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The Journal of Endocrinology Aug 2023Glucagon is the principal glucose-elevating hormone that forms the first-line defence against hypoglycaemia. Along with insulin, glucagon also plays a key role in... (Review)
Review
Glucagon is the principal glucose-elevating hormone that forms the first-line defence against hypoglycaemia. Along with insulin, glucagon also plays a key role in maintaining systemic glucose homeostasis. The cells that secrete glucagon, pancreatic α-cells, are electrically excitable cells and use electrical activity to couple its hormone secretion to changes in ambient glucose levels. Exactly how glucose regulates α-cells has been a topic of debate for decades but it is clear that electrical signals generated by the cells play an important role in glucagon secretory response. Decades of studies have already revealed the key players involved in the generation of these electrical signals and possible mechanisms controlling them to tune glucagon release. This has offered the opportunity to fully understand the enigmatic α-cell physiology. In this review, we describe the current knowledge on cellular electrophysiology and factors regulating excitability, glucose sensing, and glucagon secretion. We also discuss α-cell pathophysiology and the perspective of addressing glucagon secretory defects in diabetes for developing better diabetes treatment, which bears the hope of eliminating hypoglycaemia as a clinical problem in diabetes care.
Topics: Humans; Glucagon; Glucagon-Secreting Cells; Insulin; Glucose; Diabetes Mellitus; Hypoglycemia; Cell Physiological Phenomena; Electrophysiology
PubMed: 37159865
DOI: 10.1530/JOE-22-0295 -
Diabetologia Oct 2023Hyperglycaemia is associated with alpha cell dysfunction, leading to dysregulated glucagon secretion in type 1 and type 2 diabetes; however, the mechanisms involved are...
AIM/HYPOTHESIS
Hyperglycaemia is associated with alpha cell dysfunction, leading to dysregulated glucagon secretion in type 1 and type 2 diabetes; however, the mechanisms involved are still elusive. The nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) plays a major role in the maintenance of alpha cell mass and function. We studied the regulation of alpha cell mTORC1 by nutrients and its role in the development of hyperglucagonaemia in diabetes.
METHODS
Alpha cell mTORC1 activity was assessed by immunostaining for phosphorylation of its downstream target, the ribosomal protein S6, and glucagon, followed by confocal microscopy on pancreatic sections and flow cytometry on dispersed human and mouse islets and the alpha cell line, αTC1-6. Metabolomics and metabolic flux were studied by C glucose labelling in 2.8 or 16.7 mmol/l glucose followed by LC-MS analysis. To study the role of mTORC1 in mediating hyperglucagonaemia in diabetes, we generated an inducible alpha cell-specific Rptor knockout in the Akita mouse model of diabetes and tested the effects on glucose tolerance by IPGTT and on glucagon secretion.
RESULTS
mTORC1 activity was increased in alpha cells from diabetic Akita mice in parallel to the development of hyperglycaemia and hyperglucagonaemia (two- to eightfold increase). Acute exposure of mouse and human islets to amino acids stimulated alpha cell mTORC1 (3.5-fold increase), whereas high glucose concentrations inhibited mTORC1 (1.4-fold decrease). The mTORC1 response to glucose was abolished in human and mouse diabetic alpha cells following prolonged islet exposure to high glucose levels, resulting in sustained activation of mTORC1, along with increased glucagon secretion. Metabolomics and metabolic flux analysis showed that exposure to high glucose levels enhanced glycolysis, glucose oxidation and the synthesis of glucose-derived amino acids. In addition, chronic exposure to high glucose levels increased the expression of Slc7a2 and Slc38a4, which encode amino acid transporters, as well as the levels of branched-chain amino acids and methionine cycle metabolites (~1.3-fold increase for both). Finally, conditional Rptor knockout in alpha cells from adult diabetic mice inhibited mTORC1, thereby inhibiting glucagon secretion (~sixfold decrease) and improving diabetes, despite persistent insulin deficiency.
CONCLUSIONS/INTERPRETATION
Alpha cell exposure to hyperglycaemia enhances amino acid synthesis and transport, resulting in sustained activation of mTORC1, thereby increasing glucagon secretion. mTORC1 therefore plays a major role in mediating alpha cell dysfunction in diabetes.
DATA AVAILABILITY
All sequencing data are available from the Gene Expression Omnibus (GEO) repository (accession no. GSE154126; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154126 ).
Topics: Adult; Humans; Animals; Glucagon; Diabetes Mellitus, Type 2; Diabetes Mellitus, Experimental; Hyperglycemia; Mechanistic Target of Rapamycin Complex 1; Glucose; Mammals
PubMed: 37480416
DOI: 10.1007/s00125-023-05967-8 -
Endocrine-related Cancer May 2024
Topics: Humans; Insulin; Glucagon; Blood Glucose
PubMed: 38631379
DOI: 10.1530/ERC-23-0345 -
ELife Jan 2024The secretion of insulin from the pancreas relies on both gap junctions and subpopulations of beta cells with specific intrinsic properties.
The secretion of insulin from the pancreas relies on both gap junctions and subpopulations of beta cells with specific intrinsic properties.
Topics: Pancreas; Gap Junctions; Insulin; Insulin-Secreting Cells
PubMed: 38270512
DOI: 10.7554/eLife.95103 -
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 -
Advances in Surgery Sep 2023Chronic pancreatitis is a progressive and irreversible process of pancreatic inflammation and fibrosis that can lead to intractable abdominal pain and severely impaired... (Review)
Review
Chronic pancreatitis is a progressive and irreversible process of pancreatic inflammation and fibrosis that can lead to intractable abdominal pain and severely impaired quality of life (QoL). Often patients are refractory to standard medical or endoscopic treatments. Total pancreatectomy (TP) and islet auto-transplantation (TP-IAT) can offer pain relief to patients by removing the entire pancreas and the auto-transplant component ameliorates the resulting diabetes. QoL is significantly improved after TP-IAT when insulin independence is present. Recent data support offering TP-IAT rather than TP alone and treating with exogenous insulin for patients with debilitating chronic pancreatitis.
Topics: Humans; Pancreatectomy; Quality of Life; Treatment Outcome; Pancreatitis, Chronic; Islets of Langerhans Transplantation; Insulin; Transplantation, Autologous; Insulin, Regular, Human
PubMed: 37536850
DOI: 10.1016/j.yasu.2023.03.002 -
Endocrine Practice : Official Journal... Aug 2023Advances in diabetes technology, especially in the last few decades, have transformed our ability to deliver care to persons with diabetes (PWDs). Developments in... (Review)
Review
OBJECTIVE
Advances in diabetes technology, especially in the last few decades, have transformed our ability to deliver care to persons with diabetes (PWDs). Developments in glucose monitoring, especially continuous glucose monitoring (CGM) systems, have revolutionized diabetes care and empowered our patients to manage their disease. CGM has also played an integral role in advancing automated insulin delivery systems.
OBSERVATIONS
Currently available and upcoming advanced hybrid closed-loop systems aim to decrease patient involvement and are approaching the functionality of a fully automated artificial pancreas. Other advances, such as smart insulin pens and daily patch pumps, offer more options for patients and require less complicated and costly technology. Evidence to support the role of diabetes technology is growing, and PWD and clinicians must choose the right type of technology with a personalized strategy to manage diabetes effectively.
CONCLUSION AND RELEVANCE
Here, we review currently available diabetes technologies, summarize their individual features, and highlight key patient factors to consider when creating a personalized treatment plan. We also address current challenges and barriers to the adoption of diabetes technologies.
Topics: Humans; Diabetes Mellitus, Type 1; Blood Glucose Self-Monitoring; Blood Glucose; Insulin Infusion Systems; Technology; Insulins; Insulin; Hypoglycemic Agents
PubMed: 37100350
DOI: 10.1016/j.eprac.2023.04.007 -
Pathologie (Heidelberg, Germany) Feb 2024
Topics: Pancreas; Pancreatic Hormones
PubMed: 38289391
DOI: 10.1007/s00292-023-01290-6 -
International Journal of Molecular... Aug 2023A positive association between insulin resistance and osteoporosis has been widely established. However, crosstalk between the signalling molecules in insulin and... (Review)
Review
A positive association between insulin resistance and osteoporosis has been widely established. However, crosstalk between the signalling molecules in insulin and Wingless (Wnt)/beta-(β-)catenin transduction cascades orchestrating bone homeostasis remains not well understood. The current review aims to collate the existing evidence, reporting (a) the expression of insulin signalling molecules involved in bone-related disorders and (b) the expression of Wnt/β-catenin signalling molecules involved in governing insulin homeostasis. The downstream effector molecule, glycogen synthase kinase-3 beta (GSK3β), has been identified to be a point of convergence linking the two signal transduction networks. This review highlights that GSK3β may be a drug target in the development of novel anabolic agents and the potential use of GSK3β inhibitors to treat bone-related disorders.
Topics: Insulin; Glycogen Synthase Kinase 3 beta; beta Catenin; Bone Density; Wnt Signaling Pathway; Insulin, Regular, Human
PubMed: 37569816
DOI: 10.3390/ijms241512441