Resistant Starch Insulin Sensitivity Trial
| Status: | Archived |
|---|---|
| Conditions: | Healthy Studies, High Cholesterol, Peripheral Vascular Disease, Endocrine |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Endocrinology, Other |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 7/1/2011 |
| Start Date: | June 2010 |
| End Date: | August 2011 |
Effects of Resistant Starch on Lipid and Glucose Metabolism in Insulin Resistance
The alarming increase in the prevalence of obesity is a cause of great concern given its
association with many adverse health conditions, including insulin resistance and type 2
diabetes, which are associated with increased cardiovascular disease (CVD) risk. The
primary objective of this project is to identify effective dietary strategies, focused on
carbohydrate quantity and starch digestibility, to improve outcome variables associated with
CVD risk in insulin resistant individuals who express components of the atherogenic
lipoprotein phenotype (ALP). Current dietary guidelines emphasize substitution of
carbohydrate calories for total and saturated fat calories for prevention and management of
chronic disease. Yet, we and others have shown that high-carbohydrate diets increase the
expression of the ALP, characterized by increased plasma triglycerides, reduced HDL
cholesterol, and increased levels of small, dense LDL particles, and that this phenotype is
reversed by moderate carbohydrate restriction. We have also shown that expression of
stearoyl coenzymeA desaturase (SCD), an enzyme involved in triglyceride synthesis, is
reduced with carbohydrate restriction and that this change is correlated with plasma
triglyceride response. While carbohydrate restriction is effective for management of ALP,
the role of starch quality has not been addressed. Furthermore, there has been no study of
the effects of resistant vs. digestible starches incorporated into high- vs. lower
carbohydrate diets. Since isolated reports suggest that increased intake of resistant
starch lowers plasma triglycerides and postprandial insulinemia, we hypothesize that starch
quality is an important determinant of components of ALP, and that this may be mediated in
part by reduced adipose tissue SCD expression. Aim 1 and of this proposal will address this
hypothesis by a controlled dietary intervention in 52 insulin resistant men and women in
which changes in plasma lipids, lipoproteins and lipogenic gene expression will be
determined after substituting resistant starch for digestible starch in a high- vs.
lower-carbohydrate diet. In Aim 2, the fasting and postprandial glucose and insulin
responses to a resistant vs. digestible starch meal will be measured to test the hypothesis
that starch digestibility improves glycemic and insulinemic control in a way that relates to
diet-induced changes in plasma lipids and lipoproteins.
Clinic Visits:
Participants will visit the clinic a total of 11 times from screen to completion of the
study. This will include weekly visits with a dietician and 7 visits requiring blood draws
(screen and twice following each diet period). At each visit, participants will be weighed,
waist and hip circumferences will be measured, and blood pressure will be monitored. The
total amount of blood collected is 450ml.
Screening visit (V1: 1 hour):
Recruiters will initially determine eligibility through review of a screening questionnaire
and a telephone or personal interview. If a potential subject is eligible and interested,
an orientation package will be mailed that will include written information about the study
requirements. Interested subjects will be scheduled for a screening visit to determine
final eligibility by the Clinical staff. At the screening visit (V1), informed consent will
be obtained, anthropometric measurements obtained (height, weight, waist circumference,
blood pressure), and blood (30ml) will be drawn to assess laboratory criteria for enrollment
(total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, glucose, and insulin
for determination of HOMA-IR). Screening blood samples from individuals who are either not
eligible or unwilling to proceed with the intervention will be destroyed. We will screen for
pregnancy, and repeat pregnancy tests after all "A" visits (V2a, v3a, v4a). Menstruating
women will be given a calendar to record their menstrual cycle for the duration of the
study. Eligible individuals will be contacted within 2 weeks of this screen visit and
invited to participate in the study. We are prepared to enroll up to 64 participants in
this study to yield a target of 52 completed participants (20% dropout).
Dietitian Visits (Initial: 1 hr, Subsequent: 15 min):
Participants will meet weekly with a dietitian or dietitian aide to receive counseling
including weight management and diet review. At these meetings, participants will receive a
week's worth of frozen entrees, standardized menus with check lists, and itemized grocery
lists. Baked goods and products containing the test starches will also be provided at this
time. The form in which they will be provided (frozen or fresh) will depend on the nature
of the product and its capacity to withstand refrigerated vs. frozen storage. During the
washout period (days 28-42), subjects will continue to refrain from alcohol but will consume
their usual home diet for 7 days, followed by the baseline diet for an additional 7 days. We
anticipate that giving participants permission to eat what they want for 7 days during the
washout will improve their compliance during the remainder of the dietary protocol.
Participants will bring grocery store receipts from the previous week so that the dietitians
may ensure purchase of prescribed foods not provided by the Bionutrition Unit.
Post-diet Visits Requiring Blood Draws (A visits: 2.5 hr, B visits: 5 hr):
Participants will visit the clinic on two separate days following completion of each diet to
provide blood samples. Duplicate sampling reduces biological variability, and hence
improves the power of the study to detect significant diet-induced changes in measurement.
On the penultimate day of each diet (Visits 2A, 3A, 4A) participants will visit the clinic
in the fasting state and provide a fasting blood sample (30ml) for measurement of total,
LDL- and HDL-cholesterol, triglycerides, apolipoproteins A1 and B, and lipoprotein
subfraction analysis by ion mobility. Lipoprotein lipase and hepatic lipase activities will
also be measured in plasma (20ml) obtained 15 minutes after IV heparin (75 units/kg). On
the final day of each diet (Visits 2B, 3B, 4B), participants will provide a second fasting
blood sample (for lipids and lipoproteins as above) and an adipose tissue aspiration to
measure lipogenic gene expression. In addition a 3 hour starch tolerance meal will be
performed at visits 3B and 4B, with blood samples for measuring glucose and insulin drawn in
the fasting state and 30, 60, 120, and 180 minutes after a starch meal (60ml total).
Clinical Procedures:
Clinical measurements: Blood pressure will be measured 3 times in a sitting position and the
last 2 values averaged. Anthropometric measurements include height, weight, waist and hip
circumference, and % body fat by bioimpedance (Tanita scale). Waist circumference is
measured two times at the iliac crest and hip circumference is measured at the widest point
of the hips.
Standard Blood sampling: Using standard blood collection procedures, blood samples will be
collected from participants after a 12-14 hour fast. The blood will be collected into tubes
containing the following preservative solution: 3.0 gms EDTA (dipotassium), 1.7 mg P-Pack,
0.15 gms gentamycin sulfate, 0.15 gms chloramphenicol, 5.96 mls aprotinin (Sigma A-6279),
and 0.30 gms sodium azide all of which are diluted to 20mls with doubly deionized water.
Plasma is separated by immediate centrifugation at 4°C. Lipid and lipoprotein measurements
are performed and aliquots of plasma are frozen for future analyses.
Post-heparin Blood Sampling:
A blood sample (20ml) will be drawn 15 minutes after intravenous administration of a heparin
bolus (75U/kg, see Risk section for justification) for the analysis of plasma lipase
activity. Prior to administration, participants will be interviewed for family history of
clotting disorders or personal contraindications including use of anticoagulants, history of
bleeding or bruising abnormalities or other diseases, allergies, or recent dental work.
Following administration, participants will remain in clinic for 2 hours under observation.
They will also be provided with an information sheet regarding heparin and the procedure.
Adipose Tissue Biopsy:
Adipose biopsies will be collected from the subcutaneous flanking region by an R.N. using a
standardized, sterile procedure. Participants will be instructed not to take any drugs
within 2 days of the procedure that would impair clotting. This procedure will take place
at least 24 hours after post-heparin lipase analysis. Because the half-life of heparin is 2
hours, this is sufficient time to ensure clearance. After cleaning the area above the
participant's buttock with betadine, Lidocaine hydrochloride 1% (10mg/ml) will be injected
into the subcutaneous skin. Using a number 14G needle, 1-1.5 c.c.'s of fat will be
aspirated. Cold pressure will be held on site and then the wound will be bandaged.
Participants will be instructed to change the bandage once daily for two days. They will be
provided with two bandages, instructions for keeping the wound clean, and a telephone number
where clinical staff can be reached.
Starch Meal Test:
Immediately following adipose tissue biopsy and fasting blood draw, participants will be
given a starch meal that provides 1/3 of the daily calories to be consumed in 15 minutes. It
will be similar in macronutrient composition to the test diet to which the participant is
assigned and will either be high in amylose or amylopectin. Blood will be drawn 30, 60, 120,
and 180 minutes after meal consumption through an IV. For this procedure, an intravenous
cannula or needle will be placed in the antecubital vein. A normal saline solution will be
run at a keep open rate at the antecubital site.
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