Mechanisms of Beta Cell Function in Health and Disease

Summary

Principal Investigator: CARMELLA EVANS EVANS-MOLINA
Abstract: DESCRIPTION (provided by applicant): Emerging physiologic and genetic data suggest that dysfunction of the pancreatic beta cell is the key determinant of whether an insulin resistant individual will progress to frank hyperglycemia and diabetes. The long-range goal of this applicant is to define the pathways that govern beta cell function and survival in states of health in order to understand how these regulatory circuits are impaired in the pathologic state of Type 2 diabetes mellitus. The sarco-endoplasmic reticulum calcium ATPase or SERCA pump resides in the endoplasmic reticulum membrane and is responsible for maintaining a steep calcium concentration gradient between the cytosol and endoplasmic reticulum. In the beta cell, this gradient plays a key role in regulated insulin secretion and the maintenance of endoplasmic reticulum health and function. Preliminary and published work has revealed that expression of the predominant beta cell isoform, SERCA2, is markedly downregulated in rodent and human models of Type 2 diabetes mellitus. Furthermore, loss of SERCA2 expression leads to profound changes in beta cell secretory function and intracellular calcium flux in response to glucose. Given this background, the overall hypothesis of this proposal is that dysregulation of SERCA2 activity and expression is a key contributor to the beta cell dysfunction and death observed in Type 2 diabetes mellitus. To test this hypothesis, three aims are proposed. Aim 1: elucidate the in vivo role of SERCA2 in beta cell function using two novel mouse models of SERCA2 deficiency. Aim 2: delineate the transcriptional pathways that regulate SERCA2 expression in the pancreatic beta cell under normal conditions and in diabetes. Aim 3: elucidate the contribution of microRNAs in disruption of the SERCA2 gene regulatory network. The successful completion of these aims will precisely define the role of islet beta cell SERCA2 in metabolic and glucose homeostasis and identify the pathways that lead to its transcriptional dysregulation in Type 2 diabetes mellitus.
Funding Period: 2011-09-15 - 2016-08-31
more information: NIH RePORT

Top Publications

  1. pmc PPAR-γ activation restores pancreatic islet SERCA2 levels and prevents β-cell dysfunction under conditions of hyperglycemic and cytokine stress
    Tatsuyoshi Kono
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    Mol Endocrinol 26:257-71. 2012
  2. ncbi Shock wave lithotripsy targeting of the kidney and pancreas does not increase the severity of metabolic syndrome in a porcine model
    Rajash K Handa
    Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana Electronic address
    J Urol 192:1257-65. 2014
  3. pmc Human adipose-derived stromal/stem cells protect against STZ-induced hyperglycemia: analysis of hASC-derived paracrine effectors
    Tatsuyoshi M Kono
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Stem Cells 32:1831-42. 2014
  4. pmc A case of calciphylaxis in a patient with hypoparathyroidism and normal renal function
    Blake L Erdel
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
    Endocr Pract 20:e102-5. 2014
  5. pmc Regenerative therapeutic potential of adipose stromal cells in early stage diabetic retinopathy
    Gangaraju Rajashekhar
    Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America Vascular and Cardiac Center for Adult Stem Cell Therapy, Indiana University School of Medicine, Indianapolis, Indiana, United States of America VA Center for Regenerative Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
    PLoS ONE 9:e84671. 2014
  6. pmc Divergent compensatory responses to high-fat diet between C57BL6/J and C57BLKS/J inbred mouse strains
    Emily K Sims
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    Am J Physiol Endocrinol Metab 305:E1495-511. 2013
  7. pmc Lost in translation: endoplasmic reticulum stress and the decline of β-cell health in diabetes mellitus
    C Evans-Molina
    Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Diabetes Obes Metab 15:159-69. 2013
  8. pmc Streptozotocin is equally diabetogenic whether administered to fed or fasted mice
    Zunaira Z Chaudhry
    Departments of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
    Lab Anim 47:257-65. 2013
  9. pmc Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials
    Antoinette Moran
    University of Minnesota, Minneapolis, MN, USA
    Lancet 381:1905-15. 2013
  10. pmc Stem cells as a tool to improve outcomes of islet transplantation
    Emily Sims
    Section of Pediatric Endocrinology and Diabetology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Transplant 2012:736491. 2012

Detail Information

Publications16

  1. pmc PPAR-γ activation restores pancreatic islet SERCA2 levels and prevents β-cell dysfunction under conditions of hyperglycemic and cytokine stress
    Tatsuyoshi Kono
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    Mol Endocrinol 26:257-71. 2012
    ..We conclude that pioglitazone modulates SERCA2b expression through direct transcriptional regulation of the gene and indirectly through prevention of CDK5-induced phosphorylation of PPAR-γ...
  2. ncbi Shock wave lithotripsy targeting of the kidney and pancreas does not increase the severity of metabolic syndrome in a porcine model
    Rajash K Handa
    Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana Electronic address
    J Urol 192:1257-65. 2014
    ..We determined whether shock wave lithotripsy of the kidney of pigs with metabolic syndrome would worsen glucose tolerance or increase the risk of diabetes mellitus...
  3. pmc Human adipose-derived stromal/stem cells protect against STZ-induced hyperglycemia: analysis of hASC-derived paracrine effectors
    Tatsuyoshi M Kono
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Stem Cells 32:1831-42. 2014
    ....
  4. pmc A case of calciphylaxis in a patient with hypoparathyroidism and normal renal function
    Blake L Erdel
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
    Endocr Pract 20:e102-5. 2014
    ..To present the case of a patient with a history of thyroid cancer, postsurgical hypoparathyroidism, chronic calcitriol use, and normal renal function who presented with painful skin lesions secondary to calciphylaxis...
  5. pmc Regenerative therapeutic potential of adipose stromal cells in early stage diabetic retinopathy
    Gangaraju Rajashekhar
    Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America Vascular and Cardiac Center for Adult Stem Cell Therapy, Indiana University School of Medicine, Indianapolis, Indiana, United States of America VA Center for Regenerative Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
    PLoS ONE 9:e84671. 2014
    ..Our pre-clinical studies support the translational development of adipose stem cell-based therapy for DR to address both retinal capillary and neurodegeneration. ..
  6. pmc Divergent compensatory responses to high-fat diet between C57BL6/J and C57BLKS/J inbred mouse strains
    Emily K Sims
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
    Am J Physiol Endocrinol Metab 305:E1495-511. 2013
    ..Differences in these responses to HFD and effects of PIO reflect divergent human responses to a Western lifestyle and underscore the careful consideration needed when choosing mouse models of diet-induced obesity and diabetes treatment. ..
  7. pmc Lost in translation: endoplasmic reticulum stress and the decline of β-cell health in diabetes mellitus
    C Evans-Molina
    Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Diabetes Obes Metab 15:159-69. 2013
    ..Finally, we will discuss existing and novel therapeutic strategies that target β-cell ER stress and discuss their use in rodent and human type 1 and 2 diabetes. ..
  8. pmc Streptozotocin is equally diabetogenic whether administered to fed or fasted mice
    Zunaira Z Chaudhry
    Departments of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
    Lab Anim 47:257-65. 2013
    ..In summary, induction of experimental hyperglycemia can be achieved using the MLD-STZ protocol without repeated bouts of fasting, which have the potential to cause metabolic stress in laboratory mice...
  9. pmc Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials
    Antoinette Moran
    University of Minnesota, Minneapolis, MN, USA
    Lancet 381:1905-15. 2013
    ..We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes...
  10. pmc Stem cells as a tool to improve outcomes of islet transplantation
    Emily Sims
    Section of Pediatric Endocrinology and Diabetology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Transplant 2012:736491. 2012
    ..In this paper, we outline the manners in which stem cells have been applied to address barriers to the achievement of long-term insulin independence following islet transplantation...
  11. pmc Thyroid hormone analogues for the treatment of metabolic disorders: new potential for unmet clinical needs?
    Timothy J Shoemaker
    Department of Medicine, Indiana University School of Medicine Indianapolis, IN 46202, USA
    Endocr Pract 18:954-64. 2012
    ..To provide a comprehensive review of the discovery and development of selective thyroid hormone receptor agonists and provide a discussion of their use in hyperlipidemia, obesity, and type 2 diabetes mellitus...
  12. pmc Islet β-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model
    Sarah A Tersey
    Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
    Diabetes 61:818-27. 2012
    ....
  13. pmc Bisphenol A, obesity, and type 2 diabetes mellitus: genuine concern or unnecessary preoccupation?
    Priyadarshini Mirmira
    Park Tudor High School, Indianapolis, Ind
    Transl Res 164:13-21. 2014
    ..Last, current policies and views of national and international regulatory agencies regarding the safety of BPA use are summarized...

Research Grants30

  1. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  2. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  3. Regulation of Calcium Homeostasis in the Pancreatic Beta Cell
    CARMELLA EVANS EVANS-MOLINA; Fiscal Year: 2013
    ..The overall impact of this proposal will be the identification of key pathways that can be targeted clinically as a means of preserving beta cell function in T2DM. ..
  4. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  5. Molecular Physiology of Store-Dependant Calcium Entry in Pancreatic Beta Cells.
    MICHAEL WILLIAM ROE; Fiscal Year: 2013
    ....
  6. Molecular Regulation of Cell Development and Differentiation
    Dale R Abrahamson; Fiscal Year: 2013
    ..abstract_text> ..
  7. Modulation of beta-cell PKA activity affects glucose homeostasis
    Barton Wicksteed; Fiscal Year: 2013
    ..It will also reveal potential pitfalls of harnessing this pathway for the treatment of diabetes. ..
  8. BARRIER FUNCTION OF THE GI TRACT IN HEALTH AND DISEASE
    W Allan Walker; Fiscal Year: 2013
    ..abstract_text> ..
  9. Regulation of Islet Beta-Cell Function via Islet-Derived VGF Peptides
    SAMUEL BRANDON STEPHENS; Fiscal Year: 2013
    ..Thus, through this award, I will gain training and generate crucial reagents necessary to launch my independent research program and obtain a tenure-track assistant professorship. ..
  10. Impact of Neprilysin on Islet Function
    Sakeneh Zraika; Fiscal Year: 2013
    ..These studies will delineate a novel role for islet and intestinal NEP in modulating [unreadable]-cell function, and will have significant implications for development of therapeutics to treat [unreadable]-cell dysfunction in diabetes. ..
  11. Targeting NAD Metabolism to Improve Glucose Homeostasis in Obesity and Aging
    Joseph A Baur; Fiscal Year: 2013
    ....
  12. PANCREAS AND ISLET TRANSPLANTATION IN HUMANS
    RODERICK PAUL ROBERTSON; Fiscal Year: 2013
    ..We envision the results will provide novel insights that will pertain not only to improving outcomes in TP/AIT recipients but also insights that will improve outcomes in alloislet transplantation for type 1 diabetic patients. ..
  13. Beta-cell Compensation in Partial Pancreatectomy Mice
    JOHN L LEAHY; Fiscal Year: 2013
    ..abstract_text> ..
  14. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  15. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  16. MOLECULAR GENETICS OF COAGULATION DISORDERS
    David Ginsburg; Fiscal Year: 2013
    ..This Project will identify key genes in this system that should provide valuable new diagnostic tools as well as suggest novel approaches to treatment. ..
  17. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
    ..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
  18. Beta-cell Proliferation
    Fredric E Wondisford; Fiscal Year: 2013
    ..These studies of in vivo mechanisms of [unreadable]-cell proliferation may provide therapeutic approaches for diabetes mellitus in humans. ..
  19. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  20. Hepatocyte Growth Factor and the Pancreatic Beta Cell
    Adolfo Garcia-Ocana; Fiscal Year: 2013
    ....
  21. Discovery of microRNA regulatory modules controlling human pancreatic islet funct
    Praveen Sethupathy; Fiscal Year: 2013
    ..These aims will contribute significantly toward mapping islet GRNs, which will facilitate the identification of clinically relevant pharmacological targets for addressing islet pathophysiology in diabetes. ..
  22. Role of Eosinophils in Airway Inflammation and Remodeling
    Nizar N Jarjour; Fiscal Year: 2013
    ..Given the prominence of eosinophilic inflammation in a significant proportion of severe asthma patients, these advances will have direct implications for the patients most affected by this very common illness. ..
  23. Low-grade Inflammation, Cytokines, and Beta-Cell Dysfunction in Type 2 Diabetes
    Craig S Nunemaker; Fiscal Year: 2013
    ..Identifying early stages in cytokine-mediated beta-cell dysfunction will open new avenues of therapeutic intervention to prevent beta-cell dysfunction in early T2D. ..
  24. Pancreatic beta-cell CAMKII signaling under physiological and diabetic conditions
    DAVID AARON JACOBSON; Fiscal Year: 2013
    ..This may ultimately lead to new therapeutic targets for treating type-2 diabetes. ..
  25. Hopkins Center for Health Disparities Solutions
    THOMAS ALEXIS LAVEIST; Fiscal Year: 2013
    ..abstract_text> ..
  26. Mechanisms of Glycemic Improvement Following Gastrointestinal Surgery
    David R Flum; Fiscal Year: 2013
    ..Plasma levels of GLP-1, GIP. PYY, and ghrelin will be made during standardized meals throughout these experiments in both species, to clarify roles for these gut peptides in changes we observe. ..