GIP, GLP-1 and GLP-2 in Type 2 Diabetic Hyperglucagonemia

An observational study of Type 2 Diabetes Mellitus, run by Herlev Hospital at 1 site in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Trial summary

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… Read more about this study

Who is it for?: Ages 35 years and older
Conditions the study is for: Type 2 Diabetes Mellitus
What is being tested?: Glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2)
Type of treatment: Pill or oral medicine, Injection or infusion
How many people: 10 participants
Where: 1 siteDenmark
Study dates: Jul 2008to Jul 2009
Phase: Observational
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 35 years and older
All sexes
No healthy volunteers
Adult, Older adult

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

Who may be able to join

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

Who cannot join

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

Trial locations and contacts

1 site in 1 country.

Denmark1 site

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

Other trials in Denmark

About this study

Official title: The Role of GIP, GLP-1 and GLP-2 in Type 2 Diabetic Hyperglucagonemia

Read the 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.

Conditions: Type 2 Diabetes Mellitus
Being tested: Glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2)
Keywords: Diabetes Mellitus, Glucagon, Insulin, Incretin hormones, Glucose-dependent insulinotropic polypeptide, Glucagon-like peptide-1, Glucagon-like peptide-2
Medical subject headings: Diabetes Mellitus, Type 2, Diabetes Mellitus, Insulin Resistance

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2)Biological
Also called Human GIP (glucose-dependent insulinotropic polypeptide), Human GLP-1 (glucagon-like peptide-1), Human GLP-2 (glucagon-like peptide-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.

Study groups in NCT00716170
Study group	Role	What they receive
A:		Patients with type 2 diabetes mellitus Receives: Biological: Glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2)

What is being measured

The primary outcome is the main question the study is designed to answer.

Plasma glucagon responses
Measured: 3 hours

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jul 2008Jul 2009

First posted16 Jul 2008 (estimated)
Study startJul 2008
Primary completionJul 2009
Study completionJul 2009

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (15)Papers the sponsor has linked to this study.
Other trials for Type 2 Diabetes MellitusStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Observational
Observational model: Case only
Time perspective: Cross-sectional
Enrolment: 10 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00716170
Sponsor's protocol ID: 1301831410
Status last verified: Apr 2009
First submitted: 10 Jul 2008
Last updated: 28 Nov 2013
Results posted: No
Data monitoring committee: Yes

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. doi: 10.2337/diacare.26.2007.s5. No abstract available.
PubMed 12502614
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. doi: 10.1056/NEJM198106183042504. No abstract available.
PubMed 7015132
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. doi: 10.1056/NEJM198106253042604. No abstract available.
PubMed 7015135
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. doi: 10.1210/jcem.85.11.6993.
PubMed 11095432
Knop FK, Vilsboll 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. doi: 10.1007/s00125-006-0566-z. Epub 2007 Jan 16.
PubMed 17225124
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. doi: 10.1210/jcem-63-2-492.
PubMed 3522621
Knop FK, Vilsboll T, Hojberg PV, Larsen S, Madsbad S, Volund 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. doi: 10.2337/db07-0100. Epub 2007 May 18.
PubMed 17513701
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. doi: 10.1007/BF00401145.
PubMed 8405741
Holst JJ. On the physiology of GIP and GLP-1. Horm Metab Res. 2004 Nov-Dec;36(11-12):747-54. doi: 10.1055/s-2004-826158.
PubMed 15655703
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. doi: 10.1007/s00125-003-1103-y. Epub 2003 May 23.
PubMed 12764578
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. doi: 10.1172/JCI116186.
PubMed 8423228
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. doi: 10.1007/s00125-002-0878-6. Epub 2002 Jul 4.
PubMed 12189441
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. doi: 10.1053/j.gastro.2005.10.004.
PubMed 16401467
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. doi: 10.1007/BF00291980.
PubMed 3905480
Sorensen 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. doi: 10.1038/sj.ijo.0802247.
PubMed 12664078

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 28 Nov 2013. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: The Role of GIP, GLP-1 and GLP-2 in Type 2 Diabetic Hyperglucagonemia
ClinicalTrials.gov ID: NCT00716170
Acronym / sponsor ID: 1301831410
Conditions: Type 2 Diabetes Mellitus
Keywords: Diabetes Mellitus, Glucagon, Insulin, Incretin hormones, Glucose-dependent insulinotropic polypeptide, Glucagon-like peptide-1, Glucagon-like peptide-2
Study type: Observational
Recruitment status: Completed
Enrolment: 10 participants (actual)
Lead sponsor: Herlev HospitalUniversity, hospital or other
Collaborators: University of Copenhagen, The Danish Medical Research Council, The Danish Diabetes Association
Study start: Jul 2008
Primary completion: Jul 2009 (actual)
Study completion: Jul 2009 (actual)
First posted: 16 Jul 2008 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Observational model: Case only
Time perspective: Cross-sectional
Number of arms: 1

Arm	Type	Receives
A:	–	Biological: Glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2)Patients with type 2 diabetes mellitus

Who may qualify

Ages: 35 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult
Study population: The patients will be recruted from the outpatient clinic of Department of Endocrinology, Herlev Hospital.

Key inclusion criteria (3 listed)

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

Key exclusion criteria (3 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2)Also: Human GIP (glucose-dependent insulinotropic polypeptide), Human GLP-1 (glucagon-like peptide-1), Human GLP-2 (glucagon-like peptide-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.	Biological	A:

Primary outcome

Plasma glucagon responses
Time frame: 3 hours

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 28 Nov 2013.
Background: PubMed 12502614Expert 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. doi: 10.2337/diacare.26.2007.s5. No abstract available.
Background: PubMed 7015132Unger 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. doi: 10.1056/NEJM198106183042504. No abstract available.
Background: PubMed 7015135Unger 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. doi: 10.1056/NEJM198106253042604. No abstract available.
Background: PubMed 11095432Shah 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. doi: 10.1210/jcem.85.11.6993.
Background: PubMed 17225124Knop FK, Vilsboll 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. doi: 10.1007/s00125-006-0566-z. Epub 2007 Jan 16.
Background: PubMed 3522621Nauck 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. doi: 10.1210/jcem-63-2-492.
Background: PubMed 17513701Knop FK, Vilsboll T, Hojberg PV, Larsen S, Madsbad S, Volund 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. doi: 10.2337/db07-0100. Epub 2007 May 18.
Background: PubMed 8405741Nauck 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. doi: 10.1007/BF00401145.
Background: PubMed 15655703Holst JJ. On the physiology of GIP and GLP-1. Horm Metab Res. 2004 Nov-Dec;36(11-12):747-54. doi: 10.1055/s-2004-826158.
Background: PubMed 12764578Meier 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. doi: 10.1007/s00125-003-1103-y. Epub 2003 May 23.
Background: PubMed 8423228Nauck 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. doi: 10.1172/JCI116186.
Background: PubMed 12189441Vilsboll 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. doi: 10.1007/s00125-002-0878-6. Epub 2002 Jul 4.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Tina Vilsbøll, MD DMSc study chair

Herlev Hospital

Filip K Knop, MD PhD study director

Gentofte Hospital

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

An observational study of Type 2 Diabetes Mellitus, run by Herlev Hospital at 1 site in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Nov 2013. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Plasma glucagon responses (time frame: 3 hours). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00716170, which also lists 15 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Nov 2013.