Altered islet prohormone processing: a cause or consequence of diabetes?

Area of Science:

• Endocrinology
• Molecular Biology
• Metabolic Diseases

Background:

• Peptide hormones are synthesized as prohormones requiring enzymatic cleavage for maturation.
• Prohormone convertase enzymes (PCs), particularly PC1/3 and PC2, are crucial for this processing in neuroendocrine cells.
• Differential PC expression dictates tissue-specific hormone production, e.g., glucagon in pancreas vs. GLP-1/GLP-2 in intestine.

Purpose of the Study:

• To investigate the role of prohormone processing in diabetes pathogenesis.
• To examine alterations in prohormone processing during prediabetes and diabetes.
• To assess the potential causal link between impaired prohormone processing and diabetes development.

Main Methods:

• Review of existing literature on prohormone processing and diabetes.
• Analysis of studies on proinsulin, pro-islet amyloid polypeptide (proIAPP), and proglucagon processing.
• Examination of preclinical and clinical data regarding PC activity and hormone levels in diabetes models and patients.

Main Results:

• Prohormone processing is altered in prediabetes and diabetes, affecting proinsulin, proIAPP, and proglucagon.
• Elevated proinsulin or proinsulin-to-C-peptide ratios predict diabetes progression and development.
• In diabetes, α-cells show altered proglucagon processing, increasing GLP-1 production.

Conclusions:

• Altered prohormone processing is strongly associated with diabetes.
• Current evidence is insufficient to establish a causal role for impaired prohormone processing in diabetes.
• Future research should clarify whether altered processing is a cause or consequence of diabetes.