Body energy metabolism is a finely tuned system dependent on the interactions of numerous endocrine axes. Insulin is a key regulator of metabolism and growth that maintains serum glucose and other metabolites within a narrow, predefined range. While it has been traditionally thought that insulin activity is controlled solel by its abundance in circulation, modulation of tissue insulin sensitivity has been described during [instances of environmental stress (e.g. infection/inflammation and pregnancy). It is well known that inflammation can induce insulin resistance in multiple tissues and that this response may be important for the body's response to infection.] Developing an understanding of how [inflammation regulates] tissue insulin responsiveness is important as it could provide novel insights into [pathologies] associated with tissue insulin resistance, such as metabolic syndrome and Type 2 Diabetes Mellitus. Several groups have shown that inflammation can induce insulin resistance through [direct] post-translational modification of components of the insulin-signaling cascade [by inflammation activated kinases]. The existing model suggests that resistance should develop relatively rapidly in response to inflammation, consistent with the kinetics of post-translational modifications. Paradoxically, the observed resistance to insulin requires prolonged treatment with inflammatory cytokines, suggesting that inflammation may [induce a transcriptional program that results in insulin resistance.] The goal of my Ph.D. thesis, and this proposal, is to investigate the mechanisms of [chronic inflammation induced] insulin resistance. Based upon the observed kinetics and our preliminary data, we hypothesize that chronic inflammation induces a [transcriptional program that leads to impaired tissue responsiveness to insulin. Specifically, we hypothesize that TNF? induces/suppresses previously uncharacterized protein(s) that regulate insulin signaling.] Since the liver coordinates whole body metabolism and is known to change its responsiveness to insulin signaling under inflammatory conditions, we propose to investigate the role of chronic inflammation in regulating hepatic insulin signaling using [in vivo and ex vivo models, specifically focusing on the effect of chronic TNF? treatment]. In the first aim, we will investigate the effects of [ex vivo and in vivo] chronic TNF? on [hepatocyte insulin-signaling and functional response including gluconeogenesis, glycogen synthesis, and lip genesis].
The second aim will address the [role of differential gene expression] induced by chronic inflammation and identify the [gene(s) and mechanism(s)] responsible for altering insulin signaling. Our studies represent a novel approach to understanding the mechanisms that regulate insulin signaling. Ultimately, this may lead to the development of novel therapeutic targets for metabolic syndrome and Type 2 Diabetes Mellitus.

Public Health Relevance

Altered insulin signaling in the liver is a key component of many chronic diseases affecting the population, including metabolic syndrome and type 2 diabetes. Inflammation represents a common, reversible, non- disease state that is associated with altered hepatic insulin signaling. Understanding inflammatory regulation of insulin signaling will provide insight into the mechanisms regulating insulin signaling, inform the treatment of diseases that result from altered insulin signaling, as well as identify potentially novel therapeutic targets.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZDK1-GRB-R (M1))
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Castle, Arthur
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Yale University
Schools of Medicine
New Haven
United States
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Okin, Daniel; Medzhitov, Ruslan (2016) The Effect of Sustained Inflammation on Hepatic Mevalonate Pathway Results in Hyperglycemia. Cell 165:343-56
Okin, Daniel; Medzhitov, Ruslan (2012) Evolution of inflammatory diseases. Curr Biol 22:R733-40