Zapater Joseph Louis, Nicholoff Seth Thomas, Sweis Nadia Saib, Saraf Santosh Lumdas, Layden Brian Thomas
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL 60612, USA.
Endocrinology. 2025 Apr 22;166(6). doi: 10.1210/endocr/bqaf082.
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.
血红蛋白S（HbS）对识别血糖失调构成挑战，因为红细胞更新的变化会导致血红蛋白A1c（HbA1c）不准确，以及HbA1c与其他血糖控制指标之间出现不一致。令人担忧的是，携带HbS者的糖尿病患病率正在上升，并且研究表明HbS会增加糖尿病相关并发症的风险。尽管有报道称镰状细胞变异体与HbA1c之间存在联系，但HbS影响血糖控制的具体机制尚不清楚。在此，我们利用镰状细胞病（SCD）的汤姆斯小鼠模型来分析镰状细胞性状（SCT）和SCD对葡萄糖稳态的影响。我们发现，从8到20周龄，自由进食的SCD小鼠的随意血糖和空腹血糖均高于SCT小鼠或同窝对照小鼠，并且无论性别，空腹血清胰岛素水平都随着年龄增长而下降。这并非外周葡萄糖或胰岛素耐受性明显改变、胰腺结构发生明显形态变化或胰岛中铁沉积的结果。此外，与年龄和性别匹配的SCT小鼠及同窝对照小鼠相比，我们发现20周龄的SCD雄性小鼠胰腺胰岛素含量降低，SCD雄性和雌性小鼠的胰岛面积和β细胞量均显著减少。这些发现表明，携带两份HbS基因会促进早期高血糖以及胰腺β细胞功能障碍的发展，这可能会增加该群体患糖尿病的风险。
