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The Journal of Endocrinology Sep 2023Since the discovery of glucagon 100 years ago, the hormone and the pancreatic islet alpha cells that produce it have remained enigmatic relative to insulin-producing...
Since the discovery of glucagon 100 years ago, the hormone and the pancreatic islet alpha cells that produce it have remained enigmatic relative to insulin-producing beta cells. Canonically, alpha cells have been described in the context of glucagon's role in glucose metabolism in liver, with glucose as the primary nutrient signal regulating alpha cell function. However, current data reveal a more holistic model of metabolic signalling, involving glucagon-regulated metabolism of multiple nutrients by the liver and other tissues, including amino acids and lipids, providing reciprocal feedback to regulate glucagon secretion and even alpha cell mass. Here we describe how various nutrients are sensed, transported and metabolised in alpha cells, providing an integrative model for the metabolic regulation of glucagon secretion and action. Importantly, we discuss where these nutrient-sensing pathways intersect to regulate alpha cell function and highlight key areas for future research.
Topics: Glucagon; Glucagon-Secreting Cells; Glucose; Signal Transduction; Liver; Insulin
PubMed: 37523232
DOI: 10.1530/JOE-23-0081 -
Signal Transduction and Targeted Therapy Apr 2023Disease modifying therapies aiming to preserve β-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking. Here, we conducted a multi-centre,... (Randomized Controlled Trial)
Randomized Controlled Trial
Disease modifying therapies aiming to preserve β-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking. Here, we conducted a multi-centre, randomized, controlled trial to assess the β-cell preservation effects of saxagliptin alone and saxagliptin combined with vitamin D as adjunctive therapies in adult-onset autoimmune type 1 diabetes. In this 3-arm trial, 301 participants were randomly assigned to a 24-month course of the conventional therapy (metformin with or without insulin) or adjunctive saxagliptin or adjunctive saxagliptin plus vitamin D to the conventional therapy. The primary endpoint was the change from baseline to 24 months in the fasting C-peptide. The secondary endpoints included the area under the concentration-time curve (AUC) for C-peptide level in a 2-h mixed-meal tolerance test, glycemic control, total daily insulin use and safety, respectively. The primary endpoint was not achieved in saxagliptin plus vitamin D group (P = 0.18) and saxagliptin group (P = 0.26). However, compared with the conventional therapy, 2-h C-peptide AUC from 24 months to baseline decreased less with saxagliptin plus vitamin D (-276 pmol/L vs. -419 pmol/L; P = 0.01), and not to the same degree with saxagliptin alone (-314 pmol/L; P = 0.14). Notably, for participants with higher glutamic acid decarboxylase antibody (GADA) levels, the decline of β-cell function was much lower in saxagliptin plus vitamin D group than in the conventional therapy group (P = 0.001). Insulin dose was significantly reduced in both active treatment groups than in the conventional therapy group despite all groups having similar glycemic control. In conclusion, the combination of saxagliptin and vitamin D preserves pancreatic β-cell function in adult-onset autoimmune type 1 diabetes, an effect especially efficacious in individuals with higher GADA levels. Our results provide evidence for a novel adjunct to insulin and metformin as potential initial treatment for adult-onset type 1 diabetes. (ClinicalTrials.gov identifier: NCT02407899).
Topics: Humans; Adult; Hypoglycemic Agents; Diabetes Mellitus, Type 1; Vitamin D; C-Peptide; Blood Glucose; Drug Therapy, Combination; Diabetes Mellitus, Type 2; Metformin; Insulin
PubMed: 37076476
DOI: 10.1038/s41392-023-01369-9 -
Peptides Feb 2022Glucose homeostasis is maintained by the glucoregulatory hormones, glucagon, insulin and somatostatin, secreted from the islets of Langerhans. Glucagon is the body's... (Review)
Review
Glucose homeostasis is maintained by the glucoregulatory hormones, glucagon, insulin and somatostatin, secreted from the islets of Langerhans. Glucagon is the body's most important anti-hypoglycemic hormone, mobilizing glucose from glycogen stores in the liver in response to fasting, thus maintaining plasma glucose levels within healthy limits. Glucagon secretion is regulated by both circulating nutrients, hormones and neuronal inputs. Hormones that may regulate glucagon secretion include locally produced insulin and somatostatin, but also urocortin-3, amylin and pancreatic polypeptide, and from outside the pancreas glucagon-like peptide-1 and 2, peptide tyrosine tyrosine and oxyntomodulin, glucose-dependent insulinotropic polypeptide, neurotensin and ghrelin, as well as the hypothalamic hormones arginine-vasopressin and oxytocin, and calcitonin from the thyroid. Each of these hormones have distinct effects, ranging from regulating blood glucose, to regulating appetite, stomach emptying rate and intestinal motility, which makes them interesting targets for treating metabolic diseases. Awareness regarding the potential effects of the hormones on glucagon secretion is important since secretory abnormalities could manifest as hyperglycemia or even lethal hypoglycemia. Here, we review the effects of each individual hormone on glucagon secretion, their interplay, and how treatments aimed at modulating the plasma levels of these hormones may also influence glucagon secretion and glycemic control.
Topics: Animals; Blood Glucose; Calcitonin; Gastric Inhibitory Polypeptide; Ghrelin; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Insulin; Islet Amyloid Polypeptide; Neurotensin; Oxyntomodulin; Oxytocin; Pancreas; Pancreatic Polypeptide; Somatostatin; Urocortins; Vasopressins
PubMed: 34748791
DOI: 10.1016/j.peptides.2021.170683 -
The Journal of Endocrinology Sep 2023The year 2023 marks 100 years since publication of the first report of a hyperglycemic factor in pancreatic extracts which C P Kimball and John R Murlin named glucagon...
The year 2023 marks 100 years since publication of the first report of a hyperglycemic factor in pancreatic extracts which C P Kimball and John R Murlin named glucagon (from GLUCose AGONist). Glucagon has a range of profound effects on metabolism including, but not limited to, stimulation of hepatic glucose production. Dysregulation of glucagon secretion is a key feature of both major forms of diabetes, leading to the concept that diabetes is a bihormonal disorder. Still, the work to fully understand the production and biological effects of glucagon has proceeded at a slower pace compared to that of insulin. A recent resurgence of interest in the islet alpha (α) cell, the predominant site of glucagon production, has been facilitated in part by technological innovations. This work has led to significant developments in the field, from defining how alpha cells develop and how glucagon secretion from pancreatic alpha cells is regulated to determining the role of glucagon in metabolic homeostasis and the progression of both major forms of diabetes. In addition, glucagon is considered to be a promising target for diabetes therapy, with many new potential applications arising from research in this field. This collection of reviews, led by Guest Editors James Cantley, Vincent Poitout and Rebecca Hull-Meichle, is intended to capture the field's current understanding of glucagon and alpha cell biology, as well stimulate additional interest and research on this important hormone.
Topics: Glucagon; Anniversaries and Special Events; Insulin; Glucose; Glucagon-Secreting Cells
PubMed: 37194667
DOI: 10.1530/JOE-23-0138 -
Nature Chemical Biology Jul 2022Insulin and its related peptides are found throughout the animal kingdom, in which they serve diverse functions. This includes regulation of glucose homeostasis,... (Review)
Review
Insulin and its related peptides are found throughout the animal kingdom, in which they serve diverse functions. This includes regulation of glucose homeostasis, neuronal development and cognition. The surprising recent discovery that venomous snails evolved specialized insulins to capture fish demonstrated the nefarious use of this hormone in nature. Because of their streamlined role in predation, these repurposed insulins exhibit unique characteristics that have unraveled new aspects of the chemical ecology and structural biology of this important hormone. Recently, insulins were also reported in other venomous predators and pathogenic viruses, demonstrating the broader use of insulin by one organism to manipulate the physiology of another. In this Review, we provide an overview of the discovery and biomedical application of repurposed insulins and other hormones found in nature and highlight several unique insights gained from these unusual compounds.
Topics: Animals; Insulin; Insulins
PubMed: 35761080
DOI: 10.1038/s41589-022-01068-6 -
Peptides Oct 2020Amylin is a peptide hormone that is mainly known to be produced by pancreatic β-cells in response to a meal but amylin is also produced by brain cells in discrete brain... (Review)
Review
Amylin is a peptide hormone that is mainly known to be produced by pancreatic β-cells in response to a meal but amylin is also produced by brain cells in discrete brain areas albeit in a lesser amount. Amylin receptor (AMY) is composed of the calcitonin core-receptor (CTR) and one of the 3 receptor activity modifying protein (RAMP), thus forming AMY1-3; RAMP enhances amylin binding properties to the CTR. However, amylin receptor agonist such as salmon calcitonin is able to bind CTR alone. Peripheral amylin's main binding site is located in the area postrema (AP) which then propagate the signal to the nucleus of the solitary tract and lateral parabrachial nucleus (LPBN) and it is then transmitted to the forebrain areas such as central amygdala and bed nucleus of the stria terminalis. Amylin's activation of these different brain areas mediates eating and other metabolic pathways controlling energy expenditure and glucose homeostasis. Peripheral amylin can also bind in the arcuate nucleus of the hypothalamus where it acts independently of the AP to activate POMC and NPY neurons. Amylin activation of NPY neurons has been shown to be transmitted to LPBN neurons to act on eating while amylin POMC signaling affects energy expenditure and locomotor activity. While a large amount of experiments have already been conducted, future studies will have to further investigate how amylin is taken up by forebrain areas and deepen our understanding of amylin action on peripheral metabolism.
Topics: Animals; Appetite Depressants; Brain; Eating; Humans; Islet Amyloid Polypeptide; Pancreatic Hormones; Signal Transduction
PubMed: 32634450
DOI: 10.1016/j.peptides.2020.170366 -
Frontiers in Endocrinology 2021Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With... (Review)
Review
Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development.
Topics: Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Humans; Proglucagon
PubMed: 34093449
DOI: 10.3389/fendo.2021.689678 -
Reviews in Endocrine & Metabolic... Sep 2021Neuroendocrine neoplasms (NENs) comprise a broad spectrum of tumors with widely variable biological and clinical behavior. Primary tumor site, extent of disease, tumor... (Review)
Review
Neuroendocrine neoplasms (NENs) comprise a broad spectrum of tumors with widely variable biological and clinical behavior. Primary tumor site, extent of disease, tumor differentiation and expression of so matostatin receptors, proliferation and growth rates are the major prognostic factors that determine the therapeutic strategy. Treatment options for advanced disease have considerably expanded in recent years, particularly for well differentiated tumors (NETs). Novel drugs approved over the past decade in this context include somatostatin analogues and Lu-oxodotreotide for somatostatin-receptor-positive gastroenteropancreatic (GEP) NETs, sunitinib for pancreatic NETs (P-NETs), and everolimus for P-NETs and non-functioning lung or gastrointestinal NETs. Nevertheless, chemotherapy remains an essential component of the treatment armamentarium of patients with NENs, particularly of patients with P-NETs or those with bulky, symptomatic or rapidly progressive tumors (generally G3 or high-G2 NENs). In this manuscript we will comprehensively review available evidence related to the use of chemotherapy in lung and GEP NENs and will critically discuss its role in the treatment algorithm of this family of neoplasms.
Topics: Humans; Intestinal Neoplasms; Neuroendocrine Tumors; Pancreatic Neoplasms; Somatostatin; Stomach Neoplasms
PubMed: 33843007
DOI: 10.1007/s11154-021-09638-0 -
International Journal of Molecular... Feb 2023In recent years, there has been a significant increase in age-related diseases due to the improvement in life expectancy worldwide. The pancreas undergoes various... (Review)
Review
In recent years, there has been a significant increase in age-related diseases due to the improvement in life expectancy worldwide. The pancreas undergoes various morphological and pathological changes with aging, such as pancreatic atrophy, fatty degeneration, fibrosis, inflammatory cell infiltration, and exocrine pancreatic metaplasia. Meanwhile, these may predispose the individuals to aging-related diseases, such as diabetes, dyspepsia, pancreatic ductal adenocarcinoma, and pancreatitis, as the endocrine and exocrine functions of the pancreas are significantly affected by aging. Pancreatic senescence is associated with various underlying factors including genetic damage, DNA methylation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and inflammation. This paper reviews the alternations of morphologies and functions in the aging pancreas, especially β-cells, closely related to insulin secretion. Finally, we summarize the mechanisms of pancreatic senescence to provide potential targets for treating pancreatic aging-related diseases.
Topics: Humans; Diabetes Mellitus; Pancreas; Pancreas, Exocrine; Pancreatic Diseases; Pancreatic Hormones; Pancreatic Neoplasms; Aging
PubMed: 36834922
DOI: 10.3390/ijms24043513 -
Frontiers in Endocrinology 2022Neurotransmitters are signaling molecules secreted by neurons to coordinate communication and proper function among different sections in the central neural system (CNS)... (Review)
Review
Neurotransmitters are signaling molecules secreted by neurons to coordinate communication and proper function among different sections in the central neural system (CNS) by binding with different receptors. Some neurotransmitters as well as their receptors are found in pancreatic islets and are involved in the regulation of glucose homeostasis. Neurotransmitters can act with their receptors in pancreatic islets to stimulate or inhibit the secretion of insulin (β cell), glucagon (α cell) or somatostatin (δ cell). Neurotransmitter receptors are either G-protein coupled receptors or ligand-gated channels, their effects on blood glucose are mainly decided by the number and location of them in islets. Dysfunction of neurotransmitters receptors in islets is involved in the development of β cell dysfunction and type 2 diabetes (T2D).Therapies targeting different transmitter systems have great potential in the prevention and treatment of T2D and other metabolic diseases.
Topics: Diabetes Mellitus, Type 2; Glucagon; Glucagon-Secreting Cells; Humans; Insulin; Receptors, Neurotransmitter
PubMed: 35669692
DOI: 10.3389/fendo.2022.884549