Role of Alpha-to-beta Cell Communication to Adapt Insulin Secretion to Insulin Resistance.
Purpose
Glucagon secretion from α-cells has long been viewed as primarily a counterregulatory mechanism - e.g. an agent with a role to prevent blood sugar from decreasing to levels that compromise function. Our group, along with other researchers, have begun to identify a much more complex role for α-cells, raising questions about when and how glucagon may influence blood glucose levels. This proposal looks to detail proglucagon peptide secretion from α-cells and the impact this has on β-cell function and glucose tolerance, in preclinical studies of human islets and translational studies in human subjects. This protocol registration describes Aim 2 from this NIH grant which involves 2 study populations and separate protocols but addresses a common question. Aim 3 in the grant is focused on a separate hypothesis and will be conducted and published separately from Aim 2.
Condition
- Diabetes (DM)
Eligibility
- Eligible Ages
- Between 18 Years and 60 Years
- Eligible Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- age 18-45 - Body Mass Index (BMI) < 27.0 - Fasting plasma glucose of ≤ 95 mg/dL or HbA1c value ≤ 5.8% as measured at screening visit
Exclusion Criteria
- Active medical disease: e.g. active infectious, inflammatory, neurodegenerative or mental health disorders - Personal history of diabetes or pancreatitis - Personal history of cardiac, gastrointestinal, renal or liver disease - Immediate family history of diabetes - Renal insufficiency (eGFR < 60 mL/kg/min) - Anemia (hematocrit < 34%) as measured at screening visit - Pregnant females - Consumption of daily medications that alter glucose metabolism of GI function (glucocorticoids, psychotropics, narcotics, metoclopramide) - Apparent sensitivity to the study peptide as determined by the skin test Aim 2B: Inclusion Criteria: - Age 35-60 - Body Mass Index (BMI) 27.0-35 - Fasting plasma glucose of < 125 mg/dL or HbA1c value < 6.5% as measured at screening visit Exclusion Criteria: - Active medical disease: e.g. active infectious, inflammatory, neurodegenerative or mental health disorders - Personal history of diabetes or pancreatitis - Personal history of cardiac, gastrointestinal, renal or liver disease - Immediate family history of diabetes - Renal insufficiency (eGFR < 60 mL/kg/min) - Anemia (hematocrit < 34%) as measured at screening visit - Pregnant females - Consumption of daily medications that alter glucose metabolism of GI function (glucocorticoids, psychotropics, narcotics, metoclopramide) - Apparent sensitivity to the study peptide as determined by the skin test
Study Design
- Phase
- Phase 1
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover Assignment
- Intervention Model Description
- Each subject will have paired, single day experiments performed within 4-5 weeks.
- Primary Purpose
- Basic Science
- Masking
- Single (Participant)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Placebo Comparator Aim 2A: Glucose-stimulated insulin secretion with and without GLP-1 receptor blockade |
Aim 2A: Each subject will have a 5 hr experiment with sequential hyperglycemic clamps separated by a 90-minute washout. Blood glucose will be increased with an intravenous (IV) infusion of 20% dextrose and maintained stable at a level of 2.5-3.0 mM above fasting glucose for 90 minutes. Following the washout, a second, identical hyperglycemic clamp will be performed. Subjects will receive either saline or exendin-9 (600 pmol/kg/min) during the clamps; in 10 subjects the saline/clamp will be first and in 10 subjects the exendin-9/clamp will be first; the orders will be assigned randomly. Intervention: The interventions here are the experimental hyperglycemia with and without exendin-9 |
|
|
Active Comparator Glucose stimulated insulin secretion with or without GLP-1 receptor blockade and insulin resistance |
Aim 2A: Subjects will be treated with 6 mg dexamethasone once daily for 7 days to induce insulin resistance before repeating the 5 hr glucose clamp study. The infusion of glucose with saline and exendin-9 will be performed identically to the first study. Intervention: The intervention in this arm is the induction of insulin resistance with dexamethasone treatment. |
|
|
Placebo Comparator Aim 2B: Glucose stimulated insulin secretion and insulin sensitivity |
Aim 2B: Each subject will have a 3-hour experiment with a 90-minute hyperglycemic clamp at a level of 2.5-3.0 mM above fasting glucose followed by a 60 minute hyperinsulinemic (80 units/meter2 Body Surface Area/minute), euglycemic clamp. |
|
|
Active Comparator Aim 2B: Glucose stimulated insulin secretion with GLP-1 receptor blockade and insulin sensitivity |
Aim 2B: Subjects will have an identical hyperglycemic clamp but with infusion of exendin-9 (600 pmol/kg/min). Exendin-9 infusion will be stopped before the following hyperinsulinemic clamp that will be conducted identically to the control arm. Allocation of subjects in Aim 2B to the study with and without exendin-9 will be randomized. Intervention: The intervention in this study is the administration of exendin-9 during experimental hyperglycemia. |
|
Recruiting Locations
Durham 4464368, North Carolina 4482348 27705
More Details
- Status
- Recruiting
- Sponsor
- David D'Alessio, M.D.
Detailed Description
Subjects will undergo screening for medical history, medication usage, and blood work; those who qualify will be offered participation. Study participation will last approximately 4-5 weeks depending on appointment availability. Aim 2A: Each participant will have two 5-hour hyperglycemic clamp procedures to test the effect of fasting glucagon-like peptide 1 (GLP-1) action before and after experimental insulin resistance. The effect of endogenous proglucagon peptides (glucagon and GLP-1) to stimulate insulin secretion will be determined by blockade of the GLP-1 receptor with the antagonist exendin-9 (Ex-9) during glucose infusions. Insulin secretion experiments will be repeated before and after induction of insulin resistance. To induce insulin resistance, subjects will take dexamethasone, a synthetic glucocorticoid that has been shown in published studies and in a pilot study by our group to reduce insulin sensitivity by ~30%. Aim 2B: This study will recruit non-diabetic subjects with obesity. They will be studied on two occasions using a 3 hr procedure with a hyperglycemic clamp to measure insulin secretion, followed by a hyperinsulinemic, euglycemic clamp to measure insulin sensitivity. This procedure will be done 2 times, once with saline infused during hyperglycemia as a control, and once with exendin-9 given during hyperglycemia to determine the role of GLP-1 receptor action.