1544-P: Hemoglobin S Promotes Glucose Dysregulation in the Obese State in a Mouse Model of Human Sickle Cell Disease

Résumé fourni par la source

Introduction and Objective: The prevalence of obesity and diabetes amongst persons with hemoglobin S (HbS) is rising, however incongruencies between hemoglobin A1c (HbA1c) and other glycemic measures poses a challenge to accurately diagnosing diabetes in patients with sickle cell trait (SCT) or disease (SCD) at an early stage. Recent studies indicate that sickle cell variant rs334 is associated with higher HbA1c, and having concurrent HbS and diabetes increases one’s risk for developing diabetic complications. The objective of this work is to determine the mechanisms by which HbS impacts whole-body glucose homeostasis under obesogenic conditions, which are currently not well understood. Methods: We utilized the Townes transgenic mouse model of human SCD to assess the effect of HbS on glycemic regulation. Male mice with normal human hemoglobin (WT) or SCT or SCD were fed a high fat diet for a minimum of 14 weeks. Their glycemic phenotype (weight, ad libitum glucose, fasting glucose/insulin) was assessed every four weeks. Glucose and insulin tolerance testing, along with tissue analyses, were performed at 20 weeks of age. Results: SCD mice exhibit greater fasting blood glucose at all time points compared to WT and SCT mice, as well as significantly reduced fasting serum insulin at 20 weeks, suggestive of altered pancreatic beta cell function. Following a glucose and insulin load, SCT mice exhibit a greater glucose excursion and reduced insulin sensitivity, respectively, compared to both WT and SCD mice. WT and SCD mice had comparable insulin sensitivity and glucose utilization, which may be due to reduced weight trend in SCD mice as compared to WT and SCT mice. Conclusion: HbS may alter pancreatic beta cell function and peripheral insulin sensitivity under obesogenic conditions, promoting glycemic dysregulation and diabetes. Further analyses of pancreatic beta cell insulin dynamics as well as peripheral glucose disposal are warranted to hone in on potential biochemical pathways affected by HbS. Disclosure J. Zapater: None. N. Sweis: None. S. Nicholoff: None. B.T. Layden: None.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.