RELEASE DATE:  June 25, 2002

PA NUMBER:  PA-02-117

EXPIRATION DATE:  October 1, 2005, unless reissued.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)  


o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


The National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) seeks research applications to enhance our understanding of the 
underlying metabolic and physiologic mechanisms that contribute to the 
racial and ethnic differences in the incidence and pathophysiology of 
type 2 diabetes in the United States.



It is well recognized that there are major differences in the 
prevalence of type 2 diabetes among race-ethnic groups in the United 
States.  Substantial progress has been made toward identifying 
population-based risk factors for the development of type 2 diabetes 
that might lead to these race-ethnic disparities.  Such established 
risk factors include, for example, genetic predisposition, total and 
central obesity, duration of obesity, high caloric intake, and physical 
inactivity.  Factors such as socioeconomic status, acculturation, and 
stress may also be important.  Individuals who have progressed along 
the pathogenic course toward diabetes are at higher risk of developing 
overt disease, and these individuals include those with insulin 
resistance, impaired glucose tolerance, gestational diabetes, and 
reduced beta cell function.

Although these diabetes risk factors appear to operate in all race-
ethnic groups, it is not known whether specific groups are inherently 
different in the ways they respond to risk factors, which may lead to 
their differential susceptibility to diabetes.  Environmental, genetic, 
and metabolic differences may underlie the disparity in diabetes rates, 
and physiological outcomes of risk factors may arise from a complex 
interplay of genetic and non-genetic (behavioral, lifestyle, and 
environmental) factors.

Epidemiologic studies have documented the differing risk for diabetes 
among race-ethnic groups and have established the identity of diabetes 
risk factors. However, with few exceptions, these studies have not been 
designed to examine in depth the metabolic and physiologic effects of 
diabetes risk factors in specific race-ethnic populations.  
Consequently, there is an important need for carefully designed 
clinical studies to investigate these issues in representative samples 
of the various U.S. race-ethnic groups.

Objectives and Scope

The overall objective of this Program Announcement is to determine the 
metabolic and physiologic reasons for disparities in the incidence of 
type 2 diabetes in minority race-ethnic populations.  Such information 
could lead to new prevention and treatment strategies, especially for 
high risk groups. Additionally, information from these studies would be 
important for devising cost-effective approaches to phenotyping 
patients with type 2 diabetes and individuals at risk for developing 
diabetes. The ability to characterize and identify discrete subgroups 
of type 2 diabetes would be essential in genetic studies of this 

Studies to investigate the behavioral, socioeconomic, psychosocial, 
cultural, family, and community factors that influence the individual's 
risk for developing type 2 diabetes and how these factors can lead to 
racial and ethnic disparities in incidence rates are clearly of 
importance. Understanding these issues is vital to the development of 
culturally appropriate prevention strategies to reduce risk across 
racial and ethnic groups. However, studies to investigate non-biologic 
factors should not be submitted under this Program Announcement, which 
will focus on biologic factors responsible for race/ethnic disparities 
in the incidence of type 2 diabetes.

Appropriate topics for investigation would include but are not limited 

o State-of-the-art, hypothesis-driven metabolic studies in which fat 
metabolism, glucose levels, insulin secretion, energy expenditure, 
etc., are measured in individuals from U.S. race-ethnic groups.  Such 
studies might determine, for example, whether some groups are at 
greater risk for type 2 diabetes from insulin resistance or from 
reduced beta-cell reserve; whether fat content and distribution differ 
among race-ethnic groups, and what metabolic or physiologic processes 
are responsible in the pathogenetic pathway leading to type 2 diabetes.

o The temporal relationship of changes in body weight and body 
composition, glucose tolerance, and insulin resistance in the etiology 
of type 2 diabetes.  Clinical studies could unravel the sequence of 
events leading to type 2 diabetes, especially the timing of weight gain 
with regard to glucose tolerance and insulin resistance.  A critical 
question is whether individuals who will develop diabetes first gain 
weight and then develop diabetes, with the same genes leading to both 
conditions; or whether individuals gain weight and then proceed to 
diabetes because of beta cell defects. 

o Beta-cell function.  There is growing appreciation that substantial 
beta-cell defects occur prior to the onset of type 2 diabetes.  Very 
little is known about the types of defects that actually predict or 
attend diabetes.  Most studies that have examined complex aspects of 
beta-cell function in vivo have been cross-sectional comparisons of 
high- vs. low-risk individuals.  A combination of detailed beta-cell 
assessments with longitudinal follow-up would likely yield important 
information about the pathogenesis of the beta cell defects.  Other 
phenotypic traits may also be useful in such studies, such as beta-cell 
responses to fatty acids, hyperglycemia, amino acids, and insulin 
resistance. Studies are needed to better understand whether there are 
racial/ethnic differences in the incidence and prevalence of impaired 
fasting glucose and impaired glucose tolerance, and whether there are 
differences among groups in the rates of progression to type 2 

o Fat metabolism and insulin resistance.  There is mounting evidence 
that altered fat metabolism in the whole body and, possibly, in 
skeletal muscle or adipocytes in muscle are important determinants of 
insulin resistance. Longitudinal studies employing detailed assessments 
of fatty acid turnover and/or muscle fat metabolism could yield 
important information about the relation between fat metabolism and 
insulin resistance as people change their physical activity, weight, 

o The temporal relationships among the components of  the metabolic 
syndrome (Syndrome X). The clustering of hypertension, hyperglycemia, 
obesity and insulin resistance is well documented; however, the 
temporal development of the individual components of the metabolic 
syndrome remain to be determined. In particular, the etiologic 
relationship among these components, and their relationship to type 2 
diabetes, need further investigation. Studies should examine the 
racial/ethnic differences in the constellation of metabolic 
abnormalities in this syndrome.

o The role of the in utero environment on the subsequent development of 
impaired glucose tolerance or type 2 diabetes. Extensive epidemiologic 
evidence suggests that intrauterine growth retardation is associated 
with numerous metabolic abnormalities in adults, including 
hypertension, cardiovascular disease, impaired glucose tolerance, 
hyperinsulinemia, and type 2 diabetes. However, little is known about 
the pathophysiologic mechanisms by which the intrauterine environment 
programs fetal metabolism to predispose individuals to chronic disease 
later in life. Studies are needed to assess whether abnormalities in 
the uterine environment contribute to ethnic/racial disparities in the 
incidence of type 2 diabetes, and, conversely, whether there are 
racial/ethnic differences in the response to a given in utero milieu.  

Advantage might be taken of extant cohort studies that may have been 
established for investigation of diabetes or investigation of other 
diseases.  Collaboration among investigators of these established 
cohorts would be desirable, so that these studies might jointly develop 
protocols and evaluate findings.  Alternatively, investigators may 
propose to start new cohorts, appropriately powered, to capture the 
current risks for development of type 2 diabetes.


This PA will use the National Institutes of Health (NIH) research 
project grant (R01) and the Exploratory/Development Research Grant 
(R21) award mechanisms.  Responsibility for the planning, direction, 
and execution of the proposed project will be solely that of the 
applicant.  The total project period for an R01 application submitted 
in response to this PA may not exceed 5 years. 

The R21 awards are to demonstrate feasibility and to obtain preliminary 
data testing innovative ideas that represent clear departure from 
ongoing research interests. These grants are intended to 1) provide 
initial support for new investigators; 2) allow exploration of possible 
innovative new directions for established investigators; and 3) 
stimulate investigators from other areas to lend their expertise to 
research within the scope of this solicitation. Applicants for the R21 
must limit their requests to $100,000 direct costs per year and are 
limited to two years. These R21 grants will not be renewable; 
continuation of projects developed under this program will be through 
the regular research grant (R01) program.

This PA uses just-in-time concepts.  It also uses the modular and non-
modular  format. (see 
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise, use 
the standard PHS 398 application instructions.


You may submit (an) application(s) if your institution has any of the 
following characteristics:
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign


Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support. Investigators new to 
diabetes and digestive and kidney diseases are encouraged to apply. 
Individuals from underrepresented racial and ethnic groups as well as 
individuals with disabilities are encouraged to apply for NIH programs.


We encourage inquiries concerning this PA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into 
two areas:  scientific/research, and financial or grants management 

Direct inquiries regarding programmatic issues to:

Barbara Linder, M.D, Ph.D. 
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of  Diabetes and Digestive
   And Kidney Diseases
6707 Democracy Boulevard, Room 699
Bethesda, MD 20892-5460
Telephone:  (301) 594-0021
FAX:  (301) 480-3503
E-mail:  bl99n@nih.gov

Direct inquiries regarding fiscal matters to:

Charlette Kenley
Division of Extramural Activities
Grants Management Branch
National Institute of  Diabetes and Digestive
   And Kidney Diseases
6707 Democracy Boulevard, Room 723
Bethesda, MD 20892-5456
Telephone:  (301) 594-8847 
FAX:  (301) 480-3504
E-mail: ck128k@nih.gov


Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at https://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.


All application instructions outlined in the PHS 398 application kit 
are to be followed, with the following requirements for R21 

1.  R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" 
concepts, with direct costs requested in $25,000 modules, up to the 
total direct costs limit of $100,000 per year. 

2. Although preliminary data are not required for an R21 application, 
they may be included.

3.  Sections a-d of the Research Plan of the R21 application may not 
exceed 15 pages, including tables and figures.  

4.  R21 appendix materials should be limited, as is consistent with the 
exploratory nature of the R21 mechanism, and should not be used to 
circumvent the page limit for the research plan. Copies of appendix 
material will only be provided to the assigned reviewers of the 
application and  will not be reproduced for wider distribution. The 
following materials may be included in the appendix:

o Up to 5 publications, including manuscripts (submitted or accepted 
for publication), abstracts, patents, or other printed materials 
directly relevant to the project. These may be stapled as sets.
o Surveys, questionnaires, data collection instruments, and clinical 
protocols.  These may also be stapled as sets.
o Original glossy photographs or color images of gels, micrographs, 
etc., provided that a photocopy (may be reduced in size) is also 
included within the 15 page limit of items a-d of the research plan.

APPLICATION RECEIPT DATES: Applications submitted in response to this 
program announcement will be accepted at the standard application 
deadlines, which are available at 
https://grants.nih.gov/grants/dates.htm.  Application deadlines are also 
indicated in the PHS 398 application kit.

direct costs in each year of $250,000 or less must be submitted in a 
modular grant format.  The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level 
of budgetary detail.  Applicants request direct costs in $25,000 
modules.  Section C of the research grant application instructions for 
the PHS 398 (rev. 5/2001) at 
https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at 


Applications requesting $500,000 or more in direct costs for any year 
must include a cover letter identifying the NIH staff member who has 
agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following 

1)  Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2)  Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and
3)  Identify, in a cover letter sent with the application, the staff 
member and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended 
or revised version of these grant application types. Additional 
information on this policy is available in the NIH Guide for Grants and 
Contracts, October 19, 2001 at 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the checklist, and five signed 
photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: Applications must be received by or mailed on 
or before the receipt dates described at 
https://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR 
will not accept any application in response to this PA that is 
essentially the same as one currently pending initial review unless the 
applicant withdraws the pending application.  The CSR will not accept 
any application that is essentially the same as one already reviewed.  
This does not preclude the submission of a substantial revision of an 
application already reviewed, but such application must include an 
Introduction addressing the previous critique.


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review 
group convened in accordance with the standard NIH peer review 
procedures (http://www.csr.nih.gov/refrev.htm) will evaluate 
applications for scientific and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed 
to have the highest scientific merit, generally the top half of 
applications under review, will be discussed and assigned a priority 
o Receive a second level review by the appropriate national advisory 
council or board

Review Criteria 

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health. 
In the written comments reviewers will be asked to discuss the 
following aspects of the application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals:

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

(1) Significance:  Does this study address an important problem?  If 
the aims of your application are achieved, how will scientific 
knowledge be advanced? What will be the effect of these studies on the 
concepts or methods that drive this field?

(2) Approach: Are the conceptual framework, design, methods, and 
analyses adequately developed, well-integrated, and appropriate to the 
aims of the project? Do you acknowledge potential problem areas and 
consider alternative tactics? 

(3) Innovation: Does the project employ novel concepts, approaches or 
method? Are the aims original and innovative? Does the project 
challenge existing paradigms or develop new methodologies or 

(4) Investigator: Are you appropriately trained and well-suited to 
carry out this work? Is the work proposed appropriate to your 
experience level as the principal investigator and to that of other 
researchers (if any)? 

(5) Environment: Does the scientific environment in which your work 
will be done contribute to the probability of success? Do the proposed 
experiments take advantage of unique features of the scientific 
environment or employ useful collaborative arrangements? Is there 
evidence of institutional support? 

The scientific review group will address and consider each of these 
criteria in assigning your application's overall score, weighting them 
as appropriate for each application. Your application does not need to 
be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score. For example, 
an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward. 

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  The adequacy of the proposed protection for humans, 
animals, or the environment, to the extent they may be adversely 
affected by the project proposed in the application.

INCLUSION:  The adequacy of plans to include subjects from both 
genders, all racial and ethnic groups (and subgroups), and children as 
appropriate for the scientific goals of the research.  Plans for the 
recruitment and retention of subjects will also be evaluated. (See 
Inclusion Criteria included in the section on Federal Citations, 

DATA SHARING:  The adequacy of the proposed plan to share data.

BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.


Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities


components involving Phase I and II clinical trials must include 
provisions for ssessment of patient eligibility and status, rigorous 
data management, quality assurance, and auditing procedures.  In 
addition, it is NIH policy that all clinical trials require data and 
safety monitoring, with the method and degree of monitoring being 
commensurate with the risks (NIH Policy for Data Safety and Monitoring, 
NIH Guide for Grants and Contracts, June 12, 1998: 

It is the policy of the NIH that women and members of minority groups 
and their subpopulations must be included in all NIH supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification is provided 
that inclusion is inappropriate with respect to the health of the 
subjects or the purpose of the research.  This policy results from the 
NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should 
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on October 9, 2001 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html; a 
complete copy of the updated Guidelines are available at 
 The amended policy incorporates: the use of an NIH definition of 
clinical research; updated racial and ethnic categories in compliance 
with the new OMB standards; clarification of language governing NIH-
defined Phase III clinical trials consistent with the new PHS Form 398; 
and updated roles and responsibilities of NIH staff and the extramural 
community.  The policy continues to require for all NIH-defined Phase 
III clinical trials that: a) all applications or proposals and/or 
protocols must provide a description of plans to conduct analyses, as 
appropriate, to address differences by sex/gender and/or racial/ethnic 
groups, including subgroups if applicable; and b) investigators must 
report annual accrual and progress in conducting analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

SUBJECTS:  It is the policy of NIH that children (i.e., individuals 
under the age of 21) must be included in all human subjects research, 
conducted or supported by the NIH, unless there are scientific and 
ethical reasons not to include them. This policy applies to all initial 
(Type 1) applications submitted for receipt dates after October 1, 

All investigators proposing research involving human subjects should 
read the "NIH Policy and Guidelines" on the inclusion of children as 
participants in research involving human subjects that is available at 

NIH policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement 
dated June 5, 2000, at the following website: 

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at 
https://grants.nih.gov/grants/stem_cells.htm and at  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see 
http://escr.nih.gov).   It is the responsibility of the applicant to 
provide the official NIH identifier(s)for the hESC line(s)to be used in 
the proposed research.  Applications that do not provide this 
information will be returned without review. 

The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at:

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application.

proposals for NIH funding must be self-contained within specified page 
limitations. Unless otherwise specified in an NIH solicitation, 
internet addresses (URLs) should not be used to provide information 
necessary to the review because reviewers are under no obligation to 
view the Internet sites. Reviewers are cautioned that their anonymity 
may be compromised when they directly access an Internet site.

HEALTHY PEOPLE 2010:  The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of 
"Healthy People 2010," a PHS-led national activity for setting priority 
areas. This PA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at 


This program is described in the Catalog of Federal Domestic Assistance 
No. 93.847. Awards are made under authorization of  sections 301 and 
405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and administered under NIH grants policies and Federal Regulations 42 
CFR 52 and 45 CFR Parts 74 and 92.  This program is not subject to the 
intergovernmental review requirements of Executive Order 
12372 or Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to 
provide a smoke-free workplace and promote the non-use of all tobacco 
products.  In addition, Public Law 103-227, the Pro-Children Act of 
1994, prohibits smoking in certain facilities (or in some cases, and 
portion of a facility) in which regular or routine education, library, 
day care, health care or early childhood development services are 
provided to children.  This is consistent with the PHS mission to 
protect and advance the physical and mental health of the American 

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