PMID- 23932846 OWN - NLM STAT- MEDLINE DCOM- 20140106 LR - 20220409 IS - 1532-8600 (Electronic) IS - 0026-0495 (Print) IS - 0026-0495 (Linking) VI - 62 IP - 11 DP - 2013 Nov TI - Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance. PG - 1543-52 LID - S0026-0495(13)00209-6 [pii] LID - 10.1016/j.metabol.2013.07.001 [doi] AB - Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40-50 years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance is associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contributes to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin-angiotensin-aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance. CI - (c) 2013. FAU - Aroor, Annayya R AU - Aroor AR AD - Division of Endocrinology, Diabetes and Metabolism, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA; Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA. FAU - McKarns, Susan AU - McKarns S FAU - Demarco, Vincent G AU - Demarco VG FAU - Jia, Guanghong AU - Jia G FAU - Sowers, James R AU - Sowers JR LA - eng GR - R01 HL073101/HL/NHLBI NIH HHS/United States GR - R01 HL107910/HL/NHLBI NIH HHS/United States GR - R01 HL107910-01/HL/NHLBI NIH HHS/United States GR - R01 HL73101-01A/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. PT - Review DEP - 20130808 PL - United States TA - Metabolism JT - Metabolism: clinical and experimental JID - 0375267 RN - 0 (Insulin) RN - EC 2.7.10.1 (Receptor, Insulin) SB - IM MH - Adaptive Immunity MH - Animals MH - Cardio-Renal Syndrome/immunology MH - Cardiovascular System/*immunology MH - Diabetes Mellitus/immunology MH - Disease Progression MH - Humans MH - Hypertension, Renal/immunology MH - Inflammation/*immunology MH - Insulin/immunology/*metabolism MH - Insulin Resistance/*immunology MH - Lymphocytes/immunology MH - Macrophages/immunology MH - Obesity/*immunology MH - Premenopause MH - Receptor, Insulin/metabolism MH - Renin-Angiotensin System/*immunology MH - Sedentary Behavior MH - Sex Factors MH - T-Lymphocytes, Regulatory/immunology PMC - PMC3809332 MID - NIHMS504622 OTO - NOTNLM OT - (SOD)3 OT - ARBs OT - AT1R OT - Akt OT - Ang II OT - Ang II receptor blockers OT - C-Jun kinase OT - CKD OT - CVB3 OT - CVD OT - CVO OT - DPP-4 OT - ENOS OT - ERK1/2 OT - FFAs OT - FoxP3 OT - GIP OT - GLP-1 OT - GLP-1 receptor OT - GLP-1R OT - Gender OT - HFCS OT - IFN-gamma OT - IL-10 OT - IL-6 OT - IRS OT - Immunity OT - Interleukin 10 OT - JNK OT - LPS OT - MTOR OT - NO OT - Obesity OT - PET OT - PI3-K OT - PKC OT - RAAS OT - ROS OT - S6K OT - SNS OT - SOC3-3 OT - T2DM OT - TGF-beta OT - TLR-4 OT - TNF-alpha OT - Toll-like receptor 4 OT - Tregs OT - Uric acid OT - WAT OT - WD OT - Western Diet OT - angiotensin II OT - angiotensin II type 1 receptor OT - cardiovascular disease OT - chronic kidney disease OT - circumventricular organs OT - coxsackievirus B3 OT - cytokine signaling 3 OT - dipetidyl peptidase 4 OT - endothelial nitric oxide synthase OT - extracellular regulated kinases (1/2) OT - forkhead/winged helix transcription factor 3 OT - free fatty acids OT - glucagon like peptide-1 OT - glucose-dependent insulinotrophic peptide OT - high-fructose corn syrup OT - insulin receptor substrate OT - interferon gamma OT - interleukin 6 OT - lipopolysaccharide OT - mammalian target of rapamycin OT - nitric oxide OT - p70 S6 kinase OT - phosphatidylinositol 3 kinase OT - positron emission tomography OT - protein kinase B OT - protein kinase C OT - reactive oxygen species OT - regulatory T cells OT - renin angiotensin aldosterone system OT - superoxide dismutase OT - sympathetic nervous system OT - transforming growth factor beta OT - tumor necrosis factor alpha OT - type 2 diabetes mellitus OT - white adipose tissue EDAT- 2013/08/13 06:00 MHDA- 2014/01/07 06:00 PMCR- 2014/11/01 CRDT- 2013/08/13 06:00 PHST- 2013/06/13 00:00 [received] PHST- 2013/07/02 00:00 [revised] PHST- 2013/07/04 00:00 [accepted] PHST- 2013/08/13 06:00 [entrez] PHST- 2013/08/13 06:00 [pubmed] PHST- 2014/01/07 06:00 [medline] PHST- 2014/11/01 00:00 [pmc-release] AID - S0026-0495(13)00209-6 [pii] AID - 10.1016/j.metabol.2013.07.001 [doi] PST - ppublish SO - Metabolism. 2013 Nov;62(11):1543-52. doi: 10.1016/j.metabol.2013.07.001. Epub 2013 Aug 8.