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Mechanisms of the Regulation and Dysregulation of Glucagon Secretion.
Onyango, AN
Oxidative medicine and cellular longevity. 2020;:3089139
Abstract
Glucagon, a hormone secreted by pancreatic alpha cells, contributes to the maintenance of normal blood glucose concentration by inducing hepatic glucose production in response to declining blood glucose. However, glucagon hypersecretion contributes to the pathogenesis of type 2 diabetes. Moreover, diabetes is associated with relative glucagon undersecretion at low blood glucose and oversecretion at normal and high blood glucose. The mechanisms of such alpha cell dysfunctions are not well understood. This article reviews the genesis of alpha cell dysfunctions during the pathogenesis of type 2 diabetes and after the onset of type 1 and type 2 diabetes. It unravels a signaling pathway that contributes to glucose- or hydrogen peroxide-induced glucagon secretion, whose overstimulation contributes to glucagon dysregulation, partly through oxidative stress and reduced ATP synthesis. The signaling pathway involves phosphatidylinositol-3-kinase, protein kinase B, protein kinase C delta, non-receptor tyrosine kinase Src, and phospholipase C gamma-1. This knowledge will be useful in the design of new antidiabetic agents or regimens.
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Therapies and outcomes of congenital hyperinsulinism-induced hypoglycaemia.
Banerjee, I, Salomon-Estebanez, M, Shah, P, Nicholson, J, Cosgrove, KE, Dunne, MJ
Diabetic medicine : a journal of the British Diabetic Association. 2019;(1):9-21
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Abstract
Congenital hyperinsulinism is a rare disease, but is the most frequent cause of persistent and severe hypoglycaemia in early childhood. Hypoglycaemia caused by excessive and dysregulated insulin secretion (hyperinsulinism) from disordered pancreatic β cells can often lead to irreversible brain damage with lifelong neurodisability. Although congenital hyperinsulinism has a genetic cause in a significant proportion (40%) of children, often being the result of mutations in the genes encoding the KATP channel (ABCC8 and KCNJ11), not all children have severe and persistent forms of the disease. In approximately half of those without a genetic mutation, hyperinsulinism may resolve, although timescales are unpredictable. From a histopathology perspective, congenital hyperinsulinism is broadly grouped into diffuse and focal forms, with surgical lesionectomy being the preferred choice of treatment in the latter. In contrast, in diffuse congenital hyperinsulinism, medical treatment is the best option if conservative management is safe and effective. In such cases, children receiving treatment with drugs, such as diazoxide and octreotide, should be monitored for side effects and for signs of reduction in disease severity. If hypoglycaemia is not safely managed by medical therapy, subtotal pancreatectomy may be required; however, persistent hypoglycaemia may continue after surgery and diabetes is an inevitable consequence in later life. It is important to recognize the negative cognitive impact of early-life hypoglycaemia which affects half of all children with congenital hyperinsulinism. Treatment options should be individualized to the child/young person with congenital hyperinsulinism, with full discussion regarding efficacy, side effects, outcomes and later life impact.
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The α-cell in diabetes mellitus.
Gromada, J, Chabosseau, P, Rutter, GA
Nature reviews. Endocrinology. 2018;(12):694-704
Abstract
Findings from the past 10 years have placed the glucagon-secreting pancreatic α-cell centre stage in the development of diabetes mellitus, a disease affecting almost one in every ten adults worldwide. Glucagon secretion is reduced in patients with type 1 diabetes mellitus, increasing the risk of insulin-induced hypoglycaemia, but is enhanced in type 2 diabetes mellitus, exacerbating the effects of diminished insulin release and action on blood levels of glucose. A better understanding of the mechanisms underlying these changes is therefore an important goal. RNA sequencing reveals that, despite their opposing roles in the control of blood levels of glucose, α-cells and β-cells have remarkably similar patterns of gene expression. This similarity might explain the fairly facile interconversion between these cells and the ability of the α-cell compartment to serve as a source of new β-cells in models of extreme β-cell loss that mimic type 1 diabetes mellitus. Emerging data suggest that GABA might facilitate this interconversion, whereas the amino acid glutamine serves as a liver-derived factor to promote α-cell replication and maintenance of α-cell mass. Here, we survey these developments and their therapeutic implications for patients with diabetes mellitus.
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Glucagon revisited: Coordinated actions on the liver and kidney.
Bankir, L, Bouby, N, Speth, RC, Velho, G, Crambert, G
Diabetes research and clinical practice. 2018;:119-129
Abstract
Glucagon secretion is stimulated by a low plasma glucose concentration. By activating glycogenolysis and gluconeogenesis in the liver, glucagon contributes to maintain a normal glycemia. Glucagon secretion is also stimulated by the intake of proteins, and glucagon contributes to amino acid metabolism and nitrogen excretion. Amino acids are used for gluconeogenesis and ureagenesis, two metabolic pathways that are closely associated. Intriguingly, cyclic AMP, the second messenger of glucagon action in the liver, is released into the bloodstream becoming an extracellular messenger. These effects depend not only on glucagon itself but on the actual glucagon/insulin ratio because insulin counteracts glucagon action on the liver. This review revisits the role of glucagon in nitrogen metabolism and in disposal of nitrogen wastes. This role involves coordinated actions of glucagon on the liver and kidney. Glucagon influences the transport of fluid and solutes in the distal tubule and collecting duct, and extracellular cAMP influences proximal tubule reabsorption. These combined effects increase the fractional excretion of urea, sodium, potassium and phosphates. Moreover, the simultaneous actions of glucagon and extracellular cAMP are responsible, at least in part, for the protein-induced rise in glomerular filtration rate that contributes to a more efficient excretion of protein-derived end products.
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5.
Role of glucagon in protein catabolism.
Thiessen, SE, Gunst, J, Van den Berghe, G
Current opinion in critical care. 2018;(4):228-234
Abstract
PURPOSE OF REVIEW Glucagon is known as a key hormone in the control of glucose and amino acid metabolism. Critical illness is hallmarked by a profound alteration in glucose and amino acid metabolism, accompanied by muscle wasting and hypoaminoacidemia. Here we review novel insights in glucagon (patho)physiology and discuss the recently discovered role of glucagon in controlling amino acid metabolism during critical illness. RECENT FINDINGS The role of glucagon in glucose metabolism is much more complex than originally anticipated, and glucagon has shown to be a key player in amino acid metabolism. During critical illness, the contribution of glucagon in bringing about hyperglycemia appeared to be quite limited, whereas increased glucagon availability seems to contribute importantly to the typical hypoaminoacidemia via stimulating hepatic amino acid breakdown, without affecting muscle wasting. Providing amino acids further increases hepatic amino acid breakdown, mediated by a further increase in glucagon. SUMMARY Glucagon plays a crucial role in amino acid metabolism during critical illness, with an apparent feedback loop between glucagon and circulating amino acids. Indeed, elevated glucagon may, to a large extent, be responsible for the hypoaminoacidemia in the critically ill and infusing amino acids increases glucagon-driven amino acid breakdown in the liver. These novel insights further question the rationale for amino acid administration during critical illness.
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Glucagon treatment in type 1 diabetes -with focus on restoring plasma glucose during mild hypoglycemia
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Ranjan, A
Danish medical journal. 2018;(2)
Abstract
Type 1 diabetes is a chronic disease caused by an autoimmune destruction of the insulin-producing cells in the pancreas, leading to a condition with insulin deficiency and elevated blood glucose levels. Individuals with type 1 diabetes are therefore recommended to frequently inject insulin subcutaneously to keep near-normal blood glucose levels, preventing the progression and onset of diabetes-related complications, i.e. kidney failure, blindness, amputation, stroke and heart attack. Unfortunately, the intensified insulin therapy is associated with risk of hypoglycemia- impeding individuals from reaching recommended treatment goals. In this PhD thesis, we hypothesized that low-dose glucagon may complement existing insulin therapy in improving glucose control by treating and preventing mild hypoglycemia.
The aim was to determine whether low-dose glucagon could treat insulin-induced mild hypoglycemia sufficiently, and to investigate conditions that might impair the efficacy of glucagon. We showed that the glucose response to low-dose glucagon was dose-dependent but was impaired during high blood levels of insulin, after one week of low carbohydrate diet and perhaps 8-9 hours after ethanol intake. These findings are clinically relevant when blood glucose levels are controlled through insulin and glucagon delivery.
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7.
Current Therapies That Modify Glucagon Secretion: What Is the Therapeutic Effect of Such Modifications?
Grøndahl, MF, Keating, DJ, Vilsbøll, T, Knop, FK
Current diabetes reports. 2017;(12):128
Abstract
PURPOSE OF REVIEW Hyperglucagonemia contributes significantly to hyperglycemia in type 2 diabetes and suppressed glucagon levels may increase the risk of hypoglycemia. Here, we give a brief overview of glucagon physiology and the role of glucagon in the pathophysiology of type 2 diabetes and provide insights into how antidiabetic drugs influence glucagon secretion as well as a perspective on the future of glucagon-targeting drugs. RECENT FINDINGS Several older as well as recent investigations have evaluated the effect of antidiabetic agents on glucagon secretion to understand how glucagon may be involved in the drugs' efficacy and safety profiles. Based on these findings, modulation of glucagon secretion seems to play a hitherto underestimated role in the efficacy and safety of several glucose-lowering drugs. Numerous drugs currently available to diabetologists are capable of altering glucagon secretion: metformin, sulfonylurea compounds, insulin, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 inhibitors and amylin mimetics. Their diverse effects on glucagon secretion are of importance for their individual efficacy and safety profiles. Understanding how these drugs interact with glucagon secretion may help to optimize treatment.
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8.
Glucose-dependent insulinotropic polypeptide: effects on insulin and glucagon secretion in humans.
Christensen, MB
Danish medical journal. 2016;(4)
Abstract
The hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted by enteroendocrine cells in the intestinal mucosa in response to nutrient ingestion. They are called incretin hormones because of their ability to enhance insulin secretion. However, in recent years it has become clear that the incretin hormones also affect glucagon secretion. While GLP-1 decreases glucagon levels, the effect of GIP on glucagon levels has been unclear. The regulation of glucagon secretion is interesting, as the combination of inadequate insulin secretion and excessive glucagon secretion are essential contributors to the hyperglycaemia that characterise patients with type 2 diabetes. Moreover, the near absence of a well-timed glucagon response contributes to an increased risk of hypoglycaemia in patients with type 1 diabetes. The overall aim of this PhD thesis was to investigate how the blood glucose level affects the glucagon and insulin responses to GIP in healthy subjects (Study 1) and patients with Type 2 diabetes (Study 2), and more specifically to investigate the effects of GIP and GLP-1 at low blood glucose in patients with Type 1 diabetes without endogenous insulin secretion (Study 3). The investigations in the three mentioned study populations have been described in three original articles. The employed study designs were in randomised, placebo-controlled, crossover set-up, in which the same research subject is subjected to several study days thereby acting as his own control. Interventions were intravenous administration of hormones GIP, GLP-1 and placebo (saline) during different blood glucose levels maintained (clamped) at a certain level. The end-points were plasma concentrations of glucagon and insulin as well as the amount of glucose used to clamp the blood glucose levels. In Study 3, we also used stable glucose isotopes to estimate the endogenous glucose production and assessed symptoms and cognitive function during hypoglycaemia. The results from the three studies indicate that GIP has effects on insulin and glucagon responses highly dependent upon the blood glucose levels. At fasting glycaemia and lower levels of glycaemia, GIP acts to increase glucagon with little effect on insulin release. At hyperglycaemia the insulin releasing effect of GIP prevail, which lead to an increase in glucose disposal by approximately 75% in healthy subjects (Study 1) and 25% in patients with Type 2 diabetes (Study 2) relative to placebo. After insulin-induced hypoglycaemia in patients with type 1 diabetes (Study 3), GIP increase glucagon release, which probably augments endogenous glucose production. This was associated with a reduced need for exogenously added glucose to prevent hypoglycaemia. In conclusion, the studies position GIP as a bifunctional blood glucose stabilising hormone that glucose-dependently regulates insulin and glucagon responses in humans.
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9.
Paracrine control of glucagon release by somatostatin (Review).
Malaisse, WJ
International journal of molecular medicine. 2014;(3):491-8
Abstract
Emphasis was recently placed on the modulation of glucagon secretion attributable to a paracrine effect of somatostatin. This review draws attention to prior findings related to such a view. The effects of nutrient secretagogues upon insulin, somatostatin and glucagon release by the perfused pancreas are first considered. Three examples of paradoxical secretory responses of insulin- and glucagon-producing cells are then given. Further experiments dealing with the possible role of somatostatin upon glucagon release and the relevance of pancreatic compartmentation are also presented. It is concluded that these prior findings provide, within limits, support to the postulated paracrine role of somatostatin in the control of glucagon secretion.
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10.
Nutrient regulation of glucagon secretion: involvement in metabolism and diabetes.
Marroquí, L, Alonso-Magdalena, P, Merino, B, Fuentes, E, Nadal, A, Quesada, I
Nutrition research reviews. 2014;(1):48-62
Abstract
Glucose homeostasis is precisely regulated by glucagon and insulin, which are released by pancreatic α- and β-cells, respectively. While β-cells have been the focus of intense research, less is known about α-cell function and the actions of glucagon. In recent years, the study of this endocrine cell type has experienced a renewed drive. The present review contains a summary of established concepts as well as new information about the regulation of α-cells by glucose, amino acids, fatty acids and other nutrients, focusing especially on glucagon release, glucagon synthesis and α-cell survival. We have also discussed the role of glucagon in glucose homeostasis and in energy and lipid metabolism as well as its potential as a modulator of food intake and body weight. In addition to the well-established action on the liver, we discuss the effects of glucagon in other organs, where the glucagon receptor is expressed. These tissues include the heart, kidneys, adipose tissue, brain, small intestine and the gustatory epithelium. Alterations in α-cell function and abnormal glucagon concentrations are present in diabetes and are thought to aggravate the hyperglycaemic state of diabetic patients. In this respect, several experimental approaches in diabetic models have shown important beneficial results in improving hyperglycaemia after the modulation of glucagon secretion or action. Moreover, glucagon receptor agonism has also been used as a therapeutic strategy to treat obesity.