ArticleDiabetologia2017
In vivo measurement and biological characterisation of the diabetes-associated mutant insulin p.R46Q (GlnB22-insulin).
Article in Diabetologia, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 20 citations in OpenAlex.
- The B22 Dilemma: Structural Basis for Conformational Differences in Proinsulin B-Chain Arg22 Mutants.Biomolecules · 2025Article
- Novel Approach for Treating Diabetes in a Patient With the Heterozygous Pathogenic Variant R46Q in the Insulin Gene.JCEM case reports · 2024Article
- Genetic perspectives on childhood monogenic diabetes: Diagnosis, management, and future directions.World journal of diabetes · 2023Review
- A Review of the Biosynthesis and Structural Implications of Insulin Gene Mutations Linked to Human Disease.Cells · 2023Review
- How do I diagnose Maturity Onset Diabetes of the Young in my patients?Clinical endocrinology · 2022Review
- UDP-glucose, cereblon-dependent proinsulin degrader.Scientific reports · 2022Article
- Article
- In celebration of a century with insulin - Update of insulin gene mutations in diabetes.Molecular metabolism · 2021Review
- Structural Lessons From the Mutant Proinsulin Syndrome.Frontiers in endocrinology · 2021Review
- Biological behaviors of mutant proinsulin contribute to the phenotypic spectrum of diabetes associated with insulin gene mutations.Molecular and cellular endocrinology · 2020Article
- Monogenic Diabetes: From Genetic Insights to Population-Based Precision in Care. Reflections From aDiabetes care · 2020Review
- Evolution of insulin at the edge of foldability and its medical implications.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes.Annals of the New York Academy of Sciences · 2018Review
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6 authors at 3 institutions in 2 countries.
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Abstract
aims/hypothesisHeterozygous mutations in the insulin gene that affect proinsulin biosynthesis and folding are associated with a spectrum of diabetes phenotypes, from permanent neonatal diabetes to MODY. In vivo studies of these mutations may lead to a better understanding of insulin mutation-associated diabetes and point to the best treatment strategy. We studied an 18-year-old woman with MODY heterozygous for the insulin mutation p.R46Q (GlnB22-insulin), measuring the secretion of mutant and wild-type insulin by LC-MS. The clinical study was combined with in vitro studies of the synthesis and secretion of p.R46Q-insulin in rat INS-1 insulinoma cells.
methodsWe performed a standard 75 g OGTT in the 18-year-old woman and measured plasma glucose and serum insulin (wild-type insulin and GlnB22-insulin), C-peptide, proinsulin, glucagon and amylin. The affinity of GlnB22-insulin was tested on human insulin receptors expressed in baby hamster kidney (BHK) cells. We also examined the subcellular localisation, secretion and impact on cellular stress markers of p.R46Q-insulin in INS-1 cells.
resultsPlasma GlnB22-insulin concentrations were 1.5 times higher than wild-type insulin at all time points during the OGTT. The insulin-receptor affinity of GlnB22-insulin was 57% of that of wild-type insulin. Expression of p.R46Q-insulin in INS-1 cells was associated with decreased insulin secretion, but not induction of endoplasmic reticulum stress. CONCLUSIONS/
interpretationThe results show that beta cells can process and secrete GlnB22-insulin both in vivo and in vitro. Our combined approach of immunoprecipitation and LC-MS to measure mutant and wild-type insulin may be useful for the study of other mutant insulin proteins. The ability to process and secrete a mutant protein may predict a more benign course of insulin mutation-related diabetes. Diabetes develops when the beta cell is stressed because of increased demand for insulin, as observed in individuals with other insulin mutations that affect the processing of proinsulin to insulin or mutations that reduce the affinity for the insulin receptor.
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