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Nutrient-Induced Cellular Mechanisms of Gut Hormone Secretion.
Lu, VB, Gribble, FM, Reimann, F
Nutrients. 2021;(3)
Abstract
The gastrointestinal tract can assess the nutrient composition of ingested food. The nutrient-sensing mechanisms in specialised epithelial cells lining the gastrointestinal tract, the enteroendocrine cells, trigger the release of gut hormones that provide important local and central feedback signals to regulate nutrient utilisation and feeding behaviour. The evidence for nutrient-stimulated secretion of two of the most studied gut hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), along with the known cellular mechanisms in enteroendocrine cells recruited by nutrients, will be the focus of this review. The mechanisms involved range from electrogenic transporters, ion channel modulation and nutrient-activated G-protein coupled receptors that converge on the release machinery controlling hormone secretion. Elucidation of these mechanisms will provide much needed insight into postprandial physiology and identify tractable dietary approaches to potentially manage nutrition and satiety by altering the secreted gut hormone profile.
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Potential for Gut Peptide-Based Therapy in Postprandial Hypotension.
Borg, MJ, Xie, C, Rayner, CK, Horowitz, M, Jones, KL, Wu, T
Nutrients. 2021;(8)
Abstract
Postprandial hypotension (PPH) is an important and under-recognised disorder resulting from inadequate compensatory cardiovascular responses to meal-induced splanchnic blood pooling. Current approaches to management are suboptimal. Recent studies have established that the cardiovascular response to a meal is modulated profoundly by gastrointestinal factors, including the type and caloric content of ingested meals, rate of gastric emptying, and small intestinal transit and absorption of nutrients. The small intestine represents the major site of nutrient-gut interactions and associated neurohormonal responses, including secretion of glucagon-like peptide-1, glucose-dependent insulinotropic peptide and somatostatin, which exert pleotropic actions relevant to the postprandial haemodynamic profile. This review summarises knowledge relating to the role of these gut peptides in the cardiovascular response to a meal and their potential application to the management of PPH.
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Evidence for the existence and potential roles of intra-islet glucagon-like peptide-1.
Campbell, SA, Johnson, J, Light, PE
Islets. 2021;(1-2):32-50
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Abstract
Glucagon-Like Peptide-1 (GLP-1) is an important peptide hormone secreted by L-cells in the gastrointestinal tract in response to nutrients. It is produced by the differential cleavage of the proglucagon peptide. GLP-1 elicits a wide variety of physiological responses in many tissues that contribute to metabolic homeostasis. For these reasons, therapies designed to either increase endogenous GLP-1 levels or introduce exogenous peptide mimetics are now widely used in the management of diabetes. In addition to GLP-1 production from L-cells, recent reports suggest that pancreatic islet alpha cells may also synthesize and secrete GLP-1. Intra-islet GLP-1 may therefore play an unappreciated role in islet health and glucose regulation, suggesting a potential functional paracrine role for islet-derived GLP-1. In this review, we assess the current literature from an islet-centric point-of-view to better understand the production, degradation, and actions of GLP-1 within the endocrine pancreas in rodents and humans. The relevance of intra-islet GLP-1 in human physiology is discussed regarding the potential role of intra-islet GLP-1 in islet health and dysfunction.
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Gut-Based Strategies to Reduce Postprandial Glycaemia in Type 2 Diabetes.
Kamruzzaman, M, Horowitz, M, Jones, KL, Marathe, CS
Frontiers in endocrinology. 2021;:661877
Abstract
Postprandial glycemic control is an important target for optimal type 2 diabetes management, but is often difficult to achieve. The gastrointestinal tract plays a major role in modulating postprandial glycaemia in both health and diabetes. The various strategies that have been proposed to modulate gastrointestinal function, particularly by slowing gastric emptying and/or stimulating incretin hormone GLP-1, are summarized in this review.
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5.
GLP-1 mimetics and cognition.
Yaribeygi, H, Rashidy-Pour, A, Atkin, SL, Jamialahmadi, T, Sahebkar, A
Life sciences. 2021;:118645
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of antidiabetic drugs that improve the glycaemia via several molecular pathways. Recent evidence suggest that they also have additional effects modulating pathophysiologic pathways included in cognitive disorders. Since some forms of cognitive dysfunction such as Alzheimer's disease are more common among diabetic patients than in the normal population, antidiabetic drugs that have neuroprotective effects affording protection for cognitive disorders would be of benefit. Therefore, we reviewed the pharmacologic effects of GLP-1 analogues and found that they may have the additional benefit of improving cognitive performance via at least eight molecular mechanisms.
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6.
GLP-1 and insulin regulation of skeletal and cardiac muscle microvascular perfusion in type 2 diabetes.
Love, KM, Liu, J, Regensteiner, JG, Reusch, JEB, Liu, Z
Journal of diabetes. 2020;(7):488-498
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Abstract
Muscle microvasculature critically regulates skeletal and cardiac muscle health and function. It provides endothelial surface area for substrate exchange between the plasma compartment and the muscle interstitium. Insulin fine-tunes muscle microvascular perfusion to regulate its own action in muscle and oxygen and nutrient supplies to muscle. Specifically, insulin increases muscle microvascular perfusion, which results in increased delivery of insulin to the capillaries that bathe the muscle cells and then facilitate its own transendothelial transport to reach the muscle interstitium. In type 2 diabetes, muscle microvascular responses to insulin are blunted and there is capillary rarefaction. Both loss of capillary density and decreased insulin-mediated capillary recruitment contribute to a decreased endothelial surface area available for substrate exchange. Vasculature expresses abundant glucagon-like peptide 1 (GLP-1) receptors. GLP-1, in addition to its well-characterized glycemic actions, improves endothelial function, increases muscle microvascular perfusion, and stimulates angiogenesis. Importantly, these actions are preserved in the insulin resistant states. Thus, treatment of insulin resistant patients with GLP-1 receptor agonists may improve skeletal and cardiac muscle microvascular perfusion and increase muscle capillarization, leading to improved delivery of oxygen, nutrients, and hormones such as insulin to the myocytes. These actions of GLP-1 impact skeletal and cardiac muscle function and systems biology such as functional exercise capacity. Preclinical studies and clinical trials involving the use of GLP-1 receptor agonists have shown salutary cardiovascular effects and improved cardiovascular outcomes in type 2 diabetes mellitus. Future studies should further examine the different roles of GLP-1 in cardiac as well as skeletal muscle function.
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7.
Risk factor reduction in type 2 diabetes demands a multifactorial approach.
Rydén, L, Ferrannini, G, Mellbin, L
European journal of preventive cardiology. 2019;(2_suppl):81-91
Abstract
Dysglycaemia (i.e. type 2 diabetes mellitus or impaired glucose tolerance) is not only common in patients with cardiovascular disease but increases the risk for future cardiovascular complications. Hyperglycaemia, the hallmark of diabetes, has since long been considered to be the link between diabetes and cardiovascular disease. Diabetes is, however, a complex, multifactorial disorder to which, for example, insulin resistance, endothelial dysfunction and factors such as increased thrombogenicity, hypertension and dyslipidaemia contribute. Thus, treatment needs to be multifactorial and to take cardiovascular aspects into account. Life-style adjustments are, together with blood pressure, lipid and glucose control, important parts of such management. Recent trial data reveal a beneficial effect on cardiovascular prognosis and mortality of blood glucose lowering agents belonging to the classes: sodium-glucose-transporter 2 inhibitors and glucagon-like peptide 1 agonists. The precise mechanisms by which certain sodium-glucose-transporter 2 inhibitors and glucagon-like peptide receptor agonists lead to these beneficial effects are only partly understood. An important impact of the benefits of sodium-glucose-transporter 2 inhibitors is a reduction in heart failure while glucagon-like peptide receptor agonists may retard the development of atherosclerotic vascular disease or stabilising plaques. Although there has been a considerable improvement in the prognosis for people with atherosclerotic diseases over the last decades there is still a gap between those with dysglycaemia, who are at higher risk, than those without dysglycaemia. This residual risk is reasonably related to two major factors: a demand for improved management and a need for new and improved therapeutic opportunities of type 2 diabetes, both routes to an improved prognosis that are at hands. This review is a comprehensive description of the possibilities to improve the prognosis for patients with dysglycaemia by a multifactorial management according to the most recent European guidelines issued in 2019 by the European Society of Cardiology in collaboration with the European Association for the Study of Diabetes.
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The effect of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 agonists on cardiovascular disease in patients with type 2 diabetes.
Dey, AK, Groenendyk, J, Mehta, NN, Gourgari, E
Clinical cardiology. 2019;(3):406-412
Abstract
Patients with type 2 diabetes have a significantly increased risk of cardiovascular disease (CVD) compared to the general population-with CVD accounting for two out of every three deaths in patients with diabetes. In 2008, the FDA suggested that CVD risk should be evaluated for any new antidiabetic therapy, leading to a multitude of large CVD outcome trials to assess CVD risk from these medications. Interestingly, several of these outcome trials with new novel antidiabetic therapies have demonstrated a clear and definite CVD advantage at mid-term follow up in high-risk patients with T2DM. In this review, we discuss two relatively new classes of diabetic drugs, sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 agonists, and their efficacy in improving cardiovascular outcomes.
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9.
The incretin system in healthy humans: The role of GIP and GLP-1.
Holst, JJ
Metabolism: clinical and experimental. 2019;:46-55
Abstract
The incretin effect, the amplification of insulin secretion occurring when glucose is taken in orally as compared to infused intravenously, is one of the factors that help the body to tolerate carbohydrate/glucose ingestion. These include 1) amount and type of carbohydrates; 2) gastric emptying rate; 3) digestion and absorption of the carbohydrates; 4) secretion and effect of the incretin hormones; 5) disposition of absorbed nutrients/glucose. The incretin effect can also be viewed as the fraction of the ingested glucose load handled via gastrointestinal mechanisms (including the incretin effect); it is calculated by comparison of the amount of glucose required to copy, by intravenous infusion, the oral load. Typically, for 75 g of oral glucose, about 25 g are required. This means that the GastroIntestinal Glucose Disposal (GIGD) is 66%. Both the GIGD and the incretin effect depend on the amount of glucose ingested: for higher doses the GIGD may amount to 80%, which shows that this effect is a major contributor to glucose tolerance. The main mechanism behind it is stimulation of insulin secretion by a proportional secretion of the insulinotropic hormones GIP and GLP-1. Recently it has become possible to estimate their contributions in healthy humans using specific and potent receptor antagonists. Both hormones act to improve glucose tolerance (i.e. the antagonists impair tolerance) and their effects are additive. GIP seems to be quantitatively the most important, particularly regarding insulin secretion, whereas the action of GLP-1 is mainly displayed via inhibition of glucagon secretion.
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A role for Glucagon-Like Peptide-1 in the regulation of β-cell autophagy.
Arden, C
Peptides. 2018;:85-93
Abstract
Autophagy is a highly conserved intracellular recycling pathway that serves to recycle damaged organelles/proteins or superfluous nutrients during times of nutritional stress to provide energy to maintain intracellular homeostasis and sustain core metabolic functions. Under these conditions, autophagy functions as a cell survival mechanism but impairment of this pathway can lead to pro-death stimuli. Due to their role in synthesising and secreting insulin, pancreatic β-cells have a high requirement for robust degradation pathways. Recent research suggests that functional autophagy is required to maintain β-cell survival and function in response to high fat diet suggesting a pro-survival role. However, a role for autophagy has also been implicated in the pathogenesis of type 2 diabetes. Thus, the pro-survival vs pro-death role of autophagy in regulating β-cell mass requires discussion. Emerging evidence suggests that Glucagon-Like Peptide-1 (GLP-1) may exert beneficial effects on glucose homeostasis via autophagy-dependent pathways both in pancreatic β-cells and in other cell types. The aim of the current review is to: i) summarise the literature surrounding β-cell autophagy and its pro-death vs pro-survival role in regulating β-cell mass; ii) review the literature describing the impact of GLP-1 on β-cell autophagy and in other cell types; iii) discuss the potential underlying mechanisms.