Long-term blood glucose control via glucose-activated transcriptional regulation of insulin analogue in type 1 diabetes mice.

Abstract

Aim: To achieve glucose-activated transcriptional regulation of insulin analogue in skeletal muscle of T1D mice, thereby controlling blood glucose levels and preventing or mitigating diabetes-related complications.

Materials and methods: We developed the GANIT (Glucose-Activated NFAT-regulated INSA-F Transcription) system, an innovative platform building upon the previously established intramuscular plasmid DNA (pDNA) delivery and expression system. In the GANIT system, skeletal muscle cells are genetically engineered to endogenously produce the insulin analogue INSA-F (Insulin Aspart with Furin cleavage sites). The transcription of INSA-F is precisely controlled by a glucose-responsive promoter containing NFAT (Nuclear Factor of Activated T-cells) regulatory motifs, which can be activated in response to changes in extracellular glucose concentrations. This design enables glucose-dependent regulation of insulin analogue expression, mimicking physiological glucose-responsive insulin secretion.

Results: T1D mice that received two GANIT treatments over a 2-month experimental period demonstrated significant improvements in glucose homeostasis, glucose tolerance and glycated haemoglobin (HbA1c) levels. Additionally, the treatment effectively reduced oxidative stress and alleviated cardiac and renal fibrosis, while maintaining a favourable biosafety profile.

Conclusion: The GANIT system provides significant advantages in terms of efficiency, convenience and cost-effectiveness, making it a promising approach for regulating blood glucose levels and alleviating diabetes-related complications in insulin-deficient diabetes.