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Gut Hormone: From Molecular Mechanism to Clinical Aspects 2021

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

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 62203

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Special Issue Editor

Prof. Dr. Bunzo Matsuura

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Department of Lifestyle-Related Medicine and Endocrinology, Graduate School of Medicine, Ehime University, Shitsukawa 454, Toon, Ehime 791-0295, Japan
Interests: gut hormone; thyroid disease; obesity; diabetes mellitus; nonalcoholic fatty liver disease
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Special Issue Information

Dear Colleagues,

Gut hormones are closely related to lifestyle and lifestyle-related disorders. Gut hormones affect appetite, gastrointestinal motility, digestion, absorption and metabolism, and hence abnormalities of gut hormones cause malnutrition, metabolic syndrome and GI disorders. Gastrin and insulin have cell proliferation activity, and therefore abnormality of these hormones or hormone receptors affects development or progression of several cancers, for example pancreatic cancer and colorectal cancer.

Understanding of the molecular basis of hormone binding and activation of receptors provides important insights into the active conformation of such receptors, providing critical information helpful for the design and refinement of receptor-active drugs. The family of guanine nucleotide-binding protein (G protein)-coupled receptors that includes receptors for many gut hormones are demonstrated as clinically useful pharmacological targets.

This topic was covered in 2019 and was very well received. This time, we decided to cover it again.

Papers related to any aspects of biochemistry, molecular biology, pharmacology, physiology, and pathology will be considered for this Special Issue. The pure clinical reports may not be accepted.

Prof. Dr. Bunzo Matsuura
Guest Editor

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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.

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Keywords

Appetite
Motility
Digestion
Absorption
Metabolism
Microbiome
Immunity
Cell proliferation
Neuroendocrine tumor (NET)
Functional dyspepsia
Irritable bowel syndrome

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Published Papers (11 papers)

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Research

Jump to: Review, Other

13 pages, 4628 KiB

Open AccessArticle

Evidence of a Gastro-Duodenal Effect on Adipose Tissue and Brain Metabolism, Potentially Mediated by Gut–Liver Inflammation: A Study with Positron Emission Tomography and Oral ¹⁸FDG in Mice

by Maria Angela Guzzardi, Federica La Rosa, Daniela Campani, Andrea Cacciato Insilla, Monica Nannipieri, Maurizia Rossana Brunetto, Ferruccio Bonino and Patricia Iozzo

Int. J. Mol. Sci. 2022, 23(5), 2659; https://doi.org/10.3390/ijms23052659 - 28 Feb 2022

Cited by 3 | Viewed by 2245

Abstract

Interventions affecting gastrointestinal (GI) physiology suggest that the GI tract plays an important role in modulating the uptake of ingested glucose by body tissues. We aimed at validating the use of positron emission tomography (PET) with oral ¹⁸FDG administration in mice, and to examine GI effects on glucose metabolism in adipose tissues, brain, heart, muscle, and liver, and interfering actions of oral lipid co-administration. We performed sequential whole-body PET studies in 3 groups of 10 mice, receiving i.p. glucose and ¹⁸FDG or oral glucose and ¹⁸FDG ± lipids, to measure tissue glucose uptake (GU) and GI transit, and compute the absorption lumped constant (LCa) as ratio of oral ¹⁸FDG-to-glucose incremental blood levels. GI and liver histology and circulating hormones were tested to generate explanatory hypothesis. Median LCa was 1.18, constant over time and not significantly affected by lipid co-ingestion. Compared to the i.p. route, the oral route (GI effect) resulted in lower GU rates in adipose tissues and brain, and a greater steatohepatitis score (+17%, p = 0.03). Lipid co-administration accelerated GI transit, in relation to the suppression in GIP, GLP1, glucagon, PP, and PYY (GI motility regulators), abolishing GI effects on subcutaneous fat GU. Duodenal crypt size, gastric wall ¹⁸FDG uptake, and macro-vesicular steatosis were inversely related to adipose tissue GU, and positively associated with liver GU. We conclude that ¹⁸FDG-PET is a suitable tool to examine the role of the GI tract on glucose transit, absorption, and bio-distribution. The GI effect consists in the suppression of glucose metabolism selectively in organs responsible for energy intake and storage, and is blunted by lipid ingestion. Modulation of gut and liver inflammation, as reflected by high GU, may be involved in the acute signalling of the energy status. Full article

(This article belongs to the Special Issue Gut Hormone: From Molecular Mechanism to Clinical Aspects 2021)

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12 pages, 1740 KiB

Open AccessArticle

Lecithin Inclusion by α-Cyclodextrin Activates SREBP2 Signaling in the Gut and Ameliorates Postprandial Hyperglycemia

by Eunyoung Lee, Xilin Zhang, Tomoe Noda, Junki Miyamoto, Ikuo Kimura, Tomoaki Tanaka, Kenichi Sakurai, Ryo Hatano and Takashi Miki

Int. J. Mol. Sci. 2021, 22(19), 10796; https://doi.org/10.3390/ijms221910796 - 6 Oct 2021

Cited by 3 | Viewed by 2738

Abstract

Background: α-cyclodextrin (α-CD) is one of the dietary fibers that may have a beneficial effect on cholesterol and/or glucose metabolism, but its efficacy and mode of action remain unclear. Methods: In the present study, we examined the anti-hyperglycemic effect of α-CD after oral loading of glucose and liquid meal in mice. Results: Administration of 2 g/kg α-CD suppressed hyperglycemia after glucose loading, which was associated with increased glucagon-like peptide 1 (GLP-1) secretion and enhanced hepatic glucose sequestration. By contrast, 1 g/kg α-CD similarly suppressed hyperglycemia, but without increasing secretions of GLP-1 and insulin. Furthermore, oral α-CD administration disrupts lipid micelle formation through its inclusion of lecithin in the gut luminal fluid. Importantly, prior inclusion of α-CD with lecithin in vitro nullified the anti-hyperglycemic effect of α-CD in vivo, which was associated with increased intestinal mRNA expressions of SREBP2-target genes (Ldlr, Hmgcr, Pcsk9, and Srebp2). Conclusions: α-CD elicits its anti-hyperglycemic effect after glucose loading by inducing lecithin inclusion in the gut lumen and activating SREBP2, which is known to induce cholecystokinin secretion to suppress hepatic glucose production via a gut/brain/liver axis. Full article

(This article belongs to the Special Issue Gut Hormone: From Molecular Mechanism to Clinical Aspects 2021)

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Review

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14 pages, 689 KiB

Open AccessReview

Substance P, A Promising Therapeutic Target in Musculoskeletal Disorders

by Kyung Rae Ko, Hyunil Lee, Soo-Hong Han, Wooyeol Ahn, Do Kyung Kim, Il-Su Kim, Bo Sung Jung and Soonchul Lee

Int. J. Mol. Sci. 2022, 23(5), 2583; https://doi.org/10.3390/ijms23052583 - 26 Feb 2022

Cited by 7 | Viewed by 3539

Abstract

A large number of studies have focused on the role of substance P (SP) and the neurokinin-1 receptor (NK1R) in the pathogenesis of a variety of medical conditions. This review provides an overview of the role of the SP-NK1R pathway in the pathogenesis of musculoskeletal disorders and the evidence for its role as a therapeutic target for these disorders, which are major public health problems in most countries. To summarize, the brief involvement of SP may affect tendon healing in an acute injury setting. SP combined with an adequate conjugate can be a regenerative therapeutic option in osteoarthritis. The NK1R antagonist is a promising agent for tendinopathy, rheumatoid arthritis, and osteoarthritis. Research on the SP-NK1R pathway will be helpful for developing novel drugs for osteoporosis. Full article

(This article belongs to the Special Issue Gut Hormone: From Molecular Mechanism to Clinical Aspects 2021)

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31 pages, 511 KiB

Open AccessReview

The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions

by Magdalena Sustkova-Fiserova, Chrysostomos Charalambous, Anna Khryakova, Alina Certilina, Marek Lapka and Romana Šlamberová

Int. J. Mol. Sci. 2022, 23(2), 761; https://doi.org/10.3390/ijms23020761 - 11 Jan 2022

Cited by 9 | Viewed by 3023

Abstract

Drug addiction causes constant serious health, social, and economic burden within the human society. The current drug dependence pharmacotherapies, particularly relapse prevention, remain limited, unsatisfactory, unreliable for opioids and tobacco, and even symptomatic for stimulants and cannabinoids, thus, new more effective treatment strategies are researched. The antagonism of the growth hormone secretagogue receptor type A (GHS-R1A) has been recently proposed as a novel alcohol addiction treatment strategy, and it has been intensively studied in experimental models of other addictive drugs, such as nicotine, stimulants, opioids and cannabinoids. The role of ghrelin signaling in these drugs effects has also been investigated. The present review aims to provide a comprehensive overview of preclinical and clinical studies focused on ghrelin’s/GHS-R1A possible involvement in these nonalcohol addictive drugs reinforcing effects and addiction. Although the investigation is still in its early stage, majority of the existing reviewed experimental results from rodents with the addition of few human studies, that searched correlations between the genetic variations of the ghrelin signaling or the ghrelin blood content with the addictive drugs effects, have indicated the importance of the ghrelin’s/GHS-R1As involvement in the nonalcohol abused drugs pro-addictive effects. Further research is necessary to elucidate the exact involved mechanisms and to verify the future potential utilization and safety of the GHS-R1A antagonism use for these drug addiction therapies, particularly for reducing the risk of relapse. Full article

(This article belongs to the Special Issue Gut Hormone: From Molecular Mechanism to Clinical Aspects 2021)

31 pages, 4970 KiB

Open AccessReview

GLP-1a: Going beyond Traditional Use

by Lucas Fornari Laurindo, Sandra Maria Barbalho, Elen Landgraf Guiguer, Maricelma da Silva Soares de Souza, Gabriela Achete de Souza, Thiago Marques Fidalgo, Adriano Cressoni Araújo, Heron F. de Souza Gonzaga, Daniel de Bortoli Teixeira, Thais de Oliveira Silva Ullmann, Katia Portero Sloan and Lance Alan Sloan

Int. J. Mol. Sci. 2022, 23(2), 739; https://doi.org/10.3390/ijms23020739 - 10 Jan 2022

Cited by 51 | Viewed by 16808

Abstract

Glucagon-like peptide-1 (GLP-1) is a human incretin hormone derived from the proglucagon molecule. GLP-1 receptor agonists are frequently used to treat type 2 diabetes mellitus and obesity. However, the hormone affects the liver, pancreas, brain, fat cells, heart, and gastrointestinal tract. The objective of this study was to perform a systematic review on the use of GLP-1 other than in treating diabetes. PubMed, Cochrane, and Embase were searched, and the PRISMA guidelines were followed. Nineteen clinical studies were selected. The results showed that GLP-1 agonists can benefit defined off-medication motor scores in Parkinson’s Disease and improve emotional well-being. In Alzheimer’s disease, GLP-1 analogs can improve the brain’s glucose metabolism by improving glucose transport across the blood–brain barrier. In depression, the analogs can improve quality of life and depression scales. GLP-1 analogs can also have a role in treating chemical dependency, inhibiting dopaminergic release in the brain’s reward centers, decreasing withdrawal effects and relapses. These medications can also improve lipotoxicity by reducing visceral adiposity and decreasing liver fat deposition, reducing insulin resistance and the development of non-alcoholic fatty liver diseases. The adverse effects are primarily gastrointestinal. Therefore, GLP-1 analogs can benefit other conditions besides traditional diabetes and obesity uses. Full article

(This article belongs to the Special Issue Gut Hormone: From Molecular Mechanism to Clinical Aspects 2021)

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36 pages, 1701 KiB

Open AccessReview

The Role of the Gastric Hormones Ghrelin and Nesfatin-1 in Reproduction

by Martha A. Schalla and Andreas Stengel

Int. J. Mol. Sci. 2021, 22(20), 11059; https://doi.org/10.3390/ijms222011059 - 14 Oct 2021

Cited by 20 | Viewed by 5074

Abstract

Ghrelin and nesfatin-1 are enteroendocrine peptide hormones expressed in rat X/A-like and human P/D1cells of the gastric mucosa. Besides their effect on food intake, both peptides are also implicated in various other physiological systems. One of these is the reproductive system. This present review illustrates the distribution of ghrelin and nesfatin-1 along the hypothalamus–pituitary–gonadal (HPG) axis, their modulation by reproductive hormones, and effects on reproductive functions as well as highlighting gaps in current knowledge to foster further research. Full article

(This article belongs to the Special Issue Gut Hormone: From Molecular Mechanism to Clinical Aspects 2021)

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14 pages, 942 KiB

Open AccessReview

New Fast Acting Glucagon for Recovery from Hypoglycemia, a Life-Threatening Situation: Nasal Powder and Injected Stable Solutions

by Lucia La Sala and Antonio E. Pontiroli

Int. J. Mol. Sci. 2021, 22(19), 10643; https://doi.org/10.3390/ijms221910643 - 30 Sep 2021

Cited by 17 | Viewed by 6306 | Correction

Abstract

The goal of diabetes care is to achieve and maintain good glycemic control over time, so as to prevent or delay the development of micro- and macrovascular complications in type 1 (T1D) and type 2 diabetes (T2D). However, numerous barriers hinder the achievement of this goal, first of all the frequent episodes of hypoglycemia typical in patients treated with insulin as T1D patients, or sulphonylureas as T2D patients. The prevention strategy and treatment of hypoglycemia are important for the well-being of patients with diabetes. Hypoglycemia is strongly associated with an increased risk of cardiovascular disease in diabetic patients, due probably to the release of inflammatory markers and prothrombotic effects triggered by hypoglycemia. Treatment of hypoglycemia is traditionally based on administration of carbohydrates or of glucagon via intramuscular (IM) or subcutaneous injection (SC). The injection of traditional glucagon is cumbersome, such that glucagon is an under-utilized drug. In 1983, it was shown for the first time that intranasal (IN) glucagon increases blood glucose levels in healthy volunteers, and in 1989–1992 that IN glucagon is similar to IM glucagon in resolving hypoglycemia in normal volunteers and in patients with diabetes, both adults and children. IN glucagon was developed in 2010 and continued in 2015; in 2019 IN glucagon obtained approval in the US, Canada, and Europe for severe hypoglycemia in children and adults. In the 2010s, two ready-to-use injectable formulations, a stable non-aqueous glucagon solution and the glucagon analog dasiglucagon, were developed, showing an efficacy similar to traditional glucagon, and approved in the US in 2020 and in 2021, respectively, for severe hypoglycemia in adults and in children. Fast-acting glucagon (nasal administration and injected solutions) appears to represent a major breakthrough in the treatment of severe hypoglycemia in insulin-treated patients with diabetes, both adults and children. It is anticipated that the availability of fast-acting glucagon will expand the use of glucagon, improve overall metabolic control, and prevent hypoglycemia-related complications, in particular cardiovascular complications and cognitive impairment. Full article

(This article belongs to the Special Issue Gut Hormone: From Molecular Mechanism to Clinical Aspects 2021)

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29 pages, 2541 KiB

Open AccessReview

Protective and Healing Effects of Ghrelin and Risk of Cancer in the Digestive System

by Grzegorz Ginter, Piotr Ceranowicz and Zygmunt Warzecha

Int. J. Mol. Sci. 2021, 22(19), 10571; https://doi.org/10.3390/ijms221910571 - 29 Sep 2021

Cited by 12 | Viewed by 4833

Abstract

Ghrelin is an endogenous ligand for the ghrelin receptor, previously known as the growth hormone secretagogue receptor. This hormone is mainly produced by endocrine cells present in the gastric mucosa. The ghrelin-producing cells are also present in other organs of the body, mainly in the digestive system, but in much smaller amount. Ghrelin exhibits a broad spectrum of physiological effects, such as stimulation of growth hormone secretion, gastric secretion, gastrointestinal motility, and food intake, as well as regulation of glucose homeostasis and bone formation, and inhibition of inflammatory processes. This review summarizes the recent findings concerning animal and human data showing protective and therapeutic effects of ghrelin in the gut, and also presents the role of growth hormone and insulin-like growth factor-1 in these effects. In addition, the current data on the possible influence of ghrelin on the carcinogenesis, its importance in predicting the risk of developing gastrointestinal malignances, as well as the potential usefulness of ghrelin in the treatment of cancer, have been presented. Full article

(This article belongs to the Special Issue Gut Hormone: From Molecular Mechanism to Clinical Aspects 2021)

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13 pages, 1008 KiB

Open AccessReview

Oral Semaglutide, the First Ingestible Glucagon-Like Peptide-1 Receptor Agonist: Could It Be a Magic Bullet for Type 2 Diabetes?

by Hwi Seung Kim and Chang Hee Jung

Int. J. Mol. Sci. 2021, 22(18), 9936; https://doi.org/10.3390/ijms22189936 - 14 Sep 2021

Cited by 16 | Viewed by 11508

Abstract

The gastrointestinal tract secretes gut hormones in response to food consumption, and some of these stimulate insulin secretion. Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone released from the lower digestive tract that stimulates insulin secretion, suppresses glucagon secretion, and decreases hunger. GLP-1 receptor agonist (GLP-1RA) mimics the action of endogenous GLP-1, consequently reversing hyperglycemia and causing weight reduction, demonstrating its efficacy as an antidiabetic and antiobesity agent. Previously restricted to injection only, the invention of the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino) caprylate resulted in the development of oral semaglutide, the first ingestible GLP-1RA. Oral semaglutide demonstrated its efficacy in glycemic management and body weight loss with a low risk of hypoglycemia as a monotherapy and in combination with other hypoglycemic medications in its clinical trial programs named Peptide Innovation for Early Diabetes Treatment. Consistent with other injectable GLP-1RAs, gastrointestinal side effects were often reported. Additionally, cardiovascular safety was established by demonstrating that oral semaglutide was not inferior to a placebo in terms of cardiovascular outcomes. Thus, oral semaglutide represents a novel treatment option that is particularly well-suited for patients with type 2 diabetes and/or obesity. Full article

(This article belongs to the Special Issue Gut Hormone: From Molecular Mechanism to Clinical Aspects 2021)

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12 pages, 740 KiB

Open AccessReview

Role of the Novel Peptide Phoenixin in Stress Response and Possible Interactions with Nesfatin-1

by Tiemo Friedrich and Andreas Stengel

Int. J. Mol. Sci. 2021, 22(17), 9156; https://doi.org/10.3390/ijms22179156 - 25 Aug 2021

Cited by 11 | Viewed by 3173

Abstract

The novel peptide phoenixin was shown to be involved in several physiological processes ranging from reproduction to food intake. Interest in this protein has steadily increased over the last few years and its known implications have become much broader, playing a role in glucose homeostasis, anxiety, nociception, and pruritus. Phoenixin is expressed in a multitude of organs such as the small intestine, pancreas, and in the hypothalamus, as well as several other brain nuclei influencing numerous physiological functions. Its highly conserved amino-acid sequence amongst species leads to the assumption, that phoenixin might be involved in essential physiological functions. Its co-expression and opposing functionality to the extensively studied peptide nesfatin-1 has given rise to the idea of a possible counterbalancing role. Several recent publications focused on phoenixin’s role in stress reactions, namely restraint stress and lipopolysaccharide-induced inflammation response, in which also nesfatin-1 is known to be altered. This review provides an overview on the phoenixins and nesfatin-1 properties and putative effects, and especially highlights the recent developments on their role and interaction in the response to response. Full article

(This article belongs to the Special Issue Gut Hormone: From Molecular Mechanism to Clinical Aspects 2021)

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