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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 - a response that is blunted in diabetes. 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 revealed that CREB is essential for normal mitochondrial function in the heart and vasculature.  Ongoing studies are unraveling the relationship between CREB, diabetes and mitochondrial dynamics (diogenesis, fission, fusion and autophagy) and mitochondrial function and reactive oxygen species (ROS) production. 

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 and plastic mitochondrial adaptation as central components of the intercellular cytoprotective homeostatic response to physiological metabolic stress.  We postulate that chronic metabolic and inflammatory stress leads to inappropriate down regulation 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 and mitochondrial dynamics. In this model mild intermittent stress enhances CREB function and mitochondrial flexibility and chronic stress leads to CREB and mitochondrial dysfunction.  Loss of homeostatic response in this context may contribute to beta cell failure and the development of diabetes.  Our goal now is to characterize the signaling pathway is contributing to failed metabolic adaptation in animal models and explore the impact of interventions that augment homeostasis in diabetes such as exercise, thiazolidinediones and incretins on beta cell failure and neuropathic and vascular complications. 

In our clinical research program Dr. Judy Regensteiner, we have rigorously characterized the underlying mechanisms for decreased functional exercise capacity in people with type 2 and type 1 diabetes.  We have previously reported that improving insulin sensitivity with a thiazolidinedione can augment exercise capacity in people with type 2 diabetes.  We are currently examining the impact of targets we have identified in rodent models as to their impact on exercise capacity in people with diabetes.  These targets include nitric oxide synthase (NOS), ROS, CREB and SIRT.  We have an ongoing clinical intervention examining the impact of glucagon like peptide 1, which can stimulate eNOS and CREB upon exercise capacity and improve vascular function in people with type 2 diabetes.  In a second set of clinical studies we are directly examining the impact of blood flow and mitochondrial function on an overall exercise capacity and adaptation to exercise training.  These translational research studies are a unique feature of the Reusch research group that enable movement of laboratory findings directly into the clinical setting.  ​

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  • Diabetes
  • Vascular Biology
  • Exercise (human and animal models)
  • CREB
  • Mitochondrial function and dynamics
  • Targeted clinical interventions to improve exercise capacity in diabetes

Selected Publications

  1. Impaired response to exercise intervention in the vasculature in metabolic syndrome.
    Knaub LA, McCune S, Chicco AJ, Miller M, Moore RL, Birdsey N, Lloyd MI, Villarreal J, Keller A, Watson PA and Reusch JEB
    Diabetes and Vascular Disease Research (August 2012-in press)
  2. Beyond phosphorylation: nuclear export in vascularremodeling.
    Reusch JE.
    Arterioscler Thromb Vasc Biol. 2011 Sep;31(9):1955-6. No abstract available.
  3. Cardiovascular disease in diabetes: where does glucose fit in?
    Reusch JE, Wang CC.
    J Clin Endocrinol Metab. 2011 Aug;96(8):2367-76. Epub 2011 May 18. Review.
  4. Reduction of reactive oxygen species prevents hypoxia-induced CREB depletion in pulmonary artery smooth muscle cells.
    Klemm DJ, Majka SM, Crossno JT Jr, Psilas JC, Reusch JE, Garat CV.
    J Cardiovasc Pharmacol. 2011 Aug;58(2):181-91.
  5. Cardiovascular function/dysfunction in adolescents with type 1 diabetes.
    Nadeau KJ, Reusch JE.
    Curr Diab Rep. 2011 Jun;11(3):185-92. Review.
  6. CREB downregulation in vascular disease: a common response to cardiovascular risk.
    Schauer IE, Knaub LA, Lloyd M, Watson PA, Gliwa C, Lewis KE, Chait A, Klemm DJ, Gunter JM, Bouchard R, McDonald TO, O'Brien KD, Reusch JE.
    Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):733-41. Epub 2010 Feb 11.
  7. Thiazolidinediones prevent PDGF-BB-induced CREB depletion in pulmonary artery smooth muscle cells by preventing upregulation of casein kinase 2 alpha' catalytic subunit.
    Garat CV, Crossno JT Jr, Sullivan TM, Reusch JE, Klemm DJ.
    J Cardiovasc Pharmacol. 2010 May;55(5):469-80.
  8. Insulin resistance in adolescents with type 1 diabetes and its relationship to cardiovascular function.
    Nadeau KJ, Regensteiner JG, Bauer TA, Brown MS, Dorosz JL, Hull A, Zeitler P, Draznin B, Reusch JE.
    J Clin Endocrinol Metab. 2010 Feb;95(2):513-21. Epub 2009 Nov 13.
  9. Women with type 2 diabetes perceive harder effort during exercise than nondiabetic women.
    Huebschmann AG, Reis EN, Emsermann C, Dickinson LM, Reusch JE, Bauer TA, Regensteiner JG.
    Appl Physiol Nutr Metab. 2009 Oct;34(5):851-7.
  10. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study.
    Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 009 Group.
    Curr Med Res Opin. 2009 Oct;25(10):2361-71.
  11. Insulin resistance in adolescents with type 2 diabetes is associated with impaired exercise capacity.
    Nadeau KJ, Zeitler PS, Bauer TA, Brown MS, Dorosz JL, Draznin B, Reusch JE, Regensteiner JG.
    J Clin Endocrinol Metab. 2009 Oct;94(10):3687-95. Epub 2009 Jul 7.
  12. Cardiac dysfunction during exercise in uncomplicated type2 diabetes.
    Regensteiner JG, Bauer TA, Reusch JE, Quaife RA, Chen MY, Smith SC, Miller TM, Groves BM, Wolfel EE.
    Med Sci Sports Exerc. 2009 May;41(5):977-84.

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​Intensive diabetes management type 1 and type 2 diabetes, exercise physiology and diabetes

Integrated team management of diabetes and its complications

Enabling primary care providers to orchestrate optimal diabetes care​


Medical Schools
MD, University of Minnesota Medical School (1986)

Undergraduate Schools
BS, University of Notre Dame (IN) (1981)

Internships
University of Colorado (University Hospital) Program (1989)

Residency Program
University of Colorado (University Hospital) Program, Internal Medicine (1989)

Fellowships
University of Colorado (University Hospital) Program, Internal Medicine - Endocrinology, Diabetes, and Metabolism (1991)

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Picture

​Name

Title

​Leslie Knaub ​Senior Professional Research Assistant
​Amy Keller, PhD ​Postdoctoral Fellow

 

Kate Geary, DO

​Fellow

 

Mark Bridenstine, MD

​Fellow

Indication

​Study Title

​Contact Name

​Contact Info

Impact of Exenatide on exercise capacity in type 2 diabetes

Relationship between oxygen delivery and oxygen utilization as determinates of exercise function in diabetes

LEADER trial:  Cardiovascular outcomes with Liraglutide

 

 

 

 

GRADE trial: Upcoming NIH multicentered trial to determine optimal staged treatment for type 2 diabetes ​