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 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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