ENHANCED ERYTHROPOIESIS BY HEMATOPOIETIC TFR2 DELETION CORRECTS HYPERGLYCEMIA IN β-THALASSEMIA

Simona Maria DI MODICA¹, Emanuele TANZI¹, Mariateresa PETTINATO ^1,3, Alessia PAGANI ^1,3, Laura SILVESTRI ^1,3, Antonella NAI^1,3

¹Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
²Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
³Vita-Salute San Raffaele University, Milan, Italy

Alterations of glucose metabolism and diabetes are common complications of β-thalassemia, mainly ascribed to organs dysfunction because of iron accumulation. However, β-thalassemia carriers, who do not experience iron overload, have a higher risk of developing glucose abnormalities compared to the general population. Thus, other factors likely contribute to metabolic dysregulation in β-thalassemia. We hypothesize that ineffective erythropoiesis (IE) might play a pivotal role. Indeed, hyperactive erythropoiesis in polycythemia mice results in systemic hypoglycemia.

Erythroid Transferrin Receptor 2 (TFR2) is a negative regulator of erythropoietin signalling. Indeed, Tfr2 deletion ameliorates anemia and IE in β-thalassemia models, likely increasing the metabolic activity of erythroid cells. Thus, hematopoietic Tfr2 deletion, stimulating erythropoiesis, might promote glucose consumption, thus improving metabolic abnormalities in β-thalassemia. To address this point, we evaluated the metabolic profile of wt and thalassemic (Hbb^th3/+) mice with or without hematopoietic Tfr2.

In line with patients’ data, Hbb^th3/+ mice were hyperglycemic both in basal and in fasting conditions, without major changes in insulin levels. Interestingly, blood glycemia inversely correlated with the degree of anemia independently from iron overload in the different genotypes, with Tfr2-deficient mice showing reduced glycemia and improved response to a glucose tolerance test. Of note, transcriptomic analysis showed an increased expression of metabolic genes in Tfr2-deficient erythroblasts, mainly at the most terminal stages of maturation, indicating that glucose uptake and metabolism strongly support terminal erythroid differentiation. Overall, these results suggest that increased glucose consumption by the Tfr2-deficient hyperactive erythropoiesis reduces systemic glucose levels, thus correcting hyperglycemia in β-thalassemic mice.