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

Abstract

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.

Bone remodeling in survivors of pediatric hematopoietic stem cell transplantation: Impact of heavy resistance training

“…Despite previous treatment with cytotoxic regimen pre‐HSCT, previous acute GvHD and the use of parenteral nutrition, found to have detrimental effects on the gastrointestinal epithelial cells, 37,38 we found a preserved gut‐bone axis with a normal postprandial suppression of CTX in these survivors. This finding is supported by a recent study from our group, where a normal incretin hormone response in long‐term survivors of pediatric HSCT was observed 3 …”

“…bone axis with a normal postprandial suppression of CTX in these survivors. This finding is supported by a recent study from our group, where a normal incretin hormone response in long-term survivors of pediatric HSCT was observed 3. Other possible treatments for osteopenia are available including calcium and vitamin D replacement therapy and treatment with bisphosphonates.…”

“…1 The transplantation of donor stem cells is preceded by an intense myeloablative conditioning regimen with high-dose chemotherapy sometimes combined with total body irradiation (TBI), which frequently causes severe acute adverse events during the first weeks after the transplantation. 2 In addition, significant late effects are seen in a large proportion of these patients during early adulthood such as cardio-metabolic disease, 3 secondary sarcopenia, 4 frailty, and osteopenia, resembling a stage of premature aging. 5 Although the exact causes of these late effects are still incompletely understood, several factors may be essential, for example, the direct effects of the cytotoxic treatment, the prolonged hospitalization with immobilization and malnutrition, as well as treatmentrelated endocrinopathies including hypogonadism and growth hormone deficiency.…”

“…The transplantation of donor stem cells is preceded by an intense myeloablative conditioning regimen with high‐dose chemotherapy sometimes combined with total body irradiation (TBI), which frequently causes severe acute adverse events during the first weeks after the transplantation 2 . In addition, significant late effects are seen in a large proportion of these patients during early adulthood such as cardio‐metabolic disease, 3 secondary sarcopenia, 4 frailty, and osteopenia, resembling a stage of premature aging 5 …”

Maintain Efficacy and Spare Toxicity: Traditional and New Radiation-Based Conditioning Regimens in Hematopoietic Stem Cell Transplantation

“…Moreover, a reduced pancreatic volume has been found after a radiation-based conditioning regimen, suggesting that RT has a direct role in the onset of insulin resistance and diabetes after HSCT [ 59 ]. Recently, a cross-sectional cohort study demonstrated an altered production of incretin hormones in HSCT survivors previously treated with TBI, with them developing dyslipidemia and abdominal adiposity [ 60 ].…”