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Role of Insulin Clearance in Insulin Action and Metabolic Diseases
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Role of Insulin Clearance in Insulin Action and Metabolic Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 28950

Special Issue Editors

Prof. Dr. Sonia Michael Najjar

E-Mail Website
Guest Editor
1. Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701-2979, USA
2. Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701-2979, USA
Interests: diabetes; hypertension; insulin resistance; metabolism; metabolic diseases; physiology
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Amalia Gastaldelli

grade E-Mail Website
Guest Editor
Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy
Interests: insulin resistance; hepatology; diabetes; hypertension; metabolic syndrome; glucose metabolism; fatty liver; metabolism; nutrition
Special Issues, Collections and Topics in MDPI journals
Dr. Hilda E. Ghadieh

E-Mail Website
Guest Editor
1. Department of Internal Medicine, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
2. AUB Diabetes, American University of Beirut, Beirut, Lebanon
Interests: liver-specific ablation; hepatic insulin resistance; glucose intolerance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Metabolic diseases are reaching an epidemic worldwide. In addition to insulin resistance, altered insulin secretion and clearance contribute to the worsening of glucose tolerance. Upon its secretion from pancreatic beta cells, insulin is metabolized mostly by the liver (the first target organ), and subsequently, by peripheral tissues, in particular skeletal muscle. Thus, peripheral insulin concentrations are the result of a balance between insulin secretion and clearance. The mechanisms underlying insulin secretion have been widely explored. In contrast, mechanisms underlying insulin clearance remain poorly understood. This special issue focuses on presenting a comprehensive view on the regulation of insulin homeostasis with an overarching goal to highlight the current knowledge on the mechanisms as well as the physiologic impact of altered insulin clearance (and secretion) on metabolic processes.

We invite investigators to contribute either original research or review articles focusing on the variety of molecular mechanisms of altered insulin secretion and clearance, and their role in the pathogenesis of cardiometabolic diseases that include, but are not limited to, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD/NASH), atherosclerosis, hypertension in animal models and in subjects with different degrees of glucose intolerance. Articles should also discuss how these mechanisms cause or contribute to the progression to type 2 diabetes and associated metabolic disease, and how they are modulated by race and environmental factors.

You may choose our Joint Special Issue in Biomedicines.

Prof. Dr. Sonia Michael Najjar
Prof. Dr. Amalia Gastaldelli
Dr. Hilda E. Ghadieh
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 secretion
  • Insulin clearance
  • Insulin endocytosis and degradation
  • Insulin signaling and metabolism
  • Mechanisms of altered insulin clearance
  • Hepatic vs. peripheral insulin extraction
  • Insulin uptake in endothelial cells and extrahepatic extraction
  • Racial disparity in insulin clearance
  • Environmental factors and insulin clearance
  • Insulin metabolism and cardiometabolic disease
  • Drugs targeting insulin clearance

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Related Special Issue

Published Papers (7 papers)

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Editorial

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4 pages, 173 KiB  
Editorial
Role of Insulin Clearance in Insulin Action and Metabolic Diseases
by Hilda E. Ghadieh, Amalia Gastaldelli and Sonia M. Najjar
Int. J. Mol. Sci. 2023, 24(8), 7156; https://doi.org/10.3390/ijms24087156 - 12 Apr 2023
Viewed by 1791
Abstract
The year 2021 marked the centenary of the discovery of insulin [...] Full article
(This article belongs to the Special Issue Role of Insulin Clearance in Insulin Action and Metabolic Diseases)

Research

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14 pages, 1761 KiB  
Article
Altered Insulin Clearance after Gastric Bypass and Sleeve Gastrectomy in the Fasting and Prandial Conditions
by Marzieh Salehi, Ralph DeFronzo and Amalia Gastaldelli
Int. J. Mol. Sci. 2022, 23(14), 7667; https://doi.org/10.3390/ijms23147667 - 11 Jul 2022
Cited by 12 | Viewed by 2754
Abstract
Background: The liver has the capacity to regulate glucose metabolism by altering the insulin clearance rate (ICR). The decreased fasting insulin concentrations and enhanced prandial hyperinsulinemia after Roux-en-Y gastric-bypass (GB) surgery and sleeve gastrectomy (SG) are well documented. Here, we investigated the [...] Read more.
Background: The liver has the capacity to regulate glucose metabolism by altering the insulin clearance rate (ICR). The decreased fasting insulin concentrations and enhanced prandial hyperinsulinemia after Roux-en-Y gastric-bypass (GB) surgery and sleeve gastrectomy (SG) are well documented. Here, we investigated the effect of GB or SG on insulin kinetics in the fasting and fed states. Method: ICR was measured (i) during a mixed-meal test (MMT) in obese non-diabetic GB (n = 9) and SG (n = 7) subjects and (ii) during a MMT combined with a hyperinsulinemic hypoglycemic clamp in the same GB and SG subjects. Five BMI-matched and non-diabetic subjects served as age-matched non-operated controls (CN). Results: The enhanced ICR during the fasting state after GB and SC compared with CN (p < 0.05) was mainly attributed to augmented hepatic insulin clearance rather than non-liver organs. The dose-response slope of the total insulin extraction rate (InsExt) of exogenous insulin per circulatory insulin value was greater in the GB and SG subjects than in the CN subjects, despite the similar peripheral insulin sensitivity among the three groups. Compared to the SG or the CN subjects, the GB subjects had greater prandial insulin secretion (ISR), independent of glycemic levels. The larger post-meal ISR following GB compared with SG was associated with a greater InsExt until it reached a plateau, leading to a similar reduction in meal-induced ICR among the GB and SG subjects. Conclusions: GB and SG alter ICR in the presence or absence of meal stimulus. Further, altered ICR after bariatric surgery results from changes in hepatic insulin clearance and not from a change in peripheral insulin sensitivity. Full article
(This article belongs to the Special Issue Role of Insulin Clearance in Insulin Action and Metabolic Diseases)
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17 pages, 3452 KiB  
Article
Nicotinamide Mononucleotide Prevents Free Fatty Acid-Induced Reduction in Glucose Tolerance by Decreasing Insulin Clearance
by Ashraf Nahle, Yemisi Deborah Joseph, Sandra Pereira, Yusaku Mori, Frankie Poon, Hilda E. Ghadieh, Aleksandar Ivovic, Tejas Desai, Simona S. Ghanem, Suman Asalla, Harrison T. Muturi, Emelien M. Jentz, Jamie W. Joseph, Sonia M. Najjar and Adria Giacca
Int. J. Mol. Sci. 2021, 22(24), 13224; https://doi.org/10.3390/ijms222413224 - 8 Dec 2021
Cited by 7 | Viewed by 4941
Abstract
The NAD-dependent deacetylase SIRT1 improves β cell function. Accordingly, nicotinamide mononucleotide (NMN), the product of the rate-limiting step in NAD synthesis, prevents β cell dysfunction and glucose intolerance in mice fed a high-fat diet. The current study was performed to assess the effects [...] Read more.
The NAD-dependent deacetylase SIRT1 improves β cell function. Accordingly, nicotinamide mononucleotide (NMN), the product of the rate-limiting step in NAD synthesis, prevents β cell dysfunction and glucose intolerance in mice fed a high-fat diet. The current study was performed to assess the effects of NMN on β cell dysfunction and glucose intolerance that are caused specifically by increased circulating free fatty acids (FFAs). NMN was intravenously infused, with or without oleate, in C57BL/6J mice over a 48-h-period to elevate intracellular NAD levels and consequently increase SIRT1 activity. Administration of NMN in the context of elevated plasma FFA levels considerably improved glucose tolerance. This was due not only to partial protection from FFA-induced β cell dysfunction but also, unexpectedly, to a significant decrease in insulin clearance. However, in conditions of normal FFA levels, NMN impaired glucose tolerance due to decreased β cell function. The presence of this dual action of NMN suggests caution in its proposed therapeutic use in humans. Full article
(This article belongs to the Special Issue Role of Insulin Clearance in Insulin Action and Metabolic Diseases)
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Review

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10 pages, 2246 KiB  
Review
The Physiology of Insulin Clearance
by Richard N. Bergman, Morvarid Kabir and Marilyn Ader
Int. J. Mol. Sci. 2022, 23(3), 1826; https://doi.org/10.3390/ijms23031826 - 5 Feb 2022
Cited by 14 | Viewed by 4033
Abstract
In the 1950’s, Dr. I. Arthur Mirsky first recognized the possible importance of insulin degradation changes to the pathogenesis of type 2 diabetes. While this mechanism was ignored for decades, insulin degradation is now being recognized as a possible factor in diabetes risk. [...] Read more.
In the 1950’s, Dr. I. Arthur Mirsky first recognized the possible importance of insulin degradation changes to the pathogenesis of type 2 diabetes. While this mechanism was ignored for decades, insulin degradation is now being recognized as a possible factor in diabetes risk. After Mirsky, the relative importance of defects in insulin release and insulin resistance were recognized as risk factors. The hyperbolic relationship between secretion and sensitivity was introduced, as was the relationship between them, as expressed as the disposition index (DI). The DI was shown to be affected by environmental and genetic factors, and it was shown to be differentiated among ethnic groups. However, the importance of differences in insulin degradation (clearance) on the disposition index relationship remains to be clarified. Direct measure of insulin clearance revealed it to be highly variable among even normal individuals, and to be affected by fat feeding and other physiologic factors. Insulin clearance is relatively lower in ethnic groups at high risk for diabetes such as African Americans and Hispanic Americans, compared to European Americans. These differences exist even for young children. Two possible mechanisms have been proposed for the importance of insulin clearance for diabetes risk: in one concept, insulin resistance per se leads to reduced clearance and diabetes risk. In a second and new concept, reduced degradation is a primary factor leading to diabetes risk, such that lower clearance (resulting from genetics or environment) leads to systemic hyperinsulinemia, insulin resistance, and beta-cell stress. Recent data by Chang and colleagues appear to support this latter hypothesis in Native Americans. The importance of insulin clearance as a risk factor for metabolic disease is becoming recognized and may be treatable. Full article
(This article belongs to the Special Issue Role of Insulin Clearance in Insulin Action and Metabolic Diseases)
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18 pages, 1809 KiB  
Review
Insulin Clearance in Obesity and Type 2 Diabetes
by Han-Chow E. Koh, Chao Cao and Bettina Mittendorfer
Int. J. Mol. Sci. 2022, 23(2), 596; https://doi.org/10.3390/ijms23020596 - 6 Jan 2022
Cited by 22 | Viewed by 5658
Abstract
Plasma insulin clearance is an important determinant of plasma insulin concentration. In this review, we provide an overview of the factors that regulate insulin removal from plasma and discuss the interrelationships among plasma insulin clearance, excess adiposity, insulin sensitivity, and type 2 diabetes [...] Read more.
Plasma insulin clearance is an important determinant of plasma insulin concentration. In this review, we provide an overview of the factors that regulate insulin removal from plasma and discuss the interrelationships among plasma insulin clearance, excess adiposity, insulin sensitivity, and type 2 diabetes (T2D). We conclude with the perspective that the commonly observed lower insulin clearance rate in people with obesity, compared with lean people, is not a compensatory response to insulin resistance but occurs because insulin sensitivity and insulin clearance are mechanistically, directly linked. Furthermore, insulin clearance decreases postprandially because of the marked increase in insulin delivery to tissues that clear insulin. The commonly observed high postprandial insulin clearance in people with obesity and T2D likely results from the relatively low insulin secretion rate, not an impaired adaptation of tissues that clear insulin. Full article
(This article belongs to the Special Issue Role of Insulin Clearance in Insulin Action and Metabolic Diseases)
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21 pages, 2071 KiB  
Review
Targeting Insulin-Degrading Enzyme in Insulin Clearance
by Malcolm A. Leissring, Carlos M. González-Casimiro, Beatriz Merino, Caitlin N. Suire and Germán Perdomo
Int. J. Mol. Sci. 2021, 22(5), 2235; https://doi.org/10.3390/ijms22052235 - 24 Feb 2021
Cited by 35 | Viewed by 5353
Abstract
Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50–80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn [...] Read more.
Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50–80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn2+-metalloprotease that degrades insulin and several other intermediate-size peptides. Both, insulin clearance and IDE activity are reduced in diabetic patients, albeit the cause-effect relationship in humans remains unproven. Because historically IDE has been proposed as the main enzyme involved in insulin degradation, efforts in the development of IDE inhibitors as therapeutics in diabetic patients has attracted attention during the last decades. In this review, we retrace the path from Mirsky’s seminal discovery of IDE to the present, highlighting the pros and cons of the development of IDE inhibitors as a pharmacological approach to treating diabetic patients. Full article
(This article belongs to the Special Issue Role of Insulin Clearance in Insulin Action and Metabolic Diseases)
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12 pages, 2303 KiB  
Review
Insulin’s Discovery: New Insights on Its Hundredth Birthday: From Insulin Action and Clearance to Sweet Networks
by Melanie Leroux, Martial Boutchueng-Djidjou and Robert Faure
Int. J. Mol. Sci. 2021, 22(3), 1030; https://doi.org/10.3390/ijms22031030 - 21 Jan 2021
Cited by 2 | Viewed by 2865
Abstract
In 2021, the 100th anniversary of the isolation of insulin and the rescue of a child with type 1 diabetes from death will be marked. In this review, we highlight advances since the ingenious work of the four discoverers, Frederick Grant Banting, John [...] Read more.
In 2021, the 100th anniversary of the isolation of insulin and the rescue of a child with type 1 diabetes from death will be marked. In this review, we highlight advances since the ingenious work of the four discoverers, Frederick Grant Banting, John James Rickard Macleod, James Bertram Collip and Charles Herbert Best. Macleoad closed his Nobel Lecture speech by raising the question of the mechanism of insulin action in the body. This challenge attracted many investigators, and the question remained unanswered until the third part of the 20th century. We summarize what has been learned, from the discovery of cell surface receptors, insulin action, and clearance, to network and precision medicine. Full article
(This article belongs to the Special Issue Role of Insulin Clearance in Insulin Action and Metabolic Diseases)
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