8):741-4.

Holst JJ. On the physiology of GIP and GLP-1. Horm Metab Res. 2004 Nov-Dec;36(11-12):747-54. Review.

Meier JJ, Gallwitz B, Siepmann N, Holst JJ, Deacon CF, Schmidt WE, Nauck MA. Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia. Diabetologia. 2003 Jun;46(6):798-801. Epub 2003 May 23.

Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993 Jan;91(1):301-7.

Vilsboll 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.

Meier JJ, Nauck MA, Pott A, Heinze K, Goetze O, Bulut K, Schmidt WE, Gallwitz B, Holst JJ. Glucagon-like peptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibits gastric acid secretion in humans. Gastroenterology. 2006 Jan;130(1):44-54.

Schmidt WE, Siegel EG, Creutzfeldt W. Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia. 1985 Sep;28(9):704-7.

Sørensen LB, Flint A, Raben A, Hartmann B, Holst JJ, Astrup A. No effect of physiological concentrations of glucagon-like peptide-2 on appetite and energy intake in normal weight subjects. Int J Obes Relat Metab Disord. 2003 Apr;27(4):450-6.

Responsible Party:	Tina Vilsbøll/ MD DMSc, Herlev Hospital
ClinicalTrials.gov Identifier:	NCT00716170 History of Changes
Other Study ID Numbers:	1301831410
Study First Received:	July 10, 2008
Last Updated:	February 24, 2010
Health Authority:	Denmark: National Board of Health; Denmark: Ethics Committee; Denmark: Danish Dataprotection Agency

Keywords provided by Herlev Hospital:

Diabetes Mellitus
Glucagon
Insulin
Incretin hormones

Glucose-dependent insulinotropic polypeptide
Glucagon-like peptide-1
Glucagon-like peptide-2

Additional relevant MeSH terms:

Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Gastric Inhibitory Polypeptide
Glucagon-Like Peptide 1
Glucagon

Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Gastrointestinal Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on February 09, 2012