The Effect of Dietary Sitosterol on Blood Sugar and Cholesterol
| Status: | Completed |
|---|---|
| Conditions: | High Cholesterol, Gastrointestinal |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Gastroenterology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 5/23/2018 |
| Start Date: | September 10, 2007 |
| End Date: | May 17, 2018 |
A Nutrigenomics Intervention for the Study of the Role of Dietary Sitosterol on Lipid, Glucose and Energy Metabolism
This study will determine if dietary supplements of sitosterol (a plant cholesterol commonly
found in vegetables) can modify blood sugar and cholesterol levels and reduce the stiffness
of the blood vessels in people with an abnormal copy of a gene that causes sitosterolemia.
People who carry only one copy of the abnormal gene are healthy but have increased blood
levels of sitosterol. People with two abnormal copies of the gene have increased levels of
sitosterol and have an increased risk of heart attack. This condition is called
sitosterolemia. Although extremely rare in the general population, up to 4% of the Amish
carry an abnormal copy of this gene.
People of Amish background who are 18 years of age or older and in whom one person carries
one copy of the abnormal gene that causes sitosterolemia and the other does not have an
abnormal gene may be eligible for this study. Subjects must be of the same sex and within 5
years of age of each other.
During two periods of one month each participants receive pills containing sitosterol and
then a special diet and meal supplements to change the levels of sitosterol in the diet.
During only one of the two study periods, subjects receive sitosterol supplements in the
pills for one month and then for 10 days in the diet. At the end of each study period,
subjects come to the NIH Clinical Center for one day for the following tests:
- Measurements of height, weight, blood pressure and heart rate.
- Adipose (fat) tissue biopsy. A small piece of fat from under the skin of the abdomen is
removed to examine how sitosterol affects fat tissue and its ability to process sugar
and fat.
- Indirect calorimetry. A plastic transparent hood is placed over the subject s head to
collect the air that is breathed for about one-half hour to study how the body uses
sugar to generate energy.
- Endothelial vascular function. An ultrasound picture of a blood vessel in the forearm is
taken and a blood pressure cuff is inflated around the arm to measure the vessel s
ability to stretch.
- Intravenous glucose tolerance test: A small plastic tube is placed in a vein in each
arm. Then over one minute the subject receives glucose through one of the tubes. Twenty
minutes later the subject is given a small amount of insulin through the same tube.
Blood samples are drawn through the tube in the other arm at frequent intervals for 3
hours. This test measures how sitosterol affects how the body processes sugar.
- DEXA scan. The subject lies on an x-ray table for 20 minutes during the scan, which
measures total body fat.
found in vegetables) can modify blood sugar and cholesterol levels and reduce the stiffness
of the blood vessels in people with an abnormal copy of a gene that causes sitosterolemia.
People who carry only one copy of the abnormal gene are healthy but have increased blood
levels of sitosterol. People with two abnormal copies of the gene have increased levels of
sitosterol and have an increased risk of heart attack. This condition is called
sitosterolemia. Although extremely rare in the general population, up to 4% of the Amish
carry an abnormal copy of this gene.
People of Amish background who are 18 years of age or older and in whom one person carries
one copy of the abnormal gene that causes sitosterolemia and the other does not have an
abnormal gene may be eligible for this study. Subjects must be of the same sex and within 5
years of age of each other.
During two periods of one month each participants receive pills containing sitosterol and
then a special diet and meal supplements to change the levels of sitosterol in the diet.
During only one of the two study periods, subjects receive sitosterol supplements in the
pills for one month and then for 10 days in the diet. At the end of each study period,
subjects come to the NIH Clinical Center for one day for the following tests:
- Measurements of height, weight, blood pressure and heart rate.
- Adipose (fat) tissue biopsy. A small piece of fat from under the skin of the abdomen is
removed to examine how sitosterol affects fat tissue and its ability to process sugar
and fat.
- Indirect calorimetry. A plastic transparent hood is placed over the subject s head to
collect the air that is breathed for about one-half hour to study how the body uses
sugar to generate energy.
- Endothelial vascular function. An ultrasound picture of a blood vessel in the forearm is
taken and a blood pressure cuff is inflated around the arm to measure the vessel s
ability to stretch.
- Intravenous glucose tolerance test: A small plastic tube is placed in a vein in each
arm. Then over one minute the subject receives glucose through one of the tubes. Twenty
minutes later the subject is given a small amount of insulin through the same tube.
Blood samples are drawn through the tube in the other arm at frequent intervals for 3
hours. This test measures how sitosterol affects how the body processes sugar.
- DEXA scan. The subject lies on an x-ray table for 20 minutes during the scan, which
measures total body fat.
The relative distribution of the various amounts of lipids in the membranes of the adipocytes
plays an important role in lipid metabolism and energy homeostasis. Sitosterolemia, a rare
genetic disease is caused by a defective ABC transporter in the gut and biliary tract, which
results in increased absorption and decreased excretion of plant sterols, ultimately leading
to accelerated atherosclerosis and premature death.
Very recently, a mutation of the ABCG8 gene, very rare in the general population, has been
described in 4% of the Old Order Amish, a well-characterized founder population in Lancaster
County, Pennsylvania. Preliminary data indicate that otherwise healthy carriers
(heterozygotes) of the mutation showed, as compared to controls, reduced body mass index,
more large buoyant LDL cholesterol, decreased carotid intima media thickness (IMT), and a
trend toward lower insulin and glucose levels, consistent with an improved metabolic syndrome
profile. These data suggest that a mild excess in plant sterols could play a role in the
modulation of the energy metabolism, and that dietary sitosterol may improve lipid profile
and other aspects of the metabolic syndrome in genetically normal subjects.
In order to characterize mechanistically the effects of sitosterol, the most abundant plant
sterol in the diet, on the development of the metabolic syndrome, we propose to study in
greater detail the carriers of the ABCG8 gene mutation; that will provide the opportunity to
analyze new insights into dietary sitosterol and its role in lipid and energy metabolism. We
hypothesize that sitosterol in the diet will affect metabolic syndrome indices differentially
in carriers of the mutation as compared to non-carriers.
We will perform a nutrigenomics intervention on 15 ABCG8 mutation carriers and sex-matched
unaffected persons (age +/- 5 years). They will be treated with high-, low- sitosterol
iso-caloric diets. Study subjects will be then evaluated in the NIH Clinical Center for
changes in the following parameters: circulating lipids and free fatty acids, glucose
disposal, resting energy expenditure and RQ, and endothelial vascular function. The Division
of Endocrinology, Diabetes and Nutrition at the University Of Maryland School of Medicine
will carry out the genotyping, study volunteer recruitment, cell membrane lipid content
analysis, and ex-vivo adipocyte analysis.
We hypothesize that carriers of the ABCG8 gene mutation will further improve metabolic
syndrome indices when challenged with a high-sitosterol diet, and will regress toward the
non-carrier controls when treated with a low-sitosterol diet. Non-carrier controls will
remain unchanged or show modest improvement in metabolic syndrome indices when challenged
with a high-sitosterol diet, which will worsen, compared to baseline and carrier sibs, when
treated with a low-sitosterol diet.
These clinical data, combined with the in vitro analysis of the effects of sitosterol on cell
membranes and adipocyte metabolism will advance knowledge in the field of lipid metabolism on
the relation of lipid composition to common disorders such as the metabolic syndrome. Data
obtained from this project could then potentially be translated into nutritional and
therapeutic interventions in the general population.
plays an important role in lipid metabolism and energy homeostasis. Sitosterolemia, a rare
genetic disease is caused by a defective ABC transporter in the gut and biliary tract, which
results in increased absorption and decreased excretion of plant sterols, ultimately leading
to accelerated atherosclerosis and premature death.
Very recently, a mutation of the ABCG8 gene, very rare in the general population, has been
described in 4% of the Old Order Amish, a well-characterized founder population in Lancaster
County, Pennsylvania. Preliminary data indicate that otherwise healthy carriers
(heterozygotes) of the mutation showed, as compared to controls, reduced body mass index,
more large buoyant LDL cholesterol, decreased carotid intima media thickness (IMT), and a
trend toward lower insulin and glucose levels, consistent with an improved metabolic syndrome
profile. These data suggest that a mild excess in plant sterols could play a role in the
modulation of the energy metabolism, and that dietary sitosterol may improve lipid profile
and other aspects of the metabolic syndrome in genetically normal subjects.
In order to characterize mechanistically the effects of sitosterol, the most abundant plant
sterol in the diet, on the development of the metabolic syndrome, we propose to study in
greater detail the carriers of the ABCG8 gene mutation; that will provide the opportunity to
analyze new insights into dietary sitosterol and its role in lipid and energy metabolism. We
hypothesize that sitosterol in the diet will affect metabolic syndrome indices differentially
in carriers of the mutation as compared to non-carriers.
We will perform a nutrigenomics intervention on 15 ABCG8 mutation carriers and sex-matched
unaffected persons (age +/- 5 years). They will be treated with high-, low- sitosterol
iso-caloric diets. Study subjects will be then evaluated in the NIH Clinical Center for
changes in the following parameters: circulating lipids and free fatty acids, glucose
disposal, resting energy expenditure and RQ, and endothelial vascular function. The Division
of Endocrinology, Diabetes and Nutrition at the University Of Maryland School of Medicine
will carry out the genotyping, study volunteer recruitment, cell membrane lipid content
analysis, and ex-vivo adipocyte analysis.
We hypothesize that carriers of the ABCG8 gene mutation will further improve metabolic
syndrome indices when challenged with a high-sitosterol diet, and will regress toward the
non-carrier controls when treated with a low-sitosterol diet. Non-carrier controls will
remain unchanged or show modest improvement in metabolic syndrome indices when challenged
with a high-sitosterol diet, which will worsen, compared to baseline and carrier sibs, when
treated with a low-sitosterol diet.
These clinical data, combined with the in vitro analysis of the effects of sitosterol on cell
membranes and adipocyte metabolism will advance knowledge in the field of lipid metabolism on
the relation of lipid composition to common disorders such as the metabolic syndrome. Data
obtained from this project could then potentially be translated into nutritional and
therapeutic interventions in the general population.
- INCLUSION CRITERIA:
- Age greater than or equal to 18 years, male or female
- Genotype ABCG8: G574 (case) or R574 (control)
- Amish ethnicity (as self-described and from the Fisher's Book)
- Informed consent (obtained in the presence of the Amish Liaison nurse)
- Control person: same sex and age +/- 5 years from case
EXCLUSION CRITERIA:
- BMI greater than or equal to 40 kg/m(2)
- History or symptoms compatible with cardiovascular disease, including hypertension
greater than or equal to 140/90 mm Hg or current therapy for hypertension or
cardiovascular disease
- Allergy to lidocaine, acetaminophen with codeine, oxycodone.
- Pregnancy
- Breastfeeding
- Use of hormonal contraceptives or estrogen replacement therapy
- Diabetes mellitus, either type 1 or 2
- Hypercholesterolemia (serum levels greater than or equal to 240 mg/dL), and/or use of
antilipemic therapy
- Liver disease or ALT serum level greater than two fold the upper laboratory reference
limit
- Renal insufficiency or estimated creatinine clearance less than or equal to 50 mL/min
- Use of medications/dietary supplements/alternative therapies known or thought to alter
lipid or carbohydrate metabolism (e.g. omega-3 fatty acids, chromium, vanadate) during
the study
- Current history or symptoms compatible with psychosis including major depression
(including history of hospitalization for depression, history of attempted suicide,
history of suicidal ideation), and/or use of antipsychotic medications
- History of drug or alcohol abuse within the last 5 years; current use of drugs or
alcohol (CAGE greater than 3)
- Keloid formation (relative to subcutaneous adipose tissue biopsy)
We found this trial at
2
sites
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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