Overview
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.
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.
Eligibility
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
- 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