Diabetes (DM)
Conditions
Keywords
insulin secretion, insulin sensitivity, GLP-1, alpha- to beta-cell communication
Brief summary
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.
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 4.5-hour 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.
Interventions
DRUGExendin-9 is a 30 amino acid peptide that is an established competitive antagonist of the GLP-1 receptor. Subjects will receive exendin-9 by intravenous infusion at a rate of 600 pmol/kg/min
Subjects in Aim 2A will receive exendin-9 on both experimental days and dexamethasone for one week before their second experimental day. Subjects in Aim 2B will receive exendin-9 on one of their two experimental days.
DRUGDexamethasone
Dexamethasone 6 mg daily
Sponsors
David D'Alessio, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Intervention model description
Each subject will have paired, single day experiments performed within 4-5 weeks.
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
Aim 2A: 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 * Poor vein access * 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 * Fasting plasma glucose of \< 126 mg/dL or HbA1c value \< 6.5% as measured at screening visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin secretion | Insulin secretion rates will be measured on both days of study in subjects participating in Aims 2A and 2B. Studies will be completed over a period of 4-5 weeks | Insulin secretion rates will be computed from deconvolution of C-peptide concentrations measured from plasma samples taken during the hyperglycemic clamps. |
| Insulin secretion with and without exendin-9: Aims 2A and 2B | 4-5 weeks | Insulin secretion rates derived from deconvolution of C-peptide will be the primary outcome for insulin secretion. This measure will be compared within subjects in Aim 2A with the difference between the saline and exendin-9 clamps on each day used as the measure of fasting GLP-1 receptor mediated insulin secretion. Comparison of GLP-1 receptor mediated insulin secretion between the placebo and dexamethasone studies will be used to determine the effect of insulin resistance. Insulin secretion rates will also be compared within subjects in Aim 2B. Here the two different study days, one with saline and one with exendin-9 will be used. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin sensitivity: Aim 2B | Insulin sensitivity will be measured in subjects participating in Aim 2B during the hyperinsulinemic clamp in each of the two days of study. The two experiments will be completed in a 4-5 week period. | Insulin sensitivity will be measured directly in subjects in Aim 2B during the hyperinsulinemic, euglycemic clamp. The glucose infusion rate necessary to maintain blood glucose a 4-5 mM divided by steady-state plasma insulin will be used as the index of insulin sensitivity. |
Countries
United States
Contacts
CONTACTJohanna Johnson, MS
CONTACTAlyssa Sudnick, MS
PRINCIPAL_INVESTIGATORDavid D'Alessio, MD
Duke University
Outcome results
None listed