title: Circulating Neutrophil Extracellular Trap Levels in Well-Controlled Type 2 Diabetes and Pathway Involved in Their Formation Induced by High-Dose Glucose.
abstract: OBJECTIVE
  Although intensive therapy for type 2 diabetes (T2D) prevents microvascular complications, 10% of well-controlled T2D patients develop microangiopathy. Therefore, the identification of risk markers for microvascular complications in well-controlled T2D patients is important. Recent studies have demonstrated that high-dose glucose induces neutrophil extracellular trap (NET) formation, which can be a risk for microvascular disorders. Thus, we attempted to determine the correlation of circulating NET levels with clinical/laboratory parameters in well-controlled T2D patients and to reveal the mechanism of NET formation induced by high-dose glucose.
  
  
  METHODS
  Circulating NET levels represented by myeloperoxidase (MPO)-DNA complexes in the serum of 11 well-controlled T2D patients and 13 healthy volunteers were determined by enzyme-linked immunosorbent assay. The pathway involved in the NET formation induced by high-dose glucose was determined using specific inhibitors.
  
  
  RESULTS
  Serum MPO-DNA complex levels were significantly higher in some well-controlled T2D patients in correlation with the clinical/laboratory parameters which have been regarded as risk markers for microvascular complications. The aldose reductase inhibitor, ranirestat, could inhibit the NET formation induced by high-dose glucose.
  
  
  CONCLUSIONS
  Elevated levels of circulating NETs can be a risk marker for microvascular complications in well-controlled T2D patients. The polyol pathway is involved in the NET formation induced by high-dose glucose.
authors.affiliation: Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Arina
authors.initials: A
authors.lastname: Miyoshi
authors.forename: Mai
authors.initials: M
authors.lastname: Yamada
authors.forename: Haruki
authors.initials: H
authors.lastname: Shida
authors.forename: Daigo
authors.initials: D
authors.lastname: Nakazawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kusunoki
authors.forename: Akinobu
authors.initials: A
authors.lastname: Nakamura
authors.forename: Hideaki
authors.initials: H
authors.lastname: Miyoshi
authors.forename: Utano
authors.initials: U
authors.lastname: Tomaru
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Atsumi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ishizu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D004247:DNA / Q000097:blood / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000150:complications* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D065206:Extracellular Traps / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D009195:Peroxidase / Q000097:blood* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011108:Polymers / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D012307:Risk Factors; D013141:Spiro Compounds / Q000494:pharmacology; D013997:Time Factors
chemical_list: D015415:Biomarkers; D007004:Hypoglycemic Agents; D011108:Polymers; D011719:Pyrazines; D011758:Pyrroles; D011799:Quinazolines; D013141:Spiro Compounds; C024617:polyol; C543528:sotrastaurin; D004247:DNA; D009195:Peroxidase; D005947:Glucose; C115070:ranirestat