NCT07224334 · David D'Alessio, M.D.
Role of Alpha-to-beta Cell Communication to Adapt Insulin Secretion to Insulin Resistance.
(UPGRADE)
What this study is about
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.
View original scientific description
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.
Interventions
DRUG
Exendin-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.
DRUG
Dexamethasone
Dexamethasone 6 mg daily
Primary outcome measures
Insulin secretion
Time frame: 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
Time frame: 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.
Who can participate
This study lists these criteria on ClinicalTrials.gov. A study coordinator reviews eligibility during screening — this page does not determine whether you qualify.
Inclusion criteria
- 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:
- Body Mass Index (BMI) ≥ 27.0
- Fasting plasma glucose of \< 126 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)
- AST and/or ALT levels \> 3x the upper limit of the normal range
- 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
Where
- Durham, North Carolina
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Frequently asked questions
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Data: ClinicalTrials.gov · synced Feb 5, 2026 · Source of record for eligibility and locations