Jane E. B. Reusch, M.D, Professor of Medicine
Dr Reusch made a fundamental observation that CREB, the cAMP Response Element Binding Protein, is a pivotal intermediate through which diabetes, hyperglycemia and oxidative stress exert their detrimental effect on cellular differentiation. Inappropriate regulation of CREB expression and phosphorylation leads to de-differentiation or death of many cells and target organs. She initially identified that insulin promoted CREB activation. This aspect of insulin action is critical for the insulin-induced differentiation of pre-adipocytes into mature adipocytes. Other studies defined a role of CREB in vascular smooth muscle cell (SMC) phenotypic modulation (maintenance of SMC contractile, highly differentiated phenotype). Hyperglycemia, oxidative stress, cytokines, aging, dyslipidemia and insulin resistance lead to a decreased vascular CREB content and CREB-dependent gene expression permitting a proliferative phenotype of SMC. Recently she has observed that intervention with calorie restriction, exercise or insulin sensitizers can restore CREB function in the heart and vasculature. These observations add insight to the mechanism of accelerated atherosclerosis in diabetes. Her group was the first to describe the role of CREB in neuronal regulation of the bcl-2 gene, an important target for neurotrophin-mediated cytoprotection. CREB prevents programmed cell death in fat cells, neurons and beta cells exposed to pro-apoptotic stimuli such as TNF-a, oxidant and cytokine injury. In addition, she has observed loss of CREB function in the nervous system of diabetic rodents and in the islet of the NOD mouse.
This body of work lead to the laboratory’s thematic hypothesis: Diabetes leads to an inappropriate regulation of CREB, which contributes to diabetic complications by loss of differentiation, promotion of apoptosis and ineffective metabolic adaptation.
We view CREB as a central component of the intercellular cytoprotective homeostatic response to physiological metabolic stress. In this role it supports cell differentiation, contributes to metabolic adaptation and prevents apoptosis. We postulate that chronic metabolic and inflammatory stress leads to inappropriate downregulation of CREB resulting in dedifferentiation, ineffective metabolic adaptation or death of many cell types and dysfunction of target organs. We propose a model wherein CREB is a key element in what might be termed the Starling Curve of the cellular homeostasis. In this model mild intermittent stress enhances CREB function and cellular defenses and chronic stress leads to CREB dysfunction and cellular dysfunction. CREB dysfunction in this context may contribute to beta cell failure and the development of diabetes. It may also contribute to the development of diabetic complications in the nervous system, heart and vasculature. Our goal now is to prove the importance of CREB in animal models and explore the impact of interventions that augment CREB function such as exercise, thiazolidinediones and incretins on beta cell failure and neuropathic and vascular complications. In vitro, cytokines and oxidants will not induce apoptosis in neurons or beta cells overexpressing CREB. If this is the case in vivo, then finding agents or behaviors that increase CREB function will prove an excellent complement to agents that decrease oxidant or cytokine mediated stress. Addressing both sides of this equation simultaneously could contribute to a cure for diabetes and its complications.
Selected Publications
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Watson PA, Reusch JE, McCune SA, Leinwand LA, Luckey SW, Konhilas JP, Brown DA, Chicco AJ, Sparagna GC, Long CS, Moore RL. Restoration of CREB Function is Linked to Completion and Stabilization of Adaptive Cardiac Hypertrophy in Response to Exercise. Am J Physiol Heart Circ Physiol. 2007. PUBMED
- Bauer TA, Reusch JE, Levi M, Regensteiner JG Skeletal Muscle Deoxygenation Following the Onset of Moderate Exercise Suggests Slowed Microvascular Blood Flow Kinetics in Type 2 Diabetes. Diabetes Care. 2007 Aug 3; PUBMED
- Reusch JE and Draznin B “Atherosclerosis and Insulin Resistance” Diabetes Obesity and Metabolism 1-9, 2006
- Huebschmann AG, Regensteiner RG, Vlassara H, Reusch JE Diabetes and advanced glycoxidation end products. Diabetes Care. 2006 Jun;29(6):1420-32. PUBMED
- Garat CV, Fankell D, Erickson PF, Reusch JE, Bauer NN, McMurtry IF, Klemm DJ. Platelet-derived growth factor BB induces nuclear export and proteasomal degradation of CREB via phosphatidylinositol 3-kinase/Akt signaling in pulmonary artery smooth muscle cells. Mol Cell Biol. 2006 Jul;26(13):4934-48 PUBMED
- Regensteiner JG, Bauer TA, Reusch JE. Rosiglitazone improves exercise capacity in individuals with type 2 diabetes. Diabetes Care. 2005 Dec;28(12):2877-83. PUBMED
- Jambal P, Masterson S, Nesterova A, Bouchard R, Bergman B, Hutton JC, Boxer LM, Reusch JE, Pugazhenthi S. Cytokine-mediated down-regulation of the transcription factor cAMP-response element-binding protein in pancreatic beta-cells. J Biol Chem. 2003 Jun 20;278(25):23055-65. PUBMED
- Pugazhenthi S, Nesterova A, Jambal P, Audesirk G, Kern M, Cabell L, Eves E, Rosner MR, Boxer LM, Reusch JE. Oxidative stress-mediated down-regulation of bcl-2 promoter in hippocampal neurons. J Neurochem. 2003 Mar;84(5):982-96. PUBMED
- Watson PA, Nesterova A, Burant CF, Klemm DJ, Reusch JE. Diabetes-related changes in cAMP response element-binding protein content enhance smooth muscle cell proliferation and migration. J Biol Chem. 2001 Dec 7;276(49):46142-50. PUBMED