Release of Incompletely Processed Proinsulin Is the Cause of the Disproportionate Proinsulinemia of NIDDM
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The production of insulin from proinsulin involves cleavage of intact proinsulin into proinsulin conversion intermediates by the processing of enzymes PC2 and PC3 before fully processed insulin is produced. Intact proinsulin and these conversion intermediates are measured in many immunoreactive insulin (IRI) assays, and therefore contribute to the absolute IRI measurement. The proportion of basal IRI made up of proinsulin (PI)-like molecules (PI/IRI) is increased in NIDDM. Whether stimulated IRI levels are similarly made up of disproportionately increased PI/IRI or whether the relative proportions of proinsulin and its conversion intermediates are altered has not been evaluated. An index of the efficiency of proinsulin processing within the pancreatic β-cell can be achieved by measuring PI/IRI immediately following acute stimulation of β-cell secretion, and then determining the proportion of intact proinsulin and proinsulin conversion intermediates contributing to circulating proinsulin-like molecules. In this study, we determined the PI/IRI levels under basal and arginine-stimulated conditions in 17 healthy and 16 NIDDM subjects; high-performance liquid chromatography (HPLC) was also performed in a subset of these subjects to measure the relative contribution of intact proinsulin and its conversion intermediates to total proinsulin-like molecules. In NIDDM subjects, levels of both basal (44.6 ± 9.6 vs. 9.3 ± 1.5 pmol/1; P = 0.0007) and stimulated (64.0 ± 12.7 vs. 19.8 ± 2.8 pmol/1; P = 0.001) proinsulin-like molecules were higher than in healthy subjects. Although IRI was higher in NIDDM than in control subjects under basal conditions (106 ± 19 vs. 65.1 ± 8.1 pmol/1; P = 0.05), it was lower in NIDDM than in control subjects following stimulation (increment: 257 ± 46 vs. 416 ±51 pmol/1; P = 0.03). PWRI ratios were increased in NTODM subjects under both basal (43.3 ± 5.0 vs. 14.0 ± 1.3%; P < 0.0001) and stimulated (increment: 10.1 ± 2.1 vs. 2.5 ± 0.2%; P = 0.0006) conditions, compatible with the release of a disproportionately increased amount of proinsulin-like products. HPLC analysis revealed that, in the stimulated state, intact proinsulin made up 40.1 ± 6.7% of proinsulin-like molecules in NIDDM individuals (n = 9) and 30.1 ± 5.6% in healthy subjects (n = 7; NS). The remainder of the proinsulin-like molecules comprised the des-31,32-split proinsulin conversion intermediate. The increase in PI/IRI in NIDDM under basal and especially under stimulated conditions suggests that proinsulin conversion is indeed perturbed in this disorder. Because the relative proportions of intact and des-31,32-split proinsulin are similar in both healthy and NIDDM subjects, the orderly cleavage of proinsulin at its two junctions appears preserved. However, at the time of exocytosis, the secretory granule in the islet of NIDDM subjects contains an increased proportion of incompletely processed proinsulin, presumably reflecting a slower rate of conversion or granules' reduced time of residence in β-cells.
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In established Type 2 diabetes, there is inefficient proinsulin processing to insulin and a reduction in the release of islet amyloid polypeptide (IAPP)/amylin.
“inefficient proinsulin processing to insulin [77, 78, 79, 80, 81, 82, 83] and a reduction in the release of islet amyloid polypeptide (IAPP), known also as amylin [84, 85, 86, 87], have been observed in established Type 2 diabetes.”
From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [83]
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- Authors
- Kahn, S. E., & Halban, P. A.
- Affiliations
- University of Washington (US)
- Laboratoires de Recherche Louis Jeantet, Centre Medical Universitaire Geneva, Switzerland
- ORCID
- Kahn, Steven E
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1997-11-01
- Volume
- 46
- Issue
- 11
- Pages
- 1725-1732
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2124706352
- Cited by
- 221
- References
- 0
- Citations by year
- 2026: 6 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 14 · 2020: 12 · 2019: 8 · 2018: 6 · 2017: 4 · 2016: 1 · 2015: 3 · 2014: 11 · 2013: 6 · 2012: 5
- FWCI
- 6.90
- Type
- journal article
- Language
- en
- Open access
- Licence
- cc-by
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (2r01dk012829-36)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 12829, DK-17047, P30DK017047)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- proinsulin, type 2 diabetes, proinsulin processing, proinsulin C-peptide, arginine stimulation, beta-cell secretion, insulin production
- MeSH terms
- Adult, Arginine, Chromatography, High Pressure Liquid, Diabetes Mellitus, Type 2, Female, Humans, Insulin, Male, Middle Aged, Proinsulin, Protein Precursors, Protein Processing, Post-Translational, Radioimmunoassay, Reference Values, Regression Analysis
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