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Jens J Holst - One of the best experts on this subject based on the ideXlab platform.
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Impaired beta cell sensitivity to Incretins in type 2 diabetes is insufficiently compensated by higher Incretin response.
Nutrition metabolism and cardiovascular diseases : NMCD, 2017Co-Authors: Andrea Tura, Jens J Holst, Tina Vilsbøll, Jonatan I. Bagger, Eleuterio Ferrannini, Filip K. Knop, A. MariAbstract:Abstract Background and aims The Incretin effect is impaired in type 2 diabetes (T2D), but the underlying mechanisms are only partially understood. We investigated the relationships between the time course of the Incretin effect and that of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during oral glucose tolerance tests (OGTTs), thereby estimating Incretin sensitivity of the beta cell, and its associated factors. Methods and results Eight patients with T2D and eight matched subjects with normal glucose tolerance (NGT) received 25, 75, and 125 g OGTTs and corresponding isoglycemic glucose infusions (IIGI). The time course of the Incretin effect, representing potentiation of insulin secretion by Incretins (PINCR), was determined by mathematical modelling as the time-dependent fold increase in insulin secretion during OGTT compared to IIGI. The time course of PINCR was correlated with that of both GIP and GLP-1 in each subject (median r = 0.67 in NGT and 0.45 in T2D). We calculated an individual beta cell sensitivity to Incretins (SINCR) using a weighted average of GIP and GLP-1 (pooled Incretin concentration, PIC), as the slope of the relationship between PINCR and PIC. SINCR was reduced in T2D (p Conclusion Relative Incretin insensitivity is partly compensated for by higher Incretin secretory responses. However, T2D shows both impairment in Incretin sensitivity and abnormal compensation by Incretin secretion.
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secretion of glucagon like peptide 1 glp 1 in type 2 diabetes what is up what is down
Diabetologia, 2011Co-Authors: M A Nauck, Jens J Holst, Carolyn F Deacon, Irfan Vardarli, Juris J MeierAbstract:The Incretin hormones gastric inhibitory polypeptide and especially glucagon-like peptide (GLP) have an important physiological function in augmenting postprandial insulin secretion. Since GLP-1 may play a role in the pathophysiology and treatment of type 2 diabetes, assessment of meal-related GLP-1 secretory responses in type 2 diabetic patients vs healthy individuals is of great interest. A common view states that GLP-1 secretion in patients with type 2 diabetes is deficient and that this applies to a lesser degree in individuals with impaired glucose tolerance. Such a deficiency is the rationale for replacing endogenous Incretins with GLP-1 receptor agonists or re-normalising active GLP-1 concentrations with dipeptidyl peptidase-4 inhibitors. This review summarises the literature on this topic, including a meta-analysis of published studies on GLP-1 secretion in individuals with and without diabetes after oral glucose and mixed meals. Our analysis does not support the contention of a generalised defect in nutrient-related GLP-1 secretory responses in type 2 diabetes patients. Rather, factors are identified that may determine individual Incretin secretory responses and explain some of the variations in published findings of group differences in GLP-1 responses to nutrient intake.
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the Incretin system and its role in type 2 diabetes mellitus
Molecular and Cellular Endocrinology, 2009Co-Authors: Jens J Holst, Tina Vilsbøll, Carolyn F DeaconAbstract:The Incretin hormones are released during meals from gut endocrine cells. They potentiate glucose-induced insulin secretion and may be responsible for up to 70% of postprandial insulin secretion. The Incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which may also promote proliferation/neogenesis of beta cells and prevent their decay (apoptosis). Both hormones contribute to insulin secretion from the beginning of a meal and their effects are progressively amplified as plasma glucose concentrations rise. The current interest in the Incretin hormones is due to the fact that the Incretin effect is severely reduced or absent in patients with type 2 diabetes mellitus (T2DM). In addition, there is hyperglucagonaemia, which is not suppressible by glucose. In such patients, the secretion of GIP is near normal, but its effect on insulin secretion, particularly the late phase, is severely impaired. The loss of GIP action is probably a consequence of diabetes, since it is also observed in patients with diabetes secondary to chronic pancreatitis, in whom the Incretin effect is also lost. GLP-1 secretion, on the other hand, is also impaired, but its insulinotropic and glucagon-suppressive actions are preserved, although the potency of GLP-1 in this respect is decreased compared to healthy subjects. However, in supraphysiological doses, GLP-1 administration may completely normalize beta as well as alpha cell sensitivity to glucose. The impaired action of GLP-1 and GIP in T2DM may be at least partly restored by improved glycaemic control, as shown in studies involving 4 weeks of intensive insulin therapy. The reduced Incretin effect is believed to contribute to impaired regulation of insulin and glucagon secretion in T2DM, and, in support of this, exogenous GLP-1 administration may restore blood glucose regulation to near normal levels. Thus, the pathogenesis of T2DM seems to involve a dysfunction of both Incretins. Enhancement of Incretin action may therefore represent a therapeutic solution. Clinical strategies therefore include the development of metabolically stable activators of the GLP-1 receptor; and inhibition of DPP-4, the enzyme that destroys native GLP-1 almost immediately. Orally active DPP-4 inhibitors and the metabolically stable activators, exenatide (Byetta), are now on the market, and numerous clinical studies have shown that both principles are associated with durable antidiabetic activity.
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glucagon like peptide 1 glucose homeostasis and diabetes
Trends in Molecular Medicine, 2008Co-Authors: Jens J Holst, Thure Krarup, Tina Vilsbøll, Carolyn F Deacon, Sten MadsbadAbstract:Incretins, enhancers of insulin secretion, are essential for glucose tolerance, and a reduction in their function might contribute to poor β-cell function in patients with type-2 diabetes mellitus. However, at supraphysiological doses, the Incretin glucagon-like peptide-1 (GLP-1) protects pancreatic β cells, and inhibits glucagon secretion, gastric emptying and food intake, leading to weight loss. GLP-1 mimetics, which are stable-peptide-based activators of the GLP-1 receptor, and Incretin enhancers, which inhibit the Incretin-degrading enzyme dipeptidyl peptidase-4, have emerged as therapies for type-2 diabetes and have recently reached the market. The pathophysiological basis the clinical use of these therapeutics is reviewed here.
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The physiology and pharmacology of Incretins in type 2 diabetes mellitus
Diabetes Obesity and Metabolism, 2008Co-Authors: Jens J HolstAbstract:Two Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1, help control blood glucose levels by affecting plasma insulin levels in response to oral glucose intake - this is known as the Incretin effect. Incretins increase plasma insulin by a number of mechanisms, most of which are mediated through GIP and GLP-1 receptors (GIPR and GLP-1R respectively). Incretins act through the pancreas to stimulate insulin release and can also act at the cellular level by increasing insulin gene transcription and insulin biosynthesis. Incretins can also lower plasma glucose through non-insulin routes including inhibition of gastric emptying and reduced food intake. In type 2 diabetes, the Incretin effect is reduced; as a result, insulin secretion is reduced and plasma glucose levels rise. However, the Incretin effect can be restored in such individuals by the administration of exogenous Incretins. Intravenous GLP-1 can stimulate insulin secretion, reduce glucagon secretion and normalize fasting plasma glucose in individuals with type 2 diabetes who were previously poorly controlled. The therapeutic potential of such agents is currently being explored.
Carolyn F Deacon - One of the best experts on this subject based on the ideXlab platform.
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a protein preload enhances the glucose lowering efficacy of vildagliptin in type 2 diabetes
Diabetes Care, 2016Co-Authors: Tongzhi Wu, Carolyn F Deacon, Tanya J Little, Michelle J Bound, Malcolm J Borg, Xiang Zhang, Michael Horowitz, Karen L Jones, Christopher K RaynerAbstract:OBJECTIVE Nutrient “preloads” given before meals can attenuate postprandial glycemic excursions, at least partly by slowing gastric emptying and stimulating secretion of the Incretins (i.e., glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]). This study was designed to evaluate whether a protein preload could improve the efficacy of the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin to increase Incretin concentrations, slow gastric emptying, and lower postprandial glycemia in type 2 diabetes. RESEARCH DESIGN AND METHODS Twenty-two patients with type 2 diabetes treated with metformin were studied on four occasions, receiving either 50 mg vildagliptin (VILD) or placebo (PLBO) on both the evening before and the morning of each study day. The latter dose was followed after 60 min by a preload drink containing either 25 g whey protein (WHEY) or control flavoring (CTRL), and after another 30 min by a 13 C-octanoate–labeled mashed potato meal. Plasma glucose and hormones, and gastric emptying, were evaluated. RESULTS Compared with PLBO/CTRL, PLBO/WHEY reduced postprandial peak glycemia, increased plasma insulin, glucagon, and Incretin hormones (total and intact), and slowed gastric emptying, whereas VILD/CTRL reduced both the peak and area under the curve for glucose, increased plasma intact Incretins, and slowed gastric emptying but suppressed plasma glucagon and total Incretins ( P P CONCLUSIONS In metformin-treated type 2 diabetes, a protein preload has the capacity to enhance the efficacy of vildagliptin to slow gastric emptying, increase plasma intact Incretins, and reduce postprandial glycemia.
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Physiology of Incretins in health and disease.
The review of diabetic studies : RDS, 2011Co-Authors: Carolyn F Deacon, Bo AhrénAbstract:The Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are gut peptides which are secreted by endocrine cells in the intestinal mucosa. Their plasma concentrations increase quickly following food ingestion, and carbohydrate, fat, and protein have all been shown to stimulate GLP-1 and GIP secretion. Although neural and hormonal mechanisms have also been proposed to regulate Incretin hormone secretion, direct stimulation of the enteroendocrine cells by the presence of nutrients in the intestinal lumen is probably the most important factor in humans. The actions of the Incretin hormones are crucial for maintaining normal islet function and glucose homeostasis. Furthermore, it is also now being recognized that Incretin hormones may have other actions in addition to their glucoregulatory effects. Studies have shown that GLP-1 and GIP levels and actions may be perturbed in disease states, but interpretation of the precise relationship between disease and Incretins is difficult. The balance of evidence seems to suggest that alterations in secretion and/or action of Incretin hormones arise secondarily to the development of insulin resistance, glucose intolerance, and/or increases in body weight rather than being causative factors. However, these impairments may contribute to the deterioration of glycemic control in diabetic patients.
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secretion of glucagon like peptide 1 glp 1 in type 2 diabetes what is up what is down
Diabetologia, 2011Co-Authors: M A Nauck, Jens J Holst, Carolyn F Deacon, Irfan Vardarli, Juris J MeierAbstract:The Incretin hormones gastric inhibitory polypeptide and especially glucagon-like peptide (GLP) have an important physiological function in augmenting postprandial insulin secretion. Since GLP-1 may play a role in the pathophysiology and treatment of type 2 diabetes, assessment of meal-related GLP-1 secretory responses in type 2 diabetic patients vs healthy individuals is of great interest. A common view states that GLP-1 secretion in patients with type 2 diabetes is deficient and that this applies to a lesser degree in individuals with impaired glucose tolerance. Such a deficiency is the rationale for replacing endogenous Incretins with GLP-1 receptor agonists or re-normalising active GLP-1 concentrations with dipeptidyl peptidase-4 inhibitors. This review summarises the literature on this topic, including a meta-analysis of published studies on GLP-1 secretion in individuals with and without diabetes after oral glucose and mixed meals. Our analysis does not support the contention of a generalised defect in nutrient-related GLP-1 secretory responses in type 2 diabetes patients. Rather, factors are identified that may determine individual Incretin secretory responses and explain some of the variations in published findings of group differences in GLP-1 responses to nutrient intake.
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the Incretin system and its role in type 2 diabetes mellitus
Molecular and Cellular Endocrinology, 2009Co-Authors: Jens J Holst, Tina Vilsbøll, Carolyn F DeaconAbstract:The Incretin hormones are released during meals from gut endocrine cells. They potentiate glucose-induced insulin secretion and may be responsible for up to 70% of postprandial insulin secretion. The Incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which may also promote proliferation/neogenesis of beta cells and prevent their decay (apoptosis). Both hormones contribute to insulin secretion from the beginning of a meal and their effects are progressively amplified as plasma glucose concentrations rise. The current interest in the Incretin hormones is due to the fact that the Incretin effect is severely reduced or absent in patients with type 2 diabetes mellitus (T2DM). In addition, there is hyperglucagonaemia, which is not suppressible by glucose. In such patients, the secretion of GIP is near normal, but its effect on insulin secretion, particularly the late phase, is severely impaired. The loss of GIP action is probably a consequence of diabetes, since it is also observed in patients with diabetes secondary to chronic pancreatitis, in whom the Incretin effect is also lost. GLP-1 secretion, on the other hand, is also impaired, but its insulinotropic and glucagon-suppressive actions are preserved, although the potency of GLP-1 in this respect is decreased compared to healthy subjects. However, in supraphysiological doses, GLP-1 administration may completely normalize beta as well as alpha cell sensitivity to glucose. The impaired action of GLP-1 and GIP in T2DM may be at least partly restored by improved glycaemic control, as shown in studies involving 4 weeks of intensive insulin therapy. The reduced Incretin effect is believed to contribute to impaired regulation of insulin and glucagon secretion in T2DM, and, in support of this, exogenous GLP-1 administration may restore blood glucose regulation to near normal levels. Thus, the pathogenesis of T2DM seems to involve a dysfunction of both Incretins. Enhancement of Incretin action may therefore represent a therapeutic solution. Clinical strategies therefore include the development of metabolically stable activators of the GLP-1 receptor; and inhibition of DPP-4, the enzyme that destroys native GLP-1 almost immediately. Orally active DPP-4 inhibitors and the metabolically stable activators, exenatide (Byetta), are now on the market, and numerous clinical studies have shown that both principles are associated with durable antidiabetic activity.
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glucagon like peptide 1 glucose homeostasis and diabetes
Trends in Molecular Medicine, 2008Co-Authors: Jens J Holst, Thure Krarup, Tina Vilsbøll, Carolyn F Deacon, Sten MadsbadAbstract:Incretins, enhancers of insulin secretion, are essential for glucose tolerance, and a reduction in their function might contribute to poor β-cell function in patients with type-2 diabetes mellitus. However, at supraphysiological doses, the Incretin glucagon-like peptide-1 (GLP-1) protects pancreatic β cells, and inhibits glucagon secretion, gastric emptying and food intake, leading to weight loss. GLP-1 mimetics, which are stable-peptide-based activators of the GLP-1 receptor, and Incretin enhancers, which inhibit the Incretin-degrading enzyme dipeptidyl peptidase-4, have emerged as therapies for type-2 diabetes and have recently reached the market. The pathophysiological basis the clinical use of these therapeutics is reviewed here.
Matthias Girndt - One of the best experts on this subject based on the ideXlab platform.
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Prevalence of Incretin-Mimetic and Sodium-Glucose-Transporter-2-Inhibitor Therapy in German Hospitalized Type-2 Diabetics Following Myocardial Revascularization: An Observational Study
Diabetes Therapy, 2020Co-Authors: Rainer U. Pliquett, Linda Golle, Andreas Wienke, Matthias GirndtAbstract:Introduction Real-world data indicate that sodium glucose transporter-2–inhibitor therapy and/or Incretin mimetics are not widely prescribed in type-2 diabetics with atherosclerotic vascular disease. We hypothesized that Incretin-mimetic therapy is associated with better overall survival and 1-year mortality in type-2 diabetics following myocardial revascularization. Methods Hospitalized type-2 diabetics of the Departments of Cardiology and Cardiothoracic Surgery (University Hospital Halle) who needed myocardial revascularization (PCI or CABG) in 2016 were included in this observational study: group 1 (Incretin-mimetic therapy), group 2 (insulin therapy without Incretin mimetics) and group 3 (oral diabetes medication without Incretins or insulin). They were asked to mail in a questionnaire on medical therapy and outcomes 1.9 years following discharge. In non-responders, vital status was obtained by local registration offices 2.4 years after discharge. Results Two hundred four patients were recruited in this study. At discharge, only 4.4% of all type-2 diabetics were on Incretin mimetic, 39.7% on insulin and 55.9% on oral diabetes medication. At the time of follow-up (response rate: 44.1%), there was no change in terms of prevalence of Incretin-mimetic therapy (5.6% of responders). Prevalence of sodium glucose transporter-2–inhibitor therapy increased from 6.9% to 15.6% in responders. In-hospital mortality (group 1: 0%, group 2: 0%, group 3: 5.2%; p = 0.092), survival after discharge (group 1: 88.9%, group 2: 86.4%, group 3: 88.0%; p = 0.942) and number of rehospitalizations within 12 months after discharge (group 1: 1.0 per capita, group 2: 1.0, group 3: 1.1; p = 0.697) were similar among prespecified groups and between group 2 and 3. By 1.9-year follow-up, hypoglycemic events were more frequent in group 2 (1.5 ± 2.9) than in group 3 (0.02 ± 0.1; p = 0.0001). Conclusion The prevalence of Incretin mimetics and sodium-glucose-transporter-2 inhibitors was low both during the index hospitalization and at a 1.9-year follow-up. When comparing group 2 and group 3 patients, survival and rehospitalizations were similar; hypoglycemic events occurred more often in insulin-treated diabetics than in the those without.
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Prevalence of Incretin-Mimetic and Sodium-Glucose-Transporter-2-Inhibitor Therapy in German Hospitalized Type-2 Diabetics Following Myocardial Revascularization: An Observational Study
Diabetes therapy : research treatment and education of diabetes and related disorders, 2020Co-Authors: Rainer U. Pliquett, Linda Golle, Andreas Wienke, Matthias GirndtAbstract:Real-world data indicate that sodium glucose transporter-2–inhibitor therapy and/or Incretin mimetics are not widely prescribed in type-2 diabetics with atherosclerotic vascular disease. We hypothesized that Incretin-mimetic therapy is associated with better overall survival and 1-year mortality in type-2 diabetics following myocardial revascularization. Hospitalized type-2 diabetics of the Departments of Cardiology and Cardiothoracic Surgery (University Hospital Halle) who needed myocardial revascularization (PCI or CABG) in 2016 were included in this observational study: group 1 (Incretin-mimetic therapy), group 2 (insulin therapy without Incretin mimetics) and group 3 (oral diabetes medication without Incretins or insulin). They were asked to mail in a questionnaire on medical therapy and outcomes 1.9 years following discharge. In non-responders, vital status was obtained by local registration offices 2.4 years after discharge. Two hundred four patients were recruited in this study. At discharge, only 4.4% of all type-2 diabetics were on Incretin mimetic, 39.7% on insulin and 55.9% on oral diabetes medication. At the time of follow-up (response rate: 44.1%), there was no change in terms of prevalence of Incretin-mimetic therapy (5.6% of responders). Prevalence of sodium glucose transporter-2–inhibitor therapy increased from 6.9% to 15.6% in responders. In-hospital mortality (group 1: 0%, group 2: 0%, group 3: 5.2%; p = 0.092), survival after discharge (group 1: 88.9%, group 2: 86.4%, group 3: 88.0%; p = 0.942) and number of rehospitalizations within 12 months after discharge (group 1: 1.0 per capita, group 2: 1.0, group 3: 1.1; p = 0.697) were similar among prespecified groups and between group 2 and 3. By 1.9-year follow-up, hypoglycemic events were more frequent in group 2 (1.5 ± 2.9) than in group 3 (0.02 ± 0.1; p = 0.0001). The prevalence of Incretin mimetics and sodium-glucose-transporter-2 inhibitors was low both during the index hospitalization and at a 1.9-year follow-up. When comparing group 2 and group 3 patients, survival and rehospitalizations were similar; hypoglycemic events occurred more often in insulin-treated diabetics than in the those without.
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Prevalence of Incretin-mimetic and Sodium-Glucose-Transporter-2-Inhibitor Therapy in Hospitalized Type-2-Diabetics following Myocardial Revascularization: an Observational Study
2020Co-Authors: Rainer U. Pliquett, Linda Golle, Andreas Wienke, Matthias GirndtAbstract:Abstract Background: We hypothesized that the recommended Incretin-mimetic therapy associates with a better outcome (1-year mortality after discharge, rehospitalizations within 12 months) and with less hypoglycemic events in type − 2 diabetics following myocardial revascularization. Methods: Hospitalized type-2 diabetics of the Departments of Cardiology and Cardiothoracic Surgery (University Hospital Halle), who had percutaneous coronary intervention (29.4%) or coronary artery bypass graft (70.6%) in 2016, were included in this observational study: Group 1 (Incretin-mimetic therapy), Group 2 (insulin therapy without Incretin mimetics) or Group 3 (oral diabetes medication without Incretins or insulin). They were asked to mail in a questionnaire on medical therapy, number of hypoglycemic episodes and rehospitalizations 2 years following discharge. In non-responders, the vital status was obtained by local registries 2.4 years after discharge. Results: 204 patients were recruited in this prospective observational study. At discharge, only 3.9% of all type-2 diabetics had an Incretin mimetic, 39.7% were on insulin, and 56.4% on oral medication. In all patient groups together, the prevalence of Incretin-mimetic therapy did not change (3.9% at discharge, 2.9% at follow-up). The prevalence of sodium glucose transporter-2–inhibitor therapy slightly increased from 6.8% at discharge to 9.2% at follow-up. However, 85 out of 173 patients (49.1%) did not provide follow-up questionnaires. In hospital mortality (Group 1: 0%, Group 2: 0%, Group 3: 5.2%; p = 0.092), 1-year mortality after discharge ( Group 1: 12.5%, Group 2: 13.6%, Group 3: 11.9%; p = 0.944), and number of rehospitalizations within 12 months after discharge (Group 1: 1.0 per capita, Group 2: 1.0, Group 3: 1.1; p = 0.697) were similar among groups. Hypoglycemic events 6 months prior to follow-up were highest in Group 2 (0.9 ± 2.3) in comparison to Group 1 (0 ± 0) and Group 3 (0.1 ± 0.3; p = 0.017). Conclusion: Even after adjusting for surviving patients not sending back questionnaires, the adherence to the recommendations regarding Incretin-mimetic and sodium-glucose transporter-2–inhibitor therapy was poor. With the limitation of a low patient number, both 1-year mortality after discharge and rehospitalizations were similar among groups. Self-reported hypoglycemic events occurred more often in insulin-treated diabetics than in the ones without.
Daniel J. Drucker - One of the best experts on this subject based on the ideXlab platform.
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Incretin based therapies for type 2 diabetes mellitus
Nature Reviews Endocrinology, 2009Co-Authors: Julie A Lovshin, Daniel J. DruckerAbstract:Incretin-based drugs have several advantages over commonly used antidiabetic agents, including a glucose-dependent mechanism of action and no risk of weight gain. However, their long-term efficacy, safety and durability are yet to be established. This Review summarizes the available data on the mechanisms of action of currently used and emerging Incretin-based agents. Incretin-based drugs, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors, are now routinely used to treat type 2 diabetes mellitus. These agents regulate glucose metabolism through multiple mechanisms, their use is associated with low rates of hypoglycemia, and they either do not affect body weight (dipeptidyl peptidase 4 inhibitors), or promote weight loss (glucagon-like peptide-1 receptor agonists). The success of exenatide and sitagliptin, the first therapies in their respective drug classes to be based on Incretins, has fostered the development of multiple new agents that are currently in late stages of clinical development or awaiting approval. This Review highlights our current understanding of the mechanisms of action of Incretin-based drugs, with an emphasis on the emerging clinical profile of new agents.
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Incretin based therapies for type 2 diabetes mellitus
Nature Reviews Endocrinology, 2009Co-Authors: Julie A Lovshin, Daniel J. DruckerAbstract:Incretin-based drugs, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors, are now routinely used to treat type 2 diabetes mellitus. These agents regulate glucose metabolism through multiple mechanisms, their use is associated with low rates of hypoglycemia, and they either do not affect body weight (dipeptidyl peptidase 4 inhibitors), or promote weight loss (glucagon-like peptide-1 receptor agonists). The success of exenatide and sitagliptin, the first therapies in their respective drug classes to be based on Incretins, has fostered the development of multiple new agents that are currently in late stages of clinical development or awaiting approval. This Review highlights our current understanding of the mechanisms of action of Incretin-based drugs, with an emphasis on the emerging clinical profile of new agents.
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GIP and GLP-1 as Incretin hormones: Lessons from single and double Incretin receptor knockout mice
Regulatory peptides, 2005Co-Authors: Tanya Hansotia, Daniel J. DruckerAbstract:Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut-derived Incretins secreted in response to nutrient ingestion. Both Incretins potentiate glucose-dependent insulin secretion and enhance beta-cell mass through regulation of beta-cell proliferation, neogenesis and apoptosis. In contrast, GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. Furthermore, human subjects with Type 2 diabetes exhibit relative resistance to the actions of GIP, but not GLP-1R agonists. The physiological importance of both Incretins has been investigated through generation and analysis of Incretin receptor knockout mice. Elimination of Incretin receptor action in GIPR-/- or GLP-1R-/- mice produces only modest impairment in glucose homeostasis. Similarly, double Incretin receptor knockout (DIRKO) mice exhibit normal body weight and normal levels of plasma glucagon and hypoglycemic responses to exogenous insulin. However, glucose-stimulated insulin secretion is significantly decreased following oral but not intraperitoneal glucose challenge in DIRKO mice and the glucose lowering actions of dipeptidyl peptidase-IV (DPP-IV) inhibitors are extinguished in DIRKO mice. Hence, Incretin receptor signaling exerts physiologically relevant actions critical for glucose homeostasis, and represents a pharmacologically attractive target for development of agents for the treatment of Type 2 diabetes.
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double Incretin receptor knockout dirko mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of dpp iv inhibitors
Diabetes, 2004Co-Authors: Tanya Hansotia, Jens J Holst, Yutaka Seino, Laurie L Baggio, Dominique Delmeire, Simon A Hinke, Yuichiro Yamada, Katsushi Tsukiyama, Frans Schuit, Daniel J. DruckerAbstract:Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived Incretins that potentiate glucose clearance following nutrient ingestion. Elimination of Incretin receptor action in GIPR−/− or GLP-1R−/− mice produces only modest impairment in glucose homeostasis, perhaps due to compensatory upregulation of the remaining Incretin. We have now studied glucose homeostasis in double Incretin receptor knockout (DIRKO) mice. DIRKO mice exhibit normal body weight and fail to exhibit an improved glycemic response after exogenous administration of GIP or the GLP-1R agonist exendin-4. Plasma glucagon and the hypoglycemic response to exogenous insulin were normal in DIRKO mice. Glycemic excursion was abnormally increased and levels of glucose-stimulated insulin secretion were decreased following oral but not intraperitoneal glucose challenge in DIRKO compared with GIPR−/− or GLP-1R−/− mice. Similarly, glucose-stimulated insulin secretion and the response to forskolin were well preserved in perifused DIRKO islets. Although the dipeptidyl peptidase-IV (DPP-IV) inhibitors valine pyrrolidide (Val-Pyr) and SYR106124 lowered glucose and increased plasma insulin in wild-type and single Incretin receptor knockout mice, the glucose-lowering actions of DPP-IV inhibitors were eliminated in DIRKO mice. These findings demonstrate that glucose-stimulated insulin secretion is maintained despite complete absence of both Incretin receptors, and they delineate a critical role for Incretin receptors as essential downstream targets for the acute glucoregulatory actions of DPP-IV inhibitors.
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therapeutic potential of dipeptidyl peptidase iv inhibitors for the treatment of type 2 diabetes
Expert Opinion on Investigational Drugs, 2003Co-Authors: Daniel J. DruckerAbstract:Incretins are peptide hormones, exemplified by glucose-dependent insulinotropic peptide and glucagon-like peptide 1 that are released from the gut in response to nutrient ingestion and enhance glucose-stimulated insulin secretion. Incretin action is terminated due to N-terminal cleavage of the peptides by the aminopeptidase dipeptidyl peptidase IV (DPP-IV). Hence, inhibition of glucose-dependent insulinotropic peptide and glucagon-like peptide 1 degradation via reduction of DPP-IV activity represents an innovative strategy for enhancing Incretin action in vivo. This review summarises the biology of Incretin action, the structure, expression and pleiotropic biological activities of DPP-IV and provides an overview of the rationale, potential merits and theoretical pitfalls in the development of DPP-IV inhibitors for the treatment of type 2 diabetes.
Rainer U. Pliquett - One of the best experts on this subject based on the ideXlab platform.
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Prevalence of Incretin-Mimetic and Sodium-Glucose-Transporter-2-Inhibitor Therapy in German Hospitalized Type-2 Diabetics Following Myocardial Revascularization: An Observational Study
Diabetes Therapy, 2020Co-Authors: Rainer U. Pliquett, Linda Golle, Andreas Wienke, Matthias GirndtAbstract:Introduction Real-world data indicate that sodium glucose transporter-2–inhibitor therapy and/or Incretin mimetics are not widely prescribed in type-2 diabetics with atherosclerotic vascular disease. We hypothesized that Incretin-mimetic therapy is associated with better overall survival and 1-year mortality in type-2 diabetics following myocardial revascularization. Methods Hospitalized type-2 diabetics of the Departments of Cardiology and Cardiothoracic Surgery (University Hospital Halle) who needed myocardial revascularization (PCI or CABG) in 2016 were included in this observational study: group 1 (Incretin-mimetic therapy), group 2 (insulin therapy without Incretin mimetics) and group 3 (oral diabetes medication without Incretins or insulin). They were asked to mail in a questionnaire on medical therapy and outcomes 1.9 years following discharge. In non-responders, vital status was obtained by local registration offices 2.4 years after discharge. Results Two hundred four patients were recruited in this study. At discharge, only 4.4% of all type-2 diabetics were on Incretin mimetic, 39.7% on insulin and 55.9% on oral diabetes medication. At the time of follow-up (response rate: 44.1%), there was no change in terms of prevalence of Incretin-mimetic therapy (5.6% of responders). Prevalence of sodium glucose transporter-2–inhibitor therapy increased from 6.9% to 15.6% in responders. In-hospital mortality (group 1: 0%, group 2: 0%, group 3: 5.2%; p = 0.092), survival after discharge (group 1: 88.9%, group 2: 86.4%, group 3: 88.0%; p = 0.942) and number of rehospitalizations within 12 months after discharge (group 1: 1.0 per capita, group 2: 1.0, group 3: 1.1; p = 0.697) were similar among prespecified groups and between group 2 and 3. By 1.9-year follow-up, hypoglycemic events were more frequent in group 2 (1.5 ± 2.9) than in group 3 (0.02 ± 0.1; p = 0.0001). Conclusion The prevalence of Incretin mimetics and sodium-glucose-transporter-2 inhibitors was low both during the index hospitalization and at a 1.9-year follow-up. When comparing group 2 and group 3 patients, survival and rehospitalizations were similar; hypoglycemic events occurred more often in insulin-treated diabetics than in the those without.
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Prevalence of Incretin-Mimetic and Sodium-Glucose-Transporter-2-Inhibitor Therapy in German Hospitalized Type-2 Diabetics Following Myocardial Revascularization: An Observational Study
Diabetes therapy : research treatment and education of diabetes and related disorders, 2020Co-Authors: Rainer U. Pliquett, Linda Golle, Andreas Wienke, Matthias GirndtAbstract:Real-world data indicate that sodium glucose transporter-2–inhibitor therapy and/or Incretin mimetics are not widely prescribed in type-2 diabetics with atherosclerotic vascular disease. We hypothesized that Incretin-mimetic therapy is associated with better overall survival and 1-year mortality in type-2 diabetics following myocardial revascularization. Hospitalized type-2 diabetics of the Departments of Cardiology and Cardiothoracic Surgery (University Hospital Halle) who needed myocardial revascularization (PCI or CABG) in 2016 were included in this observational study: group 1 (Incretin-mimetic therapy), group 2 (insulin therapy without Incretin mimetics) and group 3 (oral diabetes medication without Incretins or insulin). They were asked to mail in a questionnaire on medical therapy and outcomes 1.9 years following discharge. In non-responders, vital status was obtained by local registration offices 2.4 years after discharge. Two hundred four patients were recruited in this study. At discharge, only 4.4% of all type-2 diabetics were on Incretin mimetic, 39.7% on insulin and 55.9% on oral diabetes medication. At the time of follow-up (response rate: 44.1%), there was no change in terms of prevalence of Incretin-mimetic therapy (5.6% of responders). Prevalence of sodium glucose transporter-2–inhibitor therapy increased from 6.9% to 15.6% in responders. In-hospital mortality (group 1: 0%, group 2: 0%, group 3: 5.2%; p = 0.092), survival after discharge (group 1: 88.9%, group 2: 86.4%, group 3: 88.0%; p = 0.942) and number of rehospitalizations within 12 months after discharge (group 1: 1.0 per capita, group 2: 1.0, group 3: 1.1; p = 0.697) were similar among prespecified groups and between group 2 and 3. By 1.9-year follow-up, hypoglycemic events were more frequent in group 2 (1.5 ± 2.9) than in group 3 (0.02 ± 0.1; p = 0.0001). The prevalence of Incretin mimetics and sodium-glucose-transporter-2 inhibitors was low both during the index hospitalization and at a 1.9-year follow-up. When comparing group 2 and group 3 patients, survival and rehospitalizations were similar; hypoglycemic events occurred more often in insulin-treated diabetics than in the those without.
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Prevalence of Incretin-mimetic and Sodium-Glucose-Transporter-2-Inhibitor Therapy in Hospitalized Type-2-Diabetics following Myocardial Revascularization: an Observational Study
2020Co-Authors: Rainer U. Pliquett, Linda Golle, Andreas Wienke, Matthias GirndtAbstract:Abstract Background: We hypothesized that the recommended Incretin-mimetic therapy associates with a better outcome (1-year mortality after discharge, rehospitalizations within 12 months) and with less hypoglycemic events in type − 2 diabetics following myocardial revascularization. Methods: Hospitalized type-2 diabetics of the Departments of Cardiology and Cardiothoracic Surgery (University Hospital Halle), who had percutaneous coronary intervention (29.4%) or coronary artery bypass graft (70.6%) in 2016, were included in this observational study: Group 1 (Incretin-mimetic therapy), Group 2 (insulin therapy without Incretin mimetics) or Group 3 (oral diabetes medication without Incretins or insulin). They were asked to mail in a questionnaire on medical therapy, number of hypoglycemic episodes and rehospitalizations 2 years following discharge. In non-responders, the vital status was obtained by local registries 2.4 years after discharge. Results: 204 patients were recruited in this prospective observational study. At discharge, only 3.9% of all type-2 diabetics had an Incretin mimetic, 39.7% were on insulin, and 56.4% on oral medication. In all patient groups together, the prevalence of Incretin-mimetic therapy did not change (3.9% at discharge, 2.9% at follow-up). The prevalence of sodium glucose transporter-2–inhibitor therapy slightly increased from 6.8% at discharge to 9.2% at follow-up. However, 85 out of 173 patients (49.1%) did not provide follow-up questionnaires. In hospital mortality (Group 1: 0%, Group 2: 0%, Group 3: 5.2%; p = 0.092), 1-year mortality after discharge ( Group 1: 12.5%, Group 2: 13.6%, Group 3: 11.9%; p = 0.944), and number of rehospitalizations within 12 months after discharge (Group 1: 1.0 per capita, Group 2: 1.0, Group 3: 1.1; p = 0.697) were similar among groups. Hypoglycemic events 6 months prior to follow-up were highest in Group 2 (0.9 ± 2.3) in comparison to Group 1 (0 ± 0) and Group 3 (0.1 ± 0.3; p = 0.017). Conclusion: Even after adjusting for surviving patients not sending back questionnaires, the adherence to the recommendations regarding Incretin-mimetic and sodium-glucose transporter-2–inhibitor therapy was poor. With the limitation of a low patient number, both 1-year mortality after discharge and rehospitalizations were similar among groups. Self-reported hypoglycemic events occurred more often in insulin-treated diabetics than in the ones without.
