The Regulation Role of the Gut-Islets Axis in Diabetes

Songtao Yang,1 Jie Cao,1 Chuan Sun,2 Li Yuan1 1Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Department of Emergency Medical, Wuhan ASIA GENERAL Hospital, Wuhan, 430000, People’s Republic of ChinaCorrespondence: Li Yuan, Email [email protected]: The gut-islets axis is an important endocrine signaling axis that regulates the function of islets by modulating the gut micro-environment and its endocrine metabolism. The discovery of intestinal hormones, such as GLP-1 and GIP, has established a preliminary link between the gut and the islet, paving the way for the development of GLP-1 receptor agonists based on the regulation theory of the gut-islets axis for diabetes treatment. This discovery has created a new paradigm for diabetes management and rapidly made the regulation theory of the gut-islets axis a focal point of research attention. Recent years, with in-depth study on gut microbiota and the discovery of intestinal-derived extracellular vesicles, the concept of gut endocrine and the regulation theory of the gut-islets axis have been further expanded and updated, offering tremendous research opportunities. The gut-islets axis refers to the complex interplay between the gut and the islet, which plays a crucial role in regulating glucose homeostasis and maintaining metabolic health. The axis involves various components, including gut microbiota, intestinal hormones, amino acids and ACE2, which contribute to the communication and coordination between the gut and the islet.Keywords: islets β cell, diabetes, GLP-1, gut microbiota, ACE

Integrating the inputs that shape pancreatic islet hormone release.

The pancreatic islet is a complex mini organ composed of a variety of endocrine cells and their support cells, which together tightly control blood glucose homeostasis. Changes in glucose concentration are commonly regarded as the chief signal controlling insulin-secreting beta cells, glucagon-secreting alpha cells and somatostatin-secreting delta cells. However, each of these cell types is highly responsive to a multitude of endocrine, paracrine, nutritional and neural inputs, which collectively shape the final endocrine output of the islet. Here, we review the principal inputs for each islet-cell type and the physiological circumstances in which these signals arise, through the prism of the insights generated by the transcriptomes of each of the major endocrine-cell types. A comprehensive integration of the factors that influence blood glucose homeostasis is essential to successfully improve therapeutic strategies for better diabetes management

Treatment of type 2 diabetes by free fatty acid receptor agonists

Dietary free fatty acids (FFAs), such as ω-3 fatty acids, regulate metabolic and anti-inflammatory processes, with many of these effects attributed to FFAs interacting with a family of G protein-coupled receptors. Selective synthetic ligands for Free Fatty Acid receptors (FFA1-4) have consequently been developed as potential treatments for type 2 diabetes (T2D). In particular, clinical studies show that Fasiglifam, an agonist of the long chain FFA receptor, FFA1, improved glycaemic control and reduced HbA1c levels in T2D patients, with a reduced risk of hypoglycemia. However, this ligand was removed from clinical trials due to potential liver toxicity and determining if this is a target or a ligand-specific feature is now of major importance. Pre-clinical studies also show that FFA4 agonism increases insulin sensitivity, induces weight loss and reduces inflammation and the metabolic and anti-inflammatory effects of short chain fatty acids (SCFAs) are linked with FFA2 and FFA3 activation. In this review, we therefore show that FFA receptor agonism is a potential clinical target for T2D treatment and discuss ongoing drug development programmes within industry and academia aimed at improving the safety and effectiveness of these potential treatments

Microbiota-Produced N-Formyl Peptide fMLF Promotes Obesity-Induced Glucose Intolerance.

The composition of the gastrointestinal microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced N-formyl peptide, formyl-methionyl-leucyl-phenylalanine, are elevated in high-fat diet-induced obese mice. Genetic or pharmacological inhibition of the N-formyl peptide receptor Fpr1 leads to increased insulin levels and improved glucose tolerance, dependent upon glucagon-like peptide 1. Obese Fpr1 knockout mice also display an altered microbiome, exemplifying the dynamic relationship between host metabolism and microbiota. Overall, we describe a new mechanism by which the gut microbiota can modulate glucose metabolism, providing a potential approach for the treatment of metabolic disease

G-protein-coupled receptors for free fatty acids: nutritional and therapeutic targets

It is becoming evident that nutrients and metabolic intermediates derived from such nutrients regulate cellular function by activating a number of cell-surface G-protein coupled receptors (GPCRs). Until now, members of the GPCR family have largely been considered as the molecular targets that communicate cellular signals initiated by hormones and neurotransmitters. Recently, based on tissue expression patterns of these receptors and the concept that they may elicit the production of a range of appetite- and hunger-regulating peptides, such nutrient sensing GPCRs are attracting considerable attention due to their potential to modulate satiety, improve glucose homeostasis and supress the production of various pro-inflammatory mediators. Despite the developing interests in these nutrients sensing GPCR both as sensors of nutritional status, and targets for limiting the development of metabolic diseases, major challenges remain to exploit their potential for therapeutic purposes. Mostly, this is due to limited characterisation and validation of these receptors because of paucity of selective and high-potency/affinity pharmacological agents to define the detailed function and regulation of these receptors. However, ongoing clinical trials of agonists of free fatty acid receptor 1 suggest that this receptor and other receptors for free fatty acids may provide a successful strategy for controlling hyperglycaemia and providing novel approaches to treat diabetes. Receptors responsive to free fatty acid have been of particular interest, and some aspects of these are considered herein

Insulin secretion in health and disease: nutrients dictate the pace.

Insulin is a key hormone controlling metabolic homeostasis. Loss or dysfunction of pancreatic β-cells lead to the release of insufficient insulin to cover the organism needs, promoting diabetes development. Since dietary nutrients influence the activity of β-cells, their inadequate intake, absorption and/or utilisation can be detrimental. This review will highlight the physiological and pathological effects of nutrients on insulin secretion and discuss the underlying mechanisms. Glucose uptake and metabolism in β-cells trigger insulin secretion. This effect of glucose is potentiated by amino acids and fatty acids, as well as by entero-endocrine hormones and neuropeptides released by the digestive tract in response to nutrients. Glucose controls also basal and compensatory β-cell proliferation and, along with fatty acids, regulates insulin biosynthesis. If in the short-term nutrients promote β-cell activities, chronic exposure to nutrients can be detrimental to β-cells and causes reduced insulin transcription, increased basal secretion and impaired insulin release in response to stimulatory glucose concentrations, with a consequent increase in diabetes risk. Likewise, suboptimal early-life nutrition (e.g. parental high-fat or low-protein diet) causes altered β-cell mass and function in adulthood. The mechanisms mediating nutrient-induced β-cell dysfunction include transcriptional, post-transcriptional and translational modifications of genes involved in insulin biosynthesis and secretion, carbohydrate and lipid metabolism, cell differentiation, proliferation and survival. Altered expression of these genes is partly caused by changes in non-coding RNA transcripts induced by unbalanced nutrient uptake. A better understanding of the mechanisms leading to β-cell dysfunction will be critical to improve treatment and find a cure for diabetes

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders.

Prohormone convertase 1/3, encoded by the PCSK1 gene, is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones. Humans who are homozygous or compound heterozygous for loss-of-function mutations in PCSK1 exhibit a variable and pleiotropic syndrome consisting of some or all of the following: obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels in association with elevated circulating proinsulin-to-insulin ratio. Recently, more common variants in the PCSK1 gene have been found to be associated with alterations in body mass index, increased circulating proinsulin levels, and defects in glucose homeostasis. This review provides an overview of the endocrinopathies and other disorders observed in prohormone convertase 1/3-deficient patients, discusses the possible biochemical basis for these manifestations of the disease, and proposes a model whereby certain missense mutations in PCSK1 may result in proteins with a dominant negative action

The pharmacology and function of receptors for short-chain fatty acids

Despite some blockbuster G protein–coupled receptor (GPCR) drugs, only a small fraction (∼15%) of the more than 390 nonodorant GPCRs have been successfully targeted by the pharmaceutical industry. One way that this issue might be addressed is via translation of recent deorphanization programs that have opened the prospect of extending the reach of new medicine design to novel receptor types with potential therapeutic value. Prominent among these receptors are those that respond to short-chain free fatty acids of carbon chain length 2–6. These receptors, FFA2 (GPR43) and FFA3 (GPR41), are each predominantly activated by the short-chain fatty acids acetate, propionate, and butyrate, ligands that originate largely as fermentation by-products of anaerobic bacteria in the gut. However, the presence of FFA2 and FFA3 on pancreatic β-cells, FFA3 on neurons, and FFA2 on leukocytes and adipocytes means that the biologic role of these receptors likely extends beyond the widely accepted role of regulating peptide hormone release from enteroendocrine cells in the gut. Here, we review the physiologic roles of FFA2 and FFA3, the recent development and use of receptor-selective pharmacological tool compounds and genetic models available to study these receptors, and present evidence of the potential therapeutic value of targeting this emerging receptor pair

Investigating the physiological and pharmacological effects of the gut hormone peptide YY (PYY)

The obesity epidemic is a critical and global public health burden. Drugs that safely promote weight loss are urgently needed to halt the rising prevalence of obesity and its associated complications, such as type 2 diabetes (T2D). Gut hormones are important regulators in metabolism and have therapeutic potential as treatments for obesity and T2D. The gut hormone peptide YY (PYY) is released from the intestine after a meal. Exogenous PYY3–36 suppresses food intake in both rodents and humans, including in the obese state. PYY3–36 suppresses appetite by acting on its receptor, the Y2R. Y2R is expressed in brain appetite centres but also in the afferent vagus nerve, the main neuroanatomical link carrying information from the gut to the brain. However, the relevant contribution of the afferent vagus to the overall effects of PYY3–36 is unknown. Chemogenetic activation of vagal afferent neurones results in reduced food intake (surpassing the effects of PYY) and might have altered the immune landscape of the gastrointestinal tract. To dissect the role of the Y2R expressed in the afferent vagus, we have developed a novel microsurgical technique in the mouse. Our work suggests that vagal Y2R mediates the anorectic effect of low dose and endogenous PYY3–36 and that this vagal signalling pathway regulates short-term feeding. This anorectic effect was not caused by an aversive response. In vitro calcium imaging confirmed that PYY3–36 directly activates vagal afferents. Chronic treatment of diet-induced obese (DIO) mice with a long-acting PYY3–36 analogue, Y242, did not cause a significant body weight loss. Longitudinal tracking of individual islet function using a novel imaging platform allowed to study the effect of diet and Y242 treatment. Chronic Y242 did not improve or worsen islet function in obese mice. Therefore, PYY-based treatments might not be suitable as a single agent but have potential in combination with other gut-hormones. Vagus nerve neuromodulation has shown potential as an anti-obesity therapy and the work in this thesis adds to a better understanding of vagal afferent function which will help optimise therapeutic interventions.Open Acces

The Gut-pancreas axis in autoimmune diabetes

The gut microbiota has been suggested to be an important factor in the development of autoimmune diseases such as type 1 diabetes (T1D). Priming of islet specific T cells in the pancreatic lymph nodes (PaLN) and their migration to the pancreatic islets are critical steps in the destruction of insulin producing β-cells that leads the development of autoimmune diabetes. Perturbation of gut homeostasis by pathogenic microbes or imbalance of the gut microbiota during dysbiosis may provoke the autoimmune reactions that are associated with T1D. However, the mechanisms by which altered gut microbiota and its interaction with the immune system affect autoimmune diabetes development are unclear. In this thesis, we investigated how gut microbiota composition influences the progression of autoimmune diabetes in nonobese (NOD) mice and whether dysbiosis aggravates the immunological events associated with T1D pathogenesis. This thesis will show how compromised intestinal barrier integrity and dysbiosis promote islet-specific T cell activation and their attraction to pancreatic islets. First, we show that healthy microbiota is associated with enhanced intestinal integrity and has a beneficial effect on the progression of autoimmune diabetes. We show that induction of dysbiosis with pathogenic microbes impairs intestinal barrier function, where among other factors plasmacytoid dendritic cells (pDCs) have an important regulatory role, and promote the autoimmune responses associated with the β-cell destruction. We describe a novel shared lymphatic drainage between the gut and pancreas that allows dendritic cell and bacterial migration to PaLNs during dysbiosis. Dysbiosis enhances the activation of islet-specific T cells and their priming with chemokine receptor CXCR3 in PaLNs. Additionally, we show that dysbiosis, followed by elevated endotoxin levels, enhances CXCL10 production within the pancreatic islets, which leads to enhanced attraction of CXCR3+ lymphocytes into pancreatic islets. Our results indicate that dysbiosis may be the initial factor that promotes lymphocyte infiltration into healthy pancreatic islets. This thesis will give new insight into the effects of gut microbiota on the development of autoimmune diabetes and the role of dysbiosis in actuating the autoimmune responses associated with T1D pathogenesis.-- Suolistomikrobiston uskotaan olevan tärkeä tekijä autoimmuunisairauksien, kuten tyypin 1 diabeteksen (T1D) kehittymisessä. Tyypillisiä vaiheita autoimmuunidiabeteksen kehittymisessä ovat saareke-spesifisten T-solujen aktivoituminen haiman imusolmukkeissa ja niiden siirtyminen haiman saarekkeisiin, johtaen insuliinia tuottavien β-solujen tuhoutumiseen. Patogeenisten mikrobien tai mikrobiston epätasapainon eli dysbioosin aiheuttama suoliston homeostaasin häiriintyminen voi edesauttaa näitä T1D:ssä havaittuja autoimmuunivasteita. On kuitenkin vielä epäselvää mitkä ovat ne mekanismit, joilla epätasapainoinen suolistomikrobisto ja sen vuorovaikutus immuunijärjestelmän kanssa vaikuttavat autoimmuunidiabeteksen kehittymiseen. Tämän tutkimuksen tarkoituksena oli selvittää, miten suolistomikrobiston koostumus vaikuttaa autoimmuunidiabeteksen kehittymiseen ja kuinka dysbioosi voi pahentaa T1D-patogeneesiin liittyviä immunologisia vasteita. Tämä väitöskirja osoittaa, kuinka heikentynyt suolen seinämän eheys ja dysbioosi edistävät saareke-spesifisten T-solujen aktivaatiota ja niiden houkuttelua haiman saarekkeisiin. Osoitamme, että terveellä mikrobistolla ja hyvällä suolen seinämän eheydellä on hidastava vaikutus autoimmuunidiabeteksen kehittymisessä. Vastaavasti osoitamme, että dysbioosi edistää β-solujen tuhoutumiseen johtavia autoimmuunivasteita heikentämällä suoliston seinämän eheyttä, jossa muiden tekijöiden ohella plasmasytoidi dendriittisoluilla (pDC) on tärkeä säätelevä tehtävä. Osoitamme ennen kuvaamattoman imutieyhteyden suoliston ja haiman välillä, joka mahdollistaa dendriittisolujen ja bakteerien siirtymisen haiman imusolmukkeisiin dysbioosin aikana. Dysbioosi tehostaa saareke-spesifisten T-solujen aktivaatiota ja niiden kemokiinireseptori CXCR3 ilmentymistä. Lisäksi näytämme, kuinka dysbioosi ja siitä johtuva kohonnut endotoksiinitaso indusoi CXCL10 tuotantoa haiman saarekkeissa, mikä lisää CXCR3+ lymfosyyttien houkuttelua haiman saarekkeisiin. Tuloksemme osoittavat, että dysbioosi voi olla yksi ensimmäisistä tekijöistä lymfosyyttien tunkeutumisessa terveisiin haiman saarekkeisiin. Tämä väitöskirja tuottaa uutta tietoa suolistomikrobiston vaikutuksista autoimmuunidiabeteksen kehittymisessä ja siitä, kuinka dysbioosi voi olla merkittävä laukaiseva tekijä T1D patogeneesille tyypillisissä autoimmuunivasteissa