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Endocrinology Nov 2020Glucose homeostasis is maintained in large part due to the actions of the pancreatic islet hormones insulin and glucagon, secreted from β- and α-cells, respectively.... (Review)
Review
Glucose homeostasis is maintained in large part due to the actions of the pancreatic islet hormones insulin and glucagon, secreted from β- and α-cells, respectively. The historical narrative positions these hormones in opposition, with insulin primarily responsible for glucose-lowering and glucagon-driving elevations in glucose. Recent progress in this area has revealed a more complex relationship between insulin and glucagon, highlighted by data demonstrating that α-cell input is essential for β-cell function and glucose homeostasis. Moreover, the common perception that glucagon levels decrease following a nutrient challenge is largely shaped by the inhibitory effects of glucose administration alone on the α-cell. Largely overlooked is that a mixed nutrient challenge, which is more representative of typical human feeding, actually stimulates glucagon secretion. Thus, postprandial metabolism is associated with elevations, not decreases, in α-cell activity. This review discusses the recent advances in our understanding of how α-cells regulate metabolism, with a particular focus on the postprandial state. We highlight α- to β-cell communication, a term that describes how α-cell input into β-cells is a critical axis that regulates insulin secretion and glucose homeostasis. Finally, we discuss the open questions that have the potential to advance this field and continue to evolve our understanding of the role that α-cells play in postprandial metabolism.
Topics: Animals; Blood Glucose; Eating; Energy Metabolism; Glucagon; Glucagon-Secreting Cells; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Postprandial Period
PubMed: 32964214
DOI: 10.1210/endocr/bqaa169 -
Nutrients Apr 2022This review addresses the fasting vs. re-feeding effects of retinoic acid (RA) biosynthesis and functions, and sexually dimorphic RA actions. It also discusses other... (Review)
Review
This review addresses the fasting vs. re-feeding effects of retinoic acid (RA) biosynthesis and functions, and sexually dimorphic RA actions. It also discusses other understudied topics essential for understanding RA activities-especially interactions with energy-balance-regulating hormones, including insulin and glucagon, and sex hormones. This report will introduce RA homeostasis and hormesis to provide context. Essential context also will encompass RA effects on adiposity, muscle function and pancreatic islet development and maintenance. These comments provide background for explaining interactions among insulin, glucagon and cortisol with RA homeostasis and function. One aim would clarify the often apparent RA contradictions related to pancreagenesis vs. pancreas hormone functions. The discussion also will explore the adverse effects of RA on estrogen action, in contrast to the enhancing effects of estrogen on RA action, the adverse effects of androgens on RA receptors, and the RA induction of androgen biosynthesis.
Topics: Estrogens; Glucagon; Insulin; Receptors, Retinoic Acid; Tretinoin
PubMed: 35458115
DOI: 10.3390/nu14081553 -
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 -
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 -
Current Opinion in Gastroenterology Sep 2014This review highlights recent progress made in the field of pancreatic secretion. (Review)
Review
PURPOSE OF REVIEW
This review highlights recent progress made in the field of pancreatic secretion.
RECENT FINDINGS
This review summarizes a number of recent studies demonstrating the intracellular pathways by which hormones and neural inputs regulate pancreatic exocrine and endocrine secretion. In particular, the effects of vasoactive intestinal peptide and secretin on intra-acinar cell adenosine 3',5'-cyclic monophosphate are explored. Considerable attention is paid to regulation of β-cell function and includes studies detailing the mechanisms of regulation of insulin by somatostatin, serotonin, and melanocortins. These studies emphasize the critical role that hormonal, paracrine, and neural factors play in glucose homeostasis.
SUMMARY
Exocrine and endocrine pancreatic secretions are regulated by hormonal and neural mechanisms, and understanding these pathways will enable the discovery and design of new and improved therapies for prevention and control of diabetes and perhaps exocrine insufficiency.
Topics: Blood Glucose; Diabetes Mellitus; Hormones; Humans; Insulin; Insulin Secretion; Pancreas, Exocrine
PubMed: 25003603
DOI: 10.1097/MOG.0000000000000099 -
International Journal of Molecular... Dec 2016The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the... (Review)
Review
The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation.
Topics: Adipose Tissue; Gastrointestinal Hormones; Humans; Lipids; Muscles; Non-alcoholic Fatty Liver Disease; Pancreatic Hormones
PubMed: 27973438
DOI: 10.3390/ijms17122082 -
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