Insulin Secretion in Diabetes - Full Text View

Sponsored by:	Department of Veterans Affairs
Information provided by:	Department of Veterans Affairs
ClinicalTrials.gov Identifier:	NCT00469833

Purpose

The objective of this project is to understand defects in insulin secretion that contribute to abnormal glucose metabolism in patients with diabetes.

Condition	Intervention
Diabetes Hyperglycemia	Drug: Exendin-(9-39); 0.9% Saline; 20% Dextrose; Carnation Instant Breakfast; 95% Orleate Drug: Exendin-(9-39); 20% Dextrose; 75g oral glucose; 0.9% Saline Drug: Insulin Glargine; 20% Dextrose; 75g oral glucose; 0.9% Saline

MedlinePlus related topics: Diabetes

Drug Information available for: Insulin Dextrose Exendin (9-39) Insulin glargine

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Basic Science, Non-Randomized, Open Label, Placebo Control, Crossover Assignment, Pharmacodynamics Study
Official Title:	Pathogenesis of the Impaired Incretin Effect in Type 2 Diabetes

Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:

1)the role of reduced GIP & GLP-1 levels in mediating postprandial insulin secretion in diabetic subjects; 2)the role of endogenous GLP-1 to stimulate insulin secretion in diabetic subjects; 3)the role of hyperglycemia to impair the incretin effect [ Time Frame: 8-10 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment:	20
Study Start Date:	April 2008
Estimated Study Completion Date:	April 2013
Estimated Primary Completion Date:	April 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1 Within subjects comparison; before and after treatment.	Drug: Exendin-(9-39); 0.9% Saline; 20% Dextrose; Carnation Instant Breakfast; 95% Orleate 20% dextrose will be infused to achieve a hyperglycemic clamp. Subjects will ingest instant breakfast in skim milk during the clamp. The clamp will be performed on 2 occasions, once with and once without an infusion of Exendin-(9-39). Drug: Exendin-(9-39); 20% Dextrose; 75g oral glucose; 0.9% Saline 20% dextrose will be infused to achieve a hyperglycemic clamp. Subjects will ingest oral glucose solution during the clamp. The clamp will be performed on 2 occasions, once with and once without an infusion of Exendin-(9-39). Drug: Insulin Glargine; 20% Dextrose; 75g oral glucose; 0.9% Saline 20% dextrose will be infused to achieve a hyperglycemic clamp. Subjects will ingest oral glucose solution during the clamp. The clamp will be performed on 2 occasions, once at baseline and once after 2 months of treatment with nightly insulin glargine, titrated to reduce fasting glucose levels.

Arms

Assigned Interventions

1

Within subjects comparison; before and after treatment.

Drug: Exendin-(9-39); 0.9% Saline; 20% Dextrose; Carnation Instant Breakfast; 95% Orleate

20% dextrose will be infused to achieve a hyperglycemic clamp. Subjects will ingest instant breakfast in skim milk during the clamp. The clamp will be performed on 2 occasions, once with and once without an infusion of Exendin-(9-39).

Drug: Exendin-(9-39); 20% Dextrose; 75g oral glucose; 0.9% Saline

20% dextrose will be infused to achieve a hyperglycemic clamp. Subjects will ingest oral glucose solution during the clamp. The clamp will be performed on 2 occasions, once with and once without an infusion of Exendin-(9-39).

Drug: Insulin Glargine; 20% Dextrose; 75g oral glucose; 0.9% Saline

20% dextrose will be infused to achieve a hyperglycemic clamp. Subjects will ingest oral glucose solution during the clamp. The clamp will be performed on 2 occasions, once at baseline and once after 2 months of treatment with nightly insulin glargine, titrated to reduce fasting glucose levels.

Detailed Description:

The objective of this project is to understand defects in insulin secretion that contribute to abnormal glucose metabolism in patients with diabetes.

Diabetes is a major problem for patients receiving care at VA medical centers among whom 20% are affected. Specifically, this project will seek to determine the mechanism(s) by which the incretin effect is impaired in diabetic patients. The incretin effect refers to the action of GI hormones and neural stimuli to increase insulin secretion after food intake, and accounts for approximately 50% of postprandial insulin secretion in nondiabetic humans. There are several studies indicating that this response is severely impaired in patients with type 2 diabetes. The mechanism(s) by which this occurs has not been explained. There is some evidence to suggest that secretion of the important incretins, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), may be impaired in diabetic individuals. There is also some data to suggest that the -cells in persons with diabetes are insensitive to the incretins. The problem with the current state of knowledge in this area is that previous work has involved small numbers of diabetic subjects, and did not directly test mechanisms by which the incretin effect is altered in diabetes.

In this project we will: 1) determine the role of reduced GIP and GLP-1 levels in mediating postprandial insulin secretion in diabetic subjects. Subjects with type 2 diabetes and nondiabetic controls will have the incretin effect measured on separate occasions using test meals that cause different levels of circulating incretins. This will allow the role of reduced incretin levels in diabetes to be assessed; 2) determine the role of endogenous GLP-1 to stimulate insulin secretion in diabetic subjects. Subjects with type 2 diabetes and nondiabetic controls will have the incretin effect measured on two occasions, with and without infusion of a GLP-1 receptor antagonist. This study will compare the role of GLP-1 signaling to stimulate postprandial insulin secretion in diabetic and nondiabetic humans; 3) determine the role of hyperglycemia to impair the incretin effect. Groups of type 2 diabetic subjects will have the incretin effect measured before and after intensified diabetes treatment. This study will test the effect of chronic hyperglycemia on incretin mediated insulin secretion. In all studies, the incretin effect will be measured before and after these interventions using studies with a within subjects design. A combined glucose clamp/meal tolerance test protocol will be used to quantify the incretin effect.

These studies will allow the role of incretin secretion, incretin action, and overall metabolic milieu, on postprandial insulin secretion to be defined.

The results of these studies will add important new information for understanding abnormal -cell function in diabetes. By identifying the sites where the incretin effect is impaired this project will provide the basis for new approaches to treat diabetic patients. This is especially relevant with the recent availability of new medications that target the incretin pathways to lower blood glucose.

The blood samples will be drawn and processed in the GCRC. The samples will be frozen and stored in Building 15, Room 401. Samples will be shipped to the Genome Research Institute by staff trained in IATA shipping procedures.

Eligibility

Ages Eligible for Study:	30 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Aim 1:
- (non-diabetics)
  - male/female 30-65 yrs old,
  - free of active medical disease,
  - no history of diabetes.
- (diabetics)
  - HbA1c=6.5-8.5,
  - treated with metformin, a sulfonylurea, or combination,
  - Stable body wt with BMI 28-40.
Aim 2: Same as above
Aim 3: Diabetic with HgA1c 8.0-9.5

Exclusion Criteria:

Aim 1: For both groups: no history of: pancreatitis, cardiac, gastrointestinal, renal or liver disease.
Aim 2: Same as above
Aim 3: Same as above, plus a diagnosis of incipient diabetic nephropathy severe nonproliferative, or proliferative retinopathy.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00469833

Contacts

Contact: Colleen Rogge, RN

(513) 475-6478

MaryColleen.Rogge@va.gov

Locations

United States, Ohio
VA Medical Center, Cincinnati	Recruiting
Cincinnati, Ohio, United States, 45220
Contact: Colleen Rogge, RN 513-475-6478 MaryColleen.Rogge@va.gov
Principal Investigator: David D'Alessio, MD

Sponsors and Collaborators

Department of Veterans Affairs

Investigators

Principal Investigator:

David D'Alessio, MD

Cincinnati VA Medical Center

More Information

Publications:

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.

Schirra J, Sturm K, Leicht P, Arnold R, Goke B, Katschinski M. Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. J Clin Invest. 1998 Apr 1;101(7):1421-30.

Henchoz E, D'Alessio DA, Gillet M, Halkic N, Matzinger O, Goy JJ, Chiolero R, Tappy L, Schneiter P. Impaired insulin response after oral but not intravenous glucose in heart- and liver-transplant recipients. Transplantation. 2003 Sep 27;76(6):923-9.

Creutzfeldt W, Nauck M. Gut hormones and diabetes mellitus. Diabetes Metab Rev. 1992 Jul;8(2):149-77. Review. No abstract available.

Schirra J, Nicolaus M, Roggel R, Katschinski M, Storr M, Woerle HJ, Goke B. Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut. 2006 Feb;55(2):243-51. Epub 2005 Jun 28.

D'Alessio DA, Vahl TP. Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes. Am J Physiol Endocrinol Metab. 2004 Jun;286(6):E882-90. Review.

Responsible Party:	Department of Veterans Affairs ( D'Alessio, David - Principal Investigator )
Study ID Numbers:	ENDA-010-06S
Study First Received:	May 4, 2007
Last Updated:	March 30, 2009
ClinicalTrials.gov Identifier:	NCT00469833 History of Changes
Health Authority:	United States: Federal Government; United States: Food and Drug Administration

Keywords provided by Department of Veterans Affairs:

Diabetes
Glucose Tolerance
Incretin
Insulin

Study placed in the following topic categories:

Hypoglycemic Agents
Metabolic Diseases
Hyperglycemia
Diabetes Mellitus, Type 2
Incretins
Glargine

Diabetes Mellitus
Endocrine System Diseases
Endocrinopathy
Glucose Metabolism Disorders
Metabolic Disorder
Insulin

Additional relevant MeSH terms:

Hypoglycemic Agents
Metabolic Diseases
Hyperglycemia
Physiological Effects of Drugs
Glargine

Diabetes Mellitus
Endocrine System Diseases
Glucose Metabolism Disorders
Pharmacologic Actions
Insulin

ClinicalTrials.gov processed this record on May 06, 2009