A Serum Resistin and Multicytokine Inflammatory Pathway Is Linked With and Helps Predict All-cause Death in Diabetes

J Clin Endocrinol Metab. 2021 Oct 21;106(11):e4350-e4359. doi: 10.1210/clinem/dgab472.


Context: Type 2 diabetes (T2D) shows a high mortality rate, partly mediated by atherosclerotic plaque instability. Discovering novel biomarkers may help identify high-risk patients who would benefit from more aggressive and specific managements. We recently described a serum resistin and multicytokine inflammatory pathway (REMAP), including resistin, interleukin (IL)-1β, IL-6, IL-8, and TNF-α, that is associated with cardiovascular disease.

Objective: We investigated whether REMAP is associated with and improves the prediction of mortality in T2D.

Methods: A REMAP score was investigated in 3 cohorts comprising 1528 patients with T2D (409 incident deaths) and in 59 patients who underwent carotid endarterectomy (CEA; 24 deaths). Plaques were classified as unstable/stable according to the modified American Heart Association atherosclerosis classification.

Results: REMAP was associated with all-cause mortality in each cohort and in all 1528 individuals (fully adjusted hazard ratio [HR] for 1 SD increase = 1.34, P < .001). In CEA patients, REMAP was associated with mortality (HR = 1.64, P = .04) and a modest change was observed when plaque stability was taken into account (HR = 1.58; P = .07). REMAP improved discrimination and reclassification measures of both Estimation of Mortality Risk in Type 2 Diabetic Patients and Risk Equations for Complications of Type 2 Diabetes, well-established prediction models of mortality in T2D (P < .05-< .001).

Conclusion: REMAP is independently associated with and improves predict all-cause mortality in T2D; it can therefore be used to identify high-risk individuals to be targeted with more aggressive management. Whether REMAP can also identify patients who are more responsive to IL-6 and IL-1β monoclonal antibodies that reduce cardiovascular burden and total mortality is an intriguing possibility to be tested.

Keywords: cytokines; mortality; plaque instability; prediction models; resistin; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Atherosclerosis / blood
  • Atherosclerosis / complications
  • Atherosclerosis / therapy
  • Biomarkers / blood
  • Cohort Studies
  • Cytokines / blood*
  • Diabetes Complications / blood*
  • Diabetes Complications / therapy
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / mortality*
  • Diabetes Mellitus, Type 2 / therapy
  • Female
  • Humans
  • Inflammation / blood*
  • Inflammation / complications
  • Interleukins / blood
  • Male
  • Middle Aged
  • Plaque, Atherosclerotic / blood
  • Plaque, Atherosclerotic / etiology
  • Plaque, Atherosclerotic / pathology
  • Prospective Studies
  • Resistin / blood*
  • Risk Factors
  • Tumor Necrosis Factor-alpha / blood


  • Biomarkers
  • Cytokines
  • Interleukins
  • RETN protein, human
  • Resistin
  • Tumor Necrosis Factor-alpha