W Timothy Garvey - US grants

Insulin resistance is central to the pathogenesis of Type II diabetes (NIDDM), and is largely due to decreased activity of the glucose transport system in target tissue. However, the mechanisms responsible for reduced transport activity are unknown. In pre- liminary studies, we found both cellular depletion and impaired function of glucose transport proteins causing insulin resistance in adipocytes isolated from these patients. Therefore, in the current proposal, we will extensively examine the role of glucose transporters in the cellular insulin resistance of NIDDM, by measuring their number, structure, function, and regulation in target tissue. In adipocytes from control and NIDDM subjects, we will use both cytochalasin B binding and immunologic methods to measure the number and cellular distribution of transporters under basal conditions as well as insulin's ability to recruit intracellular carriers to the cell-surface. Function will be assessed by correlating numbers of cell-surface transporters with glucose transport rates in intact cells, and by correlating glucose transporter number and functional activity of transporters isolated from various subcellular and membrane fractions and then reconstituted into synthetic phospholipid vesicles. The Km and Vmax of substrate uptake will also be measured in whole cells since defects in these functional parameters have mechanistic implications. To test for structural abnormalities, we will combine SDS-PAGE and isoelectric focusing to determine the MW, charge heterogeneity, and extent of post-translational glycosylation of photolabeled transporters, as well as measure the non-enzymatic glycosylation of transporters using an antibody specific for glycosyl-lysine adducts. In other studies, we will try to delineate those regulatory events which impair transporter number and function in NIDDM. To determine whether transporter number is regulated at the transcriptional level, we will measure the amount of transporter mRNA in adipocytes and muscle on Northern blots using a hybridizing cDNA probe. We will also test the hypothesis that high concentrations of glucose and insulin regulate transporter number, structure, function, and mRNA levels in vitro using our primary culture method for adipocytes, and in vivo before and after a period of euglycemic therapy. Finally, we will pursue a collaborative project to raise site-specific antibodies against the transporter. Hopefully, these studies will delineate the role of glucose transporters in the mechanism and pathogenesis of insulin resistance in NIDDM, and suggest improved therapeutic strategies.

Insulin resistance is a marker for increased risk of Non-Insulin- Dependent Diabetes (NIDDM), Gestational Diabetes (GDM), hypertension, and cardiovascular disease, and is a major cause of glucose intolerance in NIDDM and GDM. However, the degree to which insulin sensitivity is determined by genetic and environmental factors is unknown, and molecular mechanisms causing insulin resistance have not been fully elucidated. In the previous cycle, the P1 found that insulin resistance in NIDDM was due to depletion of GLUT 4 glucose transporters (the major insulin- responsive isoform) in adipocytes, while GLUT 4 levels were normal in skeletal muscle indicating that either GLUT 4 translocation (to the cell surface) or functional activity was impaired. The overall goal in the proposed studies is to define the heritability of insulin resistance and to identify mechanisms which reduce glucose transport system activity in humans with and without insulin-resistant disease processes. Heritability of insulin resistance will be assessed by measuring maximally-stimulated glucose uptake in monozygotic and dizygotic twins, and estimating genetic variance based on intraclass differences and model-fitting path analyses. Muscle fiber composition and GLUT 4 content, resting metabolic rate, and body composition will also be measured so that interrelationships can be assessed within the context of the MZ/DZ twin model. Other studies will characterize molecular mechanisms causing insulin resistance in NIDDM and GDM. In NIDDM, adipocytes will be studied to determine whether nuclear proteins suppress GLUT 4 gene transcription, and the responsible cis and trans elements "will be identified. Studies in skeletal muscle will demonstrate whether insulin resistance in NIDDM and GDM is due to impaired translocation or reduced activity of GLUT 4. GLUT 4 recruitment will be measured by exploiting our ability to biopsy muscle fibers held at fixed length and to photolabel (3H-ATB-BMPA) cell-surface GLUT 4. GLUT 4 activity will be assessed in native membrane vesicles and after reconstitution in synthetic liposomes. Preliminary data in GDM indicate that GLUT 4 accumulates in an alternative membrane compartment where it then becomes refractory to insulin-mediated translocation in adipocytes. This defect will be further characterized in both fat (GDM) and muscle (NIDDM and GDM) by biochemically analyzing immuno-purified GLUT 4 vesicles including their content of small molecular weight G-proteins (smg's), assessing the subcellular distribution of other insulin-regulated proteins (GLUT 1, IGF 11 receptors), and morphologically localizing GLUT 4 using immuno- gold/EM. Finally, insulin-mediated recruitment and activity of GLUT 4 will be assessed in muscle biopsies from two groups of MZ twins concordant for upper and lower quartiles of insulin sensitivity to determine if mechanisms causing insulin resistance in subjects without overt disease are similar to those operative in diabetes. Major hypotheses are supported by preliminary data and include: 1) Insulin resistance is a highly inherited trait due in part to genetic factors which determine skeletal muscle fiber composition and GLUT 4 content; 2) In NIDDM, specific transcription factors in adipocytes repress GLUT 4 gene transcription; 3) In NIDDM and GDM, insulin resistance in skeletal muscle is due to impaired insulin-mediated translocation of GLUT 4 to the cell surface; 4) the translocation defect is associated with abnormal subcellular localization of GLUT 4 vesicles and smg's. Thus, these studies will combine basic and clinical research methodologies to directly study heritability and mechanisms of human insulin resistance, and will further elucidate the pathogenesis and role of insulin resistance in human diseases.

Non-Insulin-Dependent Diabetes Mellitus (NIDDM) has a predominant genetic component, however, diabetogenic genes have not been identified in the majority of patients. Several metabolic abnormalities contribute to the NIDDM phenotype, including insulin resistance, insulin secretory failure, and also obesity which is an inherited risk factor independent of insulin resistance. These pathogenic metabolic traits may be determined by subsets of genes which contribute to the polygenic basis of NIDDM, and constitute more proximal or refined phenotypes for susceptibility genes. Our overall goal in the proposed studies is to identify genetic markers for NIDDM and prediabetic phenotypic characteristics such as Insulin resistance and obesity. Previous efforts have employed candidate gene RFLPs in population disease-association studies or linkage analysis in small numbers of families, and have failed to identify susceptibility genes for the common NIDDM phenotype. In the proposal, we have adapted methods currently used at our center to study alcoholism, and have developed an alternative approach which involves: 1] the use of highly polymorphic microsatellite (dC-dA)n (dG-dT)n repeats as marker loci; ii] systematic exclusion mapping of the genome, or the study of targeted candidate chromosomal regions, as opposed to candidate gene RFLPs; iii] lod score and affected sib-pair analyses in larger numbers of NIDDM pedigrees; iv] extensive family studies in a relatively genetically homogeneous population with a high prevalence of NIDDM; and v] linkage analyses which incorporate a more pathophysiological understanding of NIDDM and IGT phenotypes, and which examine quantitative metabolic traits (insulin resistance, obesity) as prediabetic phenotypes. We will study 3 subsets of families: 1) Pima Indians (years 1-3). These studies will be performed in collaboration with C. Bogardus and colleagues in Phoenix who will provide us with metabolic data and genomic DNA from 800 Pimas in 100 families. The IU and Phoenix groups will each study half the genome, and employ microsatellite repeat polymorphisms (PIC>.7) selected at ~10 cM intervals to systematically screen assigned chromosomes. Our ability to detect linkage in Pimas is enhanced since genetic heterogeneity of NIDDM is likely to be reduced in this population. Genetic markers can then be tested for linkage in more genetically heterogeneous racial or ethnic groups. 2) Families recruited through American Diabetes Association Initiative "Studies on the Genetics of NIDDM" (years 3-5). Targeted candidate chromosomal regions will be genotyped using informative (dC-DA)n (dG-dT)n polymorphisms. These regions will contain i] marker loci we find linked to NIDDM or pre-diabetic phenotypes in the Pima Indians (for example, FABP2 on chromosome 4q), or ii] selected candidate genes. 3) African-American NIDDM pedigrees (years 1-5). Highly informative families with NIDDM will be identified from our large African-American patient base using an advanced computerized medical record system. In vivo insulin action, insulin secretion, body composition, and energy expenditure will be assessed using state-of-the-art methods. (dC-dA)n (dG-dT)n polymorphisms will be used as marker loci to study targeted candidate chromosal regions as described for ADA families. The study design unlike the ADA initiative, will differentiate between insulin- sensitive and insulin-resistant NIDDM phenotypes in Blacks. Taken together, our protocols optimize the search for genetic markers of NIDDM, and will direct attention to specific diabetogenic genes in linkage disequilibrium with marker loci.

glucose tolerance; sugar alcohols; urinalysis; blood chemistry; clinical research; human subject; glucose tolerance test;

lecithin cholesterol acyltransferase deficiency; medical outreach /case finding; autosomal recessive trait; lipid metabolism; blindness; cardiovascular disorder; anemia; hypertension; renal failure; clinical research; human subject;

family genetics; phenotype; genetic polymorphism; genotype; noninsulin dependent diabetes mellitus; diabetes mellitus genetics; genetic markers; clinical research; human subject;

This protocol will examine efficacy of troglitazone in reversing glucocorticoid induced insulin resistance, as well as underlying mechanisms relevant to the glucose transport system and autocrine/paracrine interactions in insulin target tissue.

A randomized Double-Blind Placebo-Controlled Multicenter Study Measuring the Effects of Cl-991 with or without insulin on reaching a treatment target in Non-insulin Dependent Diabetes Mellitus (NIDDM) patients requiring insulin. Troglitazone (Cl-991) is an orally active agent which treats insulin resistance and is currently being intestigated as a therapy for NIDDM. To further assist the NIDDM patients requiring insulin this study has been designed to detemine if Cl-991 can improve glycemic control and allow pts. to reach a treatment target.

The overall goals of this study are to better define abnormalities in fat metabolism and their relationship to the development of human insulin resistance. These in-vivo experiments will define the relationship between FFA turnover, lipid oxidation, insulin resistance, and provide a functional basis for interpreting the molecular data.

Evaluate the effect of 28 days of INS-1 oral administration on glycemic control, safety and tolerablity in IGT and Type 2 diabetic subjects.

To assess the efficacy, safety, quality of life, and patient and partner satisfaction with VIAGRA TM(sildenafil) taken as required prior to sexual activity in male diabetic outpatients with erectile dysfunction.

Insulin resistance is a marker for increased risk of Non-Insulin-Dependent Diabetes Mellitus (NIDDM), Gestational Diabetes Mellitus (GDM), hypertension, and cardiovascular disease, and is a major cause of glucose intolerance in NIDDM, GDM, and obesity. Within the context of Syndrome X, insulin resistance is thought to be a primary lesion which leads to variable manifestations of glucose intolerance, hypertension, obesity, dyslipidemia, and premature atherosclerosis. While individuals without overt disease exhibit marked differences in insulin sensitivity/resistance, the degree to which relative insulin resistance is determined by genetic and environmental factors is unknown. The overall goal in the proposed studies is to define the heritability of insulin resistance by studying monozygotic (MZ) and dizygotic (DZ) twins.

The purpose of the study is to determine DCI, MI and pinitol concentrations in blood and urine of persons with abnormal glucose tolerance (type II DM and IGT) and persons at risk for developing abnormal glucose tolerance. Specific objectives are: 1) to assess the prevalance of low DCI levels in blood and urine of persons with abnormal glucose tolerance and those at risk for its development; 2) determine blood and urine levels of MI and pinitol in persons with abnormal glucose tolerance and those at risk for its development; 3)characterize, with respect to sociodemographic and physiological data, the individual with low DCI status to better define the target population(s) for DCI nutritionals. An additional study goal is to determine the DCI to MI ratio in blood and urine of persons with abnormal glucose tolerance and at risk for its development in order to begin to establish its relevance as a screening/diagnostic test for individuals who may respond to DCI supplementation.

Pamela Binns is a third year medical student at MUSC who has become interested in diabetes mellitus from a research perspective as well as in a career in academic medicine. She has approached Dr. Garvey who will serve as mentor in the Medical Student Clinical Research Program. The Garvey laboratory is interested in the molecular, metabolic, and genetic basis of type 2 diabetes mellitus, insulin resistance, and obesity. Studies involve metabolic investigations of human subjects on a clinical research ward, cellular and molecular biology of cell and animal models, and genetic epidemiology of diseases in Gullah-speaking African Americans. The overall goal of the program is to impart an understanding of human-based research in the areas of diabetes, insulin resistance, and cardiovascular disease risk. The specific aims are for the student to: 1. Join a multidisciplinary investigative team conducting Project Sugar, a study designed to elucidate the genetic basis of diabetes and obesity in Gullah-speaking Sea Islanders living on barrier islands along the SC coast. This is the most genetically homogeneous population of African-Americans identified to-date. The student will develop a comprehensive understanding of recruitment of probands and families, phenotyping, computerization of data and database management, DNA extraction, basic aspects of genotyping, and statistical principals of genetic epidemiology. Thus, the student will be grounded firmly in approaches to the genetics of complex human diseases. 2.Participate in several other selected GCRC-based protocols examining human metabolism and cardiovascular disease risk. The PIs on these protocols include Dr. Garvey in addition to 3 other accomplished human- based investigators. This exposure will give the student a broader appreciation for hypothesis testing and methodologies in human research. Both a conceptual understanding and a hands-on appreciation of the conduct of this research will be emphasized. 3.Contribute as an investigator and author to an abstract submission and presentation at the American Diabetes Association national meetings in June, 2001. 4.Attend the GCRC Course in Clinical Research, the GCRC Elective for Medical Students in Cardiovascular Risk Factor Management, Research Ethics Grand Rounds and Research Ethics Lecture Series. 5.Participate in the intellectual life of the GCRC and the Division of Endocrinology by attending seminars, conferences, lectures, clinics, and rounds.

Insulin resistance is a critical factor in the pathogenesis of Type 2 Diabetes and cardiovascular diseases, and is due to impaired stimulation of glucose uptake in skeletal muscle. Insulin resistance is also associated with abnormalities in fat metabolism that exist independent of the degree of generalized obesity, including elevated circulating free fatty acids and increased accumulation of intramuscular lipid. Our central hypothesis is that the accumulation of intramyocellular lipid (IML) involves defects muscle fat metabolism, and is integrally related to impaired function of the glucose transport system. Our goal is for the first time to elucidate the molecular basis of abnormal muscle lipid metabolism in insulin resistant humans. Study groups include both lean and obese insulin-sensitive and - resistant individuals to discriminate between effects of obesity and insulin resistance, treatment with troglitazone and dexamethasone, and Type 2 diabetics before and after intensive euglycemic therapy. In specific aim 1, we will examine the relationship between insulin resistance and increased intramuscular lipid, and whether lipid accumulation is due to a relative defect in oxidation and/or an increase in FFA delivery. These studies will employ hyperinsulinemic clamps, palmitate turnover, AV leg balance studies, and whole-body and leg indirect calorimetry. IML will be assessed by histology and proton NMR spectroscopy. In specific aim 2, carnitine palmitoyltransferase 1 (CPT1), malonyl CoA, and acetyl CoA carboxylase will be examined in skeletal muscle as critical determinants of fuel partitioning and insulin sensitivity. In specific aim 3, in situ microdialysis will be used to study the role of TNFalpha as an autocrine/paracrine factor in regulating fatty acid metabolism and insulin sensitivity in adipose and muscle tissues The hypotheses are that dysregulation of this fuel sensing apparatus will reduce muscle CPT1 activity, inhibit entry and oxidation of long chain acyl CoAs in mitochondria, and promote accumulation of IML. Specific aim 4 will assess structure/function relationships for novel common polymorphisms in the muscle CPT1 gene that are associated with hyperglycemia, hyperinsulinemia, and insulin resistance. Fat metabolism, IML, CPT1 activity, and insulin sensitivity will be examined in vivo as a function of genotype, and specific activity of CPT1 variants will be assessed expressed in yeast. These experiments will for the first time examine relationships between muscle fat metabolism, IML, TNFalpha and insulin sensitivity in humans.

DESCRIPTION: (provided by applicant) The Insulin Resistance Syndrome (IRS) augments risk for cardiovascular disease in patients both with and without diabetes. The development of the IRS is integrally coupled to increased abdominal fat and waist/hip ratio. Our data show that an abnormal NMR lipoprotein subclass profile is associated with high waist/hip and confers increased vascular disease risk in Type 1 diabetes. The dyslipidemic pattern is identical to that observed in normoglycemic IRS and Type 2 Diabetes, and can be reserved by insulin-sensitizing thiazolidinediones. The link between increased abdominal fat and biochemical risk factors in IRS is unknown. Adipocytes secrete a large number of paracrine and endocrine factors that influence adipocyte size and function as well as whole-body physiology. The overall goal of Project 5 is to assess for the first time the effects of secreted adipocyte proteins on the biochemical risk profile and cardiovascular disease events in diabetes and IRS. The studies will involve unique national cohorts of Type 1 (DCCT/EDIC) and 2 (VA Cooperative Trial) diabetic patients, combined with in vitro studies, in order to test specific hypotheses from both epidemiological and mechanistic perspectives. In Specific Aim 1 we will measure circulating levels of novel adipocyte-derived proteins including adiponectin, acylation stimulating protein, CETP, PLTP, PAI-1, angiotensinogen, and leptin, and assess their relationship with cardiovascular risk factors and clinical events in both diabetes cohorts. In Specific Aim 2, we will determine the effects of thiazolidinedione treatment in Type 2 Diabetes on secreted adipocyte proteins, the biochemical risk profile, and cardiovascular events. In Specific Aim 3, we will study cultured adipocytes from insulin sensitive, IRS, and Type 2 diabetics, and assess the secretion rate of adipocyte proteins in vitro to directly assess whether changes in circulating levels are correlated with in vitro secretion rates. We will also study regulation of protein secretion by substrates, autocrine/paracrine factors, and thiazolidinediones. In Specific Aim 4, we will examine whether specific gene polymorphisms influence secretion of adipocyte proteins and cardiovascular disease risk in diabetes. These studies will determine whether secreted adipocyte proteins are responsible for multiple traits in the IRS cluster, and the role of the IRS in mediating increased risk for cardiovascular disease in diabetes.

DESCRIPTION (provided by applicant) Vascular Disease is the leading cause of complications and death in patients with diabetes. Risk markers and underlying mechanisms have not been fully elucidated, and may differ from those in non-diabetic individuals. The unifying theme for the Program Project is that hyperglycemia and insulin resistance alter a number of biological processes which interact in vicious cycles to accelerate atherogenesis and are consequently major underlying risk factors for vascular disease. The overall objectives are to define these unique processes and to elucidate underlying biochemical, metabolic, and genetic determinants of vascular disease complications in diabetes. Over the past 4 years, we have collaborated with the DCCT/EDIC Study Group, and have made novel observations regarding vascular disease pathogenesis in Type I Diabetes. This work has focused our studies on specific pathogenic processes. We will also incorporate a Type 2 Diabetes cohort from the VA Cooperative Study, "Glycemic Control and the Complications of Diabetes, Type 2", with high vascular disease event rates. These collaborations provide a unique opportunity to address the pathogenesis of accelerated atherogenesis in the two main types of diabetes, and will greatly augment the scientific knowledge that will be gained in the conduct of these world-class prospective trials. The Program Project has 4 projects and 3 cores. Project 1 will assess lipoproteins, glycoxidative stress, and inflammation as risk factors in studies involving Type 1 and 2 Diabetes patients and cultured cell systems. Based on preliminary data, changes in the NMR lipoprotein subclass profile will be emphasized. Project 2 will elucidate interactions between inflammation, modifications of lipoproteins, and autoimmunity in vascular disease risk. These novel concepts are also based upon exciting preliminary data pertaining to LDL-antibody complexes. Project 3 will pursue interesting preliminary data and define the role of the kallikrein-kinin system in vascular disease complications, with effects on mitogenesis and matrix production. Project 5 will assess the role of the Insulin Resistance Syndrome and novel factors secreted from adipocytes in the pathophysiology of biochemical risk factors and cardiovascular complications. Cores include an Biostatistics and Epidemiology which will link with the trials data coordinating centers, and Molecular and Statistical Genetics Core. There is true synergism among the projects at both scientific and logistical levels. The Program Project design allows for interactions among multi-disciplinary investigators studying the same cohorts, which will define how multiple pathological processes interact at the level of the arterial wall to promote atherosclerosis.

disease /disorder etiology; lipid metabolism; insulin sensitivity /resistance; glucose metabolism; glucose transport; glucose tolerance; body composition; patient oriented research; glucose tolerance test; nuclear magnetic resonance spectroscopy; human subject; photon absorptiometry; clinical research; glucose clamp technique;

human therapy evaluation; diet therapy; lipid disorder; insulin sensitivity /resistance; nutrient intake activity; lipid metabolism; glucose tolerance; body composition; noninsulin dependent diabetes mellitus; obesity; patient oriented research; human subject; clinical research;

DESCRIPTION, OVERALL (provided by applicant): This proposal will establish a new Diabetes Research and Training Center (DRTC) at the University of Alabama at Birmingham (UAB). The immediate goal of the center is to promote excellence in diabetes research. Through these efforts, the center ultimately endeavors to decrease morbidity/mortality and increase quality of life for our diabetes patients, and to provide an outstanding environment for student training and for faculty career development in diabetes research. Our specific aims are to: 1. Facilitate and enhance diabetes research by establishing core technologies expressly required by our investigator base. These technologies will be effectively provided by three biomedical resource cores, Bioanalytical Redox Biology, Animal Physiology, and Human Biology Cores, and two Prevention & Control cores, the Metrics & Health Services Research and Community Engagement Cores. 2. Augment diabetes research via a pilot & feasibility grant program that will emphasize innovation, translation, and career development of highly promising junior investigators. 3. Promote a cohesive intellectual environment for an outstanding multi-disciplinary investigator base, which will enhance learning, collaboration, collegiality, and innovation. 4. Develop and evaluate new models of diabetes patient care that incorporate multi-disciplinary health care teams to improve patient outcomes, provide venues for clinical training, and create laboratories for translational and health services delivery research. 5. Leverage the resolve of UAB leadership, substantial institutional commitments, and generous philanthropy from our community to impel the development of a pre-eminent center of diabetes research excellence in the heart of the deep south. A new DRTC will have a high impact for diabetes research at UAB for several reasons including (i) our patients who have the highest rates of diabetes in the US, (ii) the collaborative and nurturing environment afforded research centers at UAB, and, most importantly, (iii) an outstanding investigator base with diabetes research excellence in human physiology, animal physiology, free radical biology and oxidative stress, inflammation, vascular biology, health disparities, health services, and community based research. Diabetes is both a metabolic and vascular disease, and one strategy employed by the DRTC is to unite metabolic and vascular researchers around these common themes to achieve a better understanding of the mechanisms, prevention, and control of diabetes, diabetes complications, and cardiometabolic risk.

DESCRIPTION (provided by applicant): Insulin resistance is central to the pathogenesis of Type 2 Diabetes (T2DM) and the Metabolic Syndrome, and drugs or lifestyle interventions that increase insulin sensitivity constitute effective therapy and prevention. Thiazolidinedione drugs (TZDs) act through agonism of nuclear transcription factors (i.e., PPAR3) to enhance insulin sensitivity;however, TZD therapy is associated with adverse effects, including weight gain and heart failure. These untoward effects limit clinical utility, and highlight the need for alternative insulin-sensitizing medications that can act directly on muscle. We will study the NR4A family of orphan nuclear receptors, which were identified as differentially expressed genes on our human muscle cDNA microarrays. Extensive preliminary data indicate that: (i) NR4A3 is expressed at lower levels in insulin-resistant humans and rodents;(ii) TZDs induce NR4A3 suggesting that NR4A3 may be downstream of TZD action;(iii) MCK-NR4A3 transgenic mice exhibit an insulin sensitive phenotype;(iv) an increase in NR4A3 receptors can augment insulin signaling and stimulation of glucose transport;(v) PGA2 acts to increase insulin sensitivity in a NR4A3 dependent manner. To pursue these novel observations, our overall goal is to increase our understanding of the role of NR4A receptors in modulating insulin action, their role in human insulin resistance, and their rationale as a therapeutic drug target. To achieve this goal, we will apply our laboratory's capacity for translational research including human metabolism, human muscle and adipose tissue biopsies, transgenic mice, and cultured cell systems. Based on extensive preliminary data, the specific aims are: (1) Assess expression of NR4A receptors in muscle and fat in insulin sensitive, insulin resistant, and T2DM humans, before and after weight loss and TZD treatment, and in insulin resistant rodent models. (2) Establish metabolic role of NR4A3 by phenotyping transgenic mice with specific hyperexpression of NR4A3 in skeletal muscle. In both human and mouse, NR4A expression will be assessed for its ability to affect insulin sensitivity and substrate metabolism at the level of whole body and individual cells and tissues. (3) Determine mechanisms by which NR4A3 regulates insulin action by studying stable hyperexpression and shRNA- mediated suppression of NR4A3 in cultured muscle and adipose cells. These studies will address our preliminary data indicating that NR4A3 modulates insulin-stimulated glucose transport, GLUT4 translocation, and insulin-mediated phosphorylation of signaling molecules. (4) Identify lipid mediator agonists of NR4A3 based on preliminary data indicating that PGA2 increases insulin sensitivity in a NR4A3 dependent manner. Thus, this work will elucidate novel molecules and pathophysiologic processes contributing to insulin resistance, and develop new potential drug targets for the treatment and prevention of diabetes and cardiometabolic disease. PUBLIC HEALTH RELEVANCE: Insulin resistance is a critical factor causing Type 2 Diabetes and the Metabolic Syndrome. Treatment of insulin resistance can prevent diabetes and control blood sugars in patients who already have the disease;however, the available medications have serious side effects which limit their use. This research will elucidate, for the first time, the role of a novel family of orphan nuclear transcription factors (NR4A) in the cause of insulin resistance, and their potential as targets for new drugs to treat and prevent Type 2 Diabetes.

The Administrative Component will assure the effectiveness of the DRC in meeting the center?s stated goals and specific aims. This component includes the Administrative Core, the Pilot & Feasibility Grant Program, and the Enrichment & Training Program. The DRC will be led by the Director, W. Timothy Garvey MD, assisted by Stuart Frank MD, Associate Director for biomedical research, and Monika Safford MD, Associate Director for enrichment and training. The Director and Associate Directors will join other key DRC faculty in comprising the DRC Leadership Committee, Drs Anath Shalev, David Allison, and Victor Darley- Usmar. The ultimate goal of the Administrative Core is to assure the growing vitality of an intellectual community and a highly productive research program in diabetes, by effective deployment of DRC resources, for the benefit of our members, patients, and trainees. Operationally, the Core will oversee: 1. The effectiveness of the Research Core Facilities (REDOX Biology, Islet Cell Biology, Animal Physiology, Human Physiology, Interventions & Translation) 2. The Pilot & Feasibility Grant Program, directed by Stuart Frank and the Scientific Review Committee. 3. The Enrichment & Training Program. This program will be overseen by Drs. Monika Safford and Garvey assisted by Drs. Tse and Kim and the Speakers and Events Committee. 4. Coordination of meetings of the External and Internal Advisory Committees and DRC Leadership Committee, and implementation of committee recommendations. 5. The Apoprotein Mimetic Peptides Program, and the availability of peptides for investigators 6. Training and educational opportunities for our students, post-docs, and clinical trainees, as well as outreach and dissemination of knowledge. The Administrative Core will also be responsible for the network of DRC communications and website, bookkeeping, progress reports, quality control and evaluation, interface with NIH/NIDDK, and assurance of responsible fiscal management, and regulatory compliance.

While in vivo methods have proven invaluable in determining the physiological characteristics of human disease, progress in understanding rodent models has been delayed due to the lack of methods. Rapid progress in miniaturization, and in the increased sensitivity of monitoring devices has provided tools that can access information from relatively undisturbed rodents. The Animal Physiology Core (APC) brings together four experts in the areas of integrative physiology, cardiovascular physiology, imaging, and animal models to serve as a core resource for the study of diabetes. The goal of the APC is to facilitate and enhance the combined metabolic and vascular phenotyping of small animals by providing easy access to highly-specialized equipment and expertise in the areas of body composition, energetics, glucose homeostasis, cardiovascular assessment, molecular imaging, and transgenic animal models. This will enhance the capability and cost-effectiveness for DRTC members in the use of small animals for studying diabetes, diabetes complications, and cardiometabolic disease. The specific aims of the Core are to provide the following: 1 Body composition: Whole-body composition analysis by chemical carcass analysis, dual-energy X-ray absorptiometry (DXA), quantitative magnetic resonance (QMR), and micro-computed tomography. 2 Energy balance: Comprehensive assessments of metabolic rate (indirect calorimetry), food intake, fecal output, activity, and body temperature. 3 Glucose homeostasis: Glucose and insulin tolerance testing and hyperinsulinemic clamps. 4 Cardiovascular assessment: Echocardiography and myocardial function, vascular compliance, and blood pressure. 5 Metabolic/Molecular Imaging: Bioluminescence, fluorescence, and gamma-ray imaging, including SPECT/CT. 6 Transgenic animal models: Assistance with construct preparation, generation of transgenic/knock-out mice, husbandry and colony management, and genotyping. These services are based upon the expressed needs of DRTC investigators, and will incorporate expertise and current technology for both metabolism and vascular assessment, brought together in one core for combined applications by the user base. This will facilitate a more sophisticated, multidisciplinary,and comprehensive approach to diabetes research, and provide common ground for collaboration

The Human Physiology Core is a state-of-the art facility for assessing in vivo human metabolism, body composition, and cardiovascular status. It provides expertise, resources, and training in: 1. Analysis of glucose, lipids, and hormones (including obesity-related hormones, e.g., leptin, adiponectin; diabetes-related hormones, e.g., insulin, C-peptide, glucagon, GLP-1, GIP; a reproductive endocrine panel; IGF-1 and its binding proteins; cytokines and markers of inflammation; isotopically-labeled glucose and amino acids by GC/MS for use in in vivo metabolic studies; isotopically-labeled water by IRMS for use in determining body composition and energy expenditure. 2. Body composition and fat distribution [(underwater weighing and BodPod for measurement of whole body density; dual-energy X ray absorptiometry (DXA) for measurement of regional and whole-body bone, fat, and soft lean tissue; magnetic resonance imaging (MRI) for body composition; isotope dilution for assessment of total body water; multi-compartment models of body composition; CT scan analysis of regional body composition (intra-abdominal and subcutaneous abdominal adipose tissue); magnetic resonance spectroscopy (MRS) for intramyocellular lipid]. 3. Insulin sensitivity testing (frequently-sampled, intravenous, glucose tolerance test with minimal modeling; euglycemic clamp); oral glucose tolerance test with analysis of insulin and glucose; mixed-meal tolerance test for determination of insulin secretion, clearance, and sensitivity. 4. In vivo glucose and protein metabolism using stable isotopes. 5. Energy expenditure (free-living energy expenditure by doubly-labeled water and isotope-ratio mass spectrometry; 24-h energy expenditure from whole-room indirect calorimetry; resting energy expenditure via indirect calorimetry), and maximal oxygen consumption via treadmill test. 6. Cardiovascular assessment (endothelial function, arterial compliance, thoracic impedance, ambulatory blood pressure, and cardiac function during exercise testing). New Methods Development includes, 1) the validation of a non-invasive test for insulin sensitivity in children using a mixed-meal, and, 2) implementation of methodology for assessing insulin secretion and clearance using data resulting from a mixed-meal test. Core services are based on the expressed needs of funded DRTC Members, and will bring together current methods in human metabolic and vascular research for application in single protocols

The overall goal of the Metrics & Health Services Research (MHSR) Core of the DRTC is to provide the expertise and infrastructure required to create new knowledge in the prevention and control of diabetes and cardiometabolic disease; and effectively and reproducibly implement developed prevention and control strategies. Arising from over-arching programmatic needs at the national level that are clearly perceived by the DRTC's research base, the MHSR Core's 5 Specific Aims are to provide: (1) Access to state-of-the-art measurement tools in the domains relevant to diabetes prevention and control research, e.g. assessments of diet and nutrition, physical activity, behavioral/psychosocial factors, health related quality of life, and healthcare quality; (2) Design, data management, and analytic support, including econometric capacity; (3) Access to large pre-existing national datasets for secondary data analyses to test hypotheses in the prevention and control of diabetes and cardiometabolic disease; (4) Development of methodological innovations in diabetes prevention and control research; and (5) Effective implementation and dissemination support for maximizing the knowledge produced by the DRTC research base. The MHSR Core is directed by two national leaders in health services research (Kiefe) and diabetes epidemiology (Lewis), and will contain three service units, Psychosocial/Behavioral, Design/Data Management & Analysis, and Health Services Research. Core services are based on the expressed needs of funded DRTC Members, and methods will rely on state-of-the-art measurement approaches with a very high priority given to data quality control. A well-defined reporting structure, clear system of prioritization, and pre-defined chargeback system will ensure the Core's viability. State-of-the-art tools in health services and epidemiology research have tremendous potential to advance diabetes prevention and control, and the NIH Roadmap agenda of translation from bench to bedside to community. The MHSR Core will make cutting-edge expertise in these areas newly available to the DRTC research base, expanding the scientific armamentarium and capacity of diabetes researchers at UAB.

The goal of the Bio-Analytical Redox Biology (BARB) core is to provide state-of-the-art services in mitochondrial damage, function, and proteomics; oxidative stress assessment; and quantification of atherosclerosis. These services address key processes contributing to both metabolic and vascular pathology in diabetes, diabetes complications, and cardiometabolic disease. Core technologies are based on the expressed needs of funded DRTC investigators, The specific aims of the BARB core will be: 1) Provide services to DRTC Regular and Supported Members and pilot & feasibility grant awardees in: (i) mitochondrial bioanalytical analysis (multiple mitochondrial functions, mtDNA damage and haplotyping), (ii) mitochondrial proteomics (quantitative proteomics, post-translational oxidative modifications of proteins), (iii) oxidative stress assessment (isoprostanes, oxidized lipids, aconitase inactivation, GSH/GSSG, myeloperoxidase, heme oxygenase, and antioxidants), and (iv) atherosclerotic lesion quantification using state-of-the-art research facilities and specialized expertise, with emphasis on quality control of study procedures. 2) To substantially reduce cost and investigator time commitment by accessing centralized resources, as opposed to operating independent laboratories and hiring separate faculty/staff. 3) To provide investigators and their technical personnel opportunities to learn and to further develop new research methodologies through recurring workshops and initial consultations to enable optimal usage of the various services of this core. 4) Pursue and develop methodologies that allow the investigator to extend capabilities and precision in redox and free radical biology, and to foster multi-disciplinary collaborations. Because analytical technologies are continually evolving, an important role of the BARB core will be to keep DRTC investigators appraised of current technological developments in the field through a program of tutorials, seminars and mitochondrial interest group (MIG) meetings (already initiated); this will be especially important for DRTC investigators who need to employ or extend the use of these technologies in their hypothesis testing

The primary goal of the Community Engagement Core (CE Core) is to develop, implement, and evaluate a community-based infrastructure to maintain linkage (engagement) between DRTC researchers and the targeted communities, including community-based organizations, community leaders, research volunteers, and community health-care systems and providers. In addition, the Core will facilitate the study of health disparities related to diabetes. The DAB DRTC is located within the heart of the Southeast, a region with a large, historically underserved African American population and a fast-growing Hispanic population. The specific aims are: 1. To establish a coalition that will lead to effective partnerships between the community and DRTC users; 2. To promote capacity building in the targeted communities by educating and empowering the community constituents, such as community-based organizations and church representatives, and by establishing networks of well-trained community volunteers; 3. To develop a culturally appropriate plan to enhance the recruitment and retention of minorities in diabetes-related research studies, with emphasis on underserved groups; 4. To help DRTC investigators pilot-test research tools and protocols, assure cultural competency of measurement tools and interventions, and measure socio-cultural factors related to the health disparities of diabetes; 5. To engage community partners in the application and dissemination of findings from relevant diabetes research projects; 6. To develop a training program that educates DRTC investigators and staff on the best practices for conducting research in racial/ethnic minority communities with emphasis on cultural competency, bioethics, risk assessment, behavioral change, and community based participatory research principles. These core services are based on the expressed needs of funded DRTC Members, and will support a strong research base in human metabolism, interventions and trials, community based research, community participatory research, and health promotion. The CE Core leverages existing infrastructure for recruitment and community research at UAB, for targeted application to the study, prevention, and control of diabetes, diabetes complications, and cardiometabolic disease.

DESCRIPTION (provided by applicant): This proposal will continue the progress of the DRTC, first established at UAB in 2008, and the transition to a DRC. The immediate goal of the center is to promote excellence in diabetes research. Over the past 4 years, the DRC has galvanized the UAB research community around the study of diabetes resulting in an increase in membership from 115 to 159, and a 32.5% increase in extramural research funding. Through these efforts, the center ultimately endeavors to decrease diabetes morbidity/mortality, and to provide an outstanding environment for training and career development in diabetes research. Our specific aims are to: 1. Facilitate and enhance diabetes research by sponsoring research core facilities expressly required by our investigator base. The five research cores cover a broad translational spectrum: Bioanalytical REDOX Biology, Islet Cell Biology, Animal Physiology, Human Biology, and Interventions & Translation Cores. 2. Augment diabetes research via a pilot & feasibility grant program that will emphasize innovation, translation, and career development of highly promising junior investigators. 3. Sponsor an integrated Enrichment Program that promotes a cohesive environment for an outstanding multi-disciplinary investigator base, which will enhance learning, collaboration, collegiality, and innovation. 4. Build upon the progress achieved over our first 4 years by responding to the evolving needs of our investigators and through leadership that impels new ideas and lines of investigation. 5. Emphasize research, training, and outreach that are responsive to the needs of our trainees, achieve better outcomes for our patients, and lessen the high burden of diabetes in our community and nation. 6. Leverage the resolve of UAB leadership, substantial institutional commitments, and generous philanthropy from our community to further impel the development of a pre-eminent center of diabetes research excellence in the heart of the Deep South. Our DRC is located in a community with the highest rates of diabetes in the US, and unites investigators around common themes to study diabetes in the context of cardiometabolic disease.

Although there have been numerous efforts to increase the number of underrepresented researchers in universities across the country, there continues to be a lack of diversity in most disciplines, including the biomedical sciences. We will leverage our experience in training underrepresented minority students and our expertise and connections related to NIDDK mission areas to ensure that we are inspiring and developing the next generation of NIDDK researchers. The specific aims of UAB STEP-UP: Promoting Diversity through Mentored Research Experiences (UAB STEP-UP) include: 1) training promising and diverse undergraduate students from across the country by developing a career roadmap for each, to include hands-on mentored research experiences and career development opportunities; 2) utilizing existing research networks to develop a cadre of mentors invested in training undergraduate students to conduct research in the areas of diabetes and other endocrine and metabolic diseases; digestive diseases, nutritional disorders, and obesity; and kidney, urologic and hematologic diseases; 3) adapting successful on-site training programs into effective distance learning activities targeting NIDDK content areas and preparation for graduate school and/or future careers in research; 4) utilizing a combination of human interaction (i.e., Program Manager, Institutional Coordinators, mentors and other trainees) and virtual tools (e.g., web-based instruction, videoconferencing and social media) to ensure that trainees receive individual and continuous attention for several years as a cohort of learners; and 5) continuously evaluating the program and its implementation to allow for quality improvement and mid- course corrections. The UAB STEP-UP Coordinating Center will select motivated, promising undergraduate students who have completed their freshman year and provide them with the organizational, academic and research skills needed to be competitive. Elements include an intensive mentored research experience for 10 weeks in the summer (30 hours/week) enhanced by virtual group learning activities (10 hours/week), and followed by distance learning as part of a virtual learning cohort during Years 1 and 2. This is followed by virtual maintenance training during Year 3, to maintain interest and investment in the program. During this time, trainees will develop working relationships with academic researchers and will be involved with the processes and products of cutting-edge research. Although intensive training is provided only during the summer, we have designed a program with a UAB-based Program Manager and on-site Institutional Coordinators, who will help ensure that trainees remain connected to the program through virtual learning approaches and social media platforms throughout the entire year. They will facilitate contact for training, continued mentoring, evaluation and ? importantly ? to maintain connection with the program.

Obesity is among the most prevalent, costly and preventable of health problems. African Americans are 15% more likely to suffer from obesity than Whites and 70% of African Americans between the ages of 18 and 64 are overweight or obese. Obesity also places a disproportionate chronic disease burden on African Americans. Our overall goal is to establish the UAB Obesity Health Disparities Research Center of Excellence (OHDRC) with an ultimate goal of reducing and eliminating disparities in obesity between African Americans and whites. Using Alabama as a model, the OHDRC will support transdisciplinary, multi-level, multi-domain research on obesity- related health disparities to understand the complex contributors to obesity and how they vary at critical periods across the life course and develop interventions to address these contributors. To achieve this goal, we will 1) Conduct innovative interdisciplinary research to understand the complex interactions between biological, behavioral and social factors associated with obesity-related health disparities throughout the life course (two full projects); 2) Partner with the community to inform research and disseminate evidence-based practices designed to result in individual, community and system-level changes to impact obesity-related health disparities. (Academic-Community Engagement and Dissemination Core- ACED); 3) Expand the pipeline of innovative research through an Investigator Development Program of mentored pilot research for early stage investigators. (Investigator Development Core ? IDC); and 4) Establish a coordinated infrastructure to support the proposed research, IDC and ACED Cores by: a) implementing a Common Data Elements and Measurement Shared Resource to be used by OHDRC researchers, b) designing career enhancement activities that focus on transdisciplinary obesity health disparities research to prepare independent investigators (especially those from underrepresented minority groups, in partnership with minority serving institutions) for productive careers, and c) instituting a monitoring and evaluation process to ensure achievement of proposed goals. (Administrative Core). Alabama is particularly well-suited as a setting to pursue these aims. It includes some of the most impoverished rural counties and inner-city communities in the nation and, as we will highlight, Alabamians suffer from some of the highest rates of obesity and from some of the most starkly disproportionate outcomes for obesity-related chronic diseases. If our OHDRC proves successful, we will serve as a model for other states facing similar health disparities.

This is a resubmission of a renewal application for a successful training program initiated in 2002 that prepares postdoctoral scientists for careers in interdisciplinary obesity research and also provides short-term research training for medical students in the summer between freshman and sophomore years. Postdoctoral fellows enroll in a formal 2?3 year program tailored to individual interests aimed to promote development of independent research careers. Fellows are selected based on outstanding academic records in graduate school, recommendations, interviews, and a commitment to an investigative career in obesity. Training occurs in a rich intellectual environment that incorporates the research and enrichment programs of UAB's Nutrition Obesity Research Center and the Diabetes Research Center, with one or more key research center members serving as faculty mentors. The faculty's diverse disciplinary backgrounds (physicians, psychologists, statisticians, economists, physiologists, geneticists, molecular and cell biologists, epidemiologists, nutritionists, etc.) and strong collaborative ties foster team training and mentoring in innovative multidisciplinary research. Regular reviews of individual trainees are completed by the training Program Directors to ensure achievement of milestones and progress toward independent research careers. Funding is requested for 5 postdoctoral trainee slots. Our aims are: Specific Aim 1. To recruit highly talented and accomplished candidates for postdoctoral research training who have established excellence as graduate students in the biological or behavioral sciences, an interest in obesity, and a clear commitment to life-long careers as investigators. Specific Aim 2. To involve postdoctoral fellows in a career development program that features high-impact research in the context of multidisciplinary mentorship teams and a rich intellectual environment, leaving them poised to pursue innovative lines of investigation as they evolve to independence. Specific Aim 3. To maintain a stimulating intellectual environment for training, enhanced by the enrichment programs of our NIH research centers, including visiting lectureships by national and international leaders in obesity research, special events, courses, career development initiatives, grant writing, collegial interactions, a collaborative spirit, and training in the responsible and ethical conduct of research and methods for enhancing reproducibility. Specific Aim 4. To continue a productive collaboration with the Diabetes Research Center in the short-term training of medical students with career goals in academic medicine and research and who have an interest in obesity, diabetes, and cardiometabolic disease. Specific Aim 5: To launch a new generation of ethnically diverse scientists who will comprise the next generation of scientific leaders in obesity.

PROJECT SUMMARY / ABSTRACT ADMINISTRATIVE CORE The Administrative Component will assure the effectiveness of the DRC in meeting the center?s stated goals and specific aims. This component includes the Administrative Core, the Pilot & Feasibility Grant Program, and the Enrichment & Training Program. The DRC will be directed by W. Timothy Garvey MD, assisted by associate directors Drs. Barbara Gower and Anath Shalev. The Director and Associate Directors will join other key DRC faculty in comprising the DRC Action Committee, Drs. Stuart Frank, Scott Ballinger, Douglas Moellering, Tim Nagy, Andrea Cherrington, and C. Beth Lewis. The ultimate goal of the Admin Core is to assure the growing vitality of an intellectual community and a highly productive research program in diabetes, by effective deployment of DRC resources, for the benefit of our members, patients, trainees, and community. Operationally, the Core will assure productivity and effectiveness of DRC activities including the biomedical and translational research core facilities (REDOX Biology, Animal Physiology, Human Physiology, Interventions & Translation), a pilot & feasibility grant program that promotes research progress of promising investigators and innovative lines of investigation, and an enrichment program that advances the DRC as an intellectual community, promotes interactions and discussions regarding new discoveries and concepts, provides a forum for the formation of multidisciplinary collaborations, and establishes a dynamic educational environment for training and career development. The Admin Core will be responsible for the managing membership, the network of DRC communications and website, bookkeeping, progress reports, quality control and evaluation, interface with NIH/NIDDK, assurance of responsible fiscal management and regulatory compliance, and will obtain and implement recommendations of Internal and External Review Committees. Over the 9 years of UAB DRC existence, the Admin Core has overseen a progressive increase in members, publications, research grant dollars, recruitment of new faculty, and development of new research areas such as islet cell biology that have enhanced and broadened the scope of our diabetes research. The DRC has united areas of research excellence under the umbrella of diabetes and cardiometabolic disease and established a cohesive intellectual community. The Admin Core has facilitated the evolution of the DRC by initiating new core services to meet investigator needs, an enrichment program that introduces new ideas and scientific discoveries, career development of mentored members, and development of new areas of research excellence. Thus, the DRC will continue to exert a pronounced impact on diabetes research excellence at UAB and we are confident that further evolution and growth will be achieved over the next 5 years.

The decline in first-phase insulin secretion is a key event in the etiology of type 2 diabetes (T2D). Although the cause of beta-cell failure is not clear, ?lipotoxicity? has been proposed. Bariatric surgery and very-low calorie diets in patients with T2D induce disease remission, characterized by a return of first-phase insulin secretion and a depletion of pancreas lipid. However, these are extreme approaches to treating T2D, and non-invasive, sustainable, yet equally effective, treatments are needed. We have shown in individuals at risk for T2D that an intervention with a weight-maintaining low-glycemic (LG) diet selectively depletes visceral adipose tissue and ectopic lipid in muscle while preserving thigh subcutaneous adipose and lean body mass. This observation suggests that such diets are able to ?remodel? body composition by re-partitioning energy away from metabolically harmful lipid stores. Participants on the LG diet also demonstrated improved insulin sensitivity and a dramatic (9-fold) increase in first-phase insulin secretion. Thus, we hypothesize that a weight-maintaining LG diet will selectively deplete ectopic adipose tissue, including pancreatic lipid, and will permit recovery of beta-cell function in individuals with T2D. Rescue of beta-cell function may be particularly important in African-Americans (AA), who as a group demonstrate a high prevalence of T2D, for reasons that cannot be explained by lifestyle. AA are likely to be vulnerable to beta-cell failure due to inherently high beta-cell responsiveness (demonstrable in healthy young children). Further, it has been shown that pancreas lipid is a determinant of prediabetes specifically in AA. Thus, we hypothesize that an LG diet will be particularly beneficial to beta-cell function and glycemic control among AA. To test these hypotheses, we will conduct a randomized clinical trial to examine the impact a weight-maintaining LG diet vs a Control diet (ADA/USDA) with all food provided on changes in pancreatic lipid by magnetic resonance imaging (MRI) and first-phase insulin secretion by hyperglycemic clamp and oral meal test in AA and European-American (EA) individuals with early T2D (<5 yr since diagnosis). The study will be powered to examine race-specific effects (race x diet interaction). This proposal responds to PA-17-021, ?Addressing Health Disparities in NIDDK Diseases.? The results from this study could change clinical care guidelines to incorporate an LG diet, which may reduce the disproportionate burden of T2D and its complications experienced by AA.

Diabetes is responsible for a huge and growing burden of patient suffering and social costs, and the impact of this disease is shared disproportionately by minorities and in rural resource-challenged communities. In particular, the Alabama Black Belt and the Mississippi delta have the highest rates of diabetes and obesity in the United States. The need for research targeted to rural populations characterized by a heavy preponderance of minorities and low socioeconomic status is acutely needed to better understand the basis for health disparities and to identify effective interventions for diabetes treatment and prevention. With this revision application, the UAB Diabetes Research Center (DRC) re-dedicates our center to improving the health of our patients with diabetes in the Deep South. To extend our scientific reach, we will establish a primary care clinical network in rural Black Belt counties of Alabama and in the Mississippi delta as a research resource that will provide the DRC and its members with opportunities for partnership and the infrastructure to conduct translational and clinical research in those patients with the greatest need. Our specific aims are: Aim 1: Establish a Diabetes Primary Care Coalition in the rural Black Belt region of Alabama. Building upon ongoing projects, we will establish a network of primary care clinics in rural Alabama and eventually expand to the Mississippi delta as well. The coalition will feature sustainable partnerships, engagement of community health workers, and a telehealth system for communication with primary care clinic personnel, education, messaging with patients, and data capture adapted to medical records systems. Aim 2: Integrate the Primary Care Coalition and clinical network as a research resource in the DRC. The clinical network will be facilitated by the Interventions & Translation Core, and the resource will be accessible to all investigators in our DRC as well as others in our partnering centers and academic institutions. Other DRC cores will be adapted to facilitate effective hypothesis testing using this resource. Aim 3: Conduct a pilot study of an innovative lifestyle program (telehealth + community health workers) with and without metformin for diabetes prevention. This pilot trial is intended to consolidate and refine operations within the primary care coalition, and to develop data for a larger scale randomized trial evaluating a novel and sustainable approach for diabetes prevention that involves an innovative lifestyle intervention combined with metformin. The current revision application underscores the commitment of the DRC to partnerships and research that is directed at improving health in patients with diabetes and cardiometabolic disease in our communities with a particular emphasis on health disparities in rural communities. The primary care coalition is designed as a powerful resource for the study of mechanisms responsible for chronic disease disparities and developing interventions uniquely effective in these high-risk populations.

The COVID-19 pandemic has created unique challenges for vulnerable populations. As part of the mission of the OHDRC, we have maintained continuous community engagement and partnerships aimed at finding ways to reduce the impact of obesity and related chronic diseases. With the advent of COVID-19, we were quickly able to leverage these long-standing and trusting relationships to learn how COVID-19 was perceived by the residents of our partnering vulnerable communities. Through ongoing community dialogue, we know that there are substantial differences in how residents in our partner communities understand and act upon COVID-19 guidance, perhaps contributing to the alarming disparities in COVID-19 outcomes. Overall, residents feel that COVID-19 is making marginalized communities even more marginalized. In this environment, it is vital that we find ways to improve COVID-19 vaccination, testing and follow-up care through collaboration with community partners. The overall goal of this proposal, COVID-19 Testing Model for Vulnerable Populations: Revision to Address Vaccine Hesitancy and Uptake, is to expand the RADx-UP Revision to the NIMHD (U54) UAB Obesity Health Disparities Research Center (OHDRC) to explore COVID-19 vaccine hesitancy in Jefferson County, Alabama and based on these results, design and integrate a multi-level vaccine hesitancy component into the existing parent RADx-UP grant. The overall goal of the parent grant, COVID-19 Testing Model for Vulnerable Populations: From Community Engagement to Follow-Up, is to implement a three-component mobile community-based testing model and evaluate its impact for improved reach, access, acceptance, uptake, and appropriate follow-up to COVID-19 testing. We will utilize the infrastructure of the existing project, including the Scientific Advisory Board (SAB) and Community Advisory Board (SAB) as well as a strong Partner Council of community organizations. We will also partner with the Alabama Community Engagement Alliance against COVID-19 (AL CEAL), which has built an extensive infrastructure across Alabama. This study will use the results of work on COVID-19 vaccine hesitancy and uptake in Alabama conducted by AL CEAL and will conduct further qualitative and quantitative assessments to explore deep vaccine hesitancy to design and evaluate a multi-level intervention to decrease vaccine hesitancy that can be integrated into existing CEAL and RADx-UP community-level and individual-level efforts, while also addressing key systems-level influences, churches and primary care clinics.