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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 -
Physical Biology Jul 2019Controlling the excess and shortage of energy is a fundamental task for living organisms. Diabetes is a representative metabolic disease caused by the malfunction of... (Review)
Review
Controlling the excess and shortage of energy is a fundamental task for living organisms. Diabetes is a representative metabolic disease caused by the malfunction of energy homeostasis. The islets of Langerhans in the pancreas release long-range messengers, hormones, into the blood to regulate the homeostasis of the primary energy fuel, glucose. The hormone and glucose levels in the blood show rhythmic oscillations with a characteristic period of 5-10 min, and the functional roles of the oscillations are not clear. Each islet has [Formula: see text] and [Formula: see text] cells that secrete glucagon and insulin, respectively. These two counter-regulatory hormones appear sufficient to increase and decrease glucose levels. However, pancreatic islets have a third cell type, [Formula: see text] cells, which secrete somatostatin. The three cell populations have a unique spatial organization in islets, and they interact to perturb their hormone secretions. The mini-organs of islets are scattered throughout the exocrine pancreas. Considering that the human pancreas contains approximately a million islets, the coordination of hormone secretion from the multiple sources of islets and cells within the islets should have a significant effect on human physiology. In this review, we introduce the hierarchical organization of tripartite cell networks, and recent biophysical modeling to systematically understand the oscillations and interactions of [Formula: see text], [Formula: see text], and [Formula: see text] cells. Furthermore, we discuss the functional roles and clinical implications of hormonal oscillations and their phase coordination for the diagnosis of type II diabetes.
Topics: Animals; Glucagon; Glucose; Homeostasis; Humans; Insulin; Islets of Langerhans
PubMed: 31212272
DOI: 10.1088/1478-3975/ab2a9d -
Annals of the New York Academy of... Jul 2021Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic islet β cell loss and dysfunction resulting in insulin deficiency and hyperglycemia.... (Review)
Review
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic islet β cell loss and dysfunction resulting in insulin deficiency and hyperglycemia. During a presymptomatic phase of established β cell autoimmunity, β cell loss may first be evident through assessment of β cell secretory capacity, a measure of functional β cell mass. Reduction in pancreatic islet β cell reserve eventually manifests as impaired first-phase insulin response to glucose and abnormal glucose tolerance, which progresses until the functional capacity for β cell secretion can no longer meet the demand for insulin to control glycemia. A functional β cell mass of ∼25% of normal may be required to avoid symptomatic T1D but is already associated with dysregulated glucagon secretion. With symptomatic T1D, stimulated C-peptide levels >0.60 ng/mL (0.200 pmol/mL) indicate the presence of clinically meaningful residual β cell function for contributing to glycemic control, although even higher residual C-peptide appears necessary for evidencing glucose-dependent islet β and α cell function that may contribute to maintaining (near)normal glycemia. β cell replacement by islet transplantation can restore a physiologic reserve capacity for insulin secretion, confirming thresholds for functional β cell mass required for independence from insulin therapy.
Topics: Diabetes Mellitus, Type 1; Glucagon; Glucose; Humans; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells
PubMed: 33550589
DOI: 10.1111/nyas.14572 -
Journal of Molecular Medicine (Berlin,... Apr 2020The pancreatic islet is a dense cellular network comprised of several cell types with endocrine function vital in the control of glucose homeostasis, metabolism, and... (Review)
Review
The pancreatic islet is a dense cellular network comprised of several cell types with endocrine function vital in the control of glucose homeostasis, metabolism, and feeding behavior. Within the islet, endocrine hormones also form an intricate paracrine network with supportive cells (endothelial, neuronal, immune) and secondary signaling molecules regulating cellular function and survival. Modulation of these signals has potential consequences for diabetes development, progression, and therapeutic intervention. Beta cell loss, reduced endogenous insulin secretion, and dysregulated glucagon secretion are hallmark features of both type 1 and 2 diabetes that not only impact systemic regulation of glucose, but also contribute to the function and survival of cells within the islet. Advancing research and technology have revealed new islet biology (cellular identity and transcriptomes) and identified previously unrecognized paracrine signals and mechanisms (somatostatin and ghrelin paracrine actions), while shifting prior views of intraislet communication. This review will summarize the paracrine signals regulating islet endocrine function and survival, the disruption and dysfunction that occur in diabetes, and potential therapeutic targets to preserve beta cell mass and function.
Topics: Animals; Cell Survival; Ghrelin; Glucagon-Secreting Cells; Glucose; Glycogen; Humans; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Pancreatic Polypeptide; Paracrine Communication; Signal Transduction; Somatostatin; Somatostatin-Secreting Cells
PubMed: 32067063
DOI: 10.1007/s00109-020-01887-x -
Diabetes Sep 2022Glucagon and insulin are the main regulators of blood glucose. While the actions of insulin are extensively mapped, less is known about glucagon. Besides glucagon's role... (Review)
Review
Glucagon and insulin are the main regulators of blood glucose. While the actions of insulin are extensively mapped, less is known about glucagon. Besides glucagon's role in glucose homeostasis, there are additional links between the pancreatic α-cells and the hepatocytes, often collectively referred to as the liver-α-cell axis, that may be of importance for health and disease. Thus, glucagon receptor antagonism (pharmacological or genetic), which disrupts the liver-α-cell axis, results not only in lower fasting glucose but also in reduced amino acid turnover and dyslipidemia. Here, we review the actions of glucagon on glucose homeostasis, amino acid catabolism, and lipid metabolism in the context of the liver-α-cell axis. The concept of glucagon resistance is also discussed, and we argue that the various elements of the liver-α-cell axis may be differentially affected in metabolic diseases such as diabetes, obesity, and nonalcoholic fatty liver disease (NAFLD). This conceptual rethinking of glucagon biology may explain why patients with type 2 diabetes have hyperglucagonemia and how NAFLD disrupts the liver-α-cell axis, compromising the normal glucagon-mediated enhancement of substrate-induced amino acid turnover and possibly fatty acid β-oxidation. In contrast to amino acid catabolism, glucagon-induced glucose production may not be affected by NAFLD, explaining the diabetogenic effect of NAFLD-associated hyperglucagonemia. Consideration of the liver-α-cell axis is essential to understanding the complex pathophysiology underlying diabetes and other metabolic diseases.
Topics: Amino Acids; Blood Glucose; Diabetes Mellitus, Type 2; Glucagon; Glucose; Hepatocytes; Humans; Insulin; Non-alcoholic Fatty Liver Disease
PubMed: 35657688
DOI: 10.2337/dbi22-0004 -
MMW Fortschritte Der Medizin Oct 2022
Topics: Humans; Insulin; Insulin Glargine; Insulin, Long-Acting
PubMed: 36253673
DOI: 10.1007/s15006-022-2027-0 -
Translational Psychiatry Feb 2021Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of...
Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, the mechanisms by which catecholamines modulate pancreatic hormone release are not completely understood. We show that human and mouse pancreatic α- and β-cells express the catecholamine biosynthetic and signaling machinery, and that α-cells synthesize DA de novo. This locally-produced pancreatic DA signals via both α- and β-cell adrenergic and dopaminergic receptors with different affinities to regulate glucagon and insulin release. Significantly, we show DA functions as a biased agonist at α-adrenergic receptors, preferentially signaling via the canonical G protein-mediated pathway. Our findings highlight the interplay between DA and NE signaling as a novel form of regulation to modulate pancreatic hormone release. Lastly, pharmacological blockade of DA D-like receptors in human islets with APDs significantly raises insulin and glucagon release. This offers a new mechanism where APDs act directly on islet α- and β-cell targets to produce metabolic disturbances.
Topics: Adrenergic Agents; Dopamine; Glucagon; Insulin; Insulin Secretion; Norepinephrine; Pancreas
PubMed: 33589583
DOI: 10.1038/s41398-020-01171-z -
BioDrugs : Clinical Immunotherapeutics,... Aug 2020The development of biosimilar insulin products has slowly evolved with only two follow-on biologics currently available to patients in the US. Both Basaglar (insulin... (Review)
Review
The development of biosimilar insulin products has slowly evolved with only two follow-on biologics currently available to patients in the US. Both Basaglar (insulin glargine) and Admelog (insulin lispro) have undergone extensive testing, and have gained significant use by patients in the US. Despite the availability of these follow-on products, the price of insulin has remained stubbornly high. New regulatory guidance under the Biologics Price Competition and Innovations Act that came into effect in March 2020 introduced an abbreviated pathway for the approval of biosimilar insulins and introduced the option to apply for interchangeability of the biosimilar insulin with the reference product. This abbreviated clinical testing may open the doors for numerous follow-on insulin products, with unknown supply-chain and fiscal ramifications. This review will highlight the development process of biosimilar insulin in the US and the recent regulatory changes that can aid this process. We will also discuss challenges for prescribers and patients who are navigating this ever-changing landscape. These new regulations for biosimilar insulins will have ramifications for patients, healthcare providers, and third-party payers, though the direction and scope of these changes is unclear.
Topics: Biosimilar Pharmaceuticals; Drug Approval; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulins; United States
PubMed: 32681425
DOI: 10.1007/s40259-020-00431-0 -
Peptides Apr 2022The dual role of the pancreas as both an endocrine and exocrine gland is vital for food digestion and control of nutrient metabolism. The exocrine pancreas secretes... (Review)
Review
The dual role of the pancreas as both an endocrine and exocrine gland is vital for food digestion and control of nutrient metabolism. The exocrine pancreas secretes enzymes into the small intestine aiding digestion of sugars and fats, whereas the endocrine pancreas secretes a cocktail of hormones into the blood, which is responsible for blood glucose control and regulation of carbohydrate, protein and fat metabolism. Classical islet hormones, insulin, glucagon, pancreatic polypeptide and somatostatin, interact in an autocrine and paracrine manner, to fine-tube the islet function and insulin secretion to the needs of the body. Recently pancreatic islets have been reported to express a number of non-classical peptide hormones involved in metabolic signalling, whose major production site was believed to reside outside pancreas, e.g. in the small intestine. We highlight the key non-classical islet peptides, and consider their involvement, together with established islet hormones, in regulation of stimulus-secretion coupling as well as proliferation, survival and transdifferentiation of β-cells. We furthermore focus on the paracrine interaction between classical and non-classical islet hormones in the maintenance of β-cell function. Understanding the functional relationships between these islet peptides might help to develop novel, more efficient treatments for diabetes and related metabolic disorders.
Topics: Glucagon; Insulin; Islets of Langerhans; Pancreas; Peptides
PubMed: 34958851
DOI: 10.1016/j.peptides.2021.170715 -
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