Induction of Heat Shock Proteins in the Therapy of Type 2 Diabetes and Metabolic Syndrome

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Induction of Heat Shock Proteins in the Therapy of Type 2 Diabetes and Metabolic Syndrome
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  Commentary Induction of Heat Shock Proteins in the Therapy of Type 2 Diabetes andMetabolic Syndrome Philip L. Hooper Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, United States Exercise is one of the best therapies, if not the best, for the preven-tionandtreatment of type2 diabetes.Kondo,Araki, Kai and colleagues,in this issue of EBioMedicine, introduce a device that mimics exercise(1). When applied to subjects with metabolic syndrome (MS) or type2diabetes(t2DM)thetherapyimprovesthediverseparametersinheritto metabolic syndrome (MS) and type 2 diabetes (t2DM) — in fl amma-tion, hypertension, glycemia, dyslipidemia, abdominal obesity, bodyweight,andinsulinsignaling.Theresultsareaquantumleaptowardun-derstanding type 2 diabetes and treating it. The researchers are to becongratulated in their single-minded quest to move from the bench tothe bedside. As they sought methods to duplicate the bene fi cial effectsof exercise, their research moved from heat, to heat shock proteins(Hsps, also known as stress proteins), to a tailored electrical-heatstim-ulation that maximizes Hsp induction.Speci fi cally, Kondo and colleagues studied 40 patients with MS ort2DM in a randomized crossover trial of 12 weeks of therapy withmild electric stimulation and heat shock (MES + HS) versus no inter-vention for 12 weeks. The device transmits direct electric current andheat through the upper abdomen,  fi tting like a cumberbund. MES + HSwas applied for 1 h four times per week. Improvements in glycemic,lipid, and fat deposition measurements were more pronounced in t2DMthanMS. Of particularnotewas a.72% reductioninA1c int2DMsubjectswith higher baseline levels (7.6 – 10.0%) (Kondo et al., 2014). This level of reduction is similar to that seen by recently introduced drugs likesitagliptin (a dipeptidyl peptidase 4 (DPP-4) inhibitor) that drops A1c.6% when used in monotherapy (Zerilli and Pyon, 2007).Aremarkable55%dropinalbuminuriawasobservedint2DMwithadropinserumcreatinine.Thefallinalbuminuria isinthesameorderof magnitudeasobservedwithACEinhibitortherapy(Yilmazetal.,2010).The same research group has demonstrated MES + HS reduced renalfunction loss in an animal model of renal failure (Koga et al., 2012).Regarding its ef  fi cacy in reducing in fl ammation in MS, MES + HSdroppedhs-CRPby54%.hs-CRPint2DMimprovespredictionofcardio-vasculardiseaseandhasbeensuggestedthatitsmeasurementbeaddedtothede fi nitionofmetabolicsyndrome.Thereductioninin fl ammationcannot be understated, as cardiovascular disease is indeed the majorcause of mortality in these disease states (Haffner, 2006). The 54%dropinhs-CRPcomparesfavorablywiththedropobservedwithatorva-statin (35%) in t2DM patients (Sindhu et al., 2011). Low intracellular Hsps in insulin sensitive tissues like skeletalmuscle and liver may be the near sentinel event in the developmentof MET or t2DM. Low muscle intracellular Hsp precedes abnormal met-abolicfunctionbyfouryearsinnon-humanprimateswhichiscompara-ble to a decade in humans (Chichester et al., 2014). Furthermore, normo-glycemicidenticaltwinsofsiblingswithimpairedglucosetoler-ancehavelowmuscleHsp expression.RestoringthelowHsps via exer-ciseor bioactive Hsp inducers normalizes thepathologic features of MSand t2DM. Hsp induction stimulates survival pathways like AMPK thatlimits fat storage while activating fat catabolism. Mitochondria biogen-esis and mitochondrial function are improved by Hsp induction — aug-menting reduction in adipose stores. In fl ammation is markedlyimproved with major reductions in CRP and cytokine activation — blocking the vicious cycle of in fl ammation, reduced insulin signalingwhichfurther impairs Hsp expression and thus promotes more in fl am-mation (Hooper et al., 2014). MS and t2DM put organs in peril — from neuropathies, to retinopa-thies,tomyopathies,tonephropathies,tohepaticseatosis,todementia.Restoring Hsps in diabetic animal models limits the diabetic complica-tions. Reduction in systemic in fl ammation will likely reduce the vascu-lar disease so prevalent in these diseases. Mild electric stimulation(MES) indeed reduces nephropathy and fatty liver. Similarly, MES+HSaugmentspancreaticbeta-cellfunctioninanimaldiabetic models(Kondo et al., 2012).Thehealthcareproviderisoftenfrustratedbylimitedef  fi caciousther-apiesavailabletopreventandtreatthemetabolicdiseaseepidemic.Whilelife-style modi fi cation remains the initial and most effective therapy,long-term compliance often does not endure. Can the MES + HS devicebeusedthroughoutthecourseofthissyndrome-complex?Certainly,adi-abetic individual with proteinuria and an elevated serum creatinine is acandidate for a MES + HS device to use in their home. The same is truefor hepatic seatosis with progressive liver injury. Of course, how will thedevicebeusedinclinicsorathome?Howexpensivewillitbe?Canasim-ilar device be used for other therapies — arthritis, wound healing, andheartfailure — whereanaugmentedcellularstressresponsemaybebene- fi cial? MES + HS ef  fi cacy is comparable if not better than present main-stay pharmaceutical agents. Furthermore, MES + HS is broadly effectivein normalizing the whole spectrum of pathologic defects associatedwith MS and t2DM — not unlike the effect of regular exercise. Disclosure The author declared no con fl icts of interest. EBioMedicine 1 (2014) 14 – 15DOI of srcinal article: http://dx.doi.org/ 10.1016/j.ebiom.2014.11.001. E-mail address : phoopermd@gmail.com. Contents lists available at ScienceDirect EBioMedicine  journal homepage: www.ebiomedicine.com http://dx.doi.org/10.1016/j.ebiom.2014.11.0062352-3964/© 2014 The Author. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/ ).  References Chichester, L., Wylie, A.T., Craft, S., Kavanagh, K., 2014. Muscle heat shock protein 70 pre-dicts insulinresistancewith aging. J.Gerontol.A Biol.Med.Sci.(Epubahead ofprint).Haffner, S.M., 2006. The metabolic syndrome: in fl ammation, diabetes mellitus, and car-diovascular disease. Am. J. Cardiol. 97, 3A – 11A.Hooper, P.L., Balogh, G., Rivas, E., Kavanagh, K., Vigh, L., 2014. The importance of the cel-lular stress response inthe pathogenesisand treatment of type 2 diabetes. CellStressChaperones 19, 447 – 464.Koga, T., Kai,Y., Fukuda, R., et al., 2012.Mildelectricalstimulation andheatshock amelio-rates progressive proteinuria and renal in fl ammation in mouse model of Alport syn-drome. PLoS One 7, e43852.Kondo, T., Sasaki, K., Matsuyama, R., et al., 2012. Hyperthermia with mild electrical stim-ulation protects pancreatic beta-cells from cell stresses and apoptosis. Diabetes 61,838 – 847.Kondo, T., Ono, K., Kitano, S., et al., 2014. Mild electrical stimulation with heat shock re-duces visceral adiposity and improves metabolic abnormalities in subjects with met-abolic syndrome or type 2 diabetes: randomized crossover trials. EBioMedicine 1,80 – 89.Sindhu, S., Singh, H.K., Salman, M.T., Fatima, J., Verma, V.K., 2011. Effects of atorvastatinand rosuvastatin on high-sensitivity C-reactive protein and lipid pro fi le in obesetype 2 diabetes mellitus patients. J. Pharmacol. Pharmacother. 2, 261 – 265.Yilmaz,M.I.,Sonmez,A.,Saglam,M.,etal.,2010.Reducedproteinuriausing ramiprilindi-abetic CKD stage 1 decreases circulating cell death receptor activators concurrentlywith ADMA. A novel pathophysiological pathway? Nephrol. Dial. Transplant. 25,3250 – 3256.Zerilli, T., Pyon, E.Y., 2007. Sitagliptin phosphate: a DPP-4 inhibitor for the treatment of type 2 diabetes mellitus. Clin. Ther. 29, 2614 – 2634.15 P.L. Hooper / EBioMedicine 1 (2014) 14 – 15
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