The Effects of Glucagon on Hepatic Metabolism

Study Overview
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Brief Summary
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Whether impaired postprandial glucagon suppression in prediabetes and T2DM is an attempt to overcome resistance to glucagon's actions on hepatic AA catabolism, a defect in α-cell function, or a combination of both are important, unanswered questions. NAFLD is associated with T2DM risk and impaired insulin action. Unfortunately, it is unclear if glucagon resistance is caused by obesity, hepatic steatosis or both. The experiments outlined will determine if glucagon's actions on hepatic amino acid catabolism and EGP interact with hepatic lipid metabolism in lean and obese subjects with and without T2DM (and with varying degrees of hepatic steatosis).

Detailed Description
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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 intact. 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?

Official Title
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The Effects of Glucagon on Hepatic Metabolism

Conditions
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Obesity, Type2diabetes, NAFLD

Intervention / Treatment
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* Drug: Glucagon response study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to participate Able to give consent 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

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: All subjects will undergo one study designed to measure the hepatic response to glucagon. There will be 3 groups non-diabetic and non-obese, obese, people with type 2 diabetes
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Adults<br>We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon. | Drug: Glucagon response study<br>* Please see information in group descriptions<br>|
| Experimental: Obese Adults<br>We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon. | Drug: Glucagon response study<br>* Please see information in group descriptions<br>|
| Experimental: Adults with Type 2 Diabetes<br>We will study 20 subjects on one occasion using a hyperglycemic clamp with 2 doses of glucagon. | Drug: Glucagon response study<br>* Please see information in group descriptions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Amino acid catabolism in the presence / absence of glucagon | Tracer-dependent measurement of amino-acid clearance | 240 minutes of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Diabetes on amino-acid catabolism | Tracer-dependent measurement of amino-acid clearance | 240 minutes of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glucagon, insulin resistance, hepatic steatosis, amino acid metabolism