Subject: RFA HL-9l-03-P ll/9/90 NIH Guide
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Thu, 08 Nov 90 08:47 EST

Hi Paul,
   Another one.  Please post to the NIH Listserver as:
     RFAHL-91-03-P.110990
  Thanks.  Dottie
 ---------------------------- Text of forwarded message -----------------------
 
REQUEST FOR RESEARCH COOPERATIVE AGREEMENT APPLICATIONS:
RFA:  HL-91-03-P
 
INSULIN, INSULIN RESISTANCE, HYPERGLYCEMIA AND
CARDIOVASCULAR DISEASE: Field Centers, Coordinating Center and
Central Laboratories
 
P.T. 34; K.W. 0715075, 0715040, 0755018
 
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
 
Letter of Intent Receipt Date:  February 1, 1991
Application Receipt Date:  April 5, 1991
 
PURPOSE
 
The Division of Epidemiology and Clinical Applications (DECA) invites
cooperative agreement applications for investigators to participate,
with the assistance of the National Heart, Lung, and Blood Institute
(NHLBI), in a multicenter study of the relationship of insulin and
insulin resistance to cardiovascular disease (CVD) and its risk
factors over a range of glucose tolerance from normal to overt
diabetes.  This study will be performed among persons with clinical
diabetes, with asymptomatic abnormalities of glucose metabolism, and
control subjects with normal glucose metabolism.  The assistance
mechanism used to support the study is the cooperative agreement,
which is similar to the traditional NIH research grant.  It differs
from a research grant in the extent and nature of NHLBI staff
involvement.  Applications received in response to this request will
participate in a single competition.  A center selected as an field
center also may serve as the Coordinating Center, and/or a Central
Laboratory for the overall study.
 
DISCIPLINES AND EXPERTISE
 
The expertise appropriate for this research program includes a
knowledge of both epidemiologic and clinical aspects of
cardiovascular disease and  diabetes, as well as administrative
skills and experience in the design and conduct of collaborative
epidemiologic studies.  Skills in data base management and
statistical analysis are appropriate for the Coordinating Center.
Experience in laboratory methodology for measuring lipids,
lipoproteins, insulin, and hemostatic factors is appropriate for
applicants for the Central Laboratory.
 
BACKGROUND
 
General
 
Patients with diabetes mellitus have an increased incidence of
CVD compared to individuals with normal
glucose tolerance.  The risk of CVD also appears to be increased
among subjects with milder degrees of glucose intolerance.  A recent
review of available information by the National Diabetes Advisory
Board recommended increased research to understand the development of
CVD in diabetics.  Research to clarify the associations between
insulin and insulin resistance with CVD was recommended by an NHLBI
Workshop on Insulin, Sex Hormones and Atherosclerosis (May 1987).  A
workshop sponsored by the American Diabetes Association also
recommended further studies on the association of diabetes and
cardiovascular diseases (1).  This initiative is in response to these
recommendations.  The initiative was approved by the National Heart,
Lung and Blood Advisory Council at its September 1990 meeting.
 
Scientific Background
 
An association between overt diabetes and cardiovascular disease has
been observed in many studies (2-5).  This excess of CVD in diabetics
includes increases in both incidence and case fatality rates from
acute myocardial infarction (3,5), in mortality in the months
following discharge after an acute myocardial infarction (6), in
unexplained chronic congestive heart failure (7), in cerebrovascular
disease (8), and in peripheral vascular disease (9).  Among persons
with Type II (noninsulin dependent) diabetes mellitus in the U.S.,
60 percent of deaths are attributed to ischemic heart disease and 20
percent to other heart and vascular disease (10).
 
The association between milder degrees of glucose intolerance
(impaired glucose tolerance and mild diabetes with normal or near
normal fasting glucose concentrations (11) and CVD is less
established.  Several studies suggest a relatively continuous
gradient of increasing risk as glucose tolerance deteriorates (5,12).
In contrast, a review of several other studies found a small and
inconsistent effect of mild hyperglycemia upon CVD risk, especially
after adjustment for other known CVD risk factors (14).  Subjects
with mild abnormalities of glucose tolerance are important since they
comprise more than half of those with abnormal glucose tolerance in
the U.S. population.  In these subjects, excess CVD may be the major
adverse effect of hyperglycemia.
 
Recent studies have suggested that hyperglycemia may be part of a
syndrome involving abnormalities in adipose tissue deposition, blood
pressure, and lipid levels linked to elevations of insulin or insulin
resistance (15-18).  It has been suggested that the increased risk of
CVD associated with diabetes may develop in the prediabetic period
when glucose levels are normal or minimally elevated (19).  These
observations suggest that elevations in insulin or insulin resistance
may contribute to an increased risk of CVD in the general,
normoglycemic population.  This syndrome may affect a substantially
greater proportion of the U.S. population than the estimated 22 to 30
million with detectable abnormalities in glucose tolerance.
 
Previous studies of hyperglycemia as a risk factor for CVD and of its
associations with other CVD risk factors often utilized techniques of
risk factor and disease measurement that are crude by current
standards.  In most studies focused on diabetes, measures of vascular
disease and CVD risk factors were limited.  In most studies focused
on CVD and its risk factors, definitions of diabetes were imprecise
or inadequate numbers of diabetics were identified for detailed
study.
 
The presence of diabetes may increase the risk of CVD more in women
than in men (3).  The reasons for this difference are unknown.  In
many studies, sample sizes have been too small to investigate the
apparent differences and the contribution of other risk factors.
 
Recent advances in understanding the evolution of Type II diabetes
and in the measurement of CVD risk factors provide opportunities to
reevaluate the relationship of glucose tolerance to cardiovascular
disease and to other known CVD risk factors.  Hyperglycemia is
associated with alterations in lipoprotein distribution and
metabolism.  Hyperglycemia may promote atherogenesis by increasing
glycosylation of lipoproteins and other circulating, enzymatic, and
structural proteins.  Correlations have been described between
insulin and insulin resistance and both hypertension and
dyslipidemias.  Abnormalities in platelet function, in
characteristics of erythrocytes and in activity of the coagulation
system correlate with hyperglycemia.  Many of these risk factors have
been measured in small groups of subjects and the changes to be found
over a range of glucose tolerance are largely unknown.
 
Advances have also occurred in techniques to assess cardiovascular
disease by non-invasive measures which can be utilized in
epidemiologic studies (20,21).  Episodes of ischemia can be assessed
by exercise testing and ambulatory monitoring.  Cardiac structure and
function can be assessed by echocardiography.  Atherosclerosis can be
assessed by ultrasonography.  The application of these and/or other
measurement techniques will allow investigation of the relationships
of hyperglycemia and related metabolic factors to evidence of
disease.
 
Many reasons exist to investigate the role of insulin in the
development of atherosclerosis.  Insulin is the major hormone
controlling the assimilation and utilization of nutrients.  It has
multiple effects, not only upon carbohydrate metabolism,  but also
upon fat and amino acid metabolism, body salt and water balance, and
cell growth.  Insulin promotes development of atherosclerotic lesions
in animals (22).  Population studies indicate that hyperinsulinemia,
either fasting or following a challenge, is an independent risk
factor for CVD (13,23,24).  These associations of insulin with
vascular disease could be mediated indirectly, through changes in
risk factors, particulary lipids and blood pressure, or directly,
through stimulation of cell growth in arterial walls (22).
 
Insulin concentrations may be correlated with CVD risk factors in the
general population as well as in those with hyperglycemia.  Levels of
insulin or insulin resistance may contribute to alterations among the
previously recognized CVD risk factors of obesity, hypertension,
hyperglycemia and hyperlipidemia (15-19).  In view of the large
percentage of the adult population with at least one of these
disorders, more detailed assessments of the role of insulin in
altering CVD risk factors over a range of deteriorating glucose
tolerance are needed.
 
Despite this evidence, it is difficult to explain the excess of CVD
in diabetics solely as a consequence of elevations in insulin levels.
Insulin secretion is usually greatest in those with impaired glucose
tolerance or mild diabetes, groups at lower risk of CVD than
diabetics with fasting hyperglycemia (5,25).  Recent, more limited,
studies suggest that part of the risk previously associated with
hyperinsulinemia may be correlated more strongly with high levels of
insulin resistance.  Since insulin response to a challenge is
diminished while insulin resistance remains high or continues to
increase as glucose levels increase within the diabetic range, these
observations may help to explain the higher risk of CVD in overt
diabetics (26).  More detailed assessments of the role of insulin
resistance relative to insulin levels in altering CVD risk factors
are needed.
 
Despite several studies that indicate an increased risk of CVD
associated with hyperglycemia, it remains unclear how much of this
risk is independently associated with hyperglycemia, how much can be
explained by adverse effects on conventional CVD risk factors, and
how much may be related to risk factors that were not measured in
previous population studies.  In diabetics with fasting
hyperglycemia, the increased risk of CVD appears to be mediated both
by increases in other CVD risk factors and by hyperglycemia or
related unmeasured metabolic abnormalities (5,12).  At high
concentrations, glucose may have a direct toxic effect upon
endothelial cells (27).  In subjects with impaired glucose tolerance
or mild diabetes, most of the excess risk of CVD may be attributed to
risk factors other than hyperglycemia.  Assessments of hyperglycemia
as an independent risk factor for CVD after adjustment for other
known risk factors may underestimate the risk related to abnormal
carbohydrate metabolism since conventional risk factors, especially
blood pressure and lipids, are altered adversely as glucose tolerance
deteriorates (28-29).  The increased risk of CVD that accompanies
hyperglycemia may be mediated, at least in part, by both direct and
indirect effects of glucose and insulin concentrations and levels of
insulin resistance.  Some CVD risk factors might be altered adversely
by high or low insulin concentrations while others might be more
affected by changes in insulin resistance.
 
It appears best to investigate the relationships among CVD risk
factors over a spectrum of glucose tolerance from normal to diabetes
with fasting hyperglycemia.  No distinct shift in the risk of CVD or
in CVD risk-factor levels is found between recognized diagnostic
categories of glucose tolerance.  The  National Diabetes Data Group
and WHO criteria for the definition of diabetes and impaired glucose
tolerance are based in part upon the risk of developing microvascular
complications of diabetes and are related only indirectly to the risk
of developing CVD (11,30).  Moreover, the major changes thought
responsible for the development of impaired glucose tolerance and
Type II diabetes, increasing insulin resistance and an initial
increase and subsequent decrease of endogenous insulin secretion,
occur at glucose levels which correspond imperfectly to the
established diagnostic categories.
 
Other observations support the concept of studying risk-factor
relationships across the spectrum of glucose tolerance.  Marked
differences in levels of a risk factor may exist within the range of
glycemia encompassed by a diagnostic category.  Serum insulin
response to a glucose challenge, for example, is usually above normal
in subjects with mild diabetes but is almost uniformly below normal
in diabetic subjects with fasting hyperglycemia (25).  In addition,
the change in individual risk factors with increasing glucose
concentrations is variable and shows little relationship to the
diagnostic categories.  Abnormalities in lipids and in the
glycosylation of proteins provide examples.  With mild glucose
intolerance, lipid concentrations are increased due to increased
lipid synthesis.  With severe hyperglycemia, lipid levels are
increased further due to impaired lipid clearance (31).  With mild
glucose intolerance, protein glycosylation is essentially normal but
when fasting hyperglycemia is present, glycosylation increases
substantially.  In previous studies, the numbers of subjects studied
usually were too small to characterize risk factor differences within
diagnostic categories.  Studies are needed with adequate sample sizes
and distributions to investigate these relationships.  Such
information will help to define goals for future interventions
attempting to reduce the risk of CVD associated with hyperglycemia.
 
Several abnormalities in CVD risk factors that have been associated
with hyperglycemia are outlined below.  Only limited information is
available about their alterations in relation to levels of glucose
tolerance, insulin, or insulin resistance.
 
Obesity is both a risk factor for the development of Type II diabetes
and usually persists after the disease is manifest (32).  In
addition, obesity is associated with adverse changes in many CVD risk
factors (33).  The central distribution of body fat, as measured by
the waist-to-hip ratio, is positively associated with diabetes
prevalence (34).  This distribution of fat has been associated with
elevated levels of insulin and insulin resistance (35).  Obesity
consistently shows one of the strongest associations with increased
levels of insulin and insulin resistance.
 
The majority of the macrovascular complications of diabetes occur in
subjects with concomitant hypertension (36).  Compared to subjects
with normal glucose tolerance, blood pressure is increased in both
subjects with impaired glucose tolerance and with diabetes (28).  The
earliest changes leading to hypertension in hyperglycemic subjects
are not known.  Subclinical involvement of the kidneys by diabetic
microvascular disease has been postulated as a cause of hypertension
but probably cannot account for the excess hypertension associated
with mild glucose intolerance. Hypertension has been linked with
hyperinsulinemia in both nondiabetic and diabetic subjects (15).  A
recent small study has found an association between increased insulin
resistance and hypertension in normal weight, normoglycemic subjects
(37).  Mechanisms underlying this association may include alterations
in renal sodium clearance and activation of the sympathetic nervous
system (38).
 
Lipid abnormalities become more pronounced as glucose concentrations
increase and suggest several ways in which hyperglycemia can
contribute to accelerated atherosclerosis.  Hypertriglyceridemia has
been recognized for decades as the most characteristic lipid
abnormality of diabetes mellitus (39).  In most diabetics, only
modest elevations are found in total cholesterol levels.  Elevations
are found in very low density lipoproteins (VLDL) and in low density
lipoproteins (LDL).  In Type II diabetic subjects,  high density
lipoproteins (HDL) are decreased and this abnormality is partially
corrected by treatment (29).  In one study, the improvement achieved
by therapy appeared related to insulin administration and not to the
degree of improvement in metabolic control, suggesting an independent
role for insulin in the control of lipoprotein metabolism (40).  The
reduced HDL concentrations found in Type II diabetics are inversely
correlated with insulin resistance (41).
 
Lipid abnormalities in diabetics also include alterations in the
metabolism and  composition of lipoprotein particles (42).  VLDL
degradation leads to an increased formation of highly atherogenic
particles which usually circulate for only brief periods.  Even in
diabetics with apparently normal total lipids the concentration of
remnant particles may be increased (43).  Specific apoprotein E
phenotypes and allele frequencies may be associated with
hyperlipidemia in diabetics (44).  Alteration of lipoprotein
molecules may increase their atherogenicity (45).  Apoproteins can
undergo glycosylation in a hyperglycemic environment.  In addition to
glycosylation of apoproteins, hyperglycemia leads to slow,
irreversible nonenzymatic glycosylation of multiple other proteins in
vivo.  A recent review indicates how these abnormalities could
contribute to accelerated atherosclerosis (46).
 
Abnormalities in platelet function, clotting factors and blood
viscosity also may contribute to the increased occurrence of CVD in
diabetics (47,48).  In some instances, these abnormalities may be
the result of damage from existing vascular disease.  Abnormalities
of platelet function have been described in diabetics but their
relationship to clinical cardiovascular disease is uncertain.
Changes in platelet function also may occur in nondiabetic subjects
with hypertension (49).  Abnormalities in clotting factors have been
described in association with diabetes or atherosclerosis (50,51).
The effects of differing degrees of hyperglycemia on these
alterations are not known.
 
Abnormalities in DNA segments may identify diabetics at increased
risk of atherosclerosis (52).  Further definition of genetic factors
that alter susceptibility to atherosclerosis could help to identify
individuals with glucose intolerance at particularly high risk of
developing macrovascular complications.
 
Studies to date on the relationship of insulin and insulin-resistance
levels to abnormalities in CVD risk factors have mainly been
conducted in Caucasian subjects.  Recent studies have suggested that
CVD risk-factor levels may have different associations with
documented risk of CVD in Hispanic vs. non-Hispanic whites (53).  The
well established relationship of insulin levels with blood pressure
levels may be reduced or absent in some American Indian tribes and
possibly in Blacks (54-56).  Studies comparing levels of glucose,
insulin, and insulin resistance, and their associations with other
CVD risk factors and prevalence of cardiovascular disease among
racial and ethnic groups within the U.S. population may help to
clarify the role of hyperglycemia and hyperinsulinemia in altering
CVD risk.
 
In addition to the relatively acute effects of hyperglycemia, more
chronic complications of diabetes may contribute to CVD mortality.
Diabetics, especially those receiving insulin therapy for many years,
have numerous abnormalities of autonomic nervous system function
(57).  When severe, these abnormalities are associated with sudden
death.  Other potential risk factors, such as an excess of silent
ischemia, have been reported in diabetics (58).
 
In summary, deficits in information from earlier epidemiologic
studies and recent advances in understanding of risk factors for CVD
and methods to measure CVD in population studies make it promising to
investigate the associations between levels of glucose, insulin and
insulin resistance, and other known CVD risk factors and their
relationship to prevalent cardiovascular disease.  It is essential
that future studies examine risk-factor levels over a wide spectrum
of glucose tolerance from normal through impaired glucose tolerance
to diabetes with fasting hyperglycemia.  Differing patterns of risk-
factor abnormalities may be found at different points on this
spectrum.  Such patterns may help to explain the different rates of
CVD and the apparent discrepancies in the independent contribution of
glucose concentration to CVD risk over the spectrum.   An improved
understanding of the relation of insulin concentrations and insulin
resistance to CVD risk factors also will help to explain a component
of CVD risk in the general, normoglycemic, population as well as in
that portion of the population that has hyperglycemia.
 
GOAL OF THE ACTIVITY
 
The primary purpose of this Request for Applications (RFA)
is to stimulate a collaborative,
multidisciplinary investigation of the relationships between blood
glucose and insulin concentrations, insulin resistance, and other CVD
risk factors and cardiovascular disease in subjects with diabetes and
in subjects with asymptomatic glucose intolerance as compared to
subjects with normal glucose tolerance.
 
OVERVIEW
 
The objective of this RFA is to assess the relationships of
increasing concentrations of glucose and changing levels of insulin
and insulin resistance to other recognized CVD risk factors, and to
the presence of atherosclerotic vascular disease using standard
methodology and a large enough population so there are adequate
numbers for comparisons of changes across the range of glucose
tolerance.  This study will provide insight into the reasons for the
changing risk of CVD at increasing glucose levels and may help to
explain the reported differences in the contribution of hyperglycemia
to the risk of CVD in men and women and in minority populations.
 
Several features of this study are specified so that applicants have
common understanding of factors necessary for the collaborative
effort, e.g. its magnitude, phases, and the handling of certain
central functions.  Many characteristics of the subjects to be
studied are specified.  However, the nature of the studies to be
carried out in the collaborative investigation of the relationships
between levels of glucose and insulin, insulin resistance, other CVD
risk factors and cardiovascular disease are in the hands of the
investigators.  A number of possible components are listed purely for
illustrative purposes.
 
The collaborative protocol will be developed by the Project Steering
Committee, composed of the awardees and the NHLBI Project Scientist.
The protocol will be subject to peer review by an uninvolved expert
group.  The study will move into its second (or operational) phase
only with the concurrence of both the awardees and the Institute.
 
SCOPE OF ACTIVITY
 
The studies are envisioned as taking place in two to four field
centers and as involving between 1600 and 1800 subjects.  Applicants
should plan the study in four phases:  (I) collaborative protocol
development, (II) sample selection, (III) sample examination, and (IV)
data analysis and reporting.  This is further described under the
section "Study Phases".  Central functions of the collaborative
activity, a Coordinating Center and a Central Laboratory, will
probably be performed by or under the direction of one or more of the
field centers.  This will require separate applications and is
described in detail under the section "Central Functions".
 
The characteristics desired of the study sample are outlined below.
To avoid bias, the subjects should be recruited from a defined
population.  A critical component of this study is to achieve a
stratified sample with subjects distributed in approximately equal
numbers across a range of  glucose concentrations from normal through
impaired glucose tolerance to overt diabetes.  In addition, efforts
should be made to recruit approximately equal numbers of men and
women over the age range 40 to 69 years.  Each group should have a
comparable range of obesity and include subjects treated and
untreated for hypertension.
 
The study will not include funding to support general population
screening for glucose tolerance.  Considerable reduction in screening
costs can be achieved by use of existing data even as simple as a
recent fasting glucose determination.  Potential subjects with
varying degrees of glucose tolerance must be available, but their
prior characterization by standardized glucose tolerance testing is
not mandatory.  Information should be provided concerning the type
and time of prior testing and the availability of test results.
 
Investigators should be aware that NIH requires applicants to give
added attention, where feasible and appropriate, to the inclusion of
minorities and women in study populations.  Gender and minority
population differences must be noted and analyzed whenever possible.
If minorities and/or women are not included in a given study, a clear
reason for their exclusion must be provided.  Merely including an
arbitrary number of minority group and women participants in a given
study is insufficient to guarantee generalization of results.
 
In view of recent evidence that the risk of CVD associated with
abnormalities in glucose and insulin homeostasis may vary among non-
Hispanic white and minority populations, investigators are strongly
encouraged to include minorities in the populations they propose for
study.  This should be done in a way that provides the strongest
scientific design to investigate the origin of the potential
differences.
 
Based upon what is known, what is needed, and what is deemed
feasible, NHLBI intends that the collaborative study will include
sufficient subjects of at least one or two minority populations to
test for possible differences.  The Institute would prefer to have
such diversity of populations at each awardee institution.  However,
the characteristics of this study may militate against this.  The
Institute may have to achieve its minority population goal by the
selection of awardees in part on the basis of the populations and mix
of populations that they will bring into the collaborative study.
Each applicant should propose the study design he or she believes
most appropriate for this project.  Each application should include a
description of the characteristics of the reference population and of
the sample to be selected.  Applicants should discuss any factors
that they believe should exclude a participant from the study.
Evidence might be presented indicating the availability of health
care records of prospective subjects for review during the screening
phase.  Since duration of hyperglycemia may be important in the
pathogenesis of vascular disease, data on duration of documented
diabetes or hyperglycemia, if available, may be particularly
valuable.  Applicants should discuss the advantages and disadvantages
of their proposed approaches to the study and describe their plan for
obtaining collaboration for the examination.
 
Whatever strategy is proposed for subject selection, applicants
should provide a detailed justification for the projected selection
plan, an estimate of the number of subjects in the source population
and in the final examination sample, as well as an estimate of the
necessary time and effort to identify the Phase III study subjects.
Applicants unable to recruit at least 400 subjects for the Phase III
examination are unlikely to receive awards.  All centers must be
willing to implement the selection and examination strategies
developed collaboratively by the Steering Committee during protocol
development and to supply their data and necessary specimens to the
Coordinating Center and other central facilities for combination and
analysis.
 
Applicants should indicate what data they propose for collection in
the collaborative endeavor and provide justification for each
component of their proposed examination.  For illustrative purposes,
tests that might be included in the study are outlined below.  This
is not intended to constrain applicants who are encouraged and
expected to propose the study design they believe best to achieve the
goals of the project.  The collaborative protocol will be developed
during Phase I.
 
Core examinations might include interview data including a limited
dietary assessment and a limited physical examination concentrating
on evidence of cardiovascular disease and CVD risk factors.  Blood
pressure and heart rate might be measured both supine and erect.
Adiposity and its distribution might be assessed.  Laboratory tests
might include assessment of evidence of CVD and CVD risk factor
levels.  Laboratory tests might include some or all of the following
and any additional tests that the applicant believes worthwhile.  It
is expected that most of the proposed measurements will be conducted
at each institution under the core protocol.  For some measurements
requiring complex techniques, however, investigators may propose to
perform tests in a defined subgroup of the study population.
Measures of cardiovascular disease:
 
 Electrocardiogram
    Additional measures of cardiac disease such as echocardiography
    Additional measures of atherosclerotic vascular disease such as
    carotid ultrasonography
 
Laboratory measurements of:
    Glucose, both fasting and after a standard load
 
 Insulin, both fasting and after a standard load
    Insulin resistance
    Glycosylated hemoglobin
 
 Insulin secretion over 24 hours
 
 Cholesterol, Triglycerides
 
 Lipoproteins (LDL, HDL, VLDL and possibly IDL)
 
 Glycosylated LDL or other lipoproteins
 
 Apoproteins, including A1, B and E
 
 Post prandial lipids
    Urinary protein excretion
 
 Coagulation measurements
  Platelet function
  Clotting factors, including fibrinogen, Factors VII and VIII
     Blood viscosity alterations
 
Applicants should discuss the relative merits of assessing each of
the risk factors they propose to measure in terms of current
knowledge, new information to be obtained, potential importance as a
cause of CVD, and the precision of available measurement techniques.
A similar discussion should be provided for each proposed measure of
existing cardiovascular disease.  They also should discuss how, when,
where, and by whom the data are to be collected as well as the
procedures essential for assuring proper collection, completeness and
accuracy of the data, and prompt transmission to the Coordinating
Center.  Applicants must be able to interact effectively with the
Coordinating Center for data transmission and editing.
 
STUDY COMPONENTS
 
A. Field Centers
 
The Field Centers will recruit subjects, review necessary records and
perform examinations for the study.  Central functions will be
performed by or under the direction of one or more of the Field
Centers.
 
B. Central Functions
 
Each Field Center applicant is  encouraged to apply to serve as one
or more of the central support units for the study.  A separate
application should be submitted for each support unit.  It is
unlikely that an award will be made for a support unit independent of
a field center award.  Applicants should discuss the special
functions of any proposed support activity, including methodology and
quality control assessment, provide a budget and an estimate of time
for the work to be completed.  The specific areas to be addressed in
applications for support units are outlined in the Review Criteria
section.
 
    1. Coordinating Center
 
The Coordinating Center will serve as the central data management
facility for the study.  This center will participate in protocol
development, produce the Manual of Operations, the data collection
forms, and oversee training for the study.  Data collected in the
Field Centers and generated in the central laboratory will be
transmitted to the Coordinating Center for storage and analysis.
This center will oversee performance of any special measurements at
other laboratories.  The Coordinating Center will play a lead role in
monitoring subject recruitment and the quality control of the study.
It will prepare reports for the Steering Committee and Data
Monitoring Board and will provide data analysis for final study
publications.
 
    2. Central Laboratory
 
The Central laboratory will perform or, in special cases, arrange
for, the laboratory determinations specified in the study protocol.
The laboratory will be responsible for developing a procedure manual
for sample acquisition and processing in the Field Centers, sample
shipment to the appropriate laboratory and analyze measurement
methodology.  Together with the Coordinating Center, it will be
responsible for monitoring quality control of all samples.  It will
be responsible for prompt performance of assays and timely
transmission of data to the Coordinating Center.
 
STUDY PHASES
 
The study may be divided into four main phases, a planning phase
(Phase I), a record review and subject selection phase (Phase II), an
examination phase (Phase III), and a data analysis and report
preparation phase (Phase IV).
 
Phase I
 
The goal of Phase I will be to design the study.  This phase should
take approximately 12 months.  Meetings of the Steering Committee
composed of the Principal Investigators and the NHLBI Project
Scientist will be held approximately 4 to 6 times during this period
in Bethesda, MD.  The primary issues to be resolved by the Steering
Committee during this phase include design of the study and
determination of eligibility criteria for participation in the sample
selection and examination Phases (II and  III).  Other key staff
involved in the study may be invited to participate in planning. This
phase will have the following objectives:
 
1. To develop a common protocol using standardized methods for
selection of subjects and review of existing records to classify them
with respect to glucose tolerance and the presence or absence of
existing CVD.
 
2. To develop a common protocol for testing subjects to assess
current level of glucose tolerance.
 
3. To develop a common protocol for a limited examination for
objective evidence of CVD and the measurement of selected CVD risk-
factor levels among members of the final (Phase III) stratified
sample.
 
Additional objectives for this phase will be to develop data
collection forms and a Manual of Operations for the study; to recruit
and train key staff in procedures for medical record review and for
the examination of subjects.  Near the conclusion of this phase, a
two to three day training session will be held.  Staff representing
each functional category requiring training should be available for a
training meeting to be held at a central location (Bethesda should be
used for cost estimation) prior to the start of examinations.  At the
end of Phase I, a pilot study will be conducted to insure that
standardization of core protocol procedures is achieved among all
centers.
 
Phases II and III
 
The goal of Phase II is the selection of the stratified sample for
the Phase III examination.  This phase should take approximately
eight months.  All participating centers must implement the common
protocol developed by the Steering Committee during Phase I.  The
Steering Committee will meet approximately twice during this phase.
 
The goal of Phase III is to conduct the examination of the stratified
sample.  This phase will take approximately sixteen months.  During
this period, the Steering Committee will meet approximately every
four months to review progress.  Additional communication will be by
telephone conference calls, approximately monthly.
 
Note: Investigators proposing to use populations with previously
defined glucose tolerance may find it more efficient and economical
to combine Phases II and III.
 
Phase IV
 
Phase IV will be a period for "close-out" activities, data analyses,
and manuscript preparation.  This phase should take approximately
twelve months.  Reduced support will be continued for a limited
period for field centers to complete final data entry and respond to
edit queries from the Coordinating Center.  The Coordinating Center
will support the preparation of study reports and manuscripts with
data analyses, statistical consultation, editorial and clerical tasks,
and coordination of meetings.  It is anticipated that at least one
meeting of the  Steering Committee, as well as periodic conference
calls, will be necessary during this period.
 
STUDY RESPONSIBILITIES, GOVERNANCE and FUNDING
 
The primary governing body of the study will be the Steering
Committee, composed of the principal investigators of the study
centers and the NHLBI Program Scientist.  Subcommittees will be
formed on such topics as study design and execution, quality control,
and publications, and will also have NHLBI representation.  Unless
otherwise explicitly provided, the non-NHLBI investigators will have
the lead role in the Steering Committee and its subcommittees.  The
first meeting of the Steering Committee will be convened by the NHLBI
Program Scientist.  All major scientific decisions will be determined
by vote of the Steering Committee.  The Committee will have primary
responsibility for the development of the study protocol,
facilitating the conduct of the study, and reporting of the study
results.
 
It is expected that data will be submitted centrally and that the
protocol will define rules regarding access to data and publications.
A Data and Safety Monitoring Board, to be appointed by the Institute,
will review progress at least annually and report to the Institute.
 
TERMS AND CONDITIONS OF AWARD
 
It is anticipated that two to four awards will be made under this RFA
for a total of approximately $7.0 million (including direct
and indirect costs for field centers and all central functions) over
a four-year period.  Funding is expected to begin on or about
September 30, 1991.  Applications from foreign institutions will be
considered only if the applicant provides detailed evidence of unique
opportunities not available in a U.S. population.
 
The administrative and funding mechanism to be used to undertake this
program will be cooperative agreements, an assistance mechanism.
Under the cooperative agreement, the NIH assists, supports and/or
stimulates and is involved substantially with recipients in
conducting a study by facilitating performance of the effort in a
"partner" role.  Consistent with this concept, the tasks and
activities in carrying out the studies will be shared among the
awardees and the Institute project scientist.  The tasks or
activities in which awardees will have substantial responsibilities
include protocol development, patient recruitment and follow-up, data
collection, quality control, interim data and safety monitoring,
final data analysis and interpretation, preparation of publications,
collaboration with other awardees, and collaboration with the NHLBI
project scientist.  The NHLBI project scientist will have substantial
responsibilities in protocol development, quality control, interim
data and safety monitoring, final data analysis and interpretation,
preparation of publications, collaboration with awardees,
coordination and performance monitoring.  It is anticipated that
awardees will have lead responsibilities in protocol development,
final data analysis and interpretation, and in the preparation of
most publications.  The NHLBI project scientist will have lead role
responsibilities in quality control and interim data and safety
monitoring and in the preparation of some publications.  The NHLBI
project scientist will have membership on the Steering Committee and
its subcommittees and on the Data and Safety Monitoring Board.
 
The Institute reserves the right to terminate or curtail the study
(or an individual award) in the event of a substantial shortfall in
(a) patient recruitment, follow-up, data reporting, quality control,
or other major breech of the protocol; or (b) substantive changes in
the agreed-upon protocol to which the Institute does not agree; or
(c) reaching a major study endpoint substantially before schedule
with persuasive statistical significance; or (d) human subject
ethical issues that may dictate a premature termination.
 
Any disagreement that may arise in scientific matters between award
recipients and NHLBI may be brought to arbitration.  An arbitration
panel will be composed of three members - one selected by the
Steering Committee (with NHLBI member not voting) or by the
individual awardee in the event of an individual disagreement, a
second member selected by NHLBI and the third member selected by the
two prior members.  This special arbitration procedure in no way
affects the awardees right to appeal an adverse action that is
otherwise appealable in accordance with the PHS regulations at 42 CFR
part 50, subpart D and HHS regulation at 45 CFR part 16.
 
These special Terms of award are in addition to, and not in lieu of,
otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations at 45 CFR part 74, and other HHS, PHS, and
NIH grant administration policy statements.
 
REVIEW PROCEDURES AND CRITERIA
 
General Considerations
 
All applicants will be judged on the basis of the scientific merit of
their proposed study and their documented ability to conduct the
essential study components as outlined in the Activities Sought and
Overview sections of this RFA.
 
Review Method
 
Upon receipt, applications will be reviewed for their responsiveness
to the objectives of this RFA.  If an application is judged
unresponsive at this stage, it will be returned to the applicant.
All applications responsive to this RFA will be reviewed initially
for scientific and technical merit by a special review group,
convened by the Division of Extramural Affairs, NHLBI, to review
these applications.  Subsequently, they  will be reviewed by the
National Heart, Lung and Blood Advisory Council, most likely at its
September 1991 meeting.
 
Following primary scientific merit review, some applicants may
receive further inquiry from Institute program staff.  This may focus
upon scientific or technical questions arising from the peer review
or upon primarily operational and administrative questions.  The
inquiry may involve no more than a telephone call or letters, or it
may take the form of a site visit or a reverse site visit.
 
If the application submitted in response to this RFA is substantially
similar to a research grant application already submitted to the NIH
for review, but that has not yet been reviewed, the applicant will be
asked to withdraw either the pending application or the new one.
Simultaneous submission of identical applications will not be
allowed, nor will essentially identical applications be reviewed by
different review committees.  Therefore, an application cannot be
submitted in response to this RFA which is essentially identical to
one that has already been reviewed.  This does not preclude the
submission of substantial revisions of applications already reviewed,
but such applications must include an Introduction addressing the
previous critique.
 
Review Criteria
 
Applicants are encouraged to submit and describe their own ideas on
how best to meet the goals of the study.  Applications will be judged
primarily on the scientific quality of the application, the
availability of a study sample with adequate numbers of subjects
across a range of glucose tolerance from normal to overt diabetes,
the ability to select and measure CVD risk factors and to identify
prevalent cardiovascular disease, the discussion of considerations
relevant to this RFA, expertise of the investigators, their
capability to perform the work proposed,  and a demonstrated
willingness to work together with other Centers, the Coordinating
Center, and NHLBI project scientist.
 
Criteria for review of the applications will include, but not
necessarily be limited to, the following:
 
For Field Centers:
 
1. Scientific merit of the proposed study design including:
 
o methods to assess glucose tolerance, insulin response, and insulin
resistance
 
o CVD risk factors to be assessed and proposed methodology
 
o measures of prevalent CVD and proposed methodology
 
  o discussion of the relative merits of measuring each of the CVD
risk factors that the applicant proposes for inclusion in the study
in terms of current knowledge, new information to be obtained, its
potential importance as a cause of CVD, and the precision of available
measurement techniques
 
o discussion of the relative merits of each of the measures of
prevalent CVD that the applicant proposes for inclusion in the study
in terms of current knowledge, new information to be obtained, and
the precision of the proposed measurement techniques.
 
2. Availability of a population with the appropriate distribution of
glucose tolerance and an adequate distribution by age, sex, and
obesity. Availability of medical records to review and the ability to
recruit participants for the examination phase including:
 
o the availability of results and distribution of glucose levels from
previous studies in the source population for study subjects
 
o the stratified sample proposed for examination
 
o the criteria proposed for exclusion of subjects
 
o evidence to indicate the likelihood of acceptable exam
participation
rates
 
o the ability to complete the work proposed in a timely manner
 
Note: Based upon what is known, what is needed, and what is deemed
feasible, NHLBI intends that the collaborative study will include
sufficient subjects of at least one or two minority populations to
test for possible differences.  The Institute would prefer to have
such diversity of populations at each awardee institution.  However,
the characteristics of this study may mitigate against this.  The
Institute may have to achieve its minority population goal by the
selection of awardees in part on the basis of the populations and mix
of populations that they will bring into the collaborative study.
 
3. Qualifications, experience, and commitment of key personnel
including:
 
o expertise of the investigators and other key personnel in the
conduct of epidemiologic studies of cardiovascular disease and/or
diabetes; expertise of investigators in cardiology and endocrinology
 
o expertise of relevant investigators in performance of proposed
special laboratory or clinical tests
 
o ability of key personnel to devote adequate time for the
effective conduct of the study
 
o administrative capabilities of the Principal Investigator and
other key team members
 
o willingness to work in cooperation with other Centers, the
Coordinating Center, and the NHLBI in the manner summarized in the
RFA, including implementation of the common protocol selected
 
Note: It is the belief of NHLBI that cooperation between experts in
cardiovascular disease and diabetes and between epidemiologists and
experts in clinical research is essential for efficient exploration
of the relationships among insulin, insulin resistance, and CVD.
Inadequate strength of proposed collaborative efforts was apparent in
many responses to the RFA on Hyperglycemia and Cardiovascular Disease
(NIH-88-HL-11-P) issued by NHLBI in July 1988 and was a factor in the
decision not to fund this earlier program.  Multidisciplinary
approaches to this problem are strongly encouraged.
 
4. Ability to implement the data collection and reporting procedures.
 
5. Appropriateness of the budget for the work proposed.
 
6. A description of facilities and resources available and/or needed
For the Coordinating Center: Criteria 3 through 6 under Field
Centers plus:
 
o ability to develop protocols including forms development and
related instructional materials and the study Manual of Operations
 
o ability to process the volume of data expected and manage the
study data base
 
o plans to assure quality control of data
 
o ability to monitor study recruitment
 
o ability to provide analytical support
 
o ability to provide interim reports to the Steering Committee
 
o ability to complete work on schedule
 
For the Central Laboratory: Criteria 3 through 6 under Field Centers
plus:
 
o ability to develop and monitor procedures for sample collection,
processing, and transportation to the required laboratory(ies)
 
o ability to process the volume of specimens and data expected
 
o ability to assure quality control of data generated
 
o laboratory methodology proposed for each test
 
o ability to complete work on schedule
 
o ability to transmit data promptly to the Coordinating Center
 
o plans for subcontracting any component(s) of the laboratory
determinations (if applicable)
 
Each applicant must submit an adequately justified budget for each 12-
month period for a total of four years of support.  Estimates of
staffing needs, including the Principal Investigator and other
professional and support staff, must be included.  To assist with
program planning, each applicant is also asked to submit a budget for
each phase of the study as an appendix to the application.
 
METHOD OF APPLYING
 
Letter of Intent
 
Prospective applicants are asked to submit a letter of intent.  This
should be brief but indicate whether the applicant intends to apply
for only a field center site or whether separate applications will
also be submitted for one or more central support functions.  It
should indicate the Principal and Co-Investigators, and identify
cooperating institutions. The Institute requests such letters only
for the purpose of providing an indication of the number and scope of
applications to be received and usually does not acknowledge their
receipt.  A letter of intent is not binding, and it will not enter
into the review of any application subsequently submitted, nor is it
a necessary requirement for applications.  This letter of intent,
which should be received no later than February 1, 1991, should be
sent to:
 
                         James C. Scheirer, Ph.D.
                         Review Branch, DEA, NHLBI
                         Westwood Building, Rm 648
                         5333 Westbard Avenue
                         Bethesda, MD 20892
 
Format for Applications
 
Submit applications on form PHS 398 (revised 10/88), the application
form for the traditional research project grant.  This form is
available in an applicant institution's office of sponsored research
or business office, or from the Division of Research Grants, Office
of Grants Inquiries, Westwood Bldg., Rm 449, 5333 Westbard Avenue,
Bethesda, MD 20892.  Use the conventional format for research project
grant applications and ensure that the points identified in the
section on "Review Procedures and Criteria" are fulfilled.
 
The format and instructions for budget estimates provided should be
followed.  Indirect costs will be awarded in the same manner as for
research grants.  All costs for travel to meetings should be
estimated on the basis of a round trip to Bethesda, MD.  Budgets will
be reviewed on the basis of appropriateness for the work proposed.
Allowable costs and policies governing the research grant programs of
the NIH will prevail.  Overlapping support or duplication of funding
will not be allowed, and a summary of all actual and pending sources
of support for each key investigator participating in the study
should be included.  These summaries of other funding should identify
by name the Principal Investigator of each award and should include
the source of the funds with identifying grant or other award number,
percent effort committed, the amount of the award for the  current
year, the total amount of the award, the project period for which the
award was made.
 
This RFA is a one-time request for applications.  To identify the
application as a response to this RFA, check "yes" on Item 2 of page
1 of the application and enter the title, Insulin, Insulin
Resistance, and Cardiovascular Disease: RFA HL-91-03-P.  For
each application, in the upper left hand corner of the face page
enter the words Field Center, Coordinating Center, or Central
Laboratory, as appropriate.
 
Application Procedure
 
THE RFA LABEL FOUND IN THE FORM PHS FORM 398 APPLICATION KIT MUST BE
AFFIXED TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL COMPLETED
APPLICATION FORM PHS 398.  FAILURE TO USE THIS LABEL MAY RESULT IN
DELAYED PROCESSING OF YOUR APPLICATION SUCH THAT IT MAY NOT REACH THE
REVIEW COMMITTEE IN TIME FOR REVIEW.
 
Send or deliver the original, signed application and four (4)
complete photocopies of it to:
 
                         Division of Research Grants
                         Westwood Building, Room 240
                         National Institutes of Health
                         Bethesda, MD 20892**
 
Send two (2) additional copies of the application to:
 
                         James C. Scheirer, Ph.D.
                         Review Branch, DEA, NHLBI
                         Westwood Building, Rm 648
                         5333 Westbard Avenue
                         Bethesda, MD 20892
                         Telephone:  (301) 496-7363
 
IT IS IMPORTANT TO SEND THESE TWO COPIES AT THE SAME TIME AS THE
ORIGINAL AND FOUR COPIES ARE SENT TO THE DIVISION OF RESEARCH GRANTS.
OTHERWISE, THE NHLBI CANNOT GUARANTEE THAT THE APPLICATION WILL BE
REVIEWED IN COMPETITION FOR THIS RFA.
 
Application must be received by April 5, 1991.  An application not
received by this date will be considered ineligible.
 
Time table
 
Letter of Intent                                 February 1, 1991
 
Application Receipt Date                         April 5, 1991
 
Review by National Heart, Lung and
Blood Advisory Council                           September 12-13, 1991
 
Anticipated Award Date                           September 30, 1991
 
Inquiries
 
Inquiries regarding this announcement may be directed to the Project
Scientist:
 
                    Peter J. Savage, M.D.
                    Clinical and Genetic Epidemiology Branch, DECA,
                     NHLBI
                    Federal Building, Rm 300
                    7750 Wisconsin Avenue
                    Bethesda, MD 20892
                    Telephone 301-496-4333
 
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18. Foster DW. Insulin resistance - a secret killer?
N Engl J Med 320:733-34, 1989.
 
19. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK.
Cardiovascular risk factors in confirmed prediabetic individuals:
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20. Poli A, Tremoli E, Colombo A, Sirtori M, Pignoli P, Paoletti R.
Ultrasonographic measurement of the common carotid arterial wall
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21. Julius S, Jamerson K, Mejia A, Krause L, Schork N, Jones K. The
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22. Stout RW. Overview of the association between insulin and
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23. Welborn TA, Wearne K. Coronary heart disease incidence and
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24. Ducimentiere P, Eschwege E, Papoz L, Richard JL, Claude JR,
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26. DeFronzo RA, Feerronnini E, Kovisto V.  New concepts in the
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27. Lorenzi M, Cagliero E, Toledo S.  Glucose toxicity for human
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28. Jarrett RJ, Keen H, McCartney M, Fuller JH, Hamilton PJS, Reid
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29. Howard BV. Lipoprotein metabolism in diabetes mellitus. J Lipid
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30. Diabetes Mellitus: Report of WHO Study Group. Technical Report
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31. Weiland D, Mondon CE, Reaven GM.  Evidence for multiple causality
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32. Dunn JP, Ipsen J, Elsom KO, Ohtani M.  Risk factors in coronary
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33. National Institutes of Health: Concensus Development Conference
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34. Feldman R, Sender AJ, Sieglaub AB. Differences in diabetic and
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35. Stern MP, Haffner SM.  Body fat distribution and hyperinsulinemia
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36. Goodkin G. Mortality factors in diabetes.  J Occup Med 17:716-
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37. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M,
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38. Landsberg L. Diet, obesity and hypertension: an hypothesis
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39. Albrink MJ, Lavietes PH, Man EB.  Vascular disease and serum
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40. Bergman M, Gidez LI, Eder HA.  High density lipoprotein
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41. Abbott WG, Lillioja S, Young AA, Zawadzki JK, Yki-J:arvinen H,
Christin L, Howard BV. Relationships between plasma lipoprotein
concentrations and insulin action in an obese hyperinsulinemic
population. Diabetes 36:897-904, 1987.
 
42. Steiner G. Hypertriglyceridemia and carbohydrate intolerance:
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1986.
 
43. Kasama T, Yoshino G, Iwatani I, Iwai M, Hatanaka H, Kazumi T,
Oimomi M, Baba S.  Increased cholesterol concentration in
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44. Eto M, Watanabe K, Iwashima Y, Morikawa A, Chonan N, Oshima E,
Sekiguchi M, Ishii K. Increased frequency of apolipoprotein E4 allele
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1987
 
45. Haberland ME, Fogelman AM. The role of altered lipoproteins in
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46. Cerami A, Vlassara H, Brownlee M. Protein glycosylation and the
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47. Ostermann H, Van de Loo J. Factors of the hemostatic system in
diabetic patients.  A survey of controlled studies. Haemostasis
16:386-416, 1986.
 
48. McMillan DE. Effects of insulin on physical factors:
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1985.
 
49. Kjeldsen SE, Lande K, Gjesdal K, Westheim A, Foss OP, Leren P,
Eide IK.  Increased platelet release reaction in 50-year old men with
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50. Kannel WB, Wolf PA, Castelli WP, D'Agostino RB.  Fibrinogen and
the risk of cardiovascular disease: the Framingham Study.  J Am Med
Assoc 258:1183-1186, 1987.
 
51. Breddin HK, Krzywanek HJ, Althoff P, Schoffing K Oberia K.  PARD:
Platelet aggregation as a risk factor in diabetics: Results of a
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52. Mandrup-Poulsen T, Owerbach D, Nerup J, Johansen K, Ingerslev J,
Hansen AT.  Insulin gene flanking sequences, diabetes mellitus and
atherosclerosis: a review.  Diabetologia 28:556-564, 1985.
 
53. Mitchell BD, Stern MP, Haffner SM, Hazuda HP, Patterson JK. Risk
factors for cardiovascular mortality in Mexican Americans and non-
Hispanic whites. San Antonio Heart Study. Am J Epidemiol 131:423-33,
1990.
 
54. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH.
Insulin and hypertension: Relationships to obesity and glucose
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55. Saad MF, Lillioja S, Nyomba B, Raz I, Zurlo F, Castillo C,
Ferraro R, Knowler WC, Bennett PH, Howard BV, Bogardus C. Ethnic
differences in the relationship between blood pressure and insulin
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56. Manolio TA, Savage PJ, Burke GL, Liu K, Wagenknecht LE, Sidney S,
Jacobs DR Jr., Roseman JM, Donahue RP, Oberman A. Association of
fasting insulin with blood pressure and lipids in young adults: the
CARDIA study. Arteriosclerosis 10:430-36, 1990.
 
57. Boulton AJM, Knight G, Drury J, Ward JD.  The prevalence of
symptomatic diabetic neuropathy in an insulin treated population.
Diab Care 8:125-128, 1985.
 
58. Nesto RW, Phillips RT. Asymptomatic myocardial ischemia in
diabetic patients.  Am J Med 80:(4C)40-7, 1986.
 
The programs of the Division of Epidemiology and Clinical
Applications, National Heart, Lung and Blood Institute, are
identified in the Catalog of Federal Domestic Assistance, Numbers
93.837-93.839.  Awards will be made under the authority of the Public
Health Service Act, Section 301 (42 U.S. 241) and administered under
PHS grant policies and Federal regulations, most specifically 42 CFR
Part 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372, or to
Health Systems Agency review.