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Metabolites
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Insulin: A Life-Saving Hormone and Key Regulator of Metabolism
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Insulin: A Life-Saving Hormone and Key Regulator of Metabolism

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 24649

Special Issue Editors

Prof. Chiara Dalla Man

E-Mail Website
Guest Editor
Department of Information Engineering, Padova University, 35131 Padova, Italy
Interests: mathematical modeling of physiological systems, in particular metabolic and endocrine systems, and development of technologies to help diabetes management
Prof. Dr. Lia Bally

E-Mail Website
Guest Editor
University Hospital of Bern and University of Bern, Bern, Switzerland
Interests: diabetes; obesity; nutrition; metabolism

Special Issue Information

Dear Colleagues,

The discovery of insulin nearly 100 years ago has saved a countless number of people with type 1 diabetes. Insulin is a peptide hormone that is produced by β-cells of the pancreas. β-Cells secrete insulin in a glucose-responsive manner, but the fine-tuning of the secretory response is further mediated by various factors including other nutrients, hormones, and neuronal inputs. Insulin clearance is an integral component of insulin metabolism as it regulates the cellular response to the hormone by decreasing insulin availability.

Insulin acts on multiple targets via membrane-bound tetrameric receptors with tyrosine kinase activity, thereby triggering various intracellular signal transduction pathways. Insulin is considered the main anabolic hormone of the body and is essential for maintaining glucose homeostasis and regulating carbohydrate, lipid, and protein metabolism. Insulin also has actions beyond the realm of energy metabolism, including actions on steroidogenesis, vascular function, fibrinolysis, and growth.

Dysregulated insulin secretion, clearance, and action are key pathophysiological features of diabetes, obesity, and related metabolic disorders.  For everyone with type 1 diabetes, and many with type 2 diabetes, exogenous insulin is required to control glucose levels. The fundamental aim of insulin therapy is to mimic the pattern of physiological insulin secretion pattern, requiring consideration of the timing and dosing of insulin according to glucose levels, route of insulin delivery, and the pharmacokinetic properties of insulin formulations. For millions of people living with diabetes, insulin is a lifesaving medication, but affordable access to the drug remains a challenge in low- and middle-income countries.

This Special Issue of Metabolites is dedicated to improving our knowledge on insulin physiology, metabolism, and replacement strategies and involves the following topics:

  • Mathematical modeling of insulin physiology in health and disease—secretion, clearance, and action;
  • Insulin release, signaling, and degradation at the molecular level;
  • Insulin targets beyond glucose control—insulin and growth/cancer, insulin and the brain, insulin and inflammation;
  • Novel approaches to reliably quantify endogenous and exogenous insulin concentrations;
  • Towards more physiological insulin delivery patterns—single/multi-hormone artificial pancreas systems, implantable delivery systems;
  • The current and future state of cell-based treatment approaches (transplantation and stem-cell approaches);
  • Next-generation insulin formulations: faster-acting or glucose-responsive insulin, oral insulin;
  • Insulin access and affordability.

We invite submissions related to any of these topics in the form of original research articles or reviews. The manuscripts will undergo the standard peer review process overseen by the Guest Editors. The submission deadline is 31 December 2020.

We look forwarding to receiving your submissions!

Prof. Chiara Dalla Man
Prof. Lia Bally
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. Metabolites 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

  • insulin measurement
  • insulin secretion
  • insulin action
  • insulin signaling
  • insulin clearance
  • transplantation
  • insulin analogues
  • insulin modeling

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Published Papers (7 papers)

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Research

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13 pages, 2312 KiB  
Article
Efficacy and Safety of Insulin Degludec/Insulin Aspart Compared with a Conventional Premixed Insulin or Basal Insulin: A Meta-Analysis
by Shinje Moon, Hye-Soo Chung, Yoon-Jung Kim, Jae-Myung Yu, Woo-Ju Jeong, Jiwon Park and Chang-Myung Oh
Metabolites 2021, 11(9), 639; https://doi.org/10.3390/metabo11090639 - 18 Sep 2021
Cited by 4 | Viewed by 3468
Abstract
Insulin degludec/insulin aspart (IDegAsp) is a novel co-formulation of 70% insulin degludec and 30% insulin aspart. The present meta-analysis was conducted to assess the efficacy and safety of IDegAsp compared with a conventional premixed insulin or basal insulin. We extracted data from citation [...] Read more.
Insulin degludec/insulin aspart (IDegAsp) is a novel co-formulation of 70% insulin degludec and 30% insulin aspart. The present meta-analysis was conducted to assess the efficacy and safety of IDegAsp compared with a conventional premixed insulin or basal insulin. We extracted data from citation databases, including PubMed, EMBASE, and the Cochrane Library, since inception to 2021. We calculated the mean differences for hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), self-measured mean glucose, and postprandial glucose (PPG) and odds ratios for confirmed hypoglycemia events. Compared with twice-daily conventional premixed insulin, twice-daily IDegAsp showed a similar effect on changes in HbA1c, but it significantly reduced FPG and self-measured mean glucose levels. Furthermore, compared to once-daily basal insulin, once-daily IDegAsp had a similar effect on changes in HbA1c, but it significantly reduced self-measured mean glucose and PPG levels. The risk of overall confirmed hypoglycemia was similar between treatments; however, the risk of nocturnal hypoglycemia events was significantly lower with IDegAsp than with conventional premixed insulin and basal insulin. Thus, IDegAsp was more effective than conventional premixed insulin and basal insulin at reducing blood glucose with fewer nocturnal hypoglycemia events. Full article
(This article belongs to the Special Issue Insulin: A Life-Saving Hormone and Key Regulator of Metabolism)
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11 pages, 996 KiB  
Article
Modeling Intraperitoneal Insulin Absorption in Patients with Type 1 Diabetes
by Michele Schiavon, Claudio Cobelli and Chiara Dalla Man
Metabolites 2021, 11(9), 600; https://doi.org/10.3390/metabo11090600 - 3 Sep 2021
Cited by 7 | Viewed by 2804
Abstract
Standard insulin therapy to treat type 1 diabetes (T1D) consists of exogenous insulin administration through the subcutaneous (SC) tissue. Despite recent advances in insulin formulations, the SC route still suffers from delays and large inter/intra-subject variability that limiting optimal glucose control. Intraperitoneal (IP) [...] Read more.
Standard insulin therapy to treat type 1 diabetes (T1D) consists of exogenous insulin administration through the subcutaneous (SC) tissue. Despite recent advances in insulin formulations, the SC route still suffers from delays and large inter/intra-subject variability that limiting optimal glucose control. Intraperitoneal (IP) insulin administration, despite its higher invasiveness, was shown to represent a valid alternative to the SC one. To date, no mathematical model describing the absorption and distribution of insulin after IP administration is available. Here, we aim to fill this gap by using data from eight patients with T1D, treated by implanted IP pump, studied in a hospitalized setting, with frequent measurements of plasma insulin and glucose concentration. A battery of models describing insulin kinetics after IP administration were tested. Model comparison and selection were performed based on model ability to predict the data, precision of parameters and parsimony criteria. The selected model assumed that the insulin absorption from the IP space was described by a linear, two-compartment model, coupled with a two-compartment model of whole-body insulin kinetics with hepatic insulin extraction controlled by hepatic insulin. Future developments include model incorporation into the UVa/Padova T1D Simulator for testing open- and closed-loop therapies with IP insulin administration. Full article
(This article belongs to the Special Issue Insulin: A Life-Saving Hormone and Key Regulator of Metabolism)
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15 pages, 1438 KiB  
Article
Defining the Relative Role of Insulin Clearance in Early Dysglycemia in Relation to Insulin Sensitivity and Insulin Secretion: The Microbiome and Insulin Longitudinal Evaluation Study (MILES)
by Alexis C. Wood, Elizabeth T. Jensen, Alain G. Bertoni, Gautam Ramesh, Stephen S. Rich, Jerome I. Rotter, Yii-Der I. Chen and Mark O. Goodarzi
Metabolites 2021, 11(7), 420; https://doi.org/10.3390/metabo11070420 - 26 Jun 2021
Cited by 7 | Viewed by 2473
Abstract
Insulin resistance and insufficient insulin secretion are well-recognized contributors to type 2 diabetes. A potential role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining decreased insulin sensitivity and secretion. The goal [...] Read more.
Insulin resistance and insufficient insulin secretion are well-recognized contributors to type 2 diabetes. A potential role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining decreased insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in a cohort of 353 non-Hispanic White and African American individuals recruited in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Participants underwent oral glucose tolerance tests from which insulin sensitivity, insulin secretion, insulin clearance, and disposition index were calculated. Regression models examined the individual and joint contributions of these traits to early dysglycemia (prediabetes or newly diagnosed diabetes). In separate models, reduced insulin sensitivity, reduced disposition index, and reduced insulin clearance were associated with dysglycemia. In a joint model, only insulin resistance and reduced insulin secretion were associated with dysglycemia. Models with insulin sensitivity, disposition index, or three insulin traits had the highest discriminative value for dysglycemia (area under the receiver operating characteristics curve of 0.82 to 0.89). These results suggest that in the race groups studied, insulin resistance and compromised insulin secretion are the main independent underlying defects leading to early dysglycemia. Full article
(This article belongs to the Special Issue Insulin: A Life-Saving Hormone and Key Regulator of Metabolism)
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13 pages, 3422 KiB  
Article
Facilitated Qualitative Determination of Insulin, Its Synthetic Analogs, and C-Peptide in Human Urine by Means of LC–HRMS
by Andreas Thomas, Lukas Benzenberg, Lia Bally and Mario Thevis
Metabolites 2021, 11(5), 309; https://doi.org/10.3390/metabo11050309 - 12 May 2021
Cited by 13 | Viewed by 3990
Abstract
The increasing importance to determine bioactive peptide hormones such as insulin, its synthetic analogs, and C-peptide in urine samples represents an analytical challenge. The physiological concentrations of insulin in urine are commonly found at sub-ng/mL levels and thus represent a complex analytical task. [...] Read more.
The increasing importance to determine bioactive peptide hormones such as insulin, its synthetic analogs, and C-peptide in urine samples represents an analytical challenge. The physiological concentrations of insulin in urine are commonly found at sub-ng/mL levels and thus represent a complex analytical task. C-peptide concentrations, on the other hand, tend to be in the moderate ng/mL range and are hence much easier to determine. Insulin and C-peptide are important in the diagnostics and management of metabolic disorders such as diabetes mellitus and are also particularly relevant target analytes in professional sports and forensics. All insulins are classified on the World Anti-Doping Agency’s (WADA) list of prohibited substances and methods in sports with a minimum required performance level (MRPL) of 50 pg/mL. Until now, methods combining immunoextraction and subsequent mass spectrometric detection have mostly been used for this purpose. With the method developed here, sample preparation has been simplified considerably and does not require an antibody-based sample purification. This was achieved by a sophisticated mixed-mode solid-phase extraction and subsequent separation with liquid chromatography coupled to high-resolution mass spectrometry. Included target insulins were human, lispro, glulisine, aspart, glargine metabolite, degludec, and additionally, human C-peptide. The method was validated for the synthetic insulin analogs considering WADA requirements including specificity, limit of detection (10–25 pg/mL), limit of identification, recovery (25–100%), robustness, carry over (<2%), and matrix effects. All sample preparation steps were controlled by two stable isotope-labeled internal standards, namely, [[2H10] LeuB6, B11, B15, B17]-insulin and [[13C6] Leu26, 30] C-peptide. Finally, the method was applied to samples from patients with diabetes mellitus treated with synthetic insulins. Full article
(This article belongs to the Special Issue Insulin: A Life-Saving Hormone and Key Regulator of Metabolism)
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17 pages, 1816 KiB  
Article
Modeling Between-Subject Variability in Subcutaneous Absorption of a Fast-Acting Insulin Analogue by a Nonlinear Mixed Effects Approach
by Edoardo Faggionato, Michele Schiavon and Chiara Dalla Man
Metabolites 2021, 11(4), 235; https://doi.org/10.3390/metabo11040235 - 12 Apr 2021
Cited by 8 | Viewed by 3212
Abstract
Despite the great progress made in insulin preparation and titration, many patients with diabetes are still experiencing dangerous fluctuations in their blood glucose levels. This is mainly due to the large between- and within-subject variability, which considerably hampers insulin therapy, leading to defective [...] Read more.
Despite the great progress made in insulin preparation and titration, many patients with diabetes are still experiencing dangerous fluctuations in their blood glucose levels. This is mainly due to the large between- and within-subject variability, which considerably hampers insulin therapy, leading to defective dosing and timing of the administration process. In this work, we present a nonlinear mixed effects model describing the between-subject variability observed in the subcutaneous absorption of fast-acting insulin. A set of 14 different models was identified on a large and frequently-sampled database of lispro pharmacokinetic data, collected from 116 subjects with type 1 diabetes. The tested models were compared, and the best one was selected on the basis of the ability to fit the data, the precision of the estimated parameters, and parsimony criteria. The selected model was able to accurately describe the typical trend of plasma insulin kinetics, as well as the between-subject variability present in the absorption process, which was found to be related to the subject’s body mass index. The model provided a deeper understanding of the insulin absorption process and can be incorporated into simulation platforms to test and develop new open- and closed-loop treatment strategies, allowing a step forward toward personalized insulin therapy. Full article
(This article belongs to the Special Issue Insulin: A Life-Saving Hormone and Key Regulator of Metabolism)
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Review

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13 pages, 779 KiB  
Review
Measurement of Pulsatile Insulin Secretion: Rationale and Methodology
by Marcello C. Laurenti, Aleksey Matveyenko and Adrian Vella
Metabolites 2021, 11(7), 409; https://doi.org/10.3390/metabo11070409 - 22 Jun 2021
Cited by 13 | Viewed by 3271
Abstract
Pancreatic β-cells are responsible for the synthesis and exocytosis of insulin in response to an increase in circulating glucose. Insulin secretion occurs in a pulsatile manner, with oscillatory pulses superimposed on a basal secretion rate. Insulin pulses are a marker of β-cell health, [...] Read more.
Pancreatic β-cells are responsible for the synthesis and exocytosis of insulin in response to an increase in circulating glucose. Insulin secretion occurs in a pulsatile manner, with oscillatory pulses superimposed on a basal secretion rate. Insulin pulses are a marker of β-cell health, and secretory parameters, such as pulse amplitude, time interval and frequency distribution, are impaired in obesity, aging and type 2 diabetes. In this review, we detail the mechanisms of insulin production and β-cell synchronization that regulate pulsatile insulin secretion, and we discuss the challenges to consider when measuring fast oscillatory secretion in vivo. These include the anatomical difficulties of measuring portal vein insulin noninvasively in humans before the hormone is extracted by the liver and quickly removed from the circulation. Peripheral concentrations of insulin or C-peptide, a peptide cosecreted with insulin, can be used to estimate their secretion profile, but mathematical deconvolution is required. Parametric and nonparametric approaches to the deconvolution problem are evaluated, alongside the assumptions and trade-offs required for their application in the quantification of unknown insulin secretory rates from known peripheral concentrations. Finally, we discuss the therapeutical implication of targeting impaired pulsatile secretion and its diagnostic value as an early indicator of β-cell stress. Full article
(This article belongs to the Special Issue Insulin: A Life-Saving Hormone and Key Regulator of Metabolism)
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12 pages, 9149 KiB  
Review
The Plasticity of Pancreatic β-Cells
by Norikiyo Honzawa and Kei Fujimoto
Metabolites 2021, 11(4), 218; https://doi.org/10.3390/metabo11040218 - 2 Apr 2021
Cited by 18 | Viewed by 3139
Abstract
Type 2 diabetes is caused by impaired insulin secretion and/or insulin resistance. Loss of pancreatic β-cell mass detected in human diabetic patients has been considered to be a major cause of impaired insulin secretion. Additionally, apoptosis is found in pancreatic β-cells; β-cell mass [...] Read more.
Type 2 diabetes is caused by impaired insulin secretion and/or insulin resistance. Loss of pancreatic β-cell mass detected in human diabetic patients has been considered to be a major cause of impaired insulin secretion. Additionally, apoptosis is found in pancreatic β-cells; β-cell mass loss is induced when cell death exceeds proliferation. Recently, however, β-cell dedifferentiation to pancreatic endocrine progenitor cells and β-cell transdifferentiation to α-cell was reported in human islets, which led to a new underlying molecular mechanism. Hyperglycemia inhibits nuclear translocation and expression of forkhead box-O1 (FoxO1) and induces the expression of neurogenin-3 (Ngn3), which is required for the development and maintenance of pancreatic endocrine progenitor cells. This new hypothesis (Foxology) is attracting attention because it explains molecular mechanism(s) underlying β-cell plasticity. The lineage tracing technique revealed that the contribution of dedifferentiation is higher than that of β-cell apoptosis retaining to β-cell mass loss. In addition, islet cells transdifferentiate each other, such as transdifferentiation of pancreatic β-cell to α-cell and vice versa. Islet cells can exhibit plasticity, and they may have the ability to redifferentiate into any cell type. This review describes recent findings in the dedifferentiation and transdifferentiation of β-cells. We outline novel treatment(s) for diabetes targeting islet cell plasticity. Full article
(This article belongs to the Special Issue Insulin: A Life-Saving Hormone and Key Regulator of Metabolism)
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