Hemoglobin S Promotes Glycemic Dysregulation in a Mouse Model of Human Sickle Cell Disease.

Hemoglobin S (HbS) presents a challenge to identifying glycemic dysregulation, as changes in red blood cell turnover produce inaccurate hemoglobin A1c (HbA1c) and incongruencies between HbA1c and other glycemic control measures. Concerningly, the prevalence of diabetes in those with HbS is rising, and studies demonstrate that HbS increases the risk of diabetes-related complications. Though a link between the sickle cell variant and HbA1c is reported, the precise mechanisms by which HbS affects glycemic control are unknown. Here, we utilized the Townes mouse model of sickle cell disease (SCD) to analyze the effect of sickle cell trait (SCT) and SCD on glucose homeostasis. We found that chow-fed SCD mice had greater ad libitum and fasting blood glucose than SCT or littermate controls from 8 to 20 weeks of age, along with declining fasting serum insulin with aging, regardless of sex. This was not a result of overt alterations in peripheral glucose or insulin tolerance, gross morphological changes in pancreatic structure, or deposition of iron in pancreatic islets. Furthermore, compared with age- and sex-matched SCT and littermate control mice, we found decreased pancreatic insulin content in 20-week-old SCD male mice and significantly reduced pancreatic islet area and β cell mass in SCD males and females. These findings suggest that having 2 copies of the HbS gene promotes early hyperglycemia and the development of pancreatic β cell dysfunction, which may enhance the risk for diabetes in this cohort.