Emerging Applications of CRISPR/Cas9 Technology in the Treatment of Diabetes Mellitus: A Narrative Review

Abstract

Diabetes mellitus (DM), both Type 1 (T1DM) and Type 2 (T2DM), remains a global health threat. The causes of T1DM are autoimmune destruction of β cells, whereas T2DM is caused by insulin resistance and β-cell dysfunction. Current treatments manage the disease but do not address the genetic or cellular abnormalities. CRISPR/Cas9 is an extremely potent gene editing tool that can potentially cure diabetes by correcting genetic mutations, controlling gene expression, and regenerating β cells. In the CRISPR systems of T1DM, CRISPR technology has been employed to create immune-evasive β-like cells from iPSCs by editing HLA genes and immune checkpoints. In T2DM, specific disease-causing genes such as TCF7L2, GLUT4, and SLC30A8 have been edited to improve insulin regulation. Further, editing of PPARG and FOXO1 has been found to improve insulin sensitivity and suppress hepatic glucose production. GCK (glucokinase), one of the important regulators of glucose sensing in β-cells, has also been a target to increase insulin secretion and normalise glucose homeostasis. The delivery systems are adeno-associated viruses, lipid nanoparticles, and electroporation, among others. Novel tools like Cpf1 improve editing efficiency, particularly in non-dividing cells. Nanocarriers have also improved delivery specificity and reduced degradation. Promising results have been seen with targeting metabolic enzymes like DPP-4 to preclude T2DM dysfunction. However, issues such as off-target effects, immune reactions, mosaicism, limitations in delivery, costs, and ethical viability still remain. Overcoming all these limitations, CRISPR-based approaches have high potential in overcoming treatment control for symptoms and offering long-term, possibly curative, diabetes therapies. Future research is required to refine delivery, enhance safety, and investigate long-term human effects.