HMGB1 is increased by CFTR loss of function, is lowered by insulin, and increases in vivo at onset of CFRD

Luisa Montanini, Francesca Cirillo, Arianna Smerieri, Giovanna Pisi, Ida Giardino, Maria D'Apolito, Cinzia Spaggiari, Sergio Bernasconi, Sergio Amarri, Maria Elisabeth Street

Research output: Contribution to journalArticlepeer-review

Abstract

Context: Cystic fibrosis-related diabetes (CFRD) is associated with worsening of inflammation and infections, and the beginning of insulin treatment is debated. Objectives: To verify high-mobility group box 1 protein (HMGB1) levels in CF patients according to glucose tolerance state, and analyze relationships with insulin secretion and resistance. To verify, in an in vitro model, whetherHMGB1gene expression and protein content were affected by insulin administration and whether these changes were dependent on CF transmembrane conductance regulator (CFTR) loss of function. Patients and Methods: Forty-three patients in stable clinical conditions and 35 age-and sexmatched controls were enrolled. Glucose tolerance was established in patients based on a 5 point oral glucose tolerance test (OGTT). Fasting glucose to insulin ratio (FGIR), HOMA-IR index, wholebody insulin sensitivity index (WIBISI), and the areas under the curve for glucose (AUCG) and insulin (AUCI) were calculated. HMGB1 was assayed in serum, in cell lysates and conditioned media using a specific ELISA kit. For the in vitro study we used CFBE41o cells, homozygous for the F508del mutation, and 16HBE14o as non-CF control. HMGB1 gene expression was studied by real-time RT-PCR. Cells were stimulated with insulin at 2.5 and 5 ng/mL. The CFTR inhibitor 172 and CFTR gene silencing were used to induce CFTR loss of function in 16HBE14o cells. Results: HMGB1 levels were increased at onset of CFRD (5.04 ± 1.2 vs 2.7 ± 0.3 ng/mL in controls; P <.05) and correlated with FGIR (R0.43; P 038), and AUCI (R 0.43; P 013). CFTR loss of function in the 16HBE14o cells increased HMGB1 and was lowered by insulin. Conclusion: HMGB1 was increased in CF patients with deranging glucose metabolism and showed relationships with indexes of glucose metabolism. The increase in HMGB1 was related to CFTR loss of function, and insulin lowered HMGB1. Further research is required to verify whether HMGB1 could potentially be a candidate marker of onset of CFRD and to establish when to start insulin treatment.

Original languageEnglish
Pages (from-to)1274-1281
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume101
Issue number3
DOIs
Publication statusPublished - Mar 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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