Clinical trial NCT05499702: The Effects of Glucagon on Hepatic Metabolism in People With Type 2 Diabetes After Caloric Restriction
Official title: The Effects of Glucagon on Hepatic Metabolism in People With Type 2 Diabetes After Caloric Restriction
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Type2diabetes
Keywords: glucagon
insulin resistance
caloric restriction
hepatic steatosis
amino acid metabolism
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
First posted: 2022-08-12
Enrollment: 20
Sex: ALL
Minimum age (years): 25
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: caloric restriction for six weeks
Primary purpose: BASIC_SCIENCE

Brief summary: Caloric restriction (and RYGB) improves insulin action and lowers fasting glucose, glucagon and EGP, without changes in postprandial EGP and glucagon concentrations. Caloric restriction also improves hepatic steatosis and lowers fasting AA. These changes may represent restoration of glucagon's hepatic actions. This experiment will determine whether caloric restriction improves glucagon's actions on hepatic amino acid, carbohydrate and lipid metabolism in T2DM in comparison to a baseline experiment performed separately in people with T2DM.

Detailed description: T2DM and prediabetes are characterized by abnormal post-prandial suppression of glucagon, which contributes to postprandial hyperglycemia by increasing EGP. Although these effects are magnified by decreased and delayed insulin secretion, they are also apparent when insulin secretion is intact5. 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? Could altered glucagon signaling precipitate a vicious cycle resulting in T2DM?

This study will determine how caloric restriction alters hepatic glucagon action. Elevated fasting AA concentrations are associated with T2DM risk. In addition, hepatic steatosis has been associated with an impaired ability of glucagon to stimulate hepatic clearance of AAs. Prior studies have shown that caloric restriction lowers fasting glucose, EGP and glucagon. However, the effects on these parameters in the postprandial period are unclear. This experiment will examine to what degree the improvements produced by caloric restriction can be explained by improved hepatic glucagon action. Because caloric restriction decreases hepatic fat content the experiment will also determine if a reduction in hepatic fat content is associated with changes in glucagon's effects on hepatic AA, glucose, and lipid metabolism.

Eligibility criteria: Inclusion Criteria:

* We will recruit up to 20 weight-stable, subjects with type 2 diabetes
* BMI ≥ 28 Kg/M2
* Diabetes is managed by diet alone or a combination of oral agents

Exclusion Criteria:

* History of prior upper abdominal surgery e.g. gastric banding, pyloroplasty, 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.

Primary outcomes:
measure: Rate of leucine oxidation in response to rising glucagon concentrations
timeFrame: 240 minutes of study
Secondary outcomes:
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Adrian Vella
role: PRINCIPAL_INVESTIGATOR
References: