Ceramides in Muscle During Insulin Resistance

NCT03731598 | Withdrawn

• 1 other identifier: DK115824
• Study Type: observational
• Target: N/A
• Locations: 1 country
• Sites: 2

Brief Summary

Overnutrition and physical inactivity promote the accumulation of sphingolipids such as ceramides which block insulin signaling and anabolic metabolism. Implementation of pharmacological or genetic interventions to reduce sphingolipid levels in rodents prevents or reverses an impressive array of metabolic pathologies (e.g. insulin resistance, diabetes, steatohepatitis, hypertension, cardiomyopathy, and atherosclerosis). To elucidate the tissue-specific mechanisms through which ceramides contribute to these diseases, mice have been produced to allow for the conditional, cell-type restricted ablation of enzymes required for ceramide biosynthesis or degradation (i.e. serine palmitoyltransferase and dihydroceramide desaturases-1) or degradation (i.e. acid ceramidase). Aims of the project include the following: To use these novel mouse models to evaluate the effect of muscle-specific ceramide depletion or induction on insulin sensitivity, muscle growth, and genomic/proteomic signatures under conditions of overnutrition and inactivity. To apply a ceramide flux assay in isolated human myotubes to identify the regulatory mechanisms that influence rates of ceramide biosynthesis; and, To determine the efficacy of a new class of inhibitors of dihydroceramide desaturases-1, our preferred target in the ceramide synthesis pathway, as therapeutics that improve muscle insulin sensitivity and prevent muscle loss in rodents. Findings obtained from these studies could uncover new nutrient-sensing machinery that modulates insulin sensitivity and muscle growth. Moreover, the translational component could lead to new pharmacological approaches for improving muscle health.

Conditions

Insulin Resistance

Outcome Measures

Primary Outcomes (1)

• Insulin resistance

  Steady state glucose infusion rate in response to constant insulin will be determined by a 3-hour hyperinsulinemic-euglycemic clamp procedure.

  Change in glucose infusion rate at Day 5 of bed rest (from Pre bed rest)

Interventions

bed rest PROCEDURE

Volunteers will be physically inactive on bed rest at the clinical research center

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Healthy older community dwelling participants in salt lake city and surrounding cities

You may qualify if:

• Age between 60 yrs and older
• Ability to sign informed consent
• Free-living, prior to admission

You may not qualify if:

• Uncontrolled endocrine or metabolic disease (e.g., hypo/hyperthyroidism, diabetes)
• Globular filtration rate \<65 mL/min/1.73m2 or evidence of kidney disease or failure
• Vascular disease or risk factors of peripheral atherosclerosis. (e.g., uncontrolled hypertension, obesity, diabetes, hypercholesterolemia \> 250 mg/dl, claudication or evidence of venous or arterial insufficiency upon palpitation of femoral, popliteal and pedal arteries)
• Risk of deep vein thrombosis including family history of thrombophilia, deep vein thrombosis, pulmonary emboli, myeloproliferative diseases including polycythemia (Hb\>18 g/dL) or thrombocytosis (platelets\>400x103/mL), and connective tissue diseases (positive lupus anticoagulant), hyperhomocysteinemia, deficiencies of factor V Leiden, proteins S and C, and antithrombin III
• Use of anticoagulant therapy (e.g., Coumadin, heparin)
• Elevated systolic pressure \>150 or a diastolic blood pressure \> 100
• Implanted electronic devices (e.g., pacemakers, electronic infusion pumps, stimulators)
• Cancer or history of successfully treated cancer (less than 1 year) other than basal cell carcinoma
• Inability to abstain from smoking for duration of study
• A history of \> 20 pack per year smoking
• HIV or hepatitis B or C
• Recent anabolic or corticosteroids use (within 3 months)
• Subjects with hemoglobin or hematocrit lower than accepted lab values
• Agitation/aggression disorder (by psychiatric history and exam)
• History of stroke with motor disability

Sponsors & Collaborators

• University of Utah: lead

Study Sites (2)

University of Utah

Salt Lake City, Utah, 84108, United States

Location

The University of Utah

Salt Lake City, Utah, 84112, United States

Location

Biospecimen

Retention: SAMPLES WITH DNA

We will collect blood and muscle biopsy specimens before (Day 1 bed rest) and after bed rest (Day 5 bed rest)

MeSH Terms

Conditions

Insulin Resistance

Interventions

Bed Rest

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Scott Summers, PhD

  University of Utah

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: November 2, 2018
• First Posted: November 6, 2018
• Study Start: May 1, 2018
• Primary Completion: January 1, 2022
• Study Completion: January 1, 2022
• Last Updated: June 22, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)