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Shah, Faraaz Ali, Hussain Mahmud, Teresa Gallego-Martin, Michael J. Jurczak, Christopher P. O’Donnell, and Bryan J. McVerry. "Therapeutic Effects of Endogenous Incretin Hormones and Exogenous Incretin-Based Medications in Sepsis." Journal of Clinical Endocrinology & Metabolism 104, no. 11 (June 19, 2019): 5274–84. http://dx.doi.org/10.1210/jc.2019-00296.
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Abstract Background Sepsis, a complex disorder characterized by a dysregulated immune response to an inciting infection, affects over one million Americans annually. Dysglycemia during sepsis hospitalization confers increased risk of organ dysfunction and death, and novel targets for the treatment of sepsis and maintenance of glucose homeostasis are needed. Incretin hormones are secreted by enteroendocrine cells in response to enteral nutrients and potentiate insulin release from pancreatic β cells in a glucose-dependent manner, thereby reducing the risk of insulin-induced hypoglycemia. Incretin hormones also reduce systemic inflammation in preclinical studies, but studies of incretins in the setting of sepsis are limited. Methods In this bench-to-bedside mini-review, we detail the evidence to support incretin hormones as a therapeutic target in patients with sepsis. We performed a PubMed search using the medical subject headings “incretins,” “glucagon-like peptide-1,” “gastric inhibitory peptide,” “inflammation,” and “sepsis.” Results Incretin-based therapies decrease immune cell activation, inhibit proinflammatory cytokine release, and reduce organ dysfunction and mortality in preclinical models of sepsis. Several small clinical trials in critically ill patients have suggested potential benefit in glycemic control using exogenous incretin infusions, but these studies had limited power and were performed in mixed populations. Further clinical studies examining incretins specifically in septic populations are needed. Conclusions Targeting the incretin hormone axis in sepsis may provide a means of not only promoting euglycemia in sepsis but also attenuating the proinflammatory response and improving clinical outcomes.
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Green, Brian D., Clifford J. Bailey, and Peter R. Flatt. "Gliptin Therapies for Inhibiting Dipeptidyl Peptidase-4 in Type 2 Diabetes." European Endocrinology 6, no. 2 (2010): 19. http://dx.doi.org/10.17925/ee.2010.06.02.19.
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Discovery of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) has led to the clinical development of incretin-based therapies for type 2 diabetes. Incretins are intestinal peptide hormones that stimulate post-prandial insulin secretion and improve glycaemic control. Gliptins are drugs that inhibit a ubiquitous enzyme, dipeptidyl peptidase-4 (DPP-4), preventing the physiological breakdown of incretins and thereby enhancing endogenous incretin action. Three ‘gliptins’ have recently been introduced into clinical practice: sitagliptin, vildagliptin and saxagliptin. This review provides an overview of these new antidiabetic agents and comments on some exciting future prospects for incretins and agents that enhance incretin action.
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Tsygankova, Oksana V., Varvara V. Veretyuk, and Alexander S. Ametov. "Incretins today: multiple effects and therapeutic potential." Diabetes mellitus 22, no. 1 (April 8, 2019): 70–78. http://dx.doi.org/10.14341/dm9841.
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Glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are the incretin hormones initially discovered in the 1960s. GIP and GLP-1 have gained great scientific interest due to their properties in increasing insulin secretion and lowering blood glucose levels. The study of these incretin hormones has progressed substantially in recent decades, in that their systemic effects has begun to be actively discussed. In particular, incretins are involved in the pathogenesis of obesity and non-alcoholic fatty liver disease. Moreover, incretins are able to improve cognitive function, suppress the formation of -amyloid plaques and provide an oncoprotective effect. Recent data show promising oncoprotective effect of GLP-1 agonists on prostate and breast cancer.
This review provides systematisation of recent data on the role and mechanisms of action of incretin hormones on carbohydrate metabolism, as well as effects not related to glucose homeostasis, which contributes to a better understanding of potential vectors for the development of incretinotropic therapy. In addition, this review offers insight into pathogenic prerequisites and highlights the current issues in creating innovative polyagonists for treatment of type 2 diabetes mellitus.
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Michałowska, Joanna, Ewa Miller-Kasprzak, and Paweł Bogdański. "Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective." Nutrients 13, no. 2 (January 25, 2021): 351. http://dx.doi.org/10.3390/nu13020351.
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The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in obesity and related metabolic disorders; therefore, incretin-based therapies have been developed to provide new therapeutic options. Incretin mimetics present glucose-lowering properties, together with a reduction of appetite and food intake, resulting in weight loss. In this review, we describe the physiology of two known incretins—glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and their role in obesity and related cardiometabolic disorders. We also focus on the available and incoming incretin-based medications that can be used in the treatment of the above-mentioned conditions.
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Deacon, CF, S. Wamberg, P. Bie, TE Hughes, and JJ Holst. "Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs." Journal of Endocrinology 172, no. 2 (February 1, 2002): 355–62. http://dx.doi.org/10.1677/joe.0.1720355.
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The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are degraded by dipeptidyl peptidase IV (DPP IV), thereby losing insulinotropic activity. DPP IV inhibition reduces exogenous GLP-1 degradation, but the extent of endogenous incretin protection has not been fully assessed, largely because suitable assays which distinguish between intact and degraded peptides have been unavailable. Using newly developed assays for intact GLP-1 and GIP, the effect of DPP IV inhibition on incretin hormone metabolism was examined. Conscious dogs were given NVP-DPP728, a specific DPP IV inhibitor, at a dose that inhibited over 90% of plasma DPP IV for the first 90 min following treatment. Total and intact incretin concentrations increased (P<0.0001) following a mixed meal, but on control days (vehicle infusion), intact peptide concentrations were lower (P<0.01) than total peptide concentrations (22.6 +/- 1.2% intact GIP; 10.1 +/- 0.4% intact GLP-1). Following inhibitor treatment, the proportion of intact peptide increased (92.5 +/- 4.3% intact GIP, P<0.0001; 99.0 +/- 22.6% intact GLP-1, P<0.02). Active (intact) incretins increased after NVP-DPP728 (from 4797 +/- 364 to 10 649 +/- 106 pM x min for GIP, P<0.03; from 646 +/- 134 to 2822 +/- 528 pM x m in for GLP-1, P<0.05). In contrast, total incretins fell (from 21 632 +/- 654 to 12 084 +/- 1723 pM x min for GIP, P<0.002; from 5145 +/- 677 to 3060 +/- 601 pM x min for GLP-1, P<0.05). Plasma glucose, insulin and glucagon concentrations were unaltered by the inhibitor. We have concluded that DPP IV inhibition with NVP-DPP728 prevents N-terminal degradation of endogenous incretins in vivo, resulting in increased plasma concentrations of intact, biologically active GIP and GLP-1. Total incretin secretion was reduced by DPP IV inhibition, suggesting the possibility of a feedback mechanism.
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Ørskov, Jens Juul Holst, Cathrine. "Incretin hormones - an update." Scandinavian Journal of Clinical and Laboratory Investigation 61, no. 234 (January 2001): 75–85. http://dx.doi.org/10.1080/clb.61.234.75.85.
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Holst, Jens Juul, and Cathrine Ørskov. "Incretin hormones - an update." Scandinavian Journal of Clinical and Laboratory Investigation 61, no. 7 (November 10, 2001): 75–85. http://dx.doi.org/10.1080/713783697.
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Phillips, Liza K., and Johannes B. Prins. "Update on incretin hormones." Annals of the New York Academy of Sciences 1243, no. 1 (December 2011): E55—E74. http://dx.doi.org/10.1111/j.1749-6632.2012.06491.x.
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Efendic, S., and N. Portwood. "Overview of Incretin Hormones." Hormone and Metabolic Research 36, no. 11/12 (November 2004): 742–46. http://dx.doi.org/10.1055/s-2004-826157.
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Holst, Jens Juul, and Cathrine Ørskov. "Incretin hormones – an update." Scandinavian Journal of Clinical and Laboratory Investigation 61, no. 7 (November 10, 2001): 75–85. http://dx.doi.org/10.1080/003655101317095455.
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Park, Jiyoung, In-Seung Lee, Kang-Hoon Kim, Yumi Kim, Eun-Jin An, and Hyeung-Jin Jang. "GI inflammation Increases Sodium-Glucose Cotransporter Sglt1." International Journal of Molecular Sciences 20, no. 10 (May 23, 2019): 2537. http://dx.doi.org/10.3390/ijms20102537.
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A correlation between gastrointestinal (GI) inflammation and gut hormones has reported that inflammatory stimuli including bacterial endotoxins, lipopolysaccharides (LPS), TNFα, IL-1β, and IL-6 induces high levels of incretin hormone leading to glucose dysregulation. Although incretin hormones are immediately secreted in response to environmental stimuli, such as nutrients, cytokines, and LPS, but studies of glucose-induced incretin secretion in an inflamed state are limited. We hypothesized that GI inflammatory conditions induce over-stimulated incretin secretion via an increase of glucose-sensing receptors. To confirm our hypothesis, we observed the alteration of glucose-induced incretin secretion and glucose-sensing receptors in a GI inflammatory mouse model, and we treated a conditioned media (Mϕ 30%) containing inflammatory cytokines in intestinal epithelium cells and enteroendocrine L-like NCI-H716 cells. In GI-inflamed mice, we observed that over-stimulated incretin secretion and insulin release in response to glucose and sodium glucose cotransporter (Sglt1) was increased. Incubation with Mϕ 30% increases Sglt1 and induces glucose-induced GLP-1 secretion with increasing intracellular calcium influx. Phloridzin, an sglt1 inhibitor, inhibits glucose-induced GLP-1 secretion, ERK activation, and calcium influx. These findings suggest that the abnormalities of incretin secretion leading to metabolic disturbances in GI inflammatory disease by an increase of Sglt1.
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Salvatore, Teresa, Riccardo Nevola, Pia Clara Pafundi, Lucio Monaco, Carmen Ricozzi, Simona Imbriani, Luca Rinaldi, and Ferdinando Carlo Sasso. "Incretin Hormones: The Link between Glycemic Index and Cardiometabolic Diseases." Nutrients 11, no. 8 (August 13, 2019): 1878. http://dx.doi.org/10.3390/nu11081878.
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This review aimed to describe the potential mechanisms by which incretin hormones could mediate the relationship between glycemic index and cardiometabolic diseases. A body of evidence from many studies suggests that low glycemic index (GI) diets reduces the risk for type 2 diabetes and coronary heart disease. In fact, despite the extensive literature on this topic, the mechanisms underlying unfavorable effects of high GI foods on health remain not well defined. The postprandial and hormonal milieu could play a key role in the relationship between GI and cardiovascular risk. Incretin hormones, glucagon-like peptide1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are important regulators of postprandial homeostasis by amplifying insulin secretory responses. Response of GIP and GLP-1 to GI have been studied more in depth, also by several studies on isomaltulose, which have been taken as an ideal model to investigate the kinetics of incretin secretion in response to foods’ GI. In addition, extrapancreatic effects of these incretin hormones were also recently observed. Emerging from this have been exciting effects on several targets, such as body weight regulation, lipid metabolism, white adipose tissue, cardiovascular system, kidney, and liver, which may importantly affect the health status.
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Myat, A., S. R. Redwood, B. J. Gersh, D. M. Yellon, and M. S. Marber. "Diabetes, incretin hormones and cardioprotection." Heart 100, no. 19 (April 19, 2014): 1550–61. http://dx.doi.org/10.1136/heartjnl-2012-303242.
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Hansen, Polly A., and John A. Corbett. "Incretin hormones and insulin sensitivity." Trends in Endocrinology & Metabolism 16, no. 4 (May 2005): 135–36. http://dx.doi.org/10.1016/j.tem.2005.03.002.
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Drucker, Daniel J. "The biology of incretin hormones." Cell Metabolism 3, no. 3 (March 2006): 153–65. http://dx.doi.org/10.1016/j.cmet.2006.01.004.
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Ahrén, B., J. Gromada, and O. Schmitz. "Incretin Hormones and Insulin Secretion." Hormone and Metabolic Research 36, no. 11/12 (November 2004): 733–34. http://dx.doi.org/10.1055/s-2004-826153.
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Jørgensen, Morten B., Thomas Idorn, Casper Rydahl, Henrik P. Hansen, Iain Bressendorff, Lisbet Brandi, Nicolai J. Wewer Albrechtsen, et al. "Effect of the Incretin Hormones on the Endocrine Pancreas in End-Stage Renal Disease." Journal of Clinical Endocrinology & Metabolism 105, no. 3 (October 14, 2019): e564-e574. http://dx.doi.org/10.1210/clinem/dgz048.
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Abstract Context The insulin-stimulating and glucagon-regulating effects of the 2 incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), contribute to maintain normal glucose homeostasis. Impaired glucose tolerance occurs with high prevalence among patients with end-stage renal disease (ESRD). Objective To evaluate the effect of the incretin hormones on endocrine pancreatic function in patients with ESRD. Design and Setting Twelve ESRD patients on chronic hemodialysis and 12 matched healthy controls, all with normal oral glucose tolerance test, were included. On 3 separate days, a 2-hour euglycemic clamp followed by a 2-hour hyperglycemic clamp (3 mM above fasting level) was performed with concomitant infusion of GLP-1 (1 pmol/kg/min), GIP (2 pmol/kg/min), or saline administered in a randomized, double-blinded fashion. A 30% lower infusion rate was used in the ESRD group to obtain comparable incretin hormone plasma levels. Results During clamps, comparable plasma glucose and intact incretin hormone concentrations were achieved. The effect of GLP-1 to increase insulin concentrations relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (50 [8–72]%, P = 0.03). Similarly, the effect of GIP relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (34 [13–50]%, P = 0.005). Glucagon was suppressed in both groups, with controls reaching lower concentrations than ESRD patients. Conclusions The effect of incretin hormones to increase insulin release is reduced in ESRD, which, together with elevated glucagon levels, could contribute to the high prevalence of impaired glucose tolerance among ESRD patients.
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Zalunin, I. A., A. S. Asrarkulova, and D. G. Kozlov. "Incretin Analogues in Therapy of Type 2 Diabetes and Obesity." Biotekhnologiya 37, no. 3 (2021): 53–64. http://dx.doi.org/10.21519/0234-2758-2021-37-3-53-64.
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Type 2 diabetes is one the most common metabolic diseases, which are obviously the price to pay for lifestyle changes in most people. Dangerous in itself, this disease provokes other metabolic disorders such as obesity, and neurodegenerative diseases, such as Alzheimer's disease. Pharmacologists are very active in creating drugs for these illnesses. The design of synthetic highly active analogues of incretins, peptide hormones produced by neuroendocrine cells, is one of the most promising research areas. Glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide are the best known incretin hormones. Analogues of the first peptide have already found application in medical practice. The next step in the creation of drugs for diabetes was the development of polyagonists, which combine the properties of several different peptide hormones responsible for glucose homeostasis. The combination of the properties of incretins gives hopes for a synergism net effect. In the past few years, the creation of such coagonists has been very fast. In some cases, the results of clinical trials have already been obtained; however, they often contradict each other. Making clear this difficult situation was the main motivation for writing the present review. incretins, glucan-like peptide-1, glucose-dependant insulintropic polypeptide, agonism, antagonism, type 2 diabetes, obesity
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Ríos, José-Luis, Isabel Andújar, Guillermo R. Schinella, and Flavio Francini. "Modulation of Diabetes by Natural Products and Medicinal Plants via Incretins." Planta Medica 85, no. 11/12 (May 7, 2019): 825–39. http://dx.doi.org/10.1055/a-0897-7492.
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AbstractIncretins are metabolic hormones released after a meal that increase insulin secretion from pancreatic β-cells. The two main incretins are the intestinal peptides glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Both induce a decrease in glycemia, slow down the absorption of nutrients, and are inactivated by the enzyme dipeptidyl peptidase-4. Recently, incretin-based therapies have become a useful tool to treat diabetic patients, and different studies have focused on the identification of glucagon-like peptide-1 receptor agonists, including those of natural origin. This review focuses on the new findings of medicinal plants and natural products as possible active agents on the potentiation of incretin receptor signaling. Among these, soluble fiber from species of Plantago and guar gum show promising effects, iridoid derivatives are relevant activators of incretin receptors, and derivatives of cyanidin, especially diglycosylated ones, are an interesting source of dipeptidyl peptidase-4 inhibitors.
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Alemdar, Serkan, Nusret Yilmaz, Sebahat Ozdem, and Ramazan Sari. "Incretin levels in patients with hypothyroidism and the evaluation of incretin levels alterations with treatment." Asian Biomedicine 13, no. 1 (December 19, 2019): 3–9. http://dx.doi.org/10.1515/abm-2019-0033.
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Abstract Background Incretin hormones may influence the effects of thyroid hormones on insulin secretion, insulin resistance, and glucose metabolism. Thyroid hormones regulate insulin secretion, and the risk of diabetes was found to be associated with thyroid hormones. Objectives To determine whether incretin hormones influence the effects of thyroid hormones on insulin resistance and glucose metabolism. Methods A total of 26 patients were included in 2 groups consisting of 13 patients with hypothyroidism and 13 healthy controls. Levels of glucose, insulin, glucagon-like peptide 1 (GLP-1), and gastric inhibitory polypeptide (GIP) levels were measured in 0, 30, 60, 90, and 120th min during the oral glucose tolerance test in the control group and before and after thyroxine treatment in the hypothyroid group. Results In the hypothyroid group, waist circumference decreased after the euthyroid state was achieved (P = 0.026). No statistically significant differences were detected in the GLP-1 and GIP levels at baseline and 30, 60, 90, and 120 min between the hypothyroidism and control groups or after ensuring the euthyroid state in patients with hypothyroidism. Peak GLP-1 levels were observed at 30 min in the control group, whereas peak GLP-1 and GIP levels were detected at 90 min in the hypothyroidism group. After achieving the euthyroid state, peak GLP-1 and GIP levels were detected at 30 min as well. Conclusion In patients with hypothyroidism, the incretin hormones, especially the peak response of the incretin system, are significantly affected. Significant changes were observed in the incretin system by correcting hypothyroidism.
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Ryan, Michael J. "Have a heart: failure to increase GLP-1 caused by heart failure increases the risk of diabetes." Clinical Science 134, no. 23 (December 2020): 3119–21. http://dx.doi.org/10.1042/cs20201029.
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Abstract Incretins represent a group of gut-derived peptide hormones that, at physiological concentrations, potentiate the release of insulin. Work leading to the discovery of incretins began as early as the late 1800s where scientists, including Claude Bernard who is widely considered the father of modern physiology (Rehfeld, J.F. The Origin and Understanding of the Incretin Concept. Front. Endocrinol. (Lausanne) (2018) 9, 387; Robin, E.D. Claude Bernard. Pioneer of regulatory biology. JAMA (1979) 242, 1283–1284), attempted to understand the pancreas as an important organ in the development of diabetes mellitus and blood glucose control. After the seminal work of Paulescu and Banting and Best in the early 1920s that led to the discovery of insulin (Murray I. Paulesco and the isolation of insulin. J. Hist. Med. Allied Sci. (1971) 26, 150–157; Raju T.N. The Nobel Chronicles. 1923: Frederick G. Banting (1891–1941), John J.R. Macleod (1876–1935). Lancet (1998) 352, 1482), attention was turned toward understanding gastrointestinal factors that might regulate insulin secretion. A series of experiments by Jean La Barre showed that a specific fraction of intestinal extract caused a reduction in blood glucose. La Barre posited that the fraction’s glucose lowering actions occurred by increasing insulin release, after which he coined the term ‘incretin’. In the 1970s, the first incretin was purified, glucose insulinotropic polypeptide (GIP) (Gupta K. and Raja A. Physiology, Gastric Inhibitory Peptide StatPearls Treasure Island (FL); 2020), followed by the discovery of a second incretin in the 1980s, glucagon-like peptide-1 (GLP-1). Interest and understanding of the incretins, has grown since that time.
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Boer, Geke Aline, and Jens Juul Holst. "Incretin Hormones and Type 2 Diabetes—Mechanistic Insights and Therapeutic Approaches." Biology 9, no. 12 (December 16, 2020): 473. http://dx.doi.org/10.3390/biology9120473.
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Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the gut upon nutrient stimulation and regulate postprandial metabolism. These hormones are known as classical incretin hormones and are responsible for a major part of postprandial insulin release. The incretin effect is severely reduced in patients with type 2 diabetes, but it was discovered that administration of GLP-1 agonists was capable of normalizing glucose control in these patients. Over the last decades, much research has been focused on the development of incretin-based therapies for type 2 diabetes. These therapies include incretin receptor agonists and inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-4. Especially the development of diverse GLP-1 receptor agonists has shown immense success, whereas studies of GIP monotherapy in patients with type 2 diabetes have consistently been disappointing. Interestingly, both GIP-GLP-1 co-agonists and GIP receptor antagonists administered in combination with GLP-1R agonists appear to be efficient with respect to both weight loss and control of diabetes, although the molecular mechanisms behind these effects remain unknown. This review describes our current knowledge of the two incretin hormones and the development of incretin-based therapies for treatment of type 2 diabetes.
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Seimon, Radhika V., Ixchel M. Brennan, Antonietta Russo, Tanya J. Little, Karen L. Jones, Scott Standfield, Judith M. Wishart, Michael Horowitz, and Christine Feinle-Bisset. "Gastric emptying, mouth-to-cecum transit, and glycemic, insulin, incretin, and energy intake responses to a mixed-nutrient liquid in lean, overweight, and obese males." American Journal of Physiology-Endocrinology and Metabolism 304, no. 3 (February 1, 2013): E294—E300. http://dx.doi.org/10.1152/ajpendo.00533.2012.
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Observations relating to the impact of obesity on gastric emptying (GE) and the secretion of gut hormones are inconsistent, probably because of a lack of studies in which GE, gastrointestinal hormone release, and energy intake (EI) have been evaluated concurrently with previous patterns of nutrient intake. GE is known to be a major determinant of postprandial glycemia and incretin secretion in health and type 2 diabetes. The aims of this study were to determine the effects of a mixed-nutrient drink on GE, oro-cecal transit, blood glucose, insulin and incretin concentrations and EI, and the relationship between the glycemic response to the drink with GE in lean, overweight, and obese subjects. Twenty lean, 20 overweight, and 20 obese males had measurements of GE, oro-cecal transit, and blood glucose, insulin, GLP-1, and GIP concentrations for 5 h after ingestion of a mixed-nutrient drink (500 ml, 532 kcal); EI at a subsequent buffet lunch was determined. Habitual EI was also quantified. Glycemic and insulinemic responses to the drink were greater in the obese (both P < 0.05) when compared with both lean and overweight, with no significant differences in GE, intragastric distribution, oro-cecal transit, incretins, or EI (buffet lunch or habitual) between groups. The magnitude of the rise in blood glucose after the drink was greater when GE was relatively more rapid ( r = −0.55, P < 0.05). In conclusion, in the absence of differences in habitual EI, both GE and incretin hormones are unaffected in the obese despite greater glucose and insulin responses, and GE is a determinant of postprandial glycemia.
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Fehmann, Hans-Christoph, Roberto Gherzi, and Burkhard Göke. "Regulation of Islet Hormone Gene Expression by Incretin Hormones." Experimental and Clinical Endocrinology & Diabetes 103, S 02 (July 15, 2009): 56–65. http://dx.doi.org/10.1055/s-0029-1211395.
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Mahaseth, Rameshwar. "Incretin System: Recent Advances in Glucagon Like Peptide-1 and Dipeptidyl Peptidase-4 Inhibitors." Journal of Patan Academy of Health Sciences 1, no. 1 (July 20, 2015): 36–42. http://dx.doi.org/10.3126/jpahs.v1i1.13015.
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The endogenous incretins, glucose-dependent insulinotropic polypeptide and Glucagon-like peptide, are peptide hormones secreted from endocrine cells in the small intestine. Glucagon-like peptide-1 stimulates insulin and suppresses glucagon secretion, delays gastric emptying, and reduces appetite and food intake, which explains the positive effect of incretin mimetics on weight. The incretins have also been shown to have a sustained improvement in glycemic control over three years. A wide range of cardiovascular benefits have also been claimed, such as lowering of blood pressure and postprandial lipids. Clinical trials with the incretin mimetic exenatide and liraglutide show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (1–2%), associated with weight loss (2–5 kg). The most common adverse event associated with Glucagon-like peptide-1 receptor agonists is nausea, which lessens over time. Orally administered Dipeptidyl Peptidase-4 inhibitors reduce hemoglobin A1c by 0·5–1·0%, with few adverse effects and no weight gain. These new classes of anti-diabetic agents also expand β-cell mass in preclinical studies. However, long-term clinical studies are still needed to determine the benefits of incretin for the treatment of type 2 diabetes. DOI: http://dx.doi.org/10.3126/jpahs.v1i1.13015 Journal of Patan Academy of Health Sciences. 2014 Jun;1(1):36-42
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Moriya, Ryuichi, Takashi Shirakura, Junko Ito, Satoshi Mashiko, and Toru Seo. "Activation of sodium-glucose cotransporter 1 ameliorates hyperglycemia by mediating incretin secretion in mice." American Journal of Physiology-Endocrinology and Metabolism 297, no. 6 (December 2009): E1358—E1365. http://dx.doi.org/10.1152/ajpendo.00412.2009.
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Glucose ingestion stimulates the secretion of the incretin hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). Despite the critical role of incretins in glucose homeostasis, the mechanism of glucose-induced incretin secretion has not been established. We investigated the underlying mechanism of glucose-induced incretin secretion in vivo in mice. Injection of glucose at 1 g/kg in the upper intestine significantly increased plasma GIP and GLP-1 levels, whereas injection of glucose in the colon did not increase GIP or GLP-1 levels. This finding indicates that the glucose sensor for glucose-induced incretin secretion is in the upper intestine. Coadministration of a sodium-glucose cotransporter-1 (SGLT1) inhibitor, phloridzin, with glucose in the upper intestine blocked glucose absorption and glucose-induced incretin secretion. α-methyl-d-glucopyranoside (MDG), an SGLT1 substrate that is a nonmetabolizable sugar, significantly increased plasma GIP and GLP-1 levels, whereas phloridzin blocked these increases, indicating that concomitant transport of sodium ions and glucose (substrate) via SGLT1 itself triggers incretin secretion without the need for subsequent glucose metabolism. Interestingly, oral administration of MDG significantly increased plasma GIP, GLP-1, and insulin levels and reduced blood glucose levels during an intraperitoneal glucose tolerance test. Furthermore, chronic MDG treatment in drinking water (3%) for 13 days reduced blood glucose levels after a 2-h fast and in an oral glucose tolerance test in diabetic db/db mice. Our findings indicate that SGLT1 serves as the intestinal glucose sensor for glucose-induced incretin secretion and that a noncalorigenic SGLT1 substrate ameliorates hyperglycemia by stimulating incretin secretion.
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Dicembrini, Ilaria, Edoardo Mannucci, and Carlo Maria Rotella. "Bone: Incretin Hormones Perceiver or Receiver?" Experimental Diabetes Research 2012 (2012): 1–5. http://dx.doi.org/10.1155/2012/519784.
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Novel incretin-based drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i), have been last introduced in the pharmacological treatment of type 2 diabetes. In the last few years, the interest on the relationship of gut hormones with bone metabolism in diabetes has been increasing. The aim of present paper is to examinein vitroandin vivoevidence on the connections between incretin hormones and bone metabolism. We also discuss results of clinical trials and metaanalysis, explore the effects of incretin drugsin vitroon osteogenic cells and osteoclasts, and speculate on the possibility of different effects of GLP-1 RA and DPP-4i on the risk of bone fractures risk in humans. Although existing preliminary evidence suggests a protective effect on the bone, at least for DPP-4i, further controlled, long-term studies with measurement of bone markers, bone density, and clinical fractures rates are needed to substantiate and confirm those findings.
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Terry, Natalie A., Erik R. Walp, Randall A. Lee, Klaus H. Kaestner, and Catherine Lee May. "Impaired enteroendocrine development in intestinal-specificIslet1mouse mutants causes impaired glucose homeostasis." American Journal of Physiology-Gastrointestinal and Liver Physiology 307, no. 10 (November 15, 2014): G979—G991. http://dx.doi.org/10.1152/ajpgi.00390.2013.
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Enteroendocrine cells secrete over a dozen different hormones responsible for coordinating digestion, absorption, metabolism, and gut motility. Loss of enteroendocrine cells is a known cause of severe congenital diarrhea. Furthermore, enteroendocrine cells regulate glucose metabolism, with the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) playing critical roles in stimulating insulin release by pancreatic β-cells. Islet1 (Isl1) is a LIM-homeodomain transcription factor expressed specifically in an array of intestinal endocrine cells, including incretin-expressing cells. To examine the impact of intestinal Isl1 on glycemic control, we set out to explore the role of intestinal Isl1 in hormone cell specification and organismal physiology. Mice with intestinal epithelial-specific ablation of Isl1 were obtained by crossing Villin-Cre transgenic animals with mice harboring a Isl1loxPallele ( Isl1intmodel). Gene ablation of Isl1 in the intestine results in loss of GLP-1, GIP, cholecystokinin (CCK), and somatostatin-expressing cells and an increase in 5-HT (serotonin)-producing cells, while the chromogranin A population was unchanged. This dramatic change in hormonal milieu results in animals with lipid malabsorption and females smaller than their littermate controls. Interestingly, when challenged with oral, not intraperitoneal glucose, the Isl-1 intestinal-deficient animals ( Isl1int) display impaired glucose tolerance, indicating loss of the incretin effect. Thus the Isl1intmodel confirms that intestinal biology is essential for organism physiology in glycemic control and susceptibility to diabetes.
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Cardoso, João Felipe R., Célia Cohen, Fernanda J. Medeiros, Fabiano M. Serfaty, and Mario F. T. Neves. "Perspectives of incretin mimetics in cardiovascular diseases." Brazilian Journal of Health and Biomedical Sciences 20, no. 1 (May 13, 2021): 55–62. http://dx.doi.org/10.12957/bjhbs.2021.59746.
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Introduction: Type 2 Diabetes (DM2) is a chronic conditionassociated with an increased risk of cardiovascular diseases,neuropathies, nephropathies and eye diseases. Incretins (GIPand GLP-1) are hormones important to insulin secretion, andtheir actions are compromised in DM2 patients. Objectives:This review considers the opportunities and challenges ofusing incretin mimetics in the treatment of DM2. Methods:Bibliographic review referring to the period from 2000 to2020, in electronic databases such as Scielo, Lilacs, PubMed,Web of Science. Results: Incretins stimulate insulin secretionby the pancreas in response to nutrient intake, with a lowerpotential to cause hypoglycemia. In addition, they have acardioprotective role, reducing blood pressure, improvingendothelial and myocardial function, and their use has beenassociated with a reduction in the risk of cardiovascularevents, including cardiovascular mortality. Clinical trialswith GLP-1R agonists (GLP-1RA) reduced albuminuria, increasednatriuresis, and decreased oxidative stress. In addition,treatment with incretin mimetics reduced the occurrence ofthe main cardiovascular outcomes related to atherosclerosis,promoted weight loss and improved lipid profile. Conclusion:Studies show the important role of incretin mimetics in thepathophysiology and treatment of DM2, with significanteffects in the cardiovascular system. However, its use must beevaluated in relation to its safety and to in which individualsthe benefits outweigh the risks associated with the treatment.Thus, its clinical relevance depends on studies with long-termfollow-up of patients, with analysis of its impact on mortalityand on the development of micro and macrovascularcomplications.
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Yoder, Stephanie M., Qing Yang, Tammy L. Kindel, and Patrick Tso. "Stimulation of incretin secretion by dietary lipid: is it dose dependent?" American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 2 (August 2009): G299—G305. http://dx.doi.org/10.1152/ajpgi.90601.2008.
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After the ingestion of nutrients, secretion of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) by the enteroendocrine cells increases rapidly. Previous studies have shown that oral ingestion of fat stimulates secretion of both incretins; however, it is unclear whether there is a dose-dependent relationship between the amount of lipid ingested and the secretion of the hormones in vivo. Recently, we found a higher concentration of the incretin hormones in intestinal lymph than in peripheral or portal plasma. We therefore used the lymph fistula rat model to test for a dose-dependent relationship between the secretion of GIP and GLP-1 and dietary lipid. Under isoflurane anesthesia, the major mesenteric lymphatic duct of male Sprague-Dawley rats was cannulated. Each animal received a single, intraduodenal bolus of saline or varying amounts of the fat emulsion Liposyn II (0.275, 0.55, 1.1, 2.2, and 4.4 kcal). Lymph was continuously collected for 3 h and analyzed for triglyceride, GIP, and GLP-1 content. In response to increasing lipid calories, secretion of triglyceride, GIP, and GLP-1 into lymph increased dose dependently. Interestingly, the response to changes in intraluminal lipid content was greater in GLP-1- than in GIP-secreting cells. The different sensitivities of the two cell types to changes in intestinal lipid support the concept that separate mechanisms may underlie lipid-induced GIP and GLP-1 secretion. Furthermore, we speculate that the increased sensitivity of GLP-1 to intestinal lipid content reflects the hormone's role in the ileal brake reflex. As lipid reaches the distal portion of the gut, GLP-1 is secreted in a dose-dependent manner to reduce intestinal motility and enhance proximal fat absorption.
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Holst, J. J. "Incretin hormones and the satiation signal." International Journal of Obesity 37, no. 9 (January 8, 2013): 1161–68. http://dx.doi.org/10.1038/ijo.2012.208.
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Druzhilov, M. A., T. Yu Kuznetsova, and G. A. Chumakova. "Multiagonists of the “incretin axis” as a promising tool for managing cardiometabolic risk in visceral obesity." Russian Journal of Cardiology 27, no. 4 (November 4, 2021): 4755. http://dx.doi.org/10.15829/29/1560-4071-2022-4755.
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Currently, the world experiences an increase in obesity prevalence, resulting in an increase in the incidence of diseases in which it is one of the leading factors, primarily type 2 diabetes and cardiovascular disease. This limits the effectiveness of preventive measures and determines the need to introduce more effective approaches. Evidence of the key role of intestinal peptide hormones (incretins) in the normalization of body weight and metabolic processes after bariatric interventions became the basis for studying pharmacological methods for treating obesity and related complications aimed at the “incretin axis”. In order to achieve greater efficacy compared to monotherapy with glucagon-like peptide-1 (GLP-1) agonists, studies are performed on unimolecular multiagonists developing on the basis of GLP-1 agonists and effecting on various components of the “incretin axis” by competitive activation of numerous receptors, in first of all, receptors for glucose-dependent insulinotropic polypeptide and glucagon. This review analyzes the results of clinical trials and discusses the prospects for introduction of “incretin axis” multi-agonists for patients with visceral obesity syndrome.
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Druzhilov, M. A., T. Yu Kuznetsova, and G. A. Chumakova. "Multiagonists of the “incretin axis” as a promising tool for managing cardiometabolic risk in visceral obesity." Russian Journal of Cardiology 27, no. 4 (November 4, 2021): 4755. http://dx.doi.org/10.15829/1560-4071-2022-4755.
Full textAbstract:
Currently, the world experiences an increase in obesity prevalence, resulting in an increase in the incidence of diseases in which it is one of the leading factors, primarily type 2 diabetes and cardiovascular disease. This limits the effectiveness of preventive measures and determines the need to introduce more effective approaches. Evidence of the key role of intestinal peptide hormones (incretins) in the normalization of body weight and metabolic processes after bariatric interventions became the basis for studying pharmacological methods for treating obesity and related complications aimed at the “incretin axis”. In order to achieve greater efficacy compared to monotherapy with glucagon-like peptide-1 (GLP-1) agonists, studies are performed on unimolecular multiagonists developing on the basis of GLP-1 agonists and effecting on various components of the “incretin axis” by competitive activation of numerous receptors, in first of all, receptors for glucose-dependent insulinotropic polypeptide and glucagon. This review analyzes the results of clinical trials and discusses the prospects for introduction of “incretin axis” multi-agonists for patients with visceral obesity syndrome.
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Tsimihodimos, Vasilis, and Moses Elisaf. "Incretins and Lipid Metabolism." Current Medicinal Chemistry 25, no. 18 (May 22, 2018): 2133–39. http://dx.doi.org/10.2174/0929867324666170414164244.
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Background: Recent findings indicate that incretin hormones and incretin-based therapies may affect the metabolism of lipoproteins, although the corresponding mechanisms are not clearly defined. Objective: To summarize the available data on the mechanisms linking incretins with the characteristics of serum lipoproteins and discuss the clinical implications of these relationships. Methods: PubMed was searched using the terms “incretins”, “GLP-1”, “GIP” and “lipids”, “dyslipidemia”, “triglycerides”, “apolipoprotein B48”. All articles published in the English language until June 2016 were assessed and the relevant information is presented here. Results: GLP-1, and therapies that increase its activity, exert a beneficial effect on lipoprotein metabolism that is translated in a reduction in the fasting and postprandial concentration of triglycerides and a small improvement in the concentration and function of HDLs. In addition, a shift towards larger, less atherogenic particles usually follows the administration of GLP-1 receptor agonists. The mechanisms that underlie these changes involve a direct effect of GLP- 1 on the hepatic and intestinal production of triglyceride-rich lipoproteins, the GLP-1 induced increase in the production and function of insulin, the activation of specific areas of central nervous system as well as the increase in the peripheral utilization of triglycerides for energy production. On the other hand, GLP-2 increases the absorption of dietary fat and the production of triglyceride-rich lipoproteins while the role of GIP on lipid metabolism remains indeterminate. Conclusion: GLP-1 and incretin-based therapies favorably affect lipid metabolism. These effects may contribute to the beneficial effects of incretin-based therapies on atherosclerosis and fatty liver disease.
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Edgerton, Dale S., Guillaume Kraft, Marta S. Smith, Lindsey M. Moore, Ben Farmer, Melanie Scott, Mary C. Moore, Michael A. Nauck, and Alan D. Cherrington. "Effect of portal glucose sensing on incretin hormone secretion in a canine model." American Journal of Physiology-Endocrinology and Metabolism 317, no. 2 (August 1, 2019): E244—E249. http://dx.doi.org/10.1152/ajpendo.00100.2019.
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It is unknown whether activation of hepato-portal vein (PV) glucose sensors plays a role in incretin hormone amplification of oral glucose-stimulated insulin secretion (GSIS). In previous studies, PV glucose infusion increased GSIS through unknown mechanisms, perhaps neural stimulation of pancreatic β-cells and/or stimulation of gut incretin hormone release. Thus, there could be a difference in the incretin effect when comparing GSIS with portal rather than leg vein (LV) glucose infusion. Plasma insulin and incretin hormones were studied in six overnight-fasted dogs. An oral glucose tolerance test (OGTT) was administered, and then 1 and 2 wk later the arterial plasma glucose profile from the OGTT was mimicked by infusing glucose into either the PV or a LV. The arterial glucose levels were nearly identical between groups (AUCs within 1% of each other). Oral glucose administration increased arterial GLP-1 and GIP levels by more than sixfold, whereas they were not elevated by PV or LV glucose infusion. Oral glucose delivery was associated with only a small incretin effect (arterial insulin and C-peptide were 21 ± 23 and 24 ± 17% greater, respectively, during the 1st hour with oral compared with PV glucose and 14 ± 37 and 13 ± 35% greater, respectively, in oral versus LV; PV versus LV responses were not significantly different from each other). Thus, following an OGTT incretin hormone release did not depend on activation of PV glucose sensors, and the insulin response was not greater with PV compared with LV glucose infusion in the dog. The small incretin effect points to species peculiarities, which is perhaps related to diet.
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Carr, Richard D., Marianne O. Larsen, Maria Sörhede Winzell, Katarina Jelic, Ola Lindgren, Carolyn F. Deacon, and Bo Ahrén. "Incretin and islet hormonal responses to fat and protein ingestion in healthy men." American Journal of Physiology-Endocrinology and Metabolism 295, no. 4 (October 2008): E779—E784. http://dx.doi.org/10.1152/ajpendo.90233.2008.
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Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) regulate islet function after carbohydrate ingestion. Whether incretin hormones are of importance for islet function after ingestion of noncarbohydrate macronutrients is not known. This study therefore examined integrated incretin and islet hormone responses to ingestion of pure fat (oleic acid; 0.88 g/kg) or protein (milk and egg protein; 2 g/kg) over 5 h in healthy men, aged 20–25 yr ( n = 12); plain water ingestion served as control. Both intact (active) and total GLP-1 and GIP levels were determined as was plasma activity of dipeptidyl peptidase-4 (DPP-4). Following water ingestion, glucose, insulin, glucagon, GLP-1, and GIP levels and DPP-4 activity were stable during the 5-h study period. Both fat and protein ingestion increased insulin, glucagon, GIP, and GLP-1 levels without affecting glucose levels or DPP-4 activity. The GLP-1 responses were similar after protein and fat, whereas the early (30 min) GIP response was higher after protein than after fat ingestion ( P < 0.001). This was associated with sevenfold higher insulin and glucagon responses compared with fat ingestion (both P < 0.001). After protein, the early GIP, but not GLP-1, responses correlated to insulin ( r2= 0.86; P = 0.0001) but not glucagon responses. In contrast, after fat ingestion, GLP-1 and GIP did not correlate to islet hormones. We conclude that, whereas protein and fat release both incretin and islet hormones, the early GIP secretion after protein ingestion may be of primary importance to islet hormone secretion.
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Saprina, Tatiana V., Ekaterina S. Timokhina, Olga K. Goncharevich, Svetlana V. Budeeva, Tatiana S. Prokhorenko, Lyubov A. Tashireva, Nadezhda N. Musina, and Irina V. Dronova. "The associations of incretin hormone concentration with gestational diabetes mellitus." Diabetes mellitus 19, no. 2 (April 4, 2016): 150–57. http://dx.doi.org/10.14341/dm2004134-37.
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Background: Enteropancreatic hormonal system disorder is a possible reason for β-cell dysfunction and carbohydrate metabolism disorder among pregnant women. However, no information is available about the state of enteroinsulin hormones [glucagon, glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide1 (GLP-1) and GLP-2] during pregnancy. The role of enteroinsulin hormones in the development of carbohydrate metabolism disorder during pregnancy is poorly understood. Aim: To quantify and compare incretin hormone secretion in groups of pregnant women with and without gestational diabetes mellitus (GDM). Materials and methods: The study included 80 patients, 50 of whom had GDM, and the control group consisted of 30 pregnant women without GDM. All patients underwent an oral glucose tolerance test; glycated haemoglobin (HbA1c) estimation; ferritin, transferrin, basal and postprandial glucagon estimation; GLP-1 and GLP-2 estimation. Results: Basal glucagon and GLP-1 levels were significantly higher (p 0. 05) in the group of women with GDM than in the control group. The most significant differences in GLP-1, basal and postprandial glucagon levels were observed during the first trimester of pregnancy. Conclusion: High GLP-1 levels in the group of women with GDM may reflect a state of ‘incretin resistance’, which is similar to hyperinsulinemia in the early stages of type 2 diabetes mellitus.
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Demidova, T. Y., K. G. Lobanova, T. N. Korotkova, and L. D. Kharchilava. "Abnormal gut microbiota and impaired incretin effect as a cause of type 2 diabetes mellitus." Medical Herald of the South of Russia 13, no. 1 (March 28, 2022): 24–42. http://dx.doi.org/10.21886/2219-8075-2022-13-1-24-42.
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It has now been established that the intestinal microbiota (CM) is one of the 11 links in the pathogenesis of type 2 diabetes mellitus (DM2). Th e fact is that when the composition of BM is disrupted and the concentration of its active metabolites changes, the processes of synthesis and secretion of incretin hormones are disrupted, the homeostasis of carbohydrates and fats in the body is disrupted, the processes of central regulation of appetite change, chronic infl ammation and insulin resistance of peripheral tissues develop. Th is review discusses possible ways of impairing the synthesis of incretin hormones and the incretin eff ect in patients with T2DM through the prism of BM and its active metabolites, and discusses possible ways of correcting the altered composition of BM with incretin drugs.A systematic literature search was carried out using the Scopus, PubMed, Web of Science databases.
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Kitaura, Hideki, Saika Ogawa, Fumitoshi Ohori, Takahiro Noguchi, Aseel Marahleh, Yasuhiko Nara, Adya Pramusita, et al. "Effects of Incretin-Related Diabetes Drugs on Bone Formation and Bone Resorption." International Journal of Molecular Sciences 22, no. 12 (June 19, 2021): 6578. http://dx.doi.org/10.3390/ijms22126578.
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Patients with type 2 diabetes have an increased risk of fracture compared to the general population. Glucose absorption is accelerated by incretin hormones, which induce insulin secretion from the pancreas. The level of the incretin hormone, glucagon-like peptide-1 (GLP-1), shows an immediate postprandial increase, and the circulating level of intact GLP-1 is reduced rapidly by dipeptidyl peptidase-4 (DPP-4)-mediated inactivation. Therefore, GLP-1 receptor agonists and DPP-4 inhibitors are effective in the treatment of type 2 diabetes. However, these incretin-related diabetic agents have been reported to affect bone metabolism, including bone formation and resorption. These agents enhance the expression of bone markers, and have been applied to improve bone quality and bone density. In addition, they have been reported to suppress chronic inflammation and reduce the levels of inflammatory cytokine expression. Previously, we reported that these incretin-related agents inhibited both the expression of inflammatory cytokines and inflammation-induced bone resorption. This review presents an overview of current knowledge regarding the effects of incretin-related diabetes drugs on osteoblast differentiation and bone formation as well as osteoclast differentiation and bone resorption. The mechanisms by which incretin-related diabetes drugs regulate bone formation and bone resorption are also discussed.
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Li, Yanwei, Lin Li, and Christian Hölscher. "Incretin-based therapy for type 2 diabetes mellitus is promising for treating neurodegenerative diseases." Reviews in the Neurosciences 27, no. 7 (October 1, 2016): 689–711. http://dx.doi.org/10.1515/revneuro-2016-0018.
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AbstractIncretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Due to their promising action on insulinotropic secretion and improving insulin resistance (IR), incretin-based therapies have become a new class of antidiabetic agents for the treatment of type 2 diabetes mellitus (T2DM). Recently, the links between neurodegenerative diseases and T2DM have been identified in a number of studies, which suggested that shared mechanisms, such as insulin dysregulation or IR, may underlie these conditions. Therefore, the effects of incretins in neurodegenerative diseases have been extensively investigated. Protease-resistant long-lasting GLP-1 mimetics such as lixisenatide, liraglutide, and exenatide not only have demonstrated promising effects for treating neurodegenerative diseases in preclinical studies but also have shown first positive results in Alzheimer’s disease (AD) and Parkinson’s disease (PD) patients in clinical trials. Furthermore, the effects of other related incretin-based therapies such as GIP agonists, dipeptidyl peptidase-IV (DPP-IV) inhibitors, oxyntomodulin (OXM), dual GLP-1/GIP, and triple GLP-1/GIP/glucagon receptor agonists on neurodegenerative diseases have been tested in preclinical studies. Incretin-based therapies are a promising approach for treating neurodegenerative diseases.
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Mathiesen, David S., Jonatan I. Bagger, Natasha C. Bergmann, Asger Lund, Mikkel B. Christensen, Tina Vilsbøll, and Filip K. Knop. "The Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion—A Review." International Journal of Molecular Sciences 20, no. 17 (August 22, 2019): 4092. http://dx.doi.org/10.3390/ijms20174092.
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The gut-derived incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion. Furthermore, GLP-1 inhibits glucagon secretion when plasma glucose concentrations are above normal fasting concentrations while GIP acts glucagonotropically at low glucose levels. A dual incretin receptor agonist designed to co-activate GLP-1 and GIP receptors was recently shown to elicit robust improvements of glycemic control (mean haemoglobin A1c reduction of 1.94%) and massive body weight loss (mean weight loss of 11.3 kg) after 26 weeks of treatment with the highest dose (15 mg once weekly) in a clinical trial including overweight/obese patients with type 2 diabetes. Here, we describe the mechanisms by which the two incretins modulate alpha cell secretion of glucagon, review the effects of co-administration of GLP-1 and GIP on glucagon secretion, and discuss the potential role of glucagon in the therapeutic effects observed with novel unimolecular dual GLP-1/GIP receptor agonists. For clinicians and researchers, this manuscript offers an understanding of incretin physiology and pharmacology, and provides mechanistic insight into future antidiabetic and obesity treatments.
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Sonne, David P. "Glucometabolic gut hormones: beyond the incretin effect." Cardiovascular Endocrinology 5, no. 3 (September 2016): 68. http://dx.doi.org/10.1097/xce.0000000000000092.
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Perfetti, Riccardo, Traci A. Brown, Rita Velikina, and Steven Busselen. "Control of Glucose Homeostasis by Incretin Hormones." Diabetes Technology & Therapeutics 1, no. 3 (September 1999): 297–305. http://dx.doi.org/10.1089/152091599317215.
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Jacob, Jordan, Jared Rosenberg, and Joon Young Kim. "Incretin as a Pathophysiological Component and Target for Treatment in Youth Type 2 Diabetes (T2D)." JOHSK 1, no. 1 (October 31, 2020): 24–27. http://dx.doi.org/10.47544/johsk.2020.1.1.24.
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Incretin hormones have recently been considered an important pathophysiological factor for T2D in adults and youth due to their role in augmenting insulin secretion (Michaliszyn et al., 2014). It is recognized that glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are glucose-dependent hormones released from the gut that stimulate insulin release from pancreatic β-cells (Muscelli et al., 2006). Thus, the insulin response to oral glucose is significantly greater than the intravenous (IV) glucose administration response; this is known as the incretin effect (Michaliszyn et al., 2014). To date, adults with T2D demonstrate a remarkable decrease in the incretin effect (Nauck et al., 1986), whereas there is lack of evidence in pediatric populations. The incretin effect is also associated with β-cell glucose sensitivity (βCGS), attesting incretins as a high-promising target for T2D treatment (Michaliszyn et al., 2014). Utilizing GLP-1 receptor agonists can be advantageous as a therapeutic option for both adults and youth (Tamborlane et al., 2019; Vanderheiden et al., 2016; Yeow et al., 2017). While metformin and insulin were the sole treatment options for Y-T2D prior to FDA approval (in 2019) for the use of GLP-1 agonists, a recent RISE (Restoring Insulin Secretion) clinical trial reported disappointing results that both metformin alone and insulin glargine for three months followed by metformin for nine months were not effective in restoring/preserving β-cell function in youth with prediabetes and T2D (RISE Consortium & RISE Consortium Investigators, 2019). On the contrary, the role of GLP-1 and the efficacy of the GLP-1 receptors in T2D signifies a strong target for potential treatment. Additional clinical trials are warranted to see if monotherapy of GLP-1 agonist vs. combined (metformin + liraglutide) therapy is effective to reserve Y-T2D to prediabetes and/or normal state. More importantly, future research should focus on disease prevention rather than treatment to avoid aggressive complications and metabolic degradations of Y-T2D (RISE Consortium & RISE Consortium Investigators, 2019). Altogether, it would be germane to investigate whether lifestyle changes (diet, physical activity, exercise medicine) can improve the incretin effect in conjunction with glycemic control in youth.
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Cira, Duygu Kalkan, Ramazan Sari, Sebahat Ozdem, Nusret Yilmaz, and Selen Bozkurt. "GLP-1 and GIP Levels in Patients With Hyperthyroidism: The Effect of Antithyroid Treatment." Annals of Pharmacotherapy 51, no. 8 (April 28, 2017): 663–68. http://dx.doi.org/10.1177/1060028017707221.
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Background:Incretin hormones (glucagon-like peptide-1 [GLP-1] and gastric inhibitory polypeptide [GIP]) may play a role in the development of glucose intolerance and hyperglycemia in patients with hyperthyroidism. Objective: We aimed to assess both incretin levels and treatment-induced changes in incretin levels in those with hyperthyroidism. Methods: A total of 24 subjects (12 with hyperthyroidism and 12 healthy) were enrolled in the study. Oral glucose tolerance test was performed and serum glucose, insulin GLP1, and GIP levels were evaluated at 0 (baseline), 30, 60, 90, and 120 minutes using ELISA. Measurements were repeated after euthyroidism was reached in subjects with hyperthyroidism. Results: The baseline glucose level was higher in those with hyperthyroidism compared with controls ( P = 0.03). GLP-1 and GIP responses to oral glucose load did not differ significantly between those with hyperthyroidism and controls. Peak GLP-1 and GIP levels were reached in both groups at 60 and 90 minutes, respectively. Areas under the curve (AUCs) for GLP1 and GIP were similar in those with hyperthyroidism and controls. Although GLP-1 and GIP levels did not change before and after antithyroid treatment in subjects with hyperthyroidism, time to peak GLP-1 and GIP levels were reached at 30 minutes after euthyroid state was achieved. Reversal of hyperthyroid to euthyroid status did not induce significant changes in AUCs for incretins. Conclusion: The findings of the present study suggest that the total incretin response to oral glucose load is preserved in patients with hypertyhroidism, but peak incretin responses may change after achieving euthyroid state.
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Muscelli, Elza, Andrea Mari, Andrea Natali, Brenno D. Astiarraga, Stefania Camastra, Silvia Frascerra, Jens J. Holst, and Ele Ferrannini. "Impact of incretin hormones on β-cell function in subjects with normal or impaired glucose tolerance." American Journal of Physiology-Endocrinology and Metabolism 291, no. 6 (December 2006): E1144—E1150. http://dx.doi.org/10.1152/ajpendo.00571.2005.
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The mechanisms by which the enteroinsular axis influences β-cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C-peptide deconvolution to calculate insulin secretion rates and mathematical modeling to quantitate β-cell function. The incretin effect was taken to be the ratio of oral to IV responses. In NGT, incretin-mediated insulin release [oral glucose tolerance test (OGTT)/IV ratio = 1.59 ± 0.18, P = 0.004] amounted to 18 ± 2 nmol/m2 (32 ± 4% of oral response), and its time course matched that of total insulin secretion. The β-cell glucose sensitivity (OGTT/IV ratio = 1.52 ± 0.26, P = 0.02), rate sensitivity (response to glucose rate of change, OGTT/IV ratio = 2.22 ± 0.37, P = 0.06), and glucose-independent potentiation were markedly higher with oral than IV glucose. In IGT, β-cell glucose sensitivity (75 ± 14 vs. 156 ± 28 pmol·min−1·m−2·mM−1 of NGT, P = 0.01) and potentiation were impaired on the OGTT. The incretin effect was not significantly different from NGT in terms of plasma glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide responses, total insulin secretion, and enhancement of β-cell glucose sensitivity (OGTT/IV ratio = 1.73 ± 0.24, P = NS vs. NGT). However, the time courses of incretin-mediated insulin secretion and potentiation were altered, with a predominance of glucose-induced vs. incretin-mediated stimulation. We conclude that, under physiological circumstances, incretin-mediated stimulation of insulin secretion results from an enhancement of all dynamic aspects of β-cell function, particularly β-cell glucose sensitivity. In IGT, β-cell function is inherently impaired, whereas the incretin effect is only partially affected.
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Yaribeygi, Habib, Mina Maleki, Stephen L. Atkin, Tannaz Jamialahmadi, and Amirhossein Sahebkar. "Impact of Incretin-Based Therapies on Adipokines and Adiponectin." Journal of Diabetes Research 2021 (October 7, 2021): 1–9. http://dx.doi.org/10.1155/2021/3331865.
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Adipokines are a family of hormones and cytokines with both pro- and anti-inflammatory effects released into the circulation to exert their hormonal effects. Adipokines are closely involved in most metabolic pathways and play an important modulatory role in lipid and carbohydrate homeostasis as they are involved in the pathophysiology of most metabolic disorders. Incretin-based therapy is a newly introduced class of antidiabetic drugs that restores euglycemia through several cellular processes; however, its effect on adipokines expression/secretion is not fully understood. In this review, we propose that incretin-based therapy may function through adipokine modulation that may result in pharmacologic properties beyond their direct antidiabetic effects, resulting in better management of diabetes and diabetes-related complications.
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Salehi, Marzieh, Amalia Gastaldelli, and David A. D’Alessio. "Beta-cell sensitivity to insulinotropic gut hormones is reduced after gastric bypass surgery." Gut 68, no. 10 (February 16, 2019): 1838–45. http://dx.doi.org/10.1136/gutjnl-2018-317760.
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ObjectivePostprandial hyperinsulinaemia after Roux-en Y gastric bypass (GB) has been attributed to rapid nutrient flux from the gut, and an enhanced incretin effect. However, it is unclear whether surgery changes islet cell responsiveness to regulatory factors. This study tested the hypothesis that β-cell sensitivity to glucagon like-peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) is attenuated after GB.DesignTen non-diabetic subjects with GB, and 9 body mass index (BMI)-matched and age-matched non-surgical controls (CN) with normal glucose tolerance had blood glucose clamped at ~7.8 mM on three separate days. Stepwise incremental infusions of GLP-1 (15, 30, 60, 120 and 300 ng/LBkg/h), GIP (75, 150, 300, 600 and 1200 ng/LBkg/h) or saline were administered from 90 to 240 min and insulin secretion measured.ResultsGB subjects had similar fasting glucose levels but lower fasting insulin compared with CN, likely due to increased insulin clearance. The average insulin secretion rates (ISRs) to 7.8 mM glucose were ~30% lower in GB relative to CN subjects. However, incretin-stimulated ISRs, adjusted for insulin sensitivity and glucose-stimulated insulin secretion, were even more attenuated in the GB subjects, by threefold to fourfold (AUCISR(90−240 min) during GLP-1 and GIP: 47±8 and 44±12 nmol in GB and 116±16 and 161±44 in CN; p<0.01).ConclusionAfter GB, the sensitivity of insulin secretion to both glucose and incretins is diminished.
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Przezak, Agnieszka, Weronika Bielka, and Andrzej Pawlik. "Incretins in the Therapy of Diabetic Kidney Disease." International Journal of Molecular Sciences 22, no. 22 (November 15, 2021): 12312. http://dx.doi.org/10.3390/ijms222212312.
Full textAbstract:
Diabetic kidney disease is a microvascular complication that occurs in patients with diabetes. It is strongly associated with increased risk of kidney replacement therapy and all-cause mortality. Incretins are peptide hormones derived from the gastrointestinal tract, that besides causing enhancement of insulin secretion after oral glucose intake, participate in many other metabolic processes. Antidiabetic drug classes, such as dipeptidyl peptidase 4 inhibitors and glucagon-like peptide receptor agonists, which way of action is based on incretins facility, not only show glucose-lowering properties but also have nephroprotective functions. The aim of this article is to present the latest information about incretin-based therapy and its influence on diabetic kidney disease appearance and progression, point its potential mechanisms of kidney protection and focus on future therapeutic possibilities bound with these two antidiabetic drug classes.
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Fujita, Yukihiro, Rhonda D. Wideman, Madeleine Speck, Ali Asadi, David S. King, Travis D. Webber, Masakazu Haneda, and Timothy J. Kieffer. "Incretin release from gut is acutely enhanced by sugar but not by sweeteners in vivo." American Journal of Physiology-Endocrinology and Metabolism 296, no. 3 (March 2009): E473—E479. http://dx.doi.org/10.1152/ajpendo.90636.2008.
Full textAbstract:
Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are released during meals from endocrine cells located in the gut mucosa and stimulate insulin secretion from pancreatic β-cells in a glucose-dependent manner. Although the gut epithelium senses luminal sugars, the mechanism of sugar sensing and its downstream events coupled to the release of the incretin hormones are not clearly elucidated. Recently, it was reported that sucralose, a sweetener that activates the sweet receptors of taste buds, triggers incretin release from a murine enteroendocrine cell line in vitro. We confirmed that immunoreactivity of α-gustducin, a key G-coupled protein involved in taste sensing, is sometimes colocalized with GIP in rat duodenum. We investigated whether secretion of incretins in response to carbohydrates is mediated via taste receptors by feeding rats the sweet-tasting compounds saccharin, acesulfame potassium, d-tryptophan, sucralose, or stevia. Oral gavage of these sweeteners did not reduce the blood glucose excursion to a subsequent intraperitoneal glucose tolerance test. Neither oral sucralose nor oral stevia reduced blood glucose levels in Zucker diabetic fatty rats. Finally, whereas oral glucose increased plasma GIP levels ∼4-fold and GLP-1 levels ∼2.5-fold postadministration, none of the sweeteners tested significantly increased levels of these incretins. Collectively, our findings do not support the concept that release of incretins from enteroendocrine cells is triggered by carbohydrates via a pathway identical to the sensation of “sweet taste” in the tongue.