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The Effect of Glucagon on Rates of Hepatic Mitochondrial Oxidation in Man Assessed by PINTA

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03965130
Recruitment Status : Active, not recruiting
First Posted : May 28, 2019
Last Update Posted : July 20, 2020
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Yale University

Brief Summary:

It is well established that alterations in the portal vein insulin:glucagon ratio play a major role in the dysregulated hepatic glucose metabolism in type 2 diabetes but the molecular mechanism by which glucagon promotes alterations in hepatic glucose production and mitochondrial oxidation remain poorly understood. This is borne out of the fact that both glucagon agonists and antagonists are being developed to treat type 2 diabetes with unclear mechanisms of action.

This study will directly assess the effects of glucagon on rates of mitochondrial oxidation and pyruvate carboxylase flux for the first time in humans using PINTA analysis. The results will have important implications for the possibility of intervening in the pathogenesis of non alcoholic fatty liver and type 2 diabetes via chronic dual GLP-1/glucagon receptor antagonism and provide an important rationale for why a dual agonist may be more efficacious for treatment of non alcoholic fatty liver and T2D than GLP-1 alone.


Condition or disease Intervention/treatment Phase
Healthy Participants Drug: Glucagon Early Phase 1

Detailed Description:

Objectives:

To examine the effects of glucagon on hepatic glucose and fat metabolism in vivo, this study will apply a novel Positional Isotopomer NMR Tracer Analysis (PINTA) method to quantify rates of hepatic mitochondrial oxidation and pyruvate carboxylase flux, which has been cross-validated in awake rodents and humans (Perry et al. Nature Communications 2017). Preliminary rodent studies have found that glucagon stimulates intrahepatic lipolysis through an InsP3R-I-dependent process, leading to increases in hepatic acetyl-CoA content, which allosterically activates pyruvate carboxylase activity and flux, and that this phenomenon explains its acute, transcription-independent effect to acutely stimulate hepatic gluconeogenesis in vivo (unpublished results). In addition, using PINTA analysis it has been shown that glucagon stimulates hepatic mitochondrial oxidation through calcium signaling in awake mice, and that this process can be exploited by short-term continuous glucagon treatment leading to two-fold increases in hepatic mitochondrial fat oxidation, which in turn results in large reductions in hepatic steatosis and marked improvements in glucose tolerance through reversal of hepatic insulin resistance in a high fat fed rat model of non alcoholic fatty liver.

Hypothesis:

  1. A physiological increase in plasma glucagon concentrations will promote a significant increase in rates of hepatic mitochondrial oxidation in healthy humans.
  2. A physiological increase in plasma glucagon concentrations will promote a significant increase in rates of hepatic pyruvate carboxylase flux in healthy humans.
  3. A physiological increase in plasma glucagon concentrations will promote a significant increase in rates of 13C4 β-hydroxybutyrate turnover (hepatic ketogenesis) in healthy humans.

Study Design - Clinical Plan:

The effects of a physiological increase in plasma glucagon on rates of hepatic mitochondrial oxidation and pyruvate carboxylase flux will be examined in 12 healthy participants (ages 21-65) using Positional Isotopomer NMR Tracer Analysis (PINTA) (Perry et al. Nature Communication 2017). Briefly rates of hepatic mitochondrial oxidation and hepatic pyruvate carboxylase flux will be assessed in 12 healthy overnight fasted participants by PINTA after a three-hour infusion of glucagon or saline. The glucagon infusion will be designed to increase peripheral and portal vein plasma glucagon concentrations 3-4 fold. The effects of a physiological increase in plasma glucagon on rates of hepatic ketogenesis will also be assessed using an infusion of 13C4 β-betahydroxybutyrate (Perry et al. Cell Metabolism 2017).

Rates of hepatic pyruvate carboxylase flux /citrate synthase flux by PINTA: Participants (n=12) will be studied by PINTA under 2 conditions: 1) following an overnight fast and a 3 hour saline infusion (Control), 2) following an overnight fast and a 3 hour glucagon infusion. Briefly, after collection of baseline blood samples a 3 hour infusion of tracers as described below will be started. Relative rates of pyruvate carboxylase to citrate synthesis flux will be assessed using a constant infusion of [3-13C] lactate and rates of glucose production will be measured using an infusion of [2H7]glucose (Perry et al. Nature Communication 2017). Rates of hepatic ketogenesis will be measured using a constant infusion of [3C β-hydroxybutyrate as previously described (Perry et al. Cell Metabolism 2017).

Whole body energy expenditure and the respiratory quotient will be assessed by indirect calorimetry.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Each participant will participate in two studies: one without and one with a 3 hour infusion of glucagon during the PINTA study
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: The Effect of Glucagon on Rates of Hepatic Mitochondrial Oxidation and Pyruvate Carboxylase Flux in Man Assessed by Positional Isotopomer NMR Tracer Analysis (PINTA)
Actual Study Start Date : May 22, 2019
Estimated Primary Completion Date : December 6, 2023
Estimated Study Completion Date : December 6, 2025

Resource links provided by the National Library of Medicine

Drug Information available for: Glucagon

Arm Intervention/treatment
Experimental: Glucagon
Participants will receive glucagon or saline during the PINTA study
Drug: Glucagon
PINTA study with or without glucagon
Other Name: hormone study




Primary Outcome Measures :
  1. Rates of Hepatic Glucose production [ Time Frame: 5 Hours ]
    Rates of fasting glucose production will be measured using D7 glucose

  2. Rates of Hepatic Mitochondrial Oxidation [ Time Frame: 5 hours ]
    Rates of pyruvate carboxylase flux and citrate synthesis flux will be assessed using GC/MS and NMR analyses of plasma glucose 13C enrichments after the [3-13C]lactate infusion

  3. Rates of Hepatic Ketogenesis [ Time Frame: 5 hours ]
    Assessment of hepatic acetyl CoA content will be estimated from rates of hepatic ketogenesis following the 13C beta-hydroxybutyrate infusion



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy
  • Normal body weight (BMI<28 Kg/m2)
  • Non smoking
  • Taking no medications except birth control

Exclusion Criteria:

  • Any systemic or organ disease
  • Smoking
  • Taking any drug or medications other than birth control (women)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03965130


Locations
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United States, Connecticut
Yale Hospital reserach Unit / YCCI
New Haven, Connecticut, United States, 06520
Sponsors and Collaborators
Yale University
Merck Sharp & Dohme Corp.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Kitt F Petersen, MD Professor
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Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT03965130    
Other Study ID Numbers: 0209020997
1R01DK113984-01 ( U.S. NIH Grant/Contract )
1R01DK124272-01 ( U.S. NIH Grant/Contract )
First Posted: May 28, 2019    Key Record Dates
Last Update Posted: July 20, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Final data to be shared with study sponsor

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Yale University:
Hepatic Glucose Metabolism
Hepatic Mitochondrial Oxidation
PINTA
Glucagon
Additional relevant MeSH terms:
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Pinta
Treponemal Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Skin Diseases, Bacterial
Spirochaetales Infections
Skin Diseases, Infectious
Infection
Skin Diseases
Glucagon
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Gastrointestinal Agents