Insulin Secretion in Diabetes Before and After Glycemic Control

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT00469833
First received: May 4, 2007
Last updated: January 6, 2015
Last verified: January 2015
  Purpose

The objective of this project is to understand defects in insulin secretion that contribute to abnormal glucose metabolism in patients with diabetes. In particular the effects of signals released from the intestine to stimulate insulin secretion will be tested. Patients with type 2 diabetes will have insulin secretion in response to glucose and intestinal factors before and after insulin treatment to lower their blood glucose. It is expected that the results of this work will provide valuable information for treating diabetic people.


Condition Intervention
Diabetes
Hyperglycemia
Drug: insulin glargine

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pathogenesis of the Impaired Incretin Effect in Type 2 Diabetes

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • ISR in Response to a Glucose Clamp and Oral Glucose Ingestion Before and After 2 Months of Insulin Treatment to Improve Average Glycemia. [ Time Frame: 180 minutes ] [ Designated as safety issue: No ]
    Subjects had glucose clamps for 270 minutes with serial sampling of blood for measurement of insulin and C-peptide. At 90 minutes into the clamp they consumed 75 g of oral glucose solution. Meal-stimulated insulin secretion was summarized as the mean plasma C-peptide from 90-270 minutes. This outcome measure was compared for each subject before treatment and after 2 months of insulin treatment to lower blood glucose. Subjects were started on 20 units of insulin glargine after their first visit and asked to measure their morning blood glucose daily. The dose of insulin was increased in increments of 4-6 units every 3 days targeting an average morning glucose level of less then 120 mg/dl. After 2 months of treatment the primary outcome was repeated with a second glucose clamp / oral glucose tolerance test, identical to the first.

  • C-peptide Concentration in Response to a Glucose Clamp and Oral Glucose Ingestion Before and After 2 Months of Insulin Treatment to Improve Average Glycemia. [ Time Frame: 180 minutes ] [ Designated as safety issue: No ]
    Subjects had glucose clamps for 270 minutes with serial sampling of blood for measurement of insulin and C-peptide. At 90 minutes into the clamp they consumed 75 g of oral glucose solution. Meal-stimulated insulin secretion was summarized as the mean plasma C-peptide from 90-270 minutes. This outcome measure was compared for each subject before treatment and after 2 months of insulin treatment to lower blood glucose. Subjects were started on 20 units of insulin glargine after their first visit and asked to measure their morning blood glucose daily. The dose of insulin was increased in increments of 4-6 units every 3 days targeting an average morning glucose level of less then 120 mg/dl. After 2 months of treatment the primary outcome was repeated with a second glucose clamp / oral glucose tolerance test, identical to the first.

  • Insulin Concentration in Response to a Glucose Clamp and Oral Glucose Ingestion Before and After 2 Months of Insulin Treatment to Improve Average Glycemia. [ Time Frame: 180 minutes ] [ Designated as safety issue: No ]
    Subjects had glucose clamps for 270 minutes with serial sampling of blood for measurement of insulin and C-peptide. At 90 minutes into the clamp they consumed 75 g of oral glucose solution. Meal-stimulated insulin secretion was summarized as the mean plasma C-peptide from 90-270 minutes. This outcome measure was compared for each subject before treatment and after 2 months of insulin treatment to lower blood glucose. Subjects were started on 20 units of insulin glargine after their first visit and asked to measure their morning blood glucose daily. The dose of insulin was increased in increments of 4-6 units every 3 days targeting an average morning glucose level of less then 120 mg/dl. After 2 months of treatment the primary outcome was repeated with a second glucose clamp / oral glucose tolerance test, identical to the first.


Secondary Outcome Measures:
  • HbA1c Before and After 2 Months of Insulin Treatment to Improve Average Glycemia. [ Time Frame: 2 months ] [ Designated as safety issue: No ]
    Type 2 diabetic subjects had HbA1c measured before and after 2 months of basal insulin glargine treatment.


Enrollment: 17
Study Start Date: April 2008
Study Completion Date: September 2012
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
Intervention: Insulin glargine treatment. The study is designed as a within subjects comparison of insulin secretion in type 2 diabetic patients before and after 2 months of insulin treatment to reduce blood glucose. Insulin secretion will be determined with a hyperglycemic clamp using 20% dextrose, and ingestion of an oral glucose solution (75 g).
Drug: insulin glargine
Diabetic subjects will be treated with insulin glargine once daily for 2 months. Subjects will monitor their blood glucose and have their insulin dose adjusted in steps of 4-6 units to achieve a goal of less than or equal to 120 mg/dl for fasting blood glucose.
Other Names:
  • Basal insulin
  • Long-acting insulin
  • Lantus

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 beta-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 determine the role of hyperglycemia to impair the incretin effect. 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 beta-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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Locations
United States, Ohio
VA Medical Center, Cincinnati
Cincinnati, Ohio, United States, 45220
Sponsors and Collaborators
Investigators
Principal Investigator: David D'Alessio, MD Cincinnati VA Medical Center
  More Information

Publications:
Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT00469833     History of Changes
Other Study ID Numbers: ENDA-010-06S
Study First Received: May 4, 2007
Results First Received: October 17, 2013
Last Updated: January 6, 2015
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by Department of Veterans Affairs:
Diabetes
Glucose Tolerance
Incretin
Insulin

Additional relevant MeSH terms:
Hyperglycemia
Glucose Metabolism Disorders
Metabolic Diseases
Glargine
Insulin
Insulin, Globin Zinc
Hypoglycemic Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 30, 2015