Islet prohormone processing in health and disease.

Area of Science:

• Endocrinology and Metabolism
• Molecular Biology
• Genetics

Background:

• Peptide hormone biosynthesis in pancreatic islet cells is crucial for metabolic homeostasis.
• Hormones like insulin are synthesized as precursors and processed by enzymes such as prohormone convertases (PCs) and carboxypeptidase E.
• Posttranslational modifications, including C-terminal amidation by peptidyl-glycine α-amidating monooxygenase (PAM), are also important.

Purpose of the Study:

• To investigate the role of genetic variations and metabolic/inflammatory stresses on prohormone processing in pancreatic islet cells.
• To explore how impaired processing of proinsulin (PI) and pro-islet amyloid polypeptide (proIAPP) contributes to beta-cell dysfunction in type 1 and type 2 diabetes (T1D and T2D).
• To examine the processing of proglucagon in alpha-cells and its potential implications.

Main Methods:

• Analysis of genome-wide association studies (GWAS) linking processing enzymes to metabolic diseases.
• Evaluation of prohormone processing defects in the context of T1D, T2D, and diabetogenic stresses.
• Investigation of specific enzyme activities, including Pc1/3, Pc2, carboxypeptidase E, and PAM.

Main Results:

• Elevated proinsulin to insulin (PI:I) ratios are a key indicator of beta-cell dysfunction in T2D.
• Defects in proIAPP processing can lead to incompletely processed forms, potentially contributing to T2D pathogenesis.
• Impaired processing of both PI and proIAPP is observed in beta-cell dysfunction associated with T1D.
• Aberrant proglucagon processing in alpha-cells, involving Pc1/3, can produce GLP-1(7-36NH2).

Conclusions:

• Genetic and acquired defects in prohormone processing enzymes significantly impact islet cell function and contribute to diabetes development.
• Understanding these processing pathways offers potential therapeutic targets for improving islet function and managing diabetes.
• Further research into the regulation of PI, proIAPP, and proglucagon processing under various stresses is warranted.