Scientists Identified the Enzyme That Produces GIP — The Other Half of the Incretin System | Research

The takeaway

Prohormone convertase 1/3 is the essential enzyme that processes the GIP precursor into active GIP hormone in the gut — without it, GIP production is severely impaired.

PC1/3 essential
Without prohormone convertase 1/3, intestinal GIP production is severely impaired — making this enzyme the gatekeeper of the GIP incretin pathway

What the researchers found

The enzyme prohormone convertase 1/3 (PC1/3) is the essential scissor that cuts the GIP precursor protein into active GIP — one of the two incretin hormones that stimulate insulin release after eating. In mice lacking PC1/3, GIP production was severely impaired. A different enzyme, PC2, can technically cut the GIP precursor but produces abnormal fragments not found in the intestine and is not present in GIP-producing cells.

The researchers confirmed this through multiple approaches: immunohistochemistry showed GIP and PC1/3 co-localize in the same intestinal cells (but PC2 does not), knockout mice lacking PC1/3 had dramatically reduced GIP, and cell line experiments confirmed PC1/3 alone is sufficient to produce active GIP.

Why it matters

GIP (glucose-dependent insulinotropic polypeptide) is one of two incretin hormones — along with GLP-1 — that account for most of the insulin response to eating. Understanding how GIP is produced at the molecular level is fundamental to incretin biology. This matters clinically because tirzepatide (Mounjaro/Zepbound), one of the most successful drugs in modern medicine, works by activating both GIP and GLP-1 receptors. Knowing that PC1/3 is the essential enzyme for GIP production could be relevant for understanding GIP deficiency states and developing new therapeutic strategies.

The numbers in context

PC1/3 essential for GIP production · PC2 not involved in intestinal GIP processing · PC1/3 co-localizes with GIP in intestinal cells · PC1/3-null mice: severely impaired GIP · PC2-null mice: normal GIP

How the study worked

Multi-approach study using PC1/3 and PC2 knockout mice, immunohistochemistry of intestinal sections, analysis of intestinal extracts, and adenovirus-mediated overexpression of proGIP in multiple cell lines (AtT-20, GH4, alpha-TC1.9) with varying PC1/3 and PC2 expression levels. GIP processing was assessed by chromatography and radioimmunoassay.

Who was studied

PC1/3-null mice, PC2-null mice, and multiple neuroendocrine cell lines

What this study cannot tell us

Mouse knockout models may not perfectly recapitulate human GIP processing. Cell line experiments use artificial overexpression systems. The study focuses on intestinal GIP production and may not account for GIP processing in other tissues. Long-term consequences of PC1/3 deficiency on incretin-mediated metabolism were not assessed.

How to read the evidence

This is a rigorous basic science study published in the Journal of Biological Chemistry using multiple convergent approaches (knockout mice, immunohistochemistry, cell lines) to reach a definitive conclusion. The 'Strong' grade reflects the methodological thoroughness and the clarity of the finding.

When this study was published

Published in 2006, this is a foundational study in incretin biology. Its findings have been confirmed by subsequent research and remain the definitive reference for GIP processing. The relevance has only increased with the success of GIP-targeting drugs like tirzepatide.

The bigger picture

The incretin system (GLP-1 + GIP) is the biological foundation of the most successful drug class in modern endocrinology. While GLP-1 processing was well understood, GIP processing was the missing piece. This study, from the lab of Jens Holst (a pioneer of incretin biology), filled that gap. As dual GIP/GLP-1 agonists like tirzepatide dominate the market, understanding the fundamental biology of GIP production becomes increasingly relevant for developing next-generation therapies.

Questions still open

Could PC1/3 deficiency or polymorphisms contribute to GIP deficiency and metabolic disease in humans?
Does PC1/3 activity change with age, potentially reducing GIP production in older adults?
Could enhancing PC1/3 activity increase endogenous GIP production as a therapeutic strategy?

Common questions

What is GIP and why does it matter for diabetes treatment?

GIP (glucose-dependent insulinotropic polypeptide) is a hormone released by your gut after eating that signals your pancreas to make insulin. Together with GLP-1, it accounts for most of the insulin response to a meal. GIP is half the target of tirzepatide (sold as Mounjaro for diabetes and Zepbound for weight loss), which activates both GIP and GLP-1 receptors for enhanced blood sugar control and weight loss.

What happens if the body can't make this enzyme?

Without prohormone convertase 1/3, the body can't properly process several important hormones including GIP. In the study's knockout mice, GIP production was severely impaired. In rare cases, humans with PC1/3 mutations develop obesity, impaired glucose metabolism, and other endocrine problems — illustrating how critical this enzyme is for normal peptide hormone production.

Read the original research

Prohormone convertase 1/3 is essential for processing of the glucose-dependent insulinotropic polypeptide precursor.

The Journal of biological chemistry, 281(16), 11050-7

View on PubMed ↗

Citation

Ugleholdt, Randi; Poulsen, Marie-Louise H; Holst, Peter J; Irminger, Jean-Claude; Orskov, Cathrine; Pedersen, Jens; Rosenkilde, Mette M; Zhu, Xiaorong; Steiner, Donald F; Holst, Jens J. (2006). Prohormone convertase 1/3 is essential for processing of the glucose-dependent insulinotropic polypeptide precursor.. The Journal of biological chemistry, 281(16), 11050-7.