IMPH Research in Diabetes

Biomarkers of Obesity, Prostate Tissue Inflammation, and BPH Progression 
Exercise and Fuel Metabolism 
Gene and Environment Interaction and Insulin Resistance 
Gluconeogenesis and Glycogenolysis - Role and Regulation 
Leveraging Patient Portals to Improve Medication Adherence in Type 2 Diabetes 
O'Brien Center Development: BPH and Obesity 
Public-Private Partnership Addressing Literacy-Numeracy to Improve Diabetes Care 
Shanghai Men's Health Study 
Using Social Learning to Improve Adolescent Diabetes Adherence Problem Solving 
Vanderbilt Center for Diabetes Translation Research 
Vanderbilt Diabetes Research Center

Biomarkers of Obesity, Prostate Tissue Inflammation, and BPH Progression

The purpose of the study is to investigate the relationship between obesity and BPH.  Obesity generates a state of chronic systemic inflammation known to enhance arthrosclerosis, diabetes, and other inflammatory diseases. Several studies also suggest that obese men are also more likely to develop lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH).  However, much of the epidemiologic evidence relies on self-reported BPH outcomes, and there are few, if any, animal models to characterize the obesity-BPH relationship. Thus, our long-term goals are to characterize the relationship between obesity and prostate tissue inflammation and hyperplasia, investigate potential mechanisms by which obesity advances BPH, develop a mouse model of BPH for mechanistic studies, and to conduct a prospective epidemiologic study to investigate the clinical impact of obesity on BPH progression. Read more.

Funding Source: NIH/NIDDK
Pi: Jay Fowke

Exercise and Fuel Metabolism

Understanding the pathogenesis of the metabolic syndrome is paramount to eliminating it. Hepatic metabolic dysfunction associated with inadequate substrate oxidation, lipid accumulation, and dyslipidemia is a hallmark of metabolic syndrome as it is evident early in its development and is associated with the severity of other symptoms. It has been speculated that liver metabolic dysfunction is a causative step in the natural progression to metabolic syndrome. Despite the central role of liver metabolism to overall "metabolic health," the mechanism for its effectiveness in healthy physically active states, the factors responsible for dysfunction, and the means to correct dysfunction are poorly understood. The protocols that comprise the extended funding period focus on three Specific Aims that are a continuation of innovative work conducted in the current funding cycle. The Speciic Aims will test in lean and high fat fed mice whether (a) the activation of hepatic energy sensors (AMPK, sirtuins, hypoxia inducible factors) are protective against insulin resistance; (b) the extracellular matrix conveys a spatial barrier or signaling event that contributes to the impaired energetics and nutrient fluxes of insulin resistance; and (c) the hepatic adaptations to high fat feeding and physical activity are AMPK-dependent. The regulation of hepatic metabolism will be studied using surgical, experimental, and isotopic tools that allow well controlled studies to be conducted in the unstressed conscious mouse. Highly innovative approaches will allow the Aims to be addressed with unprecedented resolution of a spectrum of pathophysiological events. We have developed a new, highly innovative, and comprehensive method for measurement of nutrient fluxes in the liver using stable isotopes of glucose, water, and proprionate. Hepatic ECM will be characterized by using a novel proteomic method designed to focus on the ECM, immunohistochemistry, polysaccharide binding protein, and transmission electron microscopy. The ongoing and planned studies provide mechanisms by which environmental factors (diet and exercise) interact with genes to cause or rescue hepatic metabolic dysregulation. The results of these studies will introduce new avenues to our understanding and treatment of metabolic diseases. RELEVANCE (See instructions): The metabolic syndrome is an epidemic in Western Culture. Hepatic metabolic dysfunction associated with lipid accumulation and dyslipidemia is evident early in its development and is associated with the severity of other symptoms. It has been speculated that liver metabolic dysfunction is a causative step in progression to metabolic syndrome. These studies will define how liver metabolism is regulated in the healthy liver and wherfi .<^itfis of dvsfunction lie in the nathonfinesi.q of metabolic syndrome, insulin resistance, and diabetes. Read more.

Funding Source: NIH/NIDDK
PI: David Wasserman

Gene and Environment Interaction and Insulin Resistance

Type 2 diabetes (T2D) affects more than 20 million people in the US, and its prevalence is increasing. Insulin resistance is a necessary condition for T2D to develop and results from an interaction between genetic and environmental factors. Understanding factors associated with insulin resistance and its genetic controls is of particular importance for the prevention of T2D, because insulin resistance is reversible. Major environmental risk factors for insulin resistance include obesity, central obesity, low physical activity, and dietary factors. Among dietary factors, dietary fat plays an important role in the induction of insulin resistance. The etiology of insulin resistance could derive from defects between insulin receptors and glucose transporter 4, and defects in the insulin receptor substrate may be a central feature of insulin resistance. However, there is limited evidence about the role of gene variants in the insulin-signaling pathway and prevalence of T2D or insulin resistance. Recent genome wide association studies (GWAS) have only identified a few new genes that appear to influence insulin resistance. This could be due to the failure to examine how environmental factors affect genetic susceptibility in the development of insulin resistance and/or T2D. In the proposed application we will explicitly evaluate the association of genetic polymorphisms in the first three genes in the insulin signaling pathway (the insulin receptor, INSR, and insulin receptor substrates 1 and 2, IRS1 and IRS2), glucose transporter 4 (GLUT4), and genes identified from GWAS of T2D quantitative traits with insulin resistance in the context of gene-environment interactions. Using fasting insulin and the homeostasis model assessment of insulin resistance (HOMA-IR) as proxies, we will analyze existing clinical and demographic data from 2000 non diabetic male participants of an ongoing, population-based prospective study conducted in Shanghai, China, for whom dietary factors, physical activity, anthropometric variables, and fasting glucose and insulin have already been measured. The goals of the proposed project are in concert with the parent K01 application's goal to determine gene-diet and gene-physical activity interactions associated with T2D. This application expands the overall goal of the K01 award by extending research in this important area of investigation to the study of quantitative traits associated with insulin resistance. Findings from this study can be used to aid in the prevention of T2D, since insulin resistance is a reversible condition. Read more.

Funding Source: NIH/NIDDK
PI: Raquel Villegas

Gluconeogenesis and Glycogenolysis - Role and Regulation

The objective of this proposal is to better understand the role of liver afferent and efferent nerves as they relate to insulin action in the liver, hypoglycemic counterregulation and the deleterious effect of a diet high in fat and fructose on hepatic metabolism. The specific aims are 1) To further our understanding of the interaction between the direct effects of insulin on the liver and its indirect effects mediated by insulin acton in the brain, 2) to determine the mechanism by which liver glycogen loading enhances the hormonal response to insulin induced hypoglycemia, and 3) to determine the physiologic basis for the rapid deleterious effect of a high fat/high fructose diet on hepatic glucose uptake. Studie will be carried out in normal and diet induced insulin resistant conscious dogs. Three weeks before study catheters will be inserted under general anesthesia into the femoral artery, the hepatic portal vein and the hepatic vein, as well as in other vessels and sites as needed (splenic and jejunal veins, carotid and vertebral arteries, the 3rd ventricle etc.). The canine model is unique in that it allows hepatic portal vein infusion, while at the same time permitting the direct measurement of hepatic glucose output and uptake in vivo. Somatostatin will be used when required to disable the endocrine pancreas, along with intraportal infusion of insulin and glucagon at the rates required by the experimental design. Liver glucose metabolism will be assessed using a variety of tracer and A-V difference techniques. Metabolic clamps (glucose, NEFA, amino acids) will be used as needed to fix substrate levels. Surgical (hepatic denervation etc) and pharmacologic (i.e. hepatic portal vein infusion of drugs) tools will be used to bring about the desired experimental conditions. Tissues will be taken at the end of experiments so that the physiologic response can be correlated to the associated molecular alterations. The proposed studies will clarify the role of brain insulin action in the disposition of glucose absorbd from the gut. They will also lead to a better understanding of the way in which nerves originating in the liver can impact hypoglycemic counterregulation. Finally, they will increase our understanding of how a diet high in fat and fructose can quickly impair the ability of the liver to take up and storage glucose. The knowledge gained from the proposed experiments will help lead to the development of new therapeutic approaches to the treatment of glucose intolerance and diabetes. Read more.

Funding Source: NIH/NIDDK
PI: Alan Cherrington

Leveraging Patient Portals to Improve Medication Adherence in Type 2 Diabetes

For patients with diabetes, glucose lowering agents (GLA) improve glycemic control (HbA1c), and prevent disease-related complications, and premature death. Patient adherence to prescribed regimens is necessary to reap these benefits, and studies suggest adherence is poor, ranging from 36% to 85% adherence to oral GLAs; however, fewer patients using insulin report poor adherence. Existing technologies (e.g., cell phones, Internet reminders, patient web portals) could be leveraged to provide medication adherence reminders and support to patients with diabetes and, in turn, improve clinical outcomes. This proposal describes a career development plan that will prepare the principal investigator (PI) for success as an independent investigator who can leverage various technologies to design and evaluate diabetes self-care interventions. The proposal describes a research strategy in which the PI will use Vanderbilt's patient web portal (PWP) to deliver a theory-based GLA adherence promotion intervention. As a social/health psychologist with training in health behavior change, the PI will acquire complementary, new skills for developing and using technology through this K01. The PI's immediate goal is to use a PWP to deliver an Information-Motivation-Behavioral skills (IMB) focused GLA adherence intervention to patients with diabetes. To meet this goal, the PI has proposed a career development plan that integrates advanced didactic course work, participation in local and national meetings/seminars/workshops/conferences, a mentored research experience, and active involvement in an extremely supportive research environment. This environment includes an NIDDK funded Diabetes Research and Training Center (DRTC), nationally known Department of Biomedical Informatics, state-of-the-art patient PWP, NIH funded CTSA, Center for Health Services Research (CHSR), and Program on Effective Health Communication (EHC). The research specific aims are to: (1) conduct elicitation research with diabetes patients and providers to identify barriers to using a PWP and other technologies for diabetes and medication management; (2) design a GLA adherence intervention delivered via an existing PWP, test for usability with diabetes patients, and refine the intervention prior to evaluation; and (3) perform a randomized controlled trial to test the effect of the intervention on multiple measures of adherence and HbA1c at 3- and 6-months. In addition, the PI will test whether the intervention enhances critical determinants of adherence behavior based on the IMB model, and whether changes in IMB elements map onto improvements in adherence and HbA1c across time. Lastly, the PI will test potential moderators of the effect of the IMB elements on adherence. Leveraging technology in the proposed research will augment the PI's existing training in the design and evaluation of behavior change interventions. Most importantly, it will accelerate her career as a successful independent investigator well equipped to design and evaluate cutting-edge, theoretically grounded interventions with broad application to both the field of diabetes behavioral research and clinical care. Read more.

Funding Source: NIH/NIDDK
PI: Chandra Osborn

O'Brien Center Development: BPH and Obesity

This is toward development of a Center to investigate obesity and BPH.  We conduct two epidemiologic investigations to determine if prostate tissue inflammation or LUTS severity is associated with hypothesized pathways linking obesity to BPH, including increased PGE-M (inflammation), F2-isoprostanes (oxidative stress), and adiponectin and C-peptide (insulin activity).

Funding Source: NIH/NIDDK 
IMPH Faculty: Jay Fowke

Public-Private Partnership Addressing Literacy-Numeracy to Improve Diabetes Care

Despite strong evidence about the optimal treatment of diabetes, care often remains suboptimal. One recent examination of a national sample of diabetes patients found that less than 10% of patients surveyed were in optimal blood sugar, blood pressure and cholesterol control. One recently discovered barrier to optimal diabetes care is poor health literacy. Poor health literacy affects over 90 million Americans. Our research group was one of the first to demonstrate that low health literacy was independently associated with worse diabetes knowledge, self-management, and glycemic control (A1C). Numeracy (math skills) is an understudied component of literacy that is essential for many tasks in diabetes including glucose monitoring, assessing carbohydrate intake, and medication adjustment. Recently, our group demonstrated that poor numeracy is common in adults with diabetes and significantly associated with worse diabetes self-management, self- efficacy, and A1C. Addressing literacy and numeracy represent an exciting opportunity to improve diabetes care, because these are potentially modifiable risk factors. We recently performed four trials at academic medical centers that suggest that addressing literacy and numeracy can improve diabetes control. The aim of the proposed study is to perform a cluster-randomized trial to assess the efficacy of a low- literacy/numeracy-oriented intervention to improve diabetes care in under-resourced communities in Tennessee. The state of Tennessee now has a higher prevalence of diabetes then any other state in the nation. The study will occur in Tennessee Department of Health "safety net" primary care clinics in middle Tennessee. These primary care clinics provide diabetes care for a predominantly uninsured population at high risk for poor diabetes related health. The study represents a novel partnership between the Tennessee Department of Health and the Vanderbilt Diabetes Research and Training Center to improve care for a vulnerable population of diabetes patients. Ten State Health Department Clinics located in medically underserved areas will be randomized, and a total of 400 diabetes patients will be enrolled. Health Care Providers at the 5 control sites will receive standard diabetes education and the use of educational materials from the National Diabetes Education Program. Health Care Providers at intervention sites will receive training in clear health communication skills, and a Diabetes literacy and numeracy sensitive Educational Toolkit to use in partnership with their diabetes patients. Primary outcomes will include A1C, Blood Pressure, Cholesterol, Weight, Self-Management, and Self-Efficacy at 1 year. Patients will be followed for 2 years to assess sustainability. A cost-effectiveness analysis will be performed. The products of this study (health communication skills training modules and educational materials) will be disseminated via public access on the Internet. If successful, the proposed model will be disseminated across the State and will be a model for other Health Departments and clinics across the nation. Read more.

Funding Source: NIH/NIDDK
PI: Russell Rothman

Shanghai Men's Health Study

The Shanghai Men’s Health Study (SMHS), funded by NCI since 2001, is a population-based cohort study of 61,482 men aged between 35 and 75 years and recruited from 2002 to 2006. At baseline, detailed information on dietary intakes, personal habits, occupational history, medical history, and other lifestyle factors was collected, and anthropometrics were measured. Blood or buccal cell, and  urine samples were collected from 89% of participants. The cohort has been followed through multiple in-person surveys to update exposure information and through record linkages with the population-based Shanghai Cancer Registry and Shanghai Vital Statistics Registry to obtain information on cancer occurrence and survival status. Over the years, SMHS data and biological samples have been used to evaluate many important etiologic hypotheses addressing the contributions of environmental, dietary, lifestyle, and genetic exposures to the development of cancer and other chronic diseases. The cohort supports multiple studies, including over 25 consortium projects. Read more.

Funding Source: NIH/NCI 
PI: Xiao Ou Shu

Using Social Learning to Improve Adolescent Diabetes Adherence Problem Solving

Adolescents with type 1 diabetes (T1D) are at high risk for poor adherence and glycemic control. Some of the most prevalent barriers to adherence in adolescents are psychosocial in nature, such as stress, stigma, time pressures, social situations, and communication with peers and parents. Diabetes research and professional organizations support the development of problem solving skills to resolve barriers to adolescent adherence. In order to address the needs of adolescents with T1D, parents, and clinics, we created an Internet adherence problem solving intervention, named YourWay. Initial results indicated moderate impact on adherence but variable engagement with the intervention. Based on our preliminary studies, we propose substantially advancing our intervention through three new design features: 1) a mobile data collection system using ecological momentary assessment (EMA) to populate the intervention with behavioral adherence data and multimedia content and improve awareness of adherence barriers, 2) a new homepage that integrates EMA data, BG values, and adolescent-generated multimedia content into personal adherence stories, and 3) social learning activities with peers focused on adherence problem solving. These enhanced features will provide more objective and more engaging data to guide and motivate adherence problem solving and provide intrinsically motivated social interactions with peers about adherence. Our aims include 1) establishing current behaviors and beliefs regarding adolescent use of health information technology for diabetes, and specifically those related to sharing personal health information with peers, 2) focused iterative design cycles for each of these features to identify the most engaging and acceptable interface and adherence data sharing activities, and 3) a pilot randomized trial to assess the impact of the intervention on glycemic control (A1C). There are currently no resources for this population that integrate social interactions with peers with skill building activities to improve adherence. The proposed Internet intervention will innovatively combine these features into a personal story format. The intervention has a high potential for engaging adolescents in adherence problem solving, improving adherence, and reducing the serious medical consequences related to poor glycemic control. Read more.

Funding Source: NIH/NIDDK
PI: Shelagh Mulvaney

Vanderbilt Center for Diabetes Translation Research

Goals for diabetes care are well supported by large-scale, multi-centered randomized trials. Despite the advances in our knowledge of what to do for individuals with diabetes, we continue to struggle to achieve widely agreed upon diabetes standards of care. Extensive research has identified barriers that contribute to this inability to translate knowledge into improved outcomes. We propose to establish a Center for Diabetes Translation Research at Vanderbilt so as to support a robust research base in characterizing and modifying variables that have limited the translation of evidence-based care to improved outcomes in individuals with Diabetes. This Center application builds upon considerable and ongoing success in type II diabetes translation research and specifically provides support that is germane to our user base. In response to a careful reevaluation, we have modified and expanded our current services for this application in response to the evolving needs or our user base. We, however, maintain a focus on health disparities research and continue our long standing relationship with Meharry Medical College. Aim 1: To establish three resource cores designed to equip our investigators with key services that facilitate their research. The third core, Health Informatics and Technology, will also serve as a regional core. a. Translation Methods Core b. Community Engagement Core c. Health Information and Technology Core Aim 2: To provide a pilot and feasibility program Aim 3: To provide an enrichment program in Diabetes Translation Research Aim 4: To partner with Meharry Medical College as part of a subcontract thereby providing Meharry with its own core resources for the advancement of local research projects. Read more.

Funding Source: NIH/NIDDK 
PI: Tom Elasy

Vanderbilt Diabetes Research Center

The Vanderbilt Diabetes Research and Training Center (VDRTC), in its 38th continuous year of operation as a NIH-sponsored Diabetes Center, seeks to continue its efforts to facilitate the discovery, application, and translation of scientifc knowledge to improve the care of patients with diabetes. The VDRTC is an interdisciplinary program involving 126 participating faculty distributed among 15 departments in two schools and four colleges at Vanderbilt and neighboring Mehary Medical College. The VDRTC consists of: 1) Administrative Component that coordinates the scientific, organizational, and outreach activities; 2) Biomedical Research Component that recruits and selects VDRTC-affiliated investigators and supervises the research cores that facilitate and enhance their research; 3) Pilot and Feasibility Program that facilitates the development of new investigators into independent scientists and encourages scientists in other fields to enter the field of diabetes research; and 4) Enrichment, Training, and Outreach Program that fosters an environment conducive to collaborative, interdisciplinary research (seminar series. Diabetes Day), and to training new diabetes scientists (VDRTC oversees three NIDDK-funded diabetes-related training programs). NIH support for the VDRTC is greatly amplified by: 1) Vanderbilt's sustained commitment to provide research space and additional financial resources; 2) a diverse, comprehensive array of research core services at Vanderbilt, which allows NIH funds to target unique, diabetes-related research cores; and 3) collaborative efforts with other NIH-funded research centers at Vanderbilt. The VDRTC is evolving and dynamic, including additions to its investigator base, expansion of VDRTC research areas, expanded focus on clinical and translational research, realignment and evolution of core support to provide unique, indispensable core services, and service as a regional and national resource for the diabetes research community. Because of the VDRTC and the environment it creates, VDRTC-affiliated investigators have made important scientific contributions related to diabetes, obesity, and metabolism. Read more.

Funding Source: NIH/NIDDK
PI: Al Powers