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Winter 2009 Newsletter

Message from the Director

The MDRTC is pleased to welcome three new members to the MDRTC, Toby E. Jayarantne, PhD, Assistant Research Scientist, Health Behavior and Health Education, School of Public Health, Leslie S. Satin, PhD, Professor of Pharmacology, and Joshua D. Stein MD, MS, Assistant Professor of Ophthalmology and Visual Sciences. I would like to take this opportunity to share the research interests of these new members with you.

Dr. Jayaratne’s research program explores the behavioral, social, and public health implications of the lay public’s belief that genes explain human traits and diseases. She is currently directing studies in three areas, one of which examines the effects of lay genetic explanations for type 2 diabetes on health behaviors. Results from a pilot study that Dr. Jayaratne and colleagues conducted showed that 1) individuals who believe type 2 diabetes is genetic in origin are more likely than others to believe this disease is uncontrollable and permanent, and 2) those who report a family history of type 2 diabetes and who hold a belief in genetic influence on type 2 diabetes, have a higher perceived risk for developing type 2 diabetes. These findings have important implications for diabetes prevention because they suggest that genetic explanations for type 2 diabetes are linked to fatalistic attitudes toward developing the disease. In addition to this pilot study, Dr. Jayaratne and her colleagues have submitted a proposal to NIDDK to conduct a national survey exploring genetic explanations for type 2 diabetes among White Americans, African Americans and Mexican Americans. The proposed study has four aims: 1) to understand how the lay public conceptualizes genetic influences on type 2 diabetes, 2) to examine the association between genetic explanations for the development of type 2 diabetes and perceived control over the development of type 2 diabetes, 3) to examine the association between perceived control over the development of type 2 diabetes and key attitudes and behaviors related to prevention, and 4) to investigate how genetic explanations for type 2 diabetes, perceived family history, and perceived risk together influence key attitudes and behaviors related to prevention.

Dr. Jayaratne’s two other studies focus on lay genetic explanations for a range of human attributes such as intelligence, violence, math ability, athleticism, and sexual orientation. One study, funded by NHGRI, explores White and Black American’s use of genes to account for perceived gender, class and racial differences. A second study investigates teachers’ use of genetic explanations for their students’ academic abilities and classroom behaviors.

Dr. Satin’s research focuses on understanding the cellular and molecular mechanisms mediating free calcium signaling in pancreatic islets, insulin granule exocytosis, and islet dysfunction in diabetes. Specific research projects underway in the laboratory include studies of metabolic and ionic oscillations in islets, how beta cells communicate with one another within islets, and how islets communicate within the pancreas; the development of novel sensors of beta cell metabolic activity; the modulation of islet function by fatty acids; and studies of the biophysical properties of beta cell ion channels. The overall goal of this work is to better understand the integrated function of islets in health and disease, and to develop novel targets for modulation by a new generation of diabetes drugs.

Dr. Stein is an ophthalmologist interested in using data from large claims databases to study utilization patterns (eye care visits, diagnostic and therapeutic ophthalmological services) of patients with diabetic retinopathy with the goal of identifying ways to reduce blindness associated with diabetic retinopathy. He is interested in collaborating with other investigators studying the complications associated with diabetes mellitus.

Dr. Stein recently received a seeding grant from the Midwest Eye-Banks Eye and Vision Research Program which is an independent, not-for-profit organization dedicated to the restoration of sight. Dr. Stein will use databases to gain an appreciation of the numbers of individuals in the U.S. who are chronically receiving corticosteroids for ophthalmological or non-ophthalmological purposes and whether such individuals are undergoing routine eye examinations to monitor for ocular side effects of steroids including glaucoma and cataracts.

Please join me in welcoming Drs. Jayaratne, Satin, and Stein to the MDRTC.

I would also like to remind you of the importance of citing the MDRTC in your publications when you have used MDRTC core resources. The National Institute Diabetes and Digestive and Kidney Diseases (NIDDK) is using the number of research papers citing the grant to evaluate diabetes centers. A national Diabetes Centers website has been established (see article below) which automatically retrieves publications from PubMed Central that contain the Center grant number. Less than one-third of the publications supported by the MDRTC actually cite the MDRTC grant number in the Acknowledgement section. The following language should be used to recognize the MDRTC in publications:

“This work utilized ______Core(s) of the Michigan Diabetes Research and Training Center funded by DK020572 from the National Institute of Diabetes and Digestive and Kidney Diseases.”

OR

“This work was funded by a Pilot and Feasibility Study from the Michigan Diabetes Research and Training Center (DK020572 from the National Institute of Diabetes and Digestive and Kidney Diseases).”

Also included in this newsletter is a summary of publications highlighting the scientific advances supported by MDRTC in the past year. I think you’ll agree that it is an impressive set of publications which clearly demonstrate the accomplishments of our center.

With warm regards,
Bill

MDRTC Core Updates

Animal Phenotyping Core

There is an increasing demand for insulin clamp studies (hyperinsulinemic-euglycemic clamps) and CLAMS assessments (VO2 consumption). The Animal Phenotyping Core is trying to increase its capacity to perform these studies; however, they encourage investigators to schedule their studies with the core as early as possible.

Cell & Molecular Biology Core

The University of Michigan recently joined 22 other leading academic research centers around the world to participate in Thermo Fischer Scientific's Genome-wide RNAi Global Initiative. Created in 2005, the Global Initiative serves to combine the powerful new capability of high-throughput genome-wide siRNA screening with international scientific exchange and collaboration to accelerate discovery. U-M's participation has prompted a substantial commitment of resources to develop the infrastructure to support this emerging research field.

Martha Larsen is leading the day-to-day scientific and operational activities for the High Throughput Screening (HTS), RNAi and High Content Screening efforts within the Center for Chemical Genomics (CCG).

An RNAi Review Committee was formed to review the initial applications for siRNA screening. Members of the committee include: Steve Kunkel, PhD, Eric Fearon, PhD, Gabriel Nunez, MD, Ronald J. Koenig, MD, PhD, Benjamin L. Margolis, MD, Richard Neubig, PhD and Martha Larsen.

Information about applying for screens will be available on the CCG website: http://www.lsi.umich.edu/ccg at the end of the 2008.

NIH Sponsored Medical Student Training Program for Summer 2009

The 2009 Diabetes Centers Medical Student summer internship training program is sponsored by the National Institutes of Health and allows medical students during the summer between the first and second year or second and third year to conduct independent research under the direction of established scientists in the area of diabetes, hormone action, cell signaling, islet cell function, and clinical investigation at one of the 17 nationally funded Diabetes and Endocrinology Research Center (DERC) or Diabetes Research and Training Centers (DRTC).

The objectives of this Program are to provide the opportunity for the student to conduct diabetes-related research and to gain an improved understanding of career opportunities in biomedical research. The preceptor and the medical student jointly design a research project that is then conducted over the course of the summer. In addition to working on his/her own research project, each student attends a series of web-cast seminars addressing various clinical and research aspects of diabetes mellitus and its complications. At the conclusion of the summer, each student presents a brief summary of his/her work at a scientific symposium for all Program participants. Prior research experience is not required. Students must be U.S. Citizen and/or permanent resident to participate in this Program.

The University of Michigan has been granted funds for 4 medical students. Each student will receive a stipend (currently calculated at a rate of approximately $399 per week) from which expenses for food and housing may be paid. Students are expected to spend eight-twelve (8-12) weeks in the Program, but commencement and conclusion dates are reasonably flexible.

If you know of medical students who would be interested in this program, please inform them of this opportunity. More information about the program and the application form for the program can be found at http://medicalstudentdiabetesreseach.org/program-description.php . The MDRTC will be emailing medical students about this program and posting flyers in areas where the medical students convene to encourage participation in the program once the application is available on the website.

If you are interested in becoming preceptor for a medical student, please email Linda Potter at ldpotter@umich.edu to inform her of your interest and the type of research the medical student would participate in during the summer of 2009.

Five Pilot and Feasibility Grants Awarded

The MDRTC Grants Advisory Council met in November to review eleven applications for P/FS studies from researchers across the University of Michigan. Five researchers were funded for $50,000 each. The awardees are as follows:

Peter Dempsey, PhD, Associate Professor, Pediatric Gastroenterology, "Role of ErbB4 receptor signaling in the Central Regulation of Energy Metabolism"

Carey Lumeng, MD, PhD, Assistant Professor, Pediatrics, “Depot-specific differences in adipose tissue macrophages – Michigan Macrophages in Adipose Tissue”

Sandeep Pandit, PhD, Professor, Internal Medicine-Cardiology, “Arrhythmogenesis in Type-1 Diabetes”

Rodica Pop-Busui, MD, PhD, Assistant Professor, Internal Medicine, “Stress Induced Hyperglycemia: A Predictor of Long-Term Glucose Abnormalities in Patients Undergoing Cardiovascular Surgery?”

Bhumsoo Kim, PhD, Research Assistant Professor, Neurology, “Animal models of increased Alzheimer's disease progression with diabetic background”

Diabetes Interdisciplinary Study Program (DISP) Awards

The MDRTC, the Michigan Comprehensive Diabetes Center (MCDC) and the Michigan Institute for Clinical and Health Research (MICHR) jointly funded the following proposal for $100,000 that promoted interdisciplinary collaboration among researchers.

Elif Oral, MD, Assistant Professor, Internal Medicine and John D. Birkmeyer, MD, Professor, General Surgery, “Effect of Dietary Macrocomposition on Non-Alcoholic Fatty Liver Disease in Bariatric Surgery Candidates”

Funding Opportunities

Closed Loop Technologies: Clinical and Behavioral Approaches to Improve Type 1 Diabetes Outcomes (R01)
(RFA-DK-08-012)
National Institute of Diabetes and Digestive and Kidney Diseases
Eunice Kennedy Shriver National Institute of Child Health and
Human Development
Application Receipt Date(s): March 19, 2009
http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-08-012.html


Closed Loop Technologies: Pilot and Exploratory Clinical and Behavioral Approaches to Improve Type 1 Diabetes Outcomes (R21)

(RFA-DK-08-013)
National Institute of Diabetes and Digestive and Kidney Diseases
Eunice Kennedy Shriver National Institute of Child Health and
Human Development
Application Receipt Date(s): March 19, 2009
http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-08-013.html

NIH Public Access Policy

The NIH Public Access Policy:

  1. Applies to all investigators funded by the NIH
  2. Requires that final peer reviewed manuscripts be submitted to Pub Med Central upon
    acceptance for publication
  3. Effects all final peer-reviewed manuscripts accepted for publication after April 7, 2008.

How to comply:

  1. Retain copyright
    - Retain the right to have a copy of the peer-reviewed manuscript deposited in Pub Med
    Central to meet the requirements of NIH Public Access Policy
  2. Submit your final manuscript to Pub Med Central
    -Some journals may do this for you. A list of journals that submit to Pub Med Central can be
    found at http://www.pubmedcentral.nih.gov/fprender.fcgi
    -OR you may submit your own manuscript to the NIH Manuscript Submission
    System (NIHMS) at http://nihms.nih.gov/
    -OR you may participate in UM's MLibrary pilot (nihms-library-support@umich.edu) which will
    deposit the manuscript for you into both PubMed Central and if you choose into Deep Blue
    (UM's digital repository)
  3. As of May 25, 2008, you must cite the Pubmed Central ID number (PMCID) [this is different from the Pubmed ID (PMID) number] in all NIH applications, proposals and progress reports that fall under the policy and arose from an NIH award.

NIH Announcement on Resubmissions (Amended Applications)

NIH recently announced a change in the way in which applications may be resubmitted for review. The full text of the announcement may be read at:

http://grants.nih.gov/grants/guide/notice-files/NOT-OD-09-003.html

Under the old rules, New and Competitive Renewals were allowed "3 strikes" -- an original proposal and two resubmissions. Beginning with New and Competitive Renewals submitted (for the first time) on or after January 25, 2009, the proposals will be allowed only (1) original and (1) resubmission. Additionally, if the cycle is initiated prior to January 25th, the final Amendment 2 (A-2) application must be sent no later than January 7, 2011.

Examples:
Competitive Renewal submitted on November 5, 2008, will be allowed an original, A1, and A2 application - as long as the A2 version is submitted prior to January 7, 2011

Competitive Renewal submitted March 5, 2009 will be allowed only an original and A1 application.

National Diabetes Centers Website

The newly developed National Diabetes Center website located at http://www.diabetescenters.org/ contains a wealth of information about the NIDDK-supported Diabetes Endocrinology Research Centers (DERCs) and Diabetes Research and Training Centers (DRTCs). The website provides detailed information on each DERC and DRTC and identifies key personnel, cores, and services. The site also contains recent publications from each center, new programs supported by NIDDK, and new funding opportunites. We suggest that you book mark this site for future reference.

Research Conferences

The 2008 Therapeutic Patient Education International Congress and 4th Annual DAWN Summit was held November 5-8 in Budapest, Hungary with over 600 attendees from 53 countries in attendance. This Congress attracts clinicians, educators and behavioral scientists who are experts in diabetes patient education. The MDRTC was well-represented with plenary presentations by Martha Funnell, MS, RN, CDE and Michele Heisler, MD, MPA, a workshop presentation by Robert M. Anderson, EdD and Martha Funnell, and abstract presentations by Tricia S.Tang, PhD and Jim E. Aikens, PhD.

The American Diabetes Association 69th Scientific Sessions will be held June 5-9, 2009 at the Morial Convention Center in New Orleans, Louisiana. More information is located at scientificsessions.diabetes.org .

The 91st Annual Endocrine Society Meeting will be held June 10-13, 2009 in Washington, D.C. More information is located at http://www.endo-society.org/meetings/Annual/index.cfm .

In the News

Islet Amyloid Polypeptide Protein

Building on work published earlier this year, Ayyalusamy Ramamoorthy, Associate Professor of Chemistry and Biophysics and co-workers compared the human form of Islet Amyloid Polypeptide Protein (IAPP) to the rat version which does not show cell death and showed that a difference of a single amino acid at a position designated as residue 18 accounts for the difference in toxicity. They also elucidated the structures of human and rat IAPP and then tested the ability of the two new proteins to damage membranes (the process by which human IAPP kills insulin-producing cells).

Their results suggest that the reason rat IAPP is non-toxic, while the human version is a cell killer, has to do with differences in how the two proteins fold, which in turn is dictated by the particluar amnio acid at residue 18. The new work also confirms their previous finding (published in the Journal of Amercian Chemical Society) that human IAPP does not form fibrils to kills cells, as amyloid peptides in general have been thought to do.

More adults have prediabetes, with patients (and often physicians) unsure who's at risk

As many as a fourth of U.S. adults have impaired glucose tolerance that puts them at risk for diabetes, a condition called pre-diabetes. That's a staggering number of people, but William H. Herman, MD, MPH, director of the Michigan Diabetes Research and Training Center, says in American Medical News that some simple lifestyle changes can reduce diabetes risk by 60 percent. Read more in the Dec. 9 edition of the publication produced by the American Medical Association located at http://www.ama-assn.org/amednews/2008/12/08/hlsb1208.htm.

Accolades to MDRTC Members

Gilbert S. Omenn, MD, PhD, was presented the Walsh McDermott Medal for distinguished service at the 38th annual meeting of the Institute of Medicine.

Ruma Banerjee, PhD was installed as the first Vincent Massey Collegiate Professor of Biological Chemistry in October.

Randal J. Kaufman, PhD was installed as the Warner-Lambert/Parke-Davis Professor of Medicine in October.

Publications Highlighting Scientific Advances Supported by MDRTC Cores

Animal Phenotyping Core

Huang X, Charbeneau RA, Fu Y, Kaur K, Gerin I, MacDougald OA, Neubig RR. Resistance to diet-induced obesity and improved insulin sensitivity in mice with a regulator of G protein signaling-insensitive G184S Gnai2 allele. Diabetes. 2008 Jan; 57(1):77-85. Epub 2007 Oct 10. PMID: 17928396

Description: Regulators of G protein signaling (RGSs, or RGS proteins) are responsible for the subsecond turn off of G protein signaling, which plays major roles in endocrine/metabolic function. This study explored the role of RGS proteins and Gi2 in the physiologic regulation of body weight and glucose homeostasis by studying genomic "knock-in" mice expressing RGS-insensitive Gi2 with a G184S mutation that blocks RGS protein binding and GTPase acceleration. Homozygous Gi2G184S knock-in mice show slightly reduced adiposity. On a high-fat diet, male Gi2G184S mice are resistant to weight gain, have decreased body fat, and are protected from insulin resistance. This appears to be a result of increased energy expenditure. Thus, RGS proteins and Gi2 signaling play important roles in the control of energy balance, insulin sensitivity and glucose metabolism. Identification of the specific RGS proteins involved might permit their consideration as potential therapeutic targets for obesity-related insulin resistance and type 2 diabetes.

Cell and Molecular Biology Core

Gong Y, Ishida-Takahashi R, Villanueva EC, Fingar DC, Munzberg H, Myers MG Jr. The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms. J Biol Chem. 2007 Oct 19; 282(42):31019-27. Epub 2007 Aug 28. PMID: 17726024.

Leptin plays a central role in the control of appetite, energy homeostasis and neuroendocrine function. This paper investigated the signaling pathways through which the leptin/leptin receptor (LepRb) complex function. LepRb Tyr1077 is phosphorylated during receptor activation, and that this is critical to activation (phosphorylation) of STAT5. LepRb Tyr1138 plays a secondary role in STAT5 activation. In contrast, Tyr985 phosphorylation mediates the phosphorylation of the ribosomal S6 kinase (RSK) and S6, as well as cap-dependent translation. Thus, these data demonstrate that different signaling mechanisms are used by LepRb to regulate different downstream events.

Hodish I, Rhodes CJ, Arvan P. Proinsulin maturation, misfolding, and proteotoxicity. Proc Natl Aca Sci U S A. 2007 Oct 2; 104(40:15841-6. Epub 2007 Sep 26. PMID: 17898179.

GFP was inserted into the C peptide of the human proinsulin cDNA to facilitate studies of intracellular proinsulin trafficking. The fusion protein, denoted hProCpepGFP, is processed in appropriate cells to CpepGFP and insulin, which are cosecreted in parallel with endogenous insulin. The authors next studied C(A7)Y mutant proinsulin, which causes autosomal dominant diabetes in Akita mice. They found that the mutant insulin misfolds. They used mutant and wild type proinsulin GFP constructs to demonstrate that the mutant proinsulin forms complexes with wild type version, impairs the trafficking of the wild type protein, decreases insulin production in β cells, and leads to loss of cell viability. The data suggest that proinsulin misfolding leads to β cell dysfunction and death, leading to diabetes.

Subauste AR, Burant CF. Role of FoxO1 in FFA-induced oxidative stress in adipocytes. Am J Physiol Endocrinol Metab. 2007 Jul; 293(1):E159-64. Epub 2007 Mar 20. PMID: 17374693.

Reactive oxygen species (ROS) play an important role in insulin resistance, and the transcription factor FoxO1 regulates ROS production. The authors found that treatment of adipocytes with free fatty acids (FFA) caused a decrease in the level of FoxO1 protein. FoxO1 down regulation correlated with an increase in the production of ROS and proinflammatory adipokines IL-6, plasminogen activator inhibitor-1, and monocyte chemotactic protein-1. Resveratrol, which translocates FoxO1 to the nucleus, increased FoxO1 protein levels in adipocytes exposed to FFA, decreases ROS and partially normalized the proinflammatory adipokine pattern. These data suggest that the Sirtuin-FoxO1 pathway may be a useful therapeutic target in obesity.

MIAC Core

D’Andrea-Merrins M, Chang L, Lam AD, Ernst SA, Stuenkel EL. Munc18c interaction with syntaxin 4 monomers and SNARE complex intermediates in GLUT4 vesicle trafficking. J Biol Chem. 2007 Jun 1; 282(22):16553-66. Epub 2007 Apr 5. PMID: 17412693.

Insulin stimulates glucose transport in target tissues by increasing the recruitment of GLUT4, present in vesicles, to the plasma membrane. The mechanism by which this occurs remains largely controversial. In the process of insulin-stimulated GLUT4 vesicle exocytosis, Munc18c has been proposed to control SNARE complex formation by inactivating syntaxin 4 in a self-associated conformation. In vivo fluorescence resonance energy transfer in 3T3L1 adipocytes, co-immunoprecipitation, and in vitro binding assays, revealed that Munc18c also associates with nearly equal affinity to a mutant of syntaxin 4 in a constitutively open (unfolded) state (L173A/E174A; LE). To bind to the open conformation of syntaxin 4, we found that Munc18c requires an interaction with the N terminus of syntaxin 4, which resembles Sly1 interaction with the N terminus of ER/Golgi syntaxins. However, both N and C termini of syntaxin 4 are required for Munc18c binding, since a mutation in the syntaxin 4 SNARE domain (I241A) reduces the interaction, irrespective of syntaxin 4 conformation. Use of an optical reporter for syntaxin 4-SNARE pairings in vivo revealed that Munc18c blocks recruitment of SNAP23 to wild type syntaxin 4 yet associates with syntaxin 4LE-SNAP23 Q-SNARE complexes. Fluorescent imaging of GLUT4 vesicles in 3T3L1 adipocytes revealed that syntaxin 4LE expressed with Munc18c bypasses the requirement of insulin for GLUT4 vesicle plasma membrane docking. This effect was attenuated by reducing the Munc18c-syntaxin 4LE interaction with the I241A mutation, indicating that Munc18c facilitates vesicle docking. Therefore, in contradiction to previous models, our data indicate that the conformational "opening" of syntaxin 4 rather than the dissociation of Munc18c is the critical event required for GLUT4 vesicle docking.

Kellogg AP, Wiggin TD, Larkin DD, Hayes JM, Stevens MJ, Pop-Busui R. Protective effects of cyclooxygenase-2 gene inactivation against peripheral nerve dysfunction and intraepidermal nerve fiber loss in experimental diabetes. Diabetes. 2007 Dec; 56(12):2997-3005. Epub 2007 Aug 24. PMID: 17720896.

The confocal microscope was similarly used by Dr. Pop-Busui’s group to determine intraepidermal nerve fiber density as a marker of DN. This group was examining the interrelationships between hyperglycemia, activation of the COX-2 pathway, and oxidative stress and inflammation in mediating peripheral nerve dysfunction and whether COX-2 gene inactivation attenuates nerve fiber loss in long-term experimental diabetes. Motor and sensory digital nerve conduction velocities, sciatic nerve indexes of oxidative stress, prostaglandin content, markers of inflammation, and intraepidermal nerve fiber density were measured after 6 months in control and diabetic COX-2-deficient (COX-2(-/-)) and littermate wild-type (COX-2(+/+)) mice. The effects of a selective COX-2 inhibitor, celecoxib, on these markers were also investigated in diabetic rats. These investigators made the important finding that selective COX-2 inhibition may be useful for preventing or delaying diabetic peripheral neuropathy.

Sullivan KA, Hayes JM, Wiggin TD, Backus C, Su Oh S, Lentz SI, Brosius III F, Feldman EL. Mouse models of diabetic neuropathy. Neurobiol Dis. 2007 Dec; 28(3):276-85. Epub 2007 Jul 31. PMID: 17804249.

Diabetic neuropathy (DN) is a debilitating complication of type 1 and type 2 diabetes. Rodent models of DN do not fully replicate the pathology observed in human patients. The Feldman laboratory examined DN in streptozotocin (STZ)-induced [B6] and spontaneous type 1 diabetes [B6Ins2(Akita)] and spontaneous type 2 diabetes [B6-db/db, BKS-db/db]. The confocal microscope was used to determine intraepidermal nerve fiber density, one of the measures used to assess DN. Despite persistent hyperglycemia, the STZ-treated B6 and B6Ins2(Akita) mice were resistant to the development of DN. In contrast, DN developed in both type 2 diabetes models: the B6-db/db and BKS-db/db mice. The persistence of hyperglycemia and development of DN in the B6-db/db mice required an increased fat diet while the BKS-db/db mice developed severe DN and remained hyperglycemic on standard mouse chow. Our data support the hypothesis that genetic background and diet influence the development of DN and should be considered when developing new models of DN.

Peptide and Proteomics Core

Chen XW, Leto D, Chiang SH, Wang Q, Saltiel AR. Activation of RalA is required for insulin-stimulated Glut4 trafficking to the plasma membrane via the exocyst and the motor protein Myo1c. Dev Cell. 2007 Sep; 13(3):391-404. PMID: 17765682

In this article XW Chen et al. make an important contribution towards understanding the molecular mechanisms of diabetes. They elucidated a key regulatory mechanism by which insulin stimulates glucose transport in the adipose tissue. Knowledge of the molecular mechanisms allows us to develop adequate and tailored treatment for this disease.

Insulin stimulates glucose transport in muscle and adipose tissue by producing translocation of the glucose transporter Glut4. The exocyst, an evolutionarily conserved vesicle tethering complex, is crucial for targeting Glut4 to the plasma membrane. The Saltiel group reports that insulin regulates this process via the G protein RalA, which is present in Glut4 vesicles and interacts with the exocyst in adipocytes. Insulin stimulates the activity of RalA in a PI 3-kinase-dependent manner. Disruption of RalA function by dominant-negative mutants or siRNA-mediated knockdown attenuates insulin-stimulated glucose transport. RalA also interacts with Myo1c, a molecular motor implicated in Glut4 trafficking. This interaction is modulated by Calmodulin, which functions as the light chain for Myo1c during insulin-stimulated glucose uptake. Thus, RalA serves two functions in insulin action: as a cargo receptor for the Myo1c motor, and as a signal for the unification of the exocyst to target Glut4 vesicles to the plasma membrane.

Xiao J, Xia H, Zhou J, Azmi IF, Davies BA, Katzmann DJ, Xu Z. Structural basis of Vta1 function in the multivesicular body sorting pathway. Dev. Cell. 2008 Jan; 14(1):37-49. PMID: 18194651.

The multivesicular body (MVB) sorting pathway plays an essential role in several eukaryotic cellular processes, including cell surface growth factor receptor downregulation. Proper function of the MVB pathway requires reversible membrane association of the ESCRTs, a process catalyzed by Vps4 ATPase. Vta1 regulates the Vps4 activity, but its mechanism of action was poorly understood. Xu’s group report the high-resolution crystal structures of the Did2- and Vps60-binding N-terminal domain and the Vps4-binding C-terminal domain of S. cerevisiae Vta1. This work has revealed a new mechanism of regulation by Vta1, allowing for an additional level of regulation and coordination for ESCRT-III assembly and disassembly. This work is likely to be applicable to the mechanism by which insulin receptors are downregulated.

Behavioral, Clinical and Health Systems (BCHS) Intervention Research Core

Funnell MM, Brown TL, Childs BP, Haas LB, Hosey GM, Jensen B, Maryniuk M, Peyrot M, Piette JD, Reader D, Siminerio LM, Weinger K, Weiss MA. National standards for diabetes self-management education. Diabetes Care. 2007 Jun; 30(6):1630-7. No abstract available. PMID: 17526822

The National Standards for DSME are designed to define quality diabetes self-management education and to assist diabetes educators in a variety of settings to provide evidence-based education. Because of the dynamic nature of health care and diabetes-related research, these Standards are reviewed and revised approximately every five years by key organizations and federal agencies within the diabetes education community. The Task Force was charged with reviewing the current DSME standards for their appropriateness, relevance and scientific basis. The Standards were then reviewed and revised based on the available evidence and expert consensus.

Anderson RM, Funnell MM. The art and science of diabetes education: a culture out of balance. Diabetes Educ. 2008 Jan- Feb;34(1):109-17. PMID: 18267997.

Effective diabetes education involves a combination of art and science. The design of patient education programs are expected to be based on scientifically derived evidence and standards of care. Communicating effectively with patients however is an art. No matter how carefully and scientifically designed, an education program can only be as effective as its least effective educator. The literature on diabetes education has focused exclusively on the educational and behavioral sciences and very little on the interpersonal and counseling skills and compassion of the educator. It is time to balance this equation by documenting the importance of creating a therapeutic alliance as an essential component of effective diabetes education and care.

Tang TS, Brown MB, Funnell MM, Anderson RM. Social support, quality of life, and self-care behaviors among african americans with type 2 diabetes. Diabetes Educ. 2008 Mar-Apr; 34(2):266-76. PMID: 18375776.

This study examined social support and its relationship to diabetes specific quality of life and self-care behaviors in African Americans with type 2 diabetes. Findings indicated that social support plays a role in diabetes quality of life and self-management practices. Social support encompasses multiple dimensions that differentially influence specific diabetes health-related outcomes and behaviors.

Biostatistics and Economic Modeling Core

Berlie HD, Herman WH, Brown MB, Hammad A, Jaber LA. Quality of diabetes care in Arab Americans. Diabetes Res Clin Pract. 2008 Feb; 79(2):249-55. Epub 2007 Oct 18. PMID: 17949846

Carlson N, Johnson T, Brown MB. A Bayesian approach to modeling associations between pulsatile hormones. Biometrics, Epub August 2008. PMID: 18759850

Feathers JT, Kieffer EC, Palmisano G, Anderson M, Janz N, Spencer MS, Guzman R, James SA. The development, implementation, and process evaluation of the REACH Detroit Partnership's Diabetes Lifestyle Intervention. Diabetes Educ. 2007 May-Jun; 33(3):509-20. PMID: 17570882

Johnson TD. Analysis of pulsatile hormone concentration profiles with nonconstant basal concentration: A Bayesian approach. Biometrics 2007 December; 63(4):1207-1217. PMID: 18078483

The papers by Carlson, Johnson and Brown and that by Johnson continue the development of models of pulsatile hormones by the Biostatistics and Economic Modeling Core. The paper by Carlson et al develops statistical methodology to model the association between two pulsatile hormones and derives tests to determine whether an apparent association is significant. This allows investigators to relate the secretion profiles of two pulsatile hormones. The paper by Dr. Johnson focuses on the development of a Bayesian approach to deconvolution for pulsatile secretion. There are several advantages to adopting a Bayesian approach to this problem. (1) The number, K, of secretion pulses, as well as their locations can be jointly modeled with all other parameters in the deconvolution model. (2) Incorporating non-Gaussian functional pulse shapes is straightforward in the Bayesian approach and much more difficult in a likelihood-based approach. (3) "Non-parametric" pulse shapes can easily be modeled through a "mixture", or superposition, of two or more Gaussian functions that represent a single pulse (this is similar to using mixtures of (normal) distributions as an alternative to non-parametric density estimation).

Tang T, Brown MB, Funnell MM, Anderson RM (2008). Social support, quality of life and self-care behaviors among African-Americans with Type 2 diabetes. Diabetes Educator, 2008 34: 266-276. PMID: 18375776

Tang et al describes a diabetes management program to improve social support, quality of life and self-care behaviors among African-Americans with Type 2 diabetes. The paper is a good example of how the Biostatistics and Economics Modeling Core assists a young investigator (Dr. Tang) in the design of her study and in the analysis of the data from the study.

Measurement Core

Haan MN, Aiello AE, West NA, Jagust WJ. C-reactive protein and rate of dementia in carriers and non-carriers of Apolipoprotein APOE4 genotype. Neurobiol Aging. 2007 May 29; PMID: 17540481

The MDRTC is very interested in assisting investigators exploring new risk factors. This study examined whether APOE4 modifies the effects of CRP on rate of all cause dementia, cognitive impairment or Alzheimer's disease (AD). In 5-year follow up from 1998 to 2006 in an ongoing cohort of older Latinos, the investigators found that higher CRP in those with APOE4 may be a marker of better immune function, leading to lower rate of dementia and AD.

Heisler M, Faul JD, Hayward RA, Langa KM, Blaum C, Weir D. Mechanisms for racial and ethnic disparities in glycemic control in middle-aged and older Americans in the health and retirement study. Arch Intern Med. 2007 Sep 24; 167(17):1853-60. PMID: 17893306

This paper is one of several that have come out of collaboration between MDTRC Measurement Core investigators and investigators on the Health Retirement Study, the largest cohort study of aging Americans funded by NIA. Measurement Core investigators assisted on both the design and technical aspects of obtaining supplemental survey results and A1c results (via valid at-home A1c kits) on a nationally representative sample of 1901 Americans 55 years or older with diabetes mellitus in 2003. This study examined potential etiologies for why ethnic minorities have worse glycemic control in the US. Interestingly, this study did not support the hypotheses that poorer glycemic control in ethnic minorities is due to less intensive medication treatment, lower medication adherence, or was due t other clinical or identifiable sociodemographic factors (such as income, education levels, or physical activity levels). The reasons for disparities in glycemic control between Whites, Latinos and African-Americans remains elusive, but this study could find no evidence that the differences are due to differences in medical care or self-reported medication adherence.

Kerr EA, Heisler M, Krein SL, Kabeto M, Langa KM, Weir D, Piette JD. Beyond comorbidity counts: how do comorbidity type and severity influence diabetes patients' treatment priorities and self-management? J Gen Intern Med. 2007 Dec.22 (12):1635-40. Epub 2007 Jul 24. PMID: 17647065

The Measurement Core has a long standing interest in the measurement and the clinical implications of disease severity and medical comorbidities. In this study investigators sought to understand how the number, type, and severity of comorbidities influence diabetes patients' self-management and treatment priorities. They examined 1,901 diabetes patients in the 2003 Health and Retirement Study (HRS) diabetes survey, and found that 40% of respondents had at least 1 microvascular comorbidity, 79% at least 1 macrovascular comorbidity, and 61% at least 1 non-diabetes-related comorbidity. Patients with a greater overall number of comorbidities placed lower priority on diabetes and had worse diabetes self-management ability scores. However, only macrovascular and non-diabetes-related comorbidities, but not microvascular comorbidities, were associated with lower diabetes prioritization, whereas higher numbers of microvascular, macrovascular, and non-diabetes-related conditions were all associated with lower diabetes self-management ability scores. These results suggest that the type and severity of comorbid conditions, and not just the comorbidity count, influence diabetes patients' self-management. Patients with severely symptomatic comorbidities and those with conditions they consider to be unrelated to diabetes may need additional support in making decisions about care priorities and self-management activities.