Clinical trial NCT05264727: Glucagon Suppression by Hyperglycemia in the Presence and Absence of Amino Acid Infusion
Official title: Glucagon Suppression by Hyperglycemia in the Presence and Absence of Amino Acid Infusion
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Healthy
Type 2 Diabetes
Obesity
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2022-03-03
Enrollment: 60
Sex: ALL
Minimum age (years): 25
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: This study is being done to better understand how amino acids alter the release of glucagon and insulin compared to glucose alone in health and disease.

Detailed description: T2DM and prediabetes are characterized by abnormal post-prandial suppression of glucagon, which contributes to postprandial hyperglycemia by increasing endogenous glucose production (EGP). In rodents, altered glucagon signaling changes α-cell function and mass - an effect mediated by changes in circulating AA concentrations. Are the elevated concentrations of branched-chain AA and other AA metabolites in T2DM a cause or an effect of global α-cell dysfunction? To measure glucagon secretion, as well as glucagon action, we have developed a population model of glucagon kinetics allowing us to deconvolve secretion from glucagon concentrations in a manner similar to Van Cauter's model for insulin secretion from C-peptide. This enables better characterization of α-cell function in humans. In addition to our novel methodology, we can characterize α-cell responsiveness to a graded glucose infusion, by quantifying (G50) - the change in glucose concentration necessary to suppress glucagon secretion by 50%. These experiments will determine if the glucagon secretion in response to AA differs in obese individuals with T2DM from that observed in obese individuals without T2DM.

Eligibility criteria: Inclusion Criteria - Obese Subjects with Type 2 Diabetes:

* HbA1c ≤ 8.5% (type 2 diabetic subjects).
* HbA1c ≤ 6.5% (obese and lean subjects).
* BMI ≥ 28 Kg/M\^2 (Obese subjects with and without type 2 diabetes).
* BMI ≤ 25 Kg/M\^2 (Lean subjects without type 2 diabetes).
* Use of sulfonylureas or metformin only (type 2 diabetec subjects).
* For female subjects: negative pregnancy test at the time of enrollment or study.
* No history of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
* No active systemic illness or malignancy.
* No symptomatic macrovascular or microvascular disease.
* No contraindications to MRI (e.g., metal implants, claustrophobia).
* Hematocrit \> 35%.
* TSH \> 0.4 or \< 5.5.
* Consumption of \< 2 alcohol drinks per day or \< 14 per week or a negative AUDIT questionnaire.

Exclusion Criteria - Obese Subjects with Type 2 Diabetes:

* HbA1c ³ 8.5%
* BMI ≤ 28 Kg/M2
* Use of insulin or agents other than sulfonylureas or metformin.
* For female subjects: positive pregnancy test at the time of enrollment or study
* History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
* Active systemic illness or malignancy.
* Symptomatic macrovascular or microvascular disease.
* Contraindications to MRI (e.g., metal implants, claustrophobia).
* Hematocrit \< 35%
* TSH \< 0.4 or \> 5.5.
* Consumption of \> 2 alcohol drinks per day or \> 14 per week or a positive AUDIT questionnaire.

Inclusion Criteria - Obese Subjects without Type 2 Diabetes:

* BMI ≥ 28 Kg/M2.
* \> 5% liver fat content, as determined by MRI using the proton density fat fraction (PDFF) technique.

Exclusion Criteria - Obese Subjects without Type 2 Diabetes:

* HbA1c ≥ 6.5%
* BMI ≤ 28 Kg/M2
* Use of any glucose-lowering agents including metformin or sulfonylureas.
* For female subjects: positive pregnancy test at the time of enrollment or study
* History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
* Active systemic illness or malignancy.
* Symptomatic macrovascular or microvascular disease.
* Contraindications to MRI (e.g., metal implants, claustrophobia).
* Hematocrit \< 35%
* TSH \< 0.4 or \> 5.5.
* Consumption of \> 2 alcohol drinks per day or \> 14 per week or a positive AUDIT questionnaire.

Inclusion Criteria - Lean subjects without Diabetes:

- BMI ≤ 25 Kg/M\^2).

Exclusion Criteria - Lean Subjects without Diabetes:

* HbA1c ≥ 6.5%.
* BMI ≥ 25 Kg/M\^2.
* Use of any glucose-lowering agents including metformin or sulfonylureas.
* For female subjects: positive pregnancy test at the time of enrollment or study.
* History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
* Active systemic illness or malignancy.
* Symptomatic macrovascular or microvascular disease.
* Contraindications to MRI (e.g., metal implants, claustrophobia).
* Hematocrit \< 35%.
* TSH \< 0.4 or \> 5.5.
* Consumption of \> 2 alcohol drinks per day or \> 14 per week or a positive AUDIT questionnaire.
* Liver fat content ≥ 5% as determined by MRI using the proton density fat fraction (PDFF) technique.

Primary outcomes:
measure: Change in Glucagon Suppression (G50) caused by amino acids vs. saline
timeFrame: 240 minutes of study
Secondary outcomes:
measure: Glucagon suppression (G50) is greater in people with T2DM
timeFrame: 240 minutes of study
measure: glucagon suppression (G50) is greater in obese compared to lean people without T2DM
timeFrame: 240 minutes of study
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Adrian Vella, MD
role: PRINCIPAL_INVESTIGATOR
References: