Rosiglitazone to Reverse Metabolic Defects in Diabetes
| Status: | Completed |
|---|---|
| Conditions: | Endocrine, Diabetes, Diabetes |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 22 - Any |
| Updated: | 4/21/2016 |
| Start Date: | October 2004 |
| End Date: | September 2008 |
Evaluation of Rosiglitazone in Reversing Metabolic Defects of Pre-Diabetes and Type 2 Diabetes Mellitus
This study will examine whether the anti-diabetes medicine rosiglitazone can safely and
effectively reverse the early problems of type 2 diabetes and delay the onset of disease in
people with pre-diabetes. The underlying problem in people with diabetes or pre-diabetes is
insulin resistance (lowered sensitivity to insulin) resulting in poor glucose (sugar)
regulation. Rosiglitazone improves the body's sensitivity to insulin.
Patients 21 years of age and older who have type 2 diabetes or who are pre-diabetic (glucose
intolerant/insulin resistant) may be eligible for this study. Candidates are screened with a
medical history, physical examination, blood tests, echocardiography (heart ultrasound),
exercise test, brachial artery reactivity test (see below), and possibly a muscle biopsy.
Participants take one rosiglitazone tablet daily by mouth for 2 weeks. The dose is then
increased to two tablets daily for another 2 weeks and then to 4 tablets daily for the
remainder of the 12-week treatment period. In addition to treatment, patients undergo the
following tests and procedures:
- Resting and exercise metabolic testing: The amount of oxygen taken in and carbon
dioxide exhaled during breathing is measured while the patient rests in a chair and
then while he or she exercises on a stationary bicycle or treadmill. Both at rest and
during exercise, the patient wears a facemask that measures the amount of oxygen used.
During exercise, heart rate is monitored with electrodes on the chest, arms, and
thighs. The exercise test is repeated three times, once to become familiar with the
test, again the next day to measure exercise capacity, and again 3 days later. The
third test is less strenuous and is optional.
- Muscle biopsy (optional): A small area of skin over a calf muscle is numbed with a
local anesthetic and a 1-inch incision is made over the muscle. A small amount of
muscle tissue is taken and the incision is closed with stitches.
- Brachial reactivity study: This ultrasound study tests how well the patient's arteries
widen. The subject rests on a bed for 30 minutes. An ultrasound measuring device is
placed over the artery just above the elbow. The size of the artery and blood flow
through it are measured before and after inflating a pressure cuff around the forearm.
The pressure cuff stops the flow of blood to the arm for a few minutes. After a
15-minute rest, a nitroglycerin tablet (medicine that causes blood vessels to relax) is
placed under the patient's tongue. Before and 3 minutes after the nitroglycerin is
given, the size of the artery and blood flow through it are measured again.
- Blood samples: Blood samples are collected at the beginning and end of the study and at
study visits in between.
- Study visits: Patients come to the Clinical Center biweekly or monthly for a follow-up
history, physical examination, and blood tests. At the end of the3-month treatment
period, they receive recommendations about possible treatment modifications to best
maintain glucose tolerance. Their physicians are informed of how their blood sugar was
controlled. Six months after completing the study, patients undergo a final study
evaluation and blood tests, and are then invited to return for yearly checkups after
that.
effectively reverse the early problems of type 2 diabetes and delay the onset of disease in
people with pre-diabetes. The underlying problem in people with diabetes or pre-diabetes is
insulin resistance (lowered sensitivity to insulin) resulting in poor glucose (sugar)
regulation. Rosiglitazone improves the body's sensitivity to insulin.
Patients 21 years of age and older who have type 2 diabetes or who are pre-diabetic (glucose
intolerant/insulin resistant) may be eligible for this study. Candidates are screened with a
medical history, physical examination, blood tests, echocardiography (heart ultrasound),
exercise test, brachial artery reactivity test (see below), and possibly a muscle biopsy.
Participants take one rosiglitazone tablet daily by mouth for 2 weeks. The dose is then
increased to two tablets daily for another 2 weeks and then to 4 tablets daily for the
remainder of the 12-week treatment period. In addition to treatment, patients undergo the
following tests and procedures:
- Resting and exercise metabolic testing: The amount of oxygen taken in and carbon
dioxide exhaled during breathing is measured while the patient rests in a chair and
then while he or she exercises on a stationary bicycle or treadmill. Both at rest and
during exercise, the patient wears a facemask that measures the amount of oxygen used.
During exercise, heart rate is monitored with electrodes on the chest, arms, and
thighs. The exercise test is repeated three times, once to become familiar with the
test, again the next day to measure exercise capacity, and again 3 days later. The
third test is less strenuous and is optional.
- Muscle biopsy (optional): A small area of skin over a calf muscle is numbed with a
local anesthetic and a 1-inch incision is made over the muscle. A small amount of
muscle tissue is taken and the incision is closed with stitches.
- Brachial reactivity study: This ultrasound study tests how well the patient's arteries
widen. The subject rests on a bed for 30 minutes. An ultrasound measuring device is
placed over the artery just above the elbow. The size of the artery and blood flow
through it are measured before and after inflating a pressure cuff around the forearm.
The pressure cuff stops the flow of blood to the arm for a few minutes. After a
15-minute rest, a nitroglycerin tablet (medicine that causes blood vessels to relax) is
placed under the patient's tongue. Before and 3 minutes after the nitroglycerin is
given, the size of the artery and blood flow through it are measured again.
- Blood samples: Blood samples are collected at the beginning and end of the study and at
study visits in between.
- Study visits: Patients come to the Clinical Center biweekly or monthly for a follow-up
history, physical examination, and blood tests. At the end of the3-month treatment
period, they receive recommendations about possible treatment modifications to best
maintain glucose tolerance. Their physicians are informed of how their blood sugar was
controlled. Six months after completing the study, patients undergo a final study
evaluation and blood tests, and are then invited to return for yearly checkups after
that.
The majority of insulin resistant individuals (predominantly individuals with type 2
diabetes - T2DM) develop a disproportionate incidence of cardiovascular disease burden
including hypertension, coronary artery disease, peripheral vascular disease and heart
failure. The underlying pathophysiology is multifactorial but is primarily driven by
insulin-resistance mediated regulatory events. These include augmented oxidative stress,
upregulation of pro-inflammatory and anti-thrombotic signaling pathways, detrimental effects
of advanced glycosylation end-products and perturbations in lipid and fatty acid metabolism.
Evidence is emerging to support a role of perturbed mitochondrial respiratory regulation and
subsequent endothelial dysfunction as early events in the insulin-resistance syndrome. These
in turn, are proposed to result in the subsequent development of the cardiovascular clinical
sequelae.
In the last few years, pharmacologic compounds have been developed that directly modulate
insulin resistance/sensitivity. Activation of the peroxisome proliferator-activated receptor
(PPAR) family of transcription factors has been shown to augment insulin sensitivity. Agents
that activate numerous PPAR family members, i.e. pan-PPAR agonists and PPAR gamma (PPAR
gamma) specific agonists, promote improved insulin sensitivity. Whether these compounds
modify the underlying mitochondrial and endothelial pathophysiology, with the potential of
preventing progression of cardiovascular disease in insulin-resistant subjects has not been
systematically investigated.
The hypothesis intrinsic to this proposal is that PPAR activation will improve mitochondrial
respiratory and endothelial cell function in parallel with improved insulin sensitization in
insulin-resistant and T2DM subjects. The primary objective of this study is to establish the
effects of the PPAR gamma agonist (rosiglitazone) on exercise-modulated
cardiopulmonary-metabolic function (functional measures of mitochrondrial respiratory
function) in insulin resistant and T2DM subjects that are either naive to hypoglycemic
therapy or are on current therapy with other established classes on anti-diabetic agents
with or without associated cardiovascular disease. As secondary end points we will evaluate
numerous biological assays of skeletal muscle mitochondrial function, endothelial function
and changes in parameters of insulin sensitivity. These include: 1) skeletal muscle
mitochondrial respiration, 2) skeletal muscle expression profiles of genes encoding
mitochondrial biogenesis program and mitochondrial respiratory control, 3) brachial artery
reactivity, 4) endothelial progenitor cell number and colony-forming capacity, 5) monocyte
gene expression profiling to evaluate insulin and inflammatory-mediator regulatory events
and 6) serological evaluation in change in insulin sensitivity and inflammation. The study
is designed as a phase II clinical trial where subjects will receive rosiglitazone for three
months duration. Baseline and 3 month laboratory studies will include: 1) rest and exercise
cardiopulmonary metabolic testing; 2) skeletal muscle biopsy for mitochondrial function and
gene expression profiling analysis, 3) brachial artery reactivity testing and 4) serological
and blood cell sampling to determine biochemical, cellular and genomic perturbations in
response to insulin-sensitization therapy in this cohort.
diabetes - T2DM) develop a disproportionate incidence of cardiovascular disease burden
including hypertension, coronary artery disease, peripheral vascular disease and heart
failure. The underlying pathophysiology is multifactorial but is primarily driven by
insulin-resistance mediated regulatory events. These include augmented oxidative stress,
upregulation of pro-inflammatory and anti-thrombotic signaling pathways, detrimental effects
of advanced glycosylation end-products and perturbations in lipid and fatty acid metabolism.
Evidence is emerging to support a role of perturbed mitochondrial respiratory regulation and
subsequent endothelial dysfunction as early events in the insulin-resistance syndrome. These
in turn, are proposed to result in the subsequent development of the cardiovascular clinical
sequelae.
In the last few years, pharmacologic compounds have been developed that directly modulate
insulin resistance/sensitivity. Activation of the peroxisome proliferator-activated receptor
(PPAR) family of transcription factors has been shown to augment insulin sensitivity. Agents
that activate numerous PPAR family members, i.e. pan-PPAR agonists and PPAR gamma (PPAR
gamma) specific agonists, promote improved insulin sensitivity. Whether these compounds
modify the underlying mitochondrial and endothelial pathophysiology, with the potential of
preventing progression of cardiovascular disease in insulin-resistant subjects has not been
systematically investigated.
The hypothesis intrinsic to this proposal is that PPAR activation will improve mitochondrial
respiratory and endothelial cell function in parallel with improved insulin sensitization in
insulin-resistant and T2DM subjects. The primary objective of this study is to establish the
effects of the PPAR gamma agonist (rosiglitazone) on exercise-modulated
cardiopulmonary-metabolic function (functional measures of mitochrondrial respiratory
function) in insulin resistant and T2DM subjects that are either naive to hypoglycemic
therapy or are on current therapy with other established classes on anti-diabetic agents
with or without associated cardiovascular disease. As secondary end points we will evaluate
numerous biological assays of skeletal muscle mitochondrial function, endothelial function
and changes in parameters of insulin sensitivity. These include: 1) skeletal muscle
mitochondrial respiration, 2) skeletal muscle expression profiles of genes encoding
mitochondrial biogenesis program and mitochondrial respiratory control, 3) brachial artery
reactivity, 4) endothelial progenitor cell number and colony-forming capacity, 5) monocyte
gene expression profiling to evaluate insulin and inflammatory-mediator regulatory events
and 6) serological evaluation in change in insulin sensitivity and inflammation. The study
is designed as a phase II clinical trial where subjects will receive rosiglitazone for three
months duration. Baseline and 3 month laboratory studies will include: 1) rest and exercise
cardiopulmonary metabolic testing; 2) skeletal muscle biopsy for mitochondrial function and
gene expression profiling analysis, 3) brachial artery reactivity testing and 4) serological
and blood cell sampling to determine biochemical, cellular and genomic perturbations in
response to insulin-sensitization therapy in this cohort.
- INCLUSION CRITERIA:
Adults older than 21 years.
Subjects must either have:
1. Insulin resistance as defined by a fasting blood sugar of greater than 110mg/dl and
less than 126 mg/dl and confirmed with the QUICKI test.
2. or the diagnosis of T2DM with a HBA1c less than 9%, a fasting insulin level of
greater than 6 UIU/ml and a fasting blood glucose level of greater than 125 mg/dl if
not on anti-diabetic therapy.
Subject understands protocol and provides written, informed consent
Patients must demonstrate the capacity for a near maximal to maximal effort on a
treadmill as measured by exercise ventilatory threshold. This will be measured by
achieving a peak respiratory exchange ratio greater than or equal to 1.00 during the
initial and final peak VO2 exercise tests.
EXCLUSION CRITERIA:
Significant structural heart disease (e.g. hypertrophic or dilated cardiomyopathy,
valvular heart disease) as determined by echocardiography or unstable coronary
disease within the last 3 months.
Uncontrolled hypertension.
History of Heart Failure.
Left ventricular ejection fraction less than 55% as measured by screening
echocardiogram.
Subject physically unable to perform treadmill exercise due to neurologic or
orthopedic conditions.
Insulin-dependent diabetes mellitus or current use of thiazolidinediones
History of adverse events on thiazolidinedione therapy
Women of childbearing age unless recent pregnancy test is negative.
Lactating women.
Serum creatinine greater than 2.5 mg/dl
Liver transaminase levels greater than 2.5 x upper limit of normal
History of cancer in the last 5 years
History of treatment for any illness with stem cell transplantation
Active inflammatory disease
Enrollment in a any drug studies within the last 30 days
We found this trial at
2
sites
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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