PAS-99-166: RACIAL AND ETHNIC DIFFERENCES IN THE ETIOLOGY OF TYPE 2 DIABETES IN THE UNITED STATES

Department of Health
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RACIAL AND ETHNIC DIFFERENCES IN THE ETIOLOGY OF TYPE 2 DIABETES IN THE UNITED STATES Release Date: September 14, 1999 PA NUMBER: PAS-99-166 National Institute of Diabetes and Digestive and Kidney Diseases THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE This Program Announcement (PA) solicits research to expand our understanding of the underlying metabolic, genetic, epidemiologic, sociocultural, and behavioral mechanisms that contribute to the racial and ethnic differences in the etiology of type 2 diabetes mellitus in the United States. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This PA, Racial and Ethnic Differences in the Etiology of Type 2 Diabetes in the United States, is related to the priority area of diabetes. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA must not exceed 5 years. Applications requesting $250,000 or less in direct costs in any budget period must be prepared using Modular Grant and Just-in-Time concepts. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE For FY 2000, approximately $2 million will be committed to fund applications submitted in response to this PA. It is anticipated that six to eight awards will be made. For FY 2001 and FY 2002, approximately $2 million will be committed each year to fund six to eight applications per year submitted in response to this PA. Funding is dependent on the receipt of a sufficient number of applications of high scientific merit and on the availability of funds for this purpose. Applications on this topic submitted after October 2001 (potentially fundable in FY 2003) will be considered for funding in the general NIDDK research project grant competition. RESEARCH OBJECTIVES Background 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 nongenetic (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 is to determine, through studies in representative U.S. populations, the reasons for disparities in the incidence of type 2 diabetes in minority race-ethnic populations. Additionally, information which could emerge from these studies would be important for devising cost-effective approaches to phenotyping patients with type 2 diabetes and individuals at risk for this disease. The ability to characterize and identify discrete subgroups of type 2 diabetes would be essential in genetic studies of this disease. Appropriate topics for investigation would include but are not limited to: o State-of-the-art, hypothesis-driven metabolic studies in which fat metabolism, glucose levels, insulin secretion, energy expenditure, etc., are measured in representative samples of 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, even if lifestyle and socioeconomic factors are similar, 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 (for genetic or nongenetic reasons) 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, arginine, and insulin resistance. 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, etc. o The temporal relationships among the components of Syndrome X. The constellation of hypertension, hyperglycemia, obesity, and insulin resistance is well documented. However, the temporal development of the individual components of this syndrome remain to be determined. In particular, the etiologic relationships among these components, and their relationship to type 2 diabetes, need further investigation. o Development of less expensive methods to assess beta cell function and insulin resistance and development of techniques for measuring underlying metabolic and physiologic differences among population groups. For example, studies could be supported that develop and validate techniques that will more reliably measure insulin secretion and insulin sensitivity, or evaluate fatness and fat distribution, for use in future epidemiologic and intervention studies to reduce risk of type 2 diabetes and risk of diabetes complications. o 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. A critical question is how prevention strategies to reduce risk across racial and ethnic groups should incorporate culturally-specific lifestyle factors. Advantage might be taken of extant cohort studies that may have been established for investigation of diabetes or investigation of other diseases. A collaboration among investigators of these established cohorts would be desirable, so that these studies might jointly develop protocols and evaluate findings. The results may lead to a proposal to start new cohorts, appropriately powered, to capture the current risks for development of type 2 diabetes. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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 "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at http://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 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. 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301- 435-0714, email: GrantsInfo@nih.gov. The program announcement title and number must be typed on line 2 of the face page of the application form, and the YES box must be marked. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the NIDDK program staff before submitting the application, i.e., as plans for the study are being developed. The applicant must obtain agreement from the NIDDK program staff that the NIDDK will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Use a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. o For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. o Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers to assess each individual"s qualifications for a specific role in the proposed project and to evaluate the overall qualifications of the research team. A biographical sketch is required for each of the key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page - List current position(s) and any honors - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years - List selected peer-reviewed publications, with full citations o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. It is important to identify all exclusions that were used in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Submit the signed, original, single-sided application, including the Checklist, along with five signed photocopies and five collated sets of appendix materials 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) The Center for Scientific Review (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 substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and 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, reviewer 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. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the 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. o Significance: Does this study address an important problem? If the aims of the 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? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? o 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 technologies? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? o Environment: Does the scientific environment in which the 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o Adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration to the proposed research. o The adequacy of the proposed protection of humans, animals, or the environment, to the extent that they may be adversely affected by the project proposed in the application. AWARD CRITERIA Applications will compete for available funds with all other recommended applications assigned to the National Institute of Diabetes and Digestive and Kidney Diseases. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program priority INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding scientific issues to: Maureen I. Harris, PhD, MPH Division of Diabetes, Endocrinology, and Metabolic Diseases National Institutes of Diabetes and Digestive and Kidney Diseases Building 45, Room 5AN24 Bethesda, MD 20892 Telephone: 301-594-8801 FAX: 301-480-3503 Email: harrism@extra.niddk.nih.gov Direct inquiries regarding fiscal and administrative matters to: Denise Payne Division of Extramural Activities National Institutes of Diabetes and Digestive and Kidney Diseases Building 45, Room 6AS49 Bethesda, MD 20892-6600 Telephone: (301) 594-8845 FAX: (301) 480-3504 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) 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, any 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 people.

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