Archives of Physiology and Biochemistry

Protein Engineering and Gene Editing Technologies for the Targeted Management of Metabolic Dysfunction in Diabetes

Diabetes mellitus remains one of the most prevalent chronic metabolic disorders, rooted in systemic physiological imbalances including impaired glucose homeostasis, pancreatic β-cell dysfunction, and disrupted hormonal signaling. The interplay between molecular signaling pathways, enzyme activity, and tissue-specific metabolic regulation underlies the progression of both type 1 and type 2 diabetes. Conventional therapies often fail to target the underlying biochemical and physiological mechanisms, limiting their long-term efficacy. Recent advancements in protein engineering and gene editing technologies are opening new avenues for restoring physiological balance by enabling targeted modulation of dysfunctional pathways at the molecular and genetic levels. Engineered proteins, including optimized insulin analogs and signaling peptides, offer improved metabolic control. Gene editing techniques provide tools for correcting metabolic gene dysfunctions and restoring normal enzymatic and cellular functions. This special issue focuses on leveraging these innovative strategies to unravel and address the biochemical and physiological underpinnings of diabetes. Translating protein- and gene-based approaches into viable therapeutic strategies is accompanied by multifaceted challenges. Achieving site-specific delivery to metabolically active tissues such as the pancreas, liver, and skeletal muscle remains difficult due to immune responses, limited transport mechanisms, and cellular heterogeneity. Physiological variability among diabetic individuals driven by genetics, lifestyle, and microbiota demands personalized approaches for effective intervention. At the molecular level, off-target effects, long-term tissue responses, and feedback regulation mechanisms pose significant barriers. There is a need to better understand how engineered interventions interact with endogenous metabolic circuits and physiological compensatory mechanisms.

The primary aim of this special issue is to advance the understanding and application of protein engineering and gene editing technologies and to highlight novel experimental models, mechanistic insights, and therapeutic strategies that bridge molecular interventions with systemic metabolic outcomes. We invite original research and comprehensive reviews that explore how these technologies can modify enzyme functions, hormone signaling, cellular energetics, or tissue-specific metabolism to manage or reverse diabetic dysfunction. The special issue also encourages discussions of translational strategies, from preclinical validation to physiological modeling of interventions, promoting a holistic view of metabolic restoration.

Potential topics include but are not limited to the following:

• Engineered insulin analogs with enhanced receptor specificity for improved glucose homeostasis
• Base editing approaches to restore mitochondrial genes in metabolic myopathies: implications for diabetic energy dysregulation
• Integrated protein and gene editing technologies for epigenetic and microbiome-driven metabolic reprogramming in diabetes
• Protein scaffolds and peptide modulators of glucose and lipid metabolism
• Organoids-based testing of gene-edited hepatic and pancreatic cells for personalized therapy
• Therapeutic enzyme engineering for improved glycogen metabolism in glycogen storage diseases
• Gene-protein cotargeting strategies for managing diabetic retinopathy and neuropathy
• Proteomics-based identification of engineered protein biomarkers in diabetic complications
• Engineered proteins for inhibiting advanced glycation end products (AGEs) in diabetic nephropathy
• Physiological modeling of metabolic compensation following protein- or gene-based therapy