Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance

Metabolism. 2013 Nov;62(11):1543-52. doi: 10.1016/j.metabol.2013.07.001. Epub 2013 Aug 8.


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.

Keywords: (SOD)3; ARBs; AT1R; Akt; Ang II; Ang II receptor blockers; C-Jun kinase; CKD; CVB3; CVD; CVO; DPP-4; ENOS; ERK1/2; FFAs; FoxP3; GIP; GLP-1; GLP-1 receptor; GLP-1R; Gender; HFCS; IFN-γ; IL-10; IL-6; IRS; Immunity; Interleukin 10; JNK; LPS; MTOR; NO; Obesity; PET; PI3-K; PKC; RAAS; ROS; S6K; SNS; SOC3-3; T2DM; TGF-β; TLR-4; TNF-α; Toll-like receptor 4; Tregs; Uric acid; WAT; WD; Western Diet; angiotensin II; angiotensin II type 1 receptor; cardiovascular disease; chronic kidney disease; circumventricular organs; coxsackievirus B3; cytokine signaling 3; dipetidyl peptidase 4; endothelial nitric oxide synthase; extracellular regulated kinases ½; forkhead/winged helix transcription factor 3; free fatty acids; glucagon like peptide-1; glucose-dependent insulinotrophic peptide; high-fructose corn syrup; insulin receptor substrate; interferon gamma; interleukin 6; lipopolysaccharide; mammalian target of rapamycin; nitric oxide; p70 S6 kinase; phosphatidylinositol 3 kinase; positron emission tomography; protein kinase B; protein kinase C; reactive oxygen species; regulatory T cells; renin angiotensin aldosterone system; superoxide dismutase; sympathetic nervous system; transforming growth factor beta; tumor necrosis factor alpha; type 2 diabetes mellitus; white adipose tissue.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Adaptive Immunity
  • Animals
  • Cardio-Renal Syndrome / immunology
  • Cardiovascular System / immunology*
  • Diabetes Mellitus / immunology
  • Disease Progression
  • Humans
  • Hypertension, Renal / immunology
  • Inflammation / immunology*
  • Insulin / immunology
  • Insulin / metabolism*
  • Insulin Resistance / immunology*
  • Lymphocytes / immunology
  • Macrophages / immunology
  • Obesity / immunology*
  • Premenopause
  • Receptor, Insulin / metabolism
  • Renin-Angiotensin System / immunology*
  • Sedentary Behavior
  • Sex Factors
  • T-Lymphocytes, Regulatory / immunology


  • Insulin
  • Receptor, Insulin