HEXA-FC protein therapy increases skeletal muscle glucose uptake and improves glycaemic control in mice with insulin resistance and in a mouse model of type 2 diabetes

• DOI: 10.1007/s00125-025-06413-7
• Publication Date: 2025-03-31T14:51:27Z
• Authors: Magdalene K. Mont...; Sihan Lin; Chieh-Hsin Yang; Krishneel Prasad; Zhi Li Cheng; Jacqueline Bayliss; Michael G. Leeming; Nicholas A. Willi...; Kim Loh; Li Dong; Matthew J. Watt

Abstract

Aims/hypothesis Type 2 diabetes is a chronic metabolic disorder characterised by insulin resistance and sustained hyperglycaemia, and is a major cause of blindness, kidney failure, heart attacks and stroke. Our team has recently identified hexosaminidase A (HEXA) as an endocrine factor secreted by the liver that regulates sphingolipid metabolism in skeletal muscle. Specifically, HEXA converts GM2 to GM3 gangliosides within cell-surface lipid rafts. Remodelling of ganglioside composition by HEXA enhances IGF1 signalling in skeletal muscle, increasing muscle glucose uptake and improving blood glucose control.

Methods We produced a long-acting HEXA-FC fusion protein (murine HEXA and the fragment crystallisable [FC] region from IgG1) and evaluated the effects of chronic bi-weekly HEXA-FC administration (1 mg/kg body weight) on glycaemic control in C57BL/6 mice with diet-induced obesity and insulin resistance and the db/db mouse model of severe type 2 diabetes. Outcome measures included glucose and insulin tolerance, including a stable isotope-labelled GTT and assessment of tissue-specific glucose disposal, as well as proteomics analysis to define changes in skeletal muscle metabolism.

Results Chronic administration of a long-acting recombinant HEXA-FC fusion protein led to improvements in random blood glucose, fasting blood glucose and glucose tolerance, driven by increased glucose disposal into skeletal muscle, effects that were associated with enhancement of IGF1 signalling in muscle.

Conclusions/interpretation Given that skeletal muscle is a primary site of insulin resistance in individuals with type 2 diabetes, HEXA-FC protein therapy may open new avenues for therapeutic advancement in type 2 diabetes.

Graphical Abstract