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Endocrinology and Metabolism (Seoul,... Feb 2023To maintain normal glucose homeostasis after a meal, it is essential to secrete an adequate amount of insulin from pancreatic β-cells. However, if pancreatic β-cells... (Review)
Review
To maintain normal glucose homeostasis after a meal, it is essential to secrete an adequate amount of insulin from pancreatic β-cells. However, if pancreatic β-cells solely depended on the blood glucose level for insulin secretion, a surge in blood glucose levels would be inevitable after the ingestion of a large amount of carbohydrates. To avoid a deluge of glucose in the bloodstream after a large carbohydrate- rich meal, enteroendocrine cells detect the amount of nutrient absorption from the gut lumen and secrete incretin hormones at scale. Since insulin secretion in response to incretin hormones occurs only in a hyperglycemic milieu, pancreatic β-cells can secrete a "Goldilocks" amount of insulin (i.e., not too much and not too little) to keep the blood glucose level in the normal range. In this regard, pancreatic β-cell sensitivity to glucose and incretin hormones is crucial for maintaining normal glucose homeostasis. In this Namgok lecture 2022, we review the effects of current anti-diabetic medications on pancreatic β-cell sensitivity to glucose and incretin hormones.
Topics: Humans; Incretins; Diabetes Mellitus, Type 2; Blood Glucose; Glucagon-Like Peptide 1; Insulin; Gastric Inhibitory Polypeptide; Glucose
PubMed: 36781163
DOI: 10.3803/EnM.2023.103 -
Islets Dec 2023The following review focuses on the scientific studies related to the role of endocannabinoid system (ECS) in pancreatic islet physiology and dysfunction. Different...
The following review focuses on the scientific studies related to the role of endocannabinoid system (ECS) in pancreatic islet physiology and dysfunction. Different natural or synthetic agonists and antagonists have been suggested as an alternative treatment for diabetes, obesity and metabolic syndrome. Therapeutic use of led to the discovery and characterization of the ECS, a signaling complex involved in regulation of various physiological processes, including food intake and metabolism. After the development of different agonists and antagonists, evidence have demonstrated the presence and activity of cannabinoid receptors in several organs and tissues, including pancreatic islets. Insulin and glucagon expression, stimulated secretion, and the development of diabetes and other metabolic disorders have been associated with the activity and modulation of ECS in pancreatic islets. However, according to the animal model and experimental design, either endogenous or pharmacological ligands of cannabinoid receptors have guided to contradictory and paradoxical results that suggest a complex physiological interaction. In consensus, ECS activity modulates insulin and glucagon secretions according to glucose in media; over-stimulation of cannabinoid receptors affects islets negatively, leading to glucose intolerance, meanwhile the treatment with antagonists in diabetic models and humans suggests an improvement in islets function.
Topics: Animals; Humans; Endocannabinoids; Glucagon; Metabolic Syndrome; Islets of Langerhans; Insulin; Diabetes Mellitus; Receptors, Cannabinoid
PubMed: 36598083
DOI: 10.1080/19382014.2022.2163826 -
Islets Dec 2023Pancreatic islets are mini-organs composed of hundreds or thousands of ɑ, β and δ-cells, which, respectively, secrete glucagon, insulin and somatostatin, key hormones... (Review)
Review
Pancreatic islets are mini-organs composed of hundreds or thousands of ɑ, β and δ-cells, which, respectively, secrete glucagon, insulin and somatostatin, key hormones for the regulation of blood glucose. In pancreatic islets, hormone secretion is tightly regulated by both internal and external mechanisms, including electrical communication and paracrine signaling between islet cells. Given its complexity, the experimental study of pancreatic islets has been complemented with computational modeling as a tool to gain a better understanding about how all the mechanisms involved at different levels of organization interact. In this review, we describe how multicellular models of pancreatic cells have evolved from the early models of electrically coupled β-cells to models in which experimentally derived architectures and both electrical and paracrine signals have been considered.
Topics: Islets of Langerhans; Insulin-Secreting Cells; Insulin; Glucagon; Pancreatic Hormones
PubMed: 37415423
DOI: 10.1080/19382014.2023.2231609 -
Surgical Oncology Clinics of North... Apr 2020The increased incidence and prevalence of neuroendocrine tumors (NETs) over the past few decades has been accompanied by an improvement in overall survival. There are... (Review)
Review
The increased incidence and prevalence of neuroendocrine tumors (NETs) over the past few decades has been accompanied by an improvement in overall survival. There are differences in the management of small bowel NETs versus pNETs. The management of all patients with NETs must be individualized based on patient characteristics as well tumor-related factors. This article reviews the role of somatostatin analogues, historical results with chemotherapy in gastroenteropancreatic NETs (GEPNETs), and more recent evidence for the use of cytotoxic chemotherapy in GEPNETs. The article also discusses molecular targeted therapies approved for use in GEPNETs and some ongoing clinical trials.
Topics: Animals; Antineoplastic Agents; Disease Management; Humans; Intestinal Neoplasms; Molecular Targeted Therapy; Neuroendocrine Tumors; Pancreatic Neoplasms; Somatostatin; Stomach Neoplasms
PubMed: 32151362
DOI: 10.1016/j.soc.2019.11.004 -
Current Opinion in Pharmacology Apr 2022Diabetes is the result of dysregulation of both insulin and glucagon. Still, insulin has attracted much more attention than glucagon. Glucagon is released from alpha... (Review)
Review
Diabetes is the result of dysregulation of both insulin and glucagon. Still, insulin has attracted much more attention than glucagon. Glucagon is released from alpha cells in the islets of Langerhans in response to low glucose and certain amino acids. Drugs with the primary aim of targeting glucagon signalling are scarce. However, glucagon is often administered to counteract severe hypoglycaemia, and commonly used diabetes medications such as GLP-1 analogues, sulfonylureas and SGLT2-inhibitors also affect alpha cells. Indeed, there are physiological and developmental similarities between the alpha cell and the insulin-secreting beta cell and new data confirm that alpha cells can be converted into insulin-secreting cells. These aspects and attributes, the need to find novel therapies targeting the alpha cell and more are considered in this review.
Topics: Glucagon; Glucagon-Like Peptide 1; Glucagon-Secreting Cells; Glucose; Homeostasis; Humans; Insulin; Insulin-Secreting Cells; Islets of Langerhans
PubMed: 35245797
DOI: 10.1016/j.coph.2022.102199 -
Upsala Journal of Medical Sciences May 2016Type 2 diabetes involves a ménage à trois of impaired glucose regulation of pancreatic hormone release: in addition to impaired glucose-induced insulin secretion, the... (Review)
Review
Type 2 diabetes involves a ménage à trois of impaired glucose regulation of pancreatic hormone release: in addition to impaired glucose-induced insulin secretion, the release of the hyperglycaemic hormone glucagon becomes dysregulated; these last-mentioned defects exacerbate the metabolic consequences of hypoinsulinaemia and are compounded further by hypersecretion of somatostatin (which inhibits both insulin and glucagon secretion). Glucagon secretion has been proposed to be regulated by either intrinsic or paracrine mechanisms, but their relative significance and the conditions under which they operate are debated. Importantly, the paracrine and intrinsic modes of regulation are not mutually exclusive; they could operate in parallel to control glucagon secretion. Here we have applied mathematical modelling of α-cell electrical activity as a novel means of dissecting the processes that underlie metabolic regulation of glucagon secretion. Our analyses indicate that basal hypersecretion of somatostatin and/or increased activity of somatostatin receptors may explain the loss of adequate counter-regulation under hypoglycaemic conditions, as well as the physiologically inappropriate stimulation of glucagon secretion during hyperglycaemia seen in diabetic patients. We therefore advocate studying the interaction of the paracrine and intrinsic mechanisms; unifying these processes may give a more complete picture of the regulation of glucagon secretion from α-cells than studying the individual parts.
Topics: Animals; Diabetes Mellitus, Type 2; Electrophysiology; Glucagon; Glucagon-Secreting Cells; Glucose; Humans; Hyperglycemia; Insulin; Islets of Langerhans; Mice; Models, Theoretical; Rats; Receptors, Somatostatin; Signal Transduction; Somatostatin
PubMed: 27044683
DOI: 10.3109/03009734.2016.1156789 -
International Journal of Molecular... Jan 2023Pancreatic cancer is one of the most aggressive tumors, with a dismal prognosis due to poor detection rates at early stages, rapid progression, post-surgical... (Review)
Review
Pancreatic cancer is one of the most aggressive tumors, with a dismal prognosis due to poor detection rates at early stages, rapid progression, post-surgical complications, and limited effectiveness of conventional oncologic therapies. There are no consistently reliable biomarkers or imaging modalities to accurately diagnose, classify, and predict the biological behavior of this tumor. Therefore, it is imperative to develop new and improved strategies to detect pancreatic lesions in the early stages of cancerization with greater sensitivity and specificity. Extracellular vesicles, including exosome and microvesicles, are membrane-coated cellular products that are released in the outer environment. All cells produce extracellular vesicles; however, this process is enhanced by inflammation and tumorigenesis. Based on accumulating evidence, extracellular vesicles play a crucial role in pancreatic cancer progression and chemoresistance. Moreover, they may represent potential biomarkers and promising therapy targets. The aim of the present review is to review the current evidence on the role of extracellular vesicles in pancreatic cancer.
Topics: Humans; Prognosis; Biomarkers, Tumor; Extracellular Vesicles; Pancreatic Neoplasms; Pancreatic Hormones
PubMed: 36614326
DOI: 10.3390/ijms24010885 -
Frontiers in Endocrinology 2022Glucose metabolism is primarily controlled by pancreatic hormones, with the coordinated assistance of the hormones from gastrointestine and adipose tissue. Studies have... (Review)
Review
Glucose metabolism is primarily controlled by pancreatic hormones, with the coordinated assistance of the hormones from gastrointestine and adipose tissue. Studies have unfolded a sophisticated hormonal gastrointestinal-pancreatic-adipose interaction network, which essentially maintains glucose homeostasis in response to the changes in substrates and nutrients. Free fatty acids (FFAs) are the important substrates that are involved in glucose metabolism. FFAs are able to activate the G-protein coupled membrane receptors including GPR40, GPR120, GPR41 and GPR43, which are specifically expressed in pancreatic islet cells, enteroendocrine cells as well as adipocytes. The activation of FFA receptors regulates the secretion of hormones from pancreas, gastrointestine and adipose tissue to influence glucose metabolism. This review presents the effects of the FFA receptors on glucose metabolism the hormonal gastrointestinal-pancreatic-adipose interactions and the underlying intracellular mechanisms. Furthermore, the development of therapeutic drugs targeting FFA receptors for the treatment of abnormal glucose metabolism such as type 2 diabetes mellitus is summarized.
Topics: Adipose Tissue; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose; Humans; Pancreas; Pancreatic Hormones; Receptors, G-Protein-Coupled
PubMed: 36246919
DOI: 10.3389/fendo.2022.956277 -
Cell Metabolism Feb 2022In diabetes, glucagon secretion from pancreatic α cells is dysregulated. The underlying mechanisms, and whether dysfunction occurs uniformly among cells, remain...
In diabetes, glucagon secretion from pancreatic α cells is dysregulated. The underlying mechanisms, and whether dysfunction occurs uniformly among cells, remain unclear. We examined α cells from human donors and mice using electrophysiological, transcriptomic, and computational approaches. Rising glucose suppresses α cell exocytosis by reducing P/Q-type Ca channel activity, and this is disrupted in type 2 diabetes (T2D). Upon high-fat feeding of mice, α cells shift toward a "β cell-like" electrophysiological profile in concert with indications of impaired identity. In human α cells we identified links between cell membrane properties and cell surface signaling receptors, mitochondrial respiratory chain complex assembly, and cell maturation. Cell-type classification using machine learning of electrophysiology data demonstrated a heterogenous loss of "electrophysiologic identity" in α cells from donors with type 2 diabetes. Indeed, a subset of α cells with impaired exocytosis is defined by an enrichment in progenitor and lineage markers and upregulation of an immature transcriptomic phenotype, suggesting important links between α cell maturation state and dysfunction.
Topics: Animals; Diabetes Mellitus, Type 2; Exocytosis; Glucagon; Glucagon-Secreting Cells; Insulin; Islets of Langerhans; Mice
PubMed: 35108513
DOI: 10.1016/j.cmet.2021.12.021 -
Peptides Feb 2023Pancreatic polypeptide (PP), a member of the neuropeptide Y (NPY) family of peptides, is a hormone secreted from the endocrine pancreas with established actions on... (Review)
Review
Pancreatic polypeptide (PP), a member of the neuropeptide Y (NPY) family of peptides, is a hormone secreted from the endocrine pancreas with established actions on appetite regulation. Thus, through activation of hypothalamic neuropeptide Y4 (NPY4R or Y4) receptors PP induces satiety in animals and humans, suggesting potential anti-obesity actions. In addition, despite being actively secreted from pancreatic islets and evidence of local Y4 receptor expression, PP mediated effects on the endocrine pancreas have not been fully elucidated. To date, it appears that PP possesses an acute insulinostatic effect, similar to the impact of other peptides from the NPY family. However, it is interesting that prolonged activation of pancreatic Y1 receptors leads to established benefits on beta-cell turnover, preservation of beta-cell identity and improved insulin secretory responsiveness. This may hint towards possible similar anti-diabetic actions of sustained Y4 receptor modulation, since the Y1 and Y4 receptors trigger comparable cell signalling pathways. In terms of exploiting the prospective therapeutic promise of PP, this is severely restricted by a short circulating half-life as is the case for many regulatory peptide hormones. It follows that long-acting, enzyme resistant, forms of PP will be required to determine viability of the Y4 receptor as an anti-obesity and -diabetes drug target. The current review aims to refocus interest on the biology of PP and highlight opportunities for therapeutic development.
Topics: Humans; Animals; Pancreatic Polypeptide; Receptors, Neuropeptide Y; Neuropeptide Y; Islets of Langerhans; Neuropeptides; Pancreas; Diabetes Mellitus
PubMed: 36509169
DOI: 10.1016/j.peptides.2022.170923