title: Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes.
abstract: OBJECTIVE
  Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes.
  
  
  METHODS
  The beta cell function of 118 patients with type 1 diabetes of duration of 0.75-4.97 years was tested using a standardised liquid mixed meal test (MMT). Serum samples obtained at -5 to 120 min were analysed by multiplex bead-based technology for proinflammatory (IL-6, TNF-α), anti-inflammatory (IL-1 receptor antagonist [IL-1RA]) and regulatory (IL-10, TGF-β1-3) cytokines, and by standard procedures for C-peptide. Differences in beta cell function between patient groups were assessed using stepwise multiple regression analysis adjusting for sex, age, duration of diabetes, BMI, HbA1c and fasting blood glucose.
  
  
  RESULTS
  High fasting systemic concentrations of the proinflammatory cytokines IL-6 and TNF-α were associated with increased fasting and stimulated C-peptide concentrations even after adjustment for confounders (p < 0.03). Interestingly, increased concentrations of anti-inflammatory/regulatory IL-1RA, IL-10, TGF-β1 and TGF-β2 were associated with lower fasting and stimulated C-peptide levels (p < 0.04), losing significance on adjustment for anthropometric variables. During the MMT, circulating concentrations of IL-6 and TNF-α increased (p < 0.001) while those of IL-10 and TGF-β1 decreased (p < 0.02) and IL-1RA and TGF-β2 remained unchanged.
  
  
  CONCLUSIONS
  The association between better preserved beta cell function in longer term type 1 diabetes and increased systemic proinflammatory cytokines and decreased anti-inflammatory and regulatory cytokines is suggestive of ongoing inflammatory disease activity that might be perpetuated by the remaining beta cells. These findings should be considered when designing immune intervention studies aimed at patients with longer term type 1 diabetes and residual beta cell function.
authors.affiliation: Institute for Clinical Diabetology at the German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Auf'm Hennekamp 65, 40225 Düsseldorf, Germany. mnpham@gmx.de
authors.forename: M N
authors.initials: MN
authors.lastname: Pham
authors.forename: H
authors.initials: H
authors.lastname: Kolb
authors.forename: T
authors.initials: T
authors.lastname: Battelino
authors.forename: J
authors.initials: J
authors.lastname: Ludvigsson
authors.forename: P
authors.initials: P
authors.lastname: Pozzilli
authors.forename: F
authors.initials: F
authors.lastname: Zivehe
authors.forename: M
authors.initials: M
authors.lastname: Roden
authors.forename: T
authors.initials: T
authors.lastname: Mandrup-Poulsen
authors.forename: N C
authors.initials: NC
authors.lastname: Schloot
mesh_terms: D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002096:C-Peptide / Q000097:blood; D002648:Child; D016207:Cytokines / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000378:metabolism; D004032:Diet; D005215:Fasting; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008297:Male; D013997:Time Factors; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D016207:Cytokines