Metabolic Dysregulation in Adult Survivors of Pediatric Hematopoietic Stem Cell Transplantation: The Role of Incretins

CONTEXT: Survivors of pediatric hematopoietic stem cell transplantation (HSCT) have increased risk of developing metabolic syndrome (MetS), but the mechanisms are poorly understood.

OBJECTIVE: To test the hypothesis that insufficient secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) plays a pathogenetic role in HSCT survivors with MetS.

DESIGN: Cross-sectional cohort study.

SETTING: The Danish national referral center for HSCT.

PATIENTS OR OTHER PARTICIPANTS: Forty-two male HSCT survivors (median age of 28.9 years) studied median 21.2 years from HSCT. Fifteen age- and sex-matched healthy controls.

INTERVENTION: None.

MAIN OUTCOME MEASURES: Glucose metabolism and incretin hormones (measured in an oral glucose tolerance test (OGTT)) and MetS-criteria. The hypothesis was formulated before data collection.

RESULTS: GLP-1, GIP, and glucagon during an OGTT were similar in patients and controls, with no overall difference between survivors with (24%) and without MetS. However, fasting glucagon was significantly higher in patients with hypertriglyceridemia (Mean Difference (MD): 6.1 pmol/L, 95%Confidence Interval (CI): 1.5 to 10.8, p = 0.01), and correlated with HDL (MD: 4.7 mmol/L, 95%CI: -0.6 to 9.9, p = 0.08), android-gynoid ratio (correlation coefficient (r) = 0.6, p = 0.0001) and waist-hip ratio (r = 0.5, p = 0.002). A similar pattern was seen for GIP, correlating positively with triglyceride (MD: 60%, 95%CI: 44 to 82, p = 0.002).GIP levels were significantly increased in patients treated with total body irradiation (TBI) (MD: 165%, 95%CI: 118 to 230, p = 0.004), that was found to be a significant risk factor for MetS.

CONCLUSION: This study demonstrates an altered production of incretin hormones in HSCT survivors previously treated with TBI, developing dyslipidemia and abdominal adiposity.