Regulation of Insulin Secretion by the GLP-1 Receptor
Condition: Insulin Secretion
Study type: Interventional
Phase: Phase 4

Summary: 
      AIM2: The purpose of Aim-2 of this study is to determine the role of basal GLP-1 action on
      the beta-cell response to insulin resistance. Healthy subjects will have fasting GLP-1 action
      determined with GLP-1r blockade before and after induction of experimental insulin
      resistance. The investigators hypothesize that fasting GLP-1 action will increase to
      compensate for experimental insulin resistance.

      AIM3: The purpose of Aim-3 of this study is to determine the role of basal GLP-1 action on
      fasting glucose regulation in lean, obese, pre-diabetic and type 2 diabetic (T2DM) subjects.
      A cross sectional study of age-matched subjects across the spectrum of glucose tolerance will
      be used to test the hypothesis that fasting GLP-1 action increases as beta-cell function
      declines.
    

Detailed description: 
      AIM2: The purpose of this study is to determine the role of basal GLP-1 action on the
      beta-cell response to insulin resistance. Healthy subjects will have fasting GLP-1 action
      determined with GLP-1r blockade before and after induction of experimental insulin
      resistance. The investigators hypothesize that fasting GLP-1 action will increase to
      compensate for experimental insulin resistance.

      The study will enroll up to 20-25 healthy participants and while it is anticipated that the
      screening blood draw will yield a number of screen failures, it is estimated that 10-15
      subjects will complete the entire study protocol. Enrolled participants will be asked to
      complete three study visits including the consent visit and two infusion study visits that
      will include hyperglycemic clamp procedures with the addition of the GLP-1 receptor
      antagonist Exendin (9-39) to determine the fasting GLP-1 effect. Each infusion procedure will
      last 2 hours. Subjects will be asked to take dexamethasone daily for approximately one week
      between Visit-2 and Visit-3 to induce insulin resistance.

      The investigators will enroll 6-10 additional subjects as controls for effects of time and
      repeat testing. These individuals will have identical clamps with no dexamethasone at
      approximately 1 week intervals and will be determined at random by study staff.

      The primary outcome for visits 2-3 will be to measure the effects of Ex-9 on fasting
      glucose-stimulated insulin secretion before and after experimentally induced insulin
      resistance. The primary experimental variable for analysis will be C-peptide during the
      clamp. Mean values will be compared between the period of glucose only stimulation and
      glucose with Ex-9. For each subject in the active treatment arm data will be analyzed using
      2-way ANOVA for repeated measures using time (0-60 vs 60-120 min) and treatment (Dex vs no
      Dex) as the two factors. Based on the investigators' previous studies the investigators
      expect a significant time effect due to Ex-9. If there is an interaction with treatment the
      investigators would conclude that experimental insulin resistance influences the fasting
      GLP-1 effect. Data from control subjects will be analyzed identically; here the investigators
      expect no interaction, indicating that the fasting GLP-1 is a stable measure. In the
      investigators' previous study using Ex-9 during a glucose clamp, the average coefficient of
      variation in insulin concentrations at the conclusion of each step in the ramp was 30%. Using
      this estimate of between subject variation, detecting a 20% difference between subsequent
      steps in the GLP-1 ramp with a power of 80% and significance level of 0.05 will require 8
      subjects.

      AIM3: The purpose of Aim-3 of this study is to determine the role of basal GLP-1 action on
      fasting glucose regulation in lean, obese, pre-diabetic and type 2 diabetic (T2DM) subjects.
      Approximately 15-20 subjects will complete this cross sectional study of age-matched subjects
      across the spectrum of glucose tolerance will be used to test the hypothesis that fasting
      GLP-1 action increases as beta-cell function declines.

      Enrolled participants for Aim-3 will be asked to complete two study visits including the
      consent visit and one infusion visit that will include a hyperglycemic clamp and an infusion
      of the antagonist Exendin (9-39). The infusion procedure will last approximately 2 hours.

      The primary outcome measure for Aim-3 will be the fasting GLP-1 effect. This will be defined
      as the difference in steady state glucose-stimulated insulin secretion with and without Ex-9.
      The difference will be expressed as a percentage of glucose stimulated insulin secretion
      without Ex-9, and serve as the primary variable for comparison among the lean, obese and
      diabetic cohorts.
    

Intervention name(s): Exendin (9-39); Dexamethasone; Hyperglycemic Clamp
Intervention type(s): Drug; Drug; Other
Intervention description(s): Upon establishing a hyperglycemic clamp (target blood glucose at basal +3 mM) Exendin (9-39) will be infused.; Between Visit-2 and Visit-3, Dexamethasone (4 mg tablet) once daily for 5-7 days.; A variable infusion of 20% dextrose will begin to clamp the blood glucose at basal +3 mM.
Other intervention name(s): GLP-1 receptor antagonist
Intervention MeSH terms: Dexamethasone
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Incretins; GLP-1; Exendin-9; Insulin Resistance; Diabetes; Pre-diabetes