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Biomolecules
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Biosynthesis, Structure and Self-Assembly of Insulin
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Biosynthesis, Structure and Self-Assembly of Insulin

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 12103

Special Issue Editors

Dr. Anoop Arunagiri

E-Mail Website
Guest Editor
Department of Biological Sciences, East Tennessee State University, Johnson City, TN, USA
Interests: protein folding; protein aggregation; amyloid; diabetes; proteinopathies; proteostasis; protein trafficking; ER quality control; disulfide bonds; autophagy
Special Issues, Collections and Topics in MDPI journals
Dr. Alessandra Galli

E-Mail Website
Guest Editor
Laboratory of Molecular and Cellular Physiology, Departmen of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
Interests: molecular mechanisms of insulin release; insulin processing; oxidative stress; mechanobiology of pancreatic β-cells; β-cell dysfunction and diabetes
Dr. Emily Walker

E-Mail Website
Guest Editor
Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, USA
Interests: transcriptional regulation of insulin release; pancreatic β-cell development and maturation; mitochondrial contribution to insulin release; β-cell dysfunction and diabetes

Special Issue Information

Dear Colleagues,

Successful enzymatic processing of the insulin precursor protein proinsulin in pancreatic beta cells results in the production of the insulin hormone, which is packed inside the secretory granules (SGs) mostly as zinc-bound hexamers. Upon external stimuli by secretagogues (for example, glucose), a series of events occur that include a change in beta-cell membrane potential, intracellular calcium levels, and release of insulin from the SGs to the extracellular space following granule membrane fusion. The making and export of insulin is a multistep process, including 1) folding and processing of proinsulin, 2) structural changes to insulin and its packaging in SGs, 3) beta-cell sensitivity to external stimuli, and 4) calcium signaling. Several intrinsic and extrinsic players can affect the efficiency of this process, such as nutrient availability, oxidative stress, organellar crosstalk, etc. This Special Issue will focus on these and other underappreciated factors that may influence insulin biosynthesis and secretion by pancreatic beta cells. The current issue will also concentrate on the structural dynamics and aggregation of insulin in solution and in a physiological context. Insulin is known to self-assemble to form large fibrillar aggregates, which is an obstacle to the preparation of insulin drug formulations. This Special Issue will also discuss 1) what can be done to prevent this problem and 2) how the cells avoid making such aggregates.

Dr. Anoop Arunagiri
Dr. Alessandra Galli
Dr. Emily Walker
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • proinsulin folding and processing
  • insulin biosynthesis
  • beta-cell function
  • metabolism
  • glucose homeostasis
  • insulin secretion
  • insulin structure and aggregation

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Published Papers (3 papers)

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Research

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20 pages, 15790 KiB  
Article
FK506-Binding Protein 2 Participates in Proinsulin Folding
by Carolin Hoefner, Tenna Holgersen Bryde, Celina Pihl, Sylvia Naiga Tiedemann, Sophie Emilie Bresson, Hajira Ahmed Hotiana, Muhammad Saad Khilji, Theodore Dos Santos, Michele Puglia, Paola Pisano, Mariola Majewska, Julia Durzynska, Kristian Klindt, Justyna Klusek, Marcelo J. Perone, Robert Bucki, Per Mårten Hägglund, Pontus Emanuel Gourdon, Kamil Gotfryd, Edyta Urbaniak, Malgorzata Borowiak, Michael Wierer, Patrick Edward MacDonald, Thomas Mandrup-Poulsen and Michal Tomasz Marzecadd Show full author list remove Hide full author list
Biomolecules 2023, 13(1), 152; https://doi.org/10.3390/biom13010152 - 11 Jan 2023
Cited by 3 | Viewed by 3839
Abstract
Apart from chaperoning, disulfide bond formation, and downstream processing, the molecular sequence of proinsulin folding is not completely understood. Proinsulin requires proline isomerization for correct folding. Since FK506-binding protein 2 (FKBP2) is an ER-resident proline isomerase, we hypothesized that FKBP2 contributes to proinsulin [...] Read more.
Apart from chaperoning, disulfide bond formation, and downstream processing, the molecular sequence of proinsulin folding is not completely understood. Proinsulin requires proline isomerization for correct folding. Since FK506-binding protein 2 (FKBP2) is an ER-resident proline isomerase, we hypothesized that FKBP2 contributes to proinsulin folding. We found that FKBP2 co-immunoprecipitated with proinsulin and its chaperone GRP94 and that inhibition of FKBP2 expression increased proinsulin turnover with reduced intracellular proinsulin and insulin levels. This phenotype was accompanied by an increased proinsulin secretion and the formation of proinsulin high-molecular-weight complexes, a sign of proinsulin misfolding. FKBP2 knockout in pancreatic β-cells increased apoptosis without detectable up-regulation of ER stress response genes. Interestingly, FKBP2 mRNA was overexpressed in β-cells from pancreatic islets of T2D patients. Based on molecular modeling and an in vitro enzymatic assay, we suggest that proline at position 28 of the proinsulin B-chain (P28) is the substrate of FKBP2’s isomerization activity. We propose that this isomerization step catalyzed by FKBP2 is an essential sequence required for correct proinsulin folding. Full article
(This article belongs to the Special Issue Biosynthesis, Structure and Self-Assembly of Insulin)
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Review

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38 pages, 8078 KiB  
Review
Understanding Insulin in the Age of Precision Medicine and Big Data: Under-Explored Nature of Genomics
by Taylor W. Cook, Amy M. Wilstermann, Jackson T. Mitchell, Nicholas E. Arnold, Surender Rajasekaran, Caleb P. Bupp and Jeremy W. Prokop
Biomolecules 2023, 13(2), 257; https://doi.org/10.3390/biom13020257 - 30 Jan 2023
Cited by 2 | Viewed by 3590
Abstract
Insulin is amongst the human genome’s most well-studied genes/proteins due to its connection to metabolic health. Within this article, we review literature and data to build a knowledge base of Insulin (INS) genetics that influence transcription, transcript processing, translation, hormone maturation, [...] Read more.
Insulin is amongst the human genome’s most well-studied genes/proteins due to its connection to metabolic health. Within this article, we review literature and data to build a knowledge base of Insulin (INS) genetics that influence transcription, transcript processing, translation, hormone maturation, secretion, receptor binding, and metabolism while highlighting the future needs of insulin research. The INS gene region has 2076 unique variants from population genetics. Several variants are found near the transcriptional start site, enhancers, and following the INS transcripts that might influence the readthrough fusion transcript INS–IGF2. This INS–IGF2 transcript splice site was confirmed within hundreds of pancreatic RNAseq samples, lacks drift based on human genome sequencing, and has possible elevated expression due to viral regulation within the liver. Moreover, a rare, poorly characterized African population-enriched variant of INS–IGF2 results in a loss of the stop codon. INS transcript UTR variants rs689 and rs3842753, associated with type 1 diabetes, are found in many pancreatic RNAseq datasets with an elevation of the 3′UTR alternatively spliced INS transcript. Finally, by combining literature, evolutionary profiling, and structural biology, we map rare missense variants that influence preproinsulin translation, proinsulin processing, dimer/hexamer secretory storage, receptor activation, and C-peptide detection for quasi-insulin blood measurements. Full article
(This article belongs to the Special Issue Biosynthesis, Structure and Self-Assembly of Insulin)
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22 pages, 2087 KiB  
Review
Cholesterol Redistribution in Pancreatic β-Cells: A Flexible Path to Regulate Insulin Secretion
by Alessandra Galli, Anoop Arunagiri, Nevia Dule, Michela Castagna, Paola Marciani and Carla Perego
Biomolecules 2023, 13(2), 224; https://doi.org/10.3390/biom13020224 - 24 Jan 2023
Cited by 4 | Viewed by 3343
Abstract
Pancreatic β-cells, by secreting insulin, play a key role in the control of glucose homeostasis, and their dysfunction is the basis of diabetes development. The metabolic milieu created by high blood glucose and lipids is known to play a role in this process. [...] Read more.
Pancreatic β-cells, by secreting insulin, play a key role in the control of glucose homeostasis, and their dysfunction is the basis of diabetes development. The metabolic milieu created by high blood glucose and lipids is known to play a role in this process. In the last decades, cholesterol has attracted significant attention, not only because it critically controls β-cell function but also because it is the target of lipid-lowering therapies proposed for preventing the cardiovascular complications in diabetes. Despite the remarkable progress, understanding the molecular mechanisms responsible for cholesterol-mediated β-cell function remains an open and attractive area of investigation. Studies indicate that β-cells not only regulate the total cholesterol level but also its redistribution within organelles, a process mediated by vesicular and non-vesicular transport. The aim of this review is to summarize the most current view of how cholesterol homeostasis is maintained in pancreatic β-cells and to provide new insights on the mechanisms by which cholesterol is dynamically distributed among organelles to preserve their functionality. While cholesterol may affect virtually any activity of the β-cell, the intent of this review is to focus on early steps of insulin synthesis and secretion, an area still largely unexplored. Full article
(This article belongs to the Special Issue Biosynthesis, Structure and Self-Assembly of Insulin)
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