Clinical trial NCT00469833: Insulin Secretion in Diabetes Before and After Glycemic Control
Official title: Pathogenesis of the Impaired Incretin Effect in Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes
Hyperglycemia
Keywords: Diabetes
Glucose Tolerance
Incretin
Insulin
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2007-05-07
Enrollment: 17
Sex: ALL
Minimum age (years): 30
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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 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.

Primary outcomes:
measure: ISR in Response to a Glucose Clamp and Oral Glucose Ingestion Before and After 2 Months of Insulin Treatment to Improve Average Glycemia.
timeFrame: 180 minutes
measure: 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.
timeFrame: 180 minutes
measure: Insulin Concentration in Response to a Glucose Clamp and Oral Glucose Ingestion Before and After 2 Months of Insulin Treatment to Improve Average Glycemia.
timeFrame: 180 minutes
Secondary outcomes:
measure: HbA1c Before and After 2 Months of Insulin Treatment to Improve Average Glycemia.
timeFrame: 2 months
Other outcomes:
Locations:
city: Cincinnati
country: United States
facility: VA Medical Center, Cincinnati
state: Ohio
Study officials:
affiliation: Cincinnati VA Medical Center
name: David D'Alessio, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: An Z, Prigeon RL, D'Alessio DA. Improved glycemic control enhances the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab. 2013 Dec;98(12):4702-8. doi: 10.1210/jc.2013-1199. Epub 2013 Oct 3.