Ceramides in Muscle During Insulin Resistance
| Status: | Recruiting |
|---|---|
| Conditions: | Endocrine |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 60 - Any |
| Updated: | 11/8/2018 |
| Start Date: | May 1, 2018 |
| End Date: | January 2022 |
| Contact: | Micah Drummond, PhD |
| Email: | micah.drummond@hsc.utah.edu |
| Phone: | 801-585-1310 |
The Role of Ceramides in Skeletal Muscle
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.
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.
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.
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.
Inclusion Criteria:
1. Age between 60 yrs and older
2. Ability to sign informed consent
3. Free-living, prior to admission
Exclusion Criteria:
1. Cardiac abnormalities considered exclusionary by the study physician
2. Uncontrolled endocrine or metabolic disease (e.g., hypo/hyperthyroidism, diabetes)
3. Globular filtration rate <65 mL/min/1.73m2 or evidence of kidney disease or failure
4. 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)
5. 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
6. Use of anticoagulant therapy (e.g., Coumadin, heparin)
7. Elevated systolic pressure >150 or a diastolic blood pressure > 100
8. Implanted electronic devices (e.g., pacemakers, electronic infusion pumps,
stimulators)
9. Cancer or history of successfully treated cancer (less than 1 year) other than basal
cell carcinoma
10. Inability to abstain from smoking for duration of study
11. A history of > 20 pack per year smoking
12. HIV or hepatitis B or C
13. Recent anabolic or corticosteroids use (within 3 months)
14. Subjects with hemoglobin or hematocrit lower than accepted lab values
15. Agitation/aggression disorder (by psychiatric history and exam)
16. History of stroke with motor disability
17. A recent history (<12 months) of gastrointestinal bleed
18. Liver disease
19. Respiratory disease (acute upper respiratory infection, history of chronic lung
disease with resting oxygen saturation <97% on room air)
20. Any other condition or event considered exclusionary by the PI and faculty physician
We found this trial at
1
site
201 Presidents Circle
Salt Lake City, Utah 84108
Salt Lake City, Utah 84108
801) 581-7200
Principal Investigator: Micah Drummond
Phone: 801-587-7764
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