Mayo Graduate School, 2001
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Muscle physiology - the effects of exercise, diet and hormonal levels on muscle metabolism and insulin resistance; type II diabetes
Diabetes affects 23.6 million Americans (7.8% of the population); and by 2030, the global numbers are projected to increase above 400 million. A progressive decline in the body's ability to detect and respond to stress could result in the development and/or acceleration of a number of metabolic disease states, including insulin resistance and obesity. Heat shock proteins (HSPs) are best known as molecular chaperones, but they also play key anti-inflammatory and cell signaling roles. Exercise-induced HSP expression may be associated with mitochondrial protection, the sarcoplasmic reticulum, cytoskeletal protection, maintenance of enzymatic activity, and insulin sensitivity and glucose transport. Patients with type 2 diabetes demonstrate reduced expression of heat shock protein 72 (HSP72) and a blunted exercise-induced heat stress response.
Previous studies from our laboratory and others demonstrate that the induction of HSPs via heat treatment, transgenic overexpression, or pharmacological agents is protective against high fat diet-induced skeletal muscle insulin resistance. Both low aerobic fitness and a diminished heat stress response are associated with insulin resistance in human patients; however, it is unknown if these factors are interrelated or if they cause skeletal muscle insulin resistance. Planned studies should provide compelling new information about the relationship between heat shock proteins, aerobic capacity and metabolic function. As a result, new strategies could be developed to modulate HSP-dependent pathways as a therapeutic approach to treat insulin resistance.
Our laboratory is also interested in the role of estrogen in mediating glucose homeostasis and energy balance. Clinical studies suggest that postmenopausal women are at an increased risk for type 2 diabetes, and estrogen replacement therapy can decrease this risk. The physiological actions of estrogens are mediated by two receptors, estrogen receptor (ER) a and ERb. Both ERa and ERb are expressed in a variety of tissues, with ERa more highly expressed in insulin-sensitive tissue. Increased adiposity occurs in humans and mice as a result of decreased ERa activation, and mice with global knockout of ERa exhibit impaired glucose tolerance and skeletal muscle insulin resistance. Based on this evidence, the beneficial effects of estrogens on glucose metabolism and energy balance are thought to be mediated by ERa. Our laboratory demonstrated that in vivo activation of ERα via the agonist propylpyrazoltriol (PPT), resulted in increased insulin-stimulated glucose uptake in skeletal muscles.
We also found that three days of PPT treatment decreased food intake and adiposity, and upregulated lipolysis in adipose tissue. Based on these findings, we hypothesize that activation of ERa could be protective against metabolic dysfunction resulting from estrogen loss or as a result of high fat feeding and obesity. Despite growing interest in the metabolic functions of ERa, very little is known regarding tissue-specific ERa function, or the molecular mechanisms by which ERa mediates metabolic effects. Ongoing studies in the lab aim to establish a critical role for ERa in regulating glucose homeostasis and energy balance, and identify tissue specific signaling pathways essential to the metabolic functions of ERa.
Selected Recent Publications
Gupte AA, Bomhoff GL, Geiger PC (2008). Age-related differences in skeletal muscle insulin signaling: the role of stress kinases and heat shock proteins. J Appl Physiol, 105(3), 839-48.
Morris JK, Zhang H, Gupte AA, Bomhoff GL, Stanford JA, Geiger PC (2008). Measures of striatal insulin resistance in a 6-hydroxydopamine model of Parkinson's Disease. Brain Res, 1240, 185-95.
Gupte AA, Bomhoff GL, Swerdlow RH, Geiger PC (2009). Heat treatment improves glucose tolerance and prevents skeletal muscle insulin resistance in rats fed a high fat diet. Diabetes 58(3): 567-78.
Gupte AA, Bomhoff GL, Morris JK, Gorres BK, Geiger PC (2009). Highlighted Topic: Regulation of Protein Metabolism in Rest and Exercise. Lipoic acid increases heat shock protein expression and inhibits stress kinase activation to improve insulin signaling in skeletal muscles from high fat-fed rats. J Appl Physiol 106: 1425-34.
Gupte AA, Morris JK, Zhang H, Bomhoff GL, Geiger PC, Stanford JA (2010). Age-related changes in HSP25 expression in basal ganglia and cortex of F344/BN rats. Neurosci Lett. 472:90-93. PMID:20144690
Smittkamp SE, Spalding HN, Brown JW, Gupte AA, Chen J, Nishimune H, Geiger PC, Stanford JA. (2010) Measures of bulbar and spinal motor function, muscle innervation, and mitochondrial function in ALS rats. Behavior Brain Res 211: 48-57. PMID:20211206
Morris JK, Bomhoff GL, Stanford JA, Geiger PC (2010). Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high fat diet. Am J Physiol Reg. 299(4): R1082-90. PMID:20702796
Geiger PC and Gupte AA (2011). Heat shock proteins are important mediators of skeletal muscle insulin sensitivity. Invited Review, Exerc Sport Sci Rev 39(1), Jan;39(1):34-42. PMID:21088604
Gupte AA, Bomhoff GL, Touchberry CD, Geiger PC (2011). Acute heat treatment improves insulin-stimulated glucose uptake in aged skeletal muscle. J Appl Physiol Feb;110(2):451-7. PMID:21148343
Gorres BK, Bomhoff GL, Gupte AA, Geiger PC (2011). Altered estrogen receptor expression in skeletal muscle and adipose tissue of female rats fed a high-fat diet. J Appl Physiol. 110(4):1046-53. PMID: 21233345
Gorres BK, Bomhoff GL, Morris JK, Geiger PC (2011). In vivo stimulation of ERα increases insulin-stimulated skeletal muscle glucose uptake. J Physiol. 589(Pt 8):2041-54. PMID: 21486807
Grote CW, Morris JK, Ryals JM, Geiger PC, Wright DE (2011). Insulin Receptor Substrate 2 Expression and Involvement in Neuronal Insulin Resistance in Diabetic Neuropathy. Exp Diabetes Res 2011: 212571. PMID:21754917.
Morris JK, Bomhoff GL, Gorres BK, Davis VA, Kim J, Lee S-P, Brooks WM, Gerhardt GA, Geiger PC, Stanford JA. (2011). Insulin resistance impairs nigrostiatal dopamine function. Exp Neurol. 231(1):171-80. PMID: 21703262.
Morris JK, Seim NB, Bomhoff GL, Geiger PC, Stanford JS (2011). Effects of unilateral nigrostiatal dopamine depletion on peripheral glucose tolerance and insulin signaling in middle aged rats. Neurosci Lett 504: 219-222. PMID: 21964388.
Spangenburg EE, Geiger PC, Leinward LA, Lowe DA (2012). Novel Mechanistic Insights Into the Role of Female Sex Steroids in Regulating Physiological and Metabolic Function of Striated Muscle. Invited Reivew, Med Sci Sports Exerc , 44(9):1653-62 . PMID: 22525764.
Touchberry CD, Gupte AA, Bomhoff GL, Graham ZA, Geiger PC*, Gallagher PM*(2012). Hyperthermic preconditioning protects skeletal muscle from damage and alters hypertrophic signaling. *Shared corresponding authorship. Cell Stress Chaperones, 17(6):693-705. PMID: 22589083.
Grote CW, Groover AL, Ryals JM, Geiger PC, Feldman EL, Wright DE (2013). Peripheral nervous system insulin resistance in ob/ob mice. Acta Neuropathologica Comm. May 10; 1(1):15. PMID: 24252636
Smittkamp SE, Morris JK, Bomhoff GL, Chertoff MA, Geiger PC, Stanford JS (2014). SOD1-G93A mice exhibit muscle fiber type-specific decreases in glucose uptake in the absence of whole body changes in metabolism. Neurodegenerative Diseases, 13(1):29-37. PMID: 24021858
Graham Z, Touchberry CD, Gupte AA, Bomhoff GL, Geiger PC, Gallagher PM (2014). Changes in alpha7beta1 integrin signaling after eccentric exercise in heat shocked rat soleus. Muscle and Nerve, In Press June 2014. PMID: 24956997
Paige C. Geiger, Ph.D.
3901 Rainbow Blvd.
Kansas City, KS 66160
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