Ceramides in Muscle During Insulin Resistance

Insulin Resistance Clinical Trial

Official title: The Role of Ceramides in Skeletal Muscle

Status Withdrawn

Clinical Trial 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.

Clinical Trial Description

Healthy, insulin sensitive, physically active male and female adults will be studied (N=15; 65-80 years as determined by sample size calculation below) recruited from the Salt Lake City area. Inclusion and exclusion criteria can be found in Protection of Human Subjects. Outpatient blood screening, including an oral glucose tolerance (OGTT) test, and bed rest experiments will take place in the University Center for Clinical and Translational Sciences (CCTS), a clinical service supported by an NIH Clinical and Translational Science Award. The CCTS medical supervising physician oversees procedures. Participants will arrive at the CCTS fasted on Day 1 and a euglycemic-hyperinsulinemic clamp study will be performed as done previously with this unit. Vastus lateralis muscle biopsies will be obtained before and three hours after the clamp. Periodic blood samples will be obtained as part of the clamp procedure for measurement of insulin and glucose. Muscle samples will be either cultured or flash-frozen in liquid nitrogen and stored for later analysis. After completion of the first insulin clamp experiment (Day 1), subjects will adhere to 5-days of strict bed rest as this is a clinically-relevant time frame for older adults hospitalized for acute medical illness, as well as being sufficient to induced insulin resistance. Established safety and comfort guidelines will be followed as done previously. On Day 5, after an overnight fast, a second insulin clamp study will be conducted and muscle biopsies will be again obtained. ;

Related Conditions & MeSH terms

• Insulin Resistance

• NCT number: NCT03731598
• Study type: Observational
• Source: University of Utah
• Status: Withdrawn
• Start date: May 1, 2018
• Completion date: January 2022