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Biomedicines
Special Issues
Role of Insulin Metabolism in Insulin Action and Metabolic Diseases
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Role of Insulin Metabolism in Insulin Action and Metabolic Diseases

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Endocrinology and Metabolism Research".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 15465

Special Issue Editors

Prof. Dr. Sonia Michael Najjar

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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

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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 International Journal of Molecular Sciences.

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. Biomedicines 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 2600 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 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 (5 papers)

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Research

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13 pages, 2634 KiB  
Article
Reno-Protective Effect of GLP-1 Receptor Agonists in Type1 Diabetes: Dual Action on TRPC6 and NADPH Oxidases
by Natalie Youssef, Mohamed Noureldein, Rachel Njeim, Hilda E. Ghadieh, Frederic Harb, Sami T. Azar, Nassim Fares and Assaad A. Eid
Biomedicines 2021, 9(10), 1360; https://doi.org/10.3390/biomedicines9101360 - 30 Sep 2021
Cited by 16 | Viewed by 2999
Abstract
Diabetic kidney disease (DKD), a serious diabetic complication, results in podocyte loss and proteinuria through NADPH oxidases (NOX)-mediated ROS production. DUOX1 and 2 are NOX enzymes that require calcium for their activation which enters renal cells through the pivotal TRPC channels. Hypoglycemic drugs [...] Read more.
Diabetic kidney disease (DKD), a serious diabetic complication, results in podocyte loss and proteinuria through NADPH oxidases (NOX)-mediated ROS production. DUOX1 and 2 are NOX enzymes that require calcium for their activation which enters renal cells through the pivotal TRPC channels. Hypoglycemic drugs such as liraglutide can interfere with this deleterious mechanism imparting reno-protection. Herein, we aim to investigate the reno-protective effect of GLP1 receptor agonist (GLP1-RA), via its effect on TRPC6 and NADPH oxidases. To achieve our aim, control or STZ-induced T1DM Sprague–Dawley rats were used. Rats were treated with liraglutide, metformin, or their combination. Functional, histological, and molecular parameters of the kidneys were assessed. Our results show that treatment with liraglutide, metformin or their combination ameliorates DKD by rectifying renal function tests and protecting against fibrosis paralleled by restored mRNA levels of nephrin, DUOX1 and 2, and reduced ROS production. Treatment with liraglutide reduces TRPC6 expression, while metformin treatment shows no effect. Furthermore, TRPC6 was found to be directly interacting with nephrin, and indirectly interacting with DUOX1, DUOX2 and GLP1-R. Our findings suggest that treatment with liraglutide may prevent the progression of diabetic nephropathy by modulating the crosstalk between TRPC6 and NADPH oxidases. Full article
(This article belongs to the Special Issue Role of Insulin Metabolism in Insulin Action and Metabolic Diseases)
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13 pages, 1005 KiB  
Article
Short-Term SGLT2 Inhibitor Administration Does Not Alter Systemic Insulin Clearance in Type 2 Diabetes
by Motonori Sato, Yoshifumi Tamura, Hideyoshi Kaga, Nozomu Yamasaki, Mai Kiya, Satoshi Kadowaki, Daisuke Sugimoto, Takashi Funayama, Yuki Someya, Saori Kakehi, Shuko Nojiri, Hiroaki Satoh, Ryuzo Kawamori and Hirotaka Watada
Biomedicines 2021, 9(9), 1154; https://doi.org/10.3390/biomedicines9091154 - 3 Sep 2021
Cited by 3 | Viewed by 2702
Abstract
Background: Decreased insulin clearance could be a relatively upstream abnormality in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Previous studies have shown that sodium-glucose cotransporter 2 inhibitor (SGLT2i) increases insulin–C-peptide ratio, a marker of insulin clearance, and improves metabolic parameters. We evaluated [...] Read more.
Background: Decreased insulin clearance could be a relatively upstream abnormality in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Previous studies have shown that sodium-glucose cotransporter 2 inhibitor (SGLT2i) increases insulin–C-peptide ratio, a marker of insulin clearance, and improves metabolic parameters. We evaluated the effects of the SGLT2i tofogliflozin on metabolic clearance rate of insulin (MCRI) with a hyperinsulinemic euglycemic clamp study, the gold standard for measuring systemic insulin clearance. Methods: Study participants were 12 Japanese men with type 2 diabetes. We evaluated MCRI and tissue-specific insulin sensitivity with a hyperinsulinemic euglycemic clamp (insulin infusion rate, 40 mU/m2·min) before and immediately after a single dose (n = 12) and 8 weeks (n = 9) of tofogliflozin. We also measured ectopic fat in muscle and liver and the abdominal fat area using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively, before and after 8 weeks of tofogliflozin. Results: MCRI did not change after a single dose of tofogliflozin (594.7 ± 67.7 mL/min·m2 and 608.3 ± 90.9 mL/min·m2, p = 0.61) or after 8 weeks (582.5 ± 67.3 mL/min·m2 and 602.3 ± 67.0 mL/min·m2, p = 0.41). The 8-week treatment significantly improved glycated hemoglobin and decreased body weight (1.7%) and the subcutaneous fat area (6.4%), whereas insulin sensitivity and ectopic fat in muscle and liver did not change significantly. Conclusions: MCRI did not change after a single dose or 8 weeks of tofogliflozin. Increased MCRI does not precede a decrease in body fat or improved glycemic control. Full article
(This article belongs to the Special Issue Role of Insulin Metabolism in Insulin Action and Metabolic Diseases)
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12 pages, 2083 KiB  
Article
Hepatic and Extrahepatic Insulin Clearance in Mice with Double Deletion of Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide Receptors
by Micaela Morettini, Agnese Piersanti, Laura Burattini, Giovanni Pacini, Christian Göbl, Bo Ahrén and Andrea Tura
Biomedicines 2021, 9(8), 973; https://doi.org/10.3390/biomedicines9080973 - 6 Aug 2021
Cited by 1 | Viewed by 2134
Abstract
The aim of this study was to investigate whether incretins, at physiological levels, affect hepatic and/or extrahepatic insulin clearance. Hepatic and extrahepatic insulin clearance was studied in 31 double incretin receptor knockout (DIRKO) and 45 wild-type (WT) mice, which underwent an Intravenous Glucose [...] Read more.
The aim of this study was to investigate whether incretins, at physiological levels, affect hepatic and/or extrahepatic insulin clearance. Hepatic and extrahepatic insulin clearance was studied in 31 double incretin receptor knockout (DIRKO) and 45 wild-type (WT) mice, which underwent an Intravenous Glucose Tolerance Test (IVGTT). A novel methodology based on mathematical modeling was designed to provide two sets of values (FEL-P1, CLP-P1; FEL-P2, CLP-P2) accounting for hepatic and extrahepatic clearance in the IVGTT first and second phases, respectively, plus the respective total clearances, CLT-P1 and CLT-P2. A statistically significant difference between DIRKO and WT was found in CLT-P1 (0.61 [0.48–0.82] vs. 0.51 [0.46–0.65] (median [interquartile range]); p = 0.02), which was reflected in the peripheral component, CLP-P1 (0.18 [0.13–0.27] vs. 0.15 [0.11–0.22]; p = 0.04), but not in the hepatic component, FEL-P1 (29.7 [26.7–34.9] vs. 28.9 [25.7–32.0]; p = 0.18). No difference was detected between DIRKO and WT in CLT-P2 (1.38 [1.13–1.75] vs. 1.69 [1.48–1.87]; p = 0.10), neither in CLP-P2 (0.72 [0.64–0.81] vs. 0.79 [0.69–0.87]; p = 0.27) nor in FEL-P2 (37.8 [35.1–43.1] vs. 39.8 [35.8–44.2]; p = 0.46). In conclusion, our findings suggest that the higher insulin clearance observed in DIRKO compared with WT during the IVGTT first phase may be due to its extrahepatic component. Full article
(This article belongs to the Special Issue Role of Insulin Metabolism in Insulin Action and Metabolic Diseases)
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7 pages, 2535 KiB  
Article
The Insulin Receptor Mediates Insulin’s Early Plasma Clearance by Liver, Muscle, and Kidney
by Rick I. Meijer and Eugene J. Barrett
Biomedicines 2021, 9(1), 37; https://doi.org/10.3390/biomedicines9010037 - 5 Jan 2021
Cited by 11 | Viewed by 2806
Abstract
The role of the insulin receptor in mediating tissue-specific insulin clearance in vivo has not been reported. Using physiologic insulin doses, we measured the initial clearance rate (first 5 min) of intravenously injected ([125I]TyrA14)-insulin by muscle, liver, and kidney [...] Read more.
The role of the insulin receptor in mediating tissue-specific insulin clearance in vivo has not been reported. Using physiologic insulin doses, we measured the initial clearance rate (first 5 min) of intravenously injected ([125I]TyrA14)-insulin by muscle, liver, and kidney in healthy rats in the presence and absence of the insulin receptor blocker S961. We also tested whether 4 weeks of high-fat diet (HFD) affected the initial rate of insulin clearance. Pre-treatment with S961 for 60 min prior to administering labeled insulin raised plasma ([125I]TyrA14)insulin concentration approximately 5-fold (p < 0.001), demonstrating receptor dependency for plasma insulin clearance. Uptake by muscle (p < 0.01), liver (p < 0.05), and kidney (p < 0.001) were each inhibited by receptor blockade, undoubtedly contributing to the reduced plasma clearance. The initial plasma insulin clearance was not significantly affected by HFD, nor was muscle-specific clearance. However, HFD modestly decreased liver clearance (p = 0.056) while increasing renal clearance by >50% (p < 0.01), suggesting a significant role for renal insulin clearance in limiting the hyperinsulinemia that accompanies HFD. We conclude that the insulin receptor is a major mediator of initial insulin clearance from plasma and for its clearance by liver, kidney, and muscle. HFD feeding increases renal insulin clearance to limit systemic hyperinsulinemia. Full article
(This article belongs to the Special Issue Role of Insulin Metabolism in Insulin Action and Metabolic Diseases)
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Review

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14 pages, 1698 KiB  
Review
Regulation of Insulin Clearance by Non-Esterified Fatty Acids
by Sonia M. Najjar, Raziyeh Abdolahipour, Hilda E. Ghadieh, Marziyeh Salehi Jahromi, John A. Najjar, Basil A. M. Abuamreh, Sobia Zaidi, Sivarajan Kumarasamy and Harrison T. Muturi
Biomedicines 2022, 10(8), 1899; https://doi.org/10.3390/biomedicines10081899 - 5 Aug 2022
Cited by 9 | Viewed by 3322
Abstract
Insulin stores lipid in adipocytes and prevents lipolysis and the release of non-esterified fatty acids (NEFA). Excessive release of NEFA during sustained energy supply and increase in abdominal adiposity trigger systemic insulin resistance, including in the liver, a major site of insulin clearance. [...] Read more.
Insulin stores lipid in adipocytes and prevents lipolysis and the release of non-esterified fatty acids (NEFA). Excessive release of NEFA during sustained energy supply and increase in abdominal adiposity trigger systemic insulin resistance, including in the liver, a major site of insulin clearance. This causes a reduction in insulin clearance as a compensatory mechanism to insulin resistance in obesity. On the other hand, reduced insulin clearance in the liver can cause chronic hyperinsulinemia, followed by downregulation of insulin receptor and insulin resistance. Delineating the cause–effect relationship between reduced insulin clearance and insulin resistance has been complicated by the fact that insulin action and clearance are mechanistically linked to insulin binding to its receptors. This review discusses how NEFA mobilization contributes to the reciprocal relationship between insulin resistance and reduced hepatic insulin clearance, and how this may be implicated in the pathogenesis of non-alcoholic fatty liver disease. Full article
(This article belongs to the Special Issue Role of Insulin Metabolism in Insulin Action and Metabolic Diseases)
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