scholarly journals Incretin-Based Therapy for Prevention of Diabetic Vascular Complications

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Akira Mima
Keyword(s):  
Microvascular Complications ◽  
Vascular Complications ◽  
Polyol Pathway ◽  
Therapeutic Interventions ◽  
Mortality And Morbidity ◽  
Dipeptidyl Peptidase 4 ◽  
Diabetic Vascular Complications ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Glucagon Like Peptide 1 ◽  
Artery Disease

Diabetic vascular complications are the most common cause of mortality and morbidity worldwide, with numbers of affected individuals steadily increasing. Diabetic vascular complications can be divided into two categories: macrovascular and　microvascular complications. Macrovascular complications include coronary artery disease　and cerebrovascular disease, while microvascular complications include retinopathy and chronic kidney disease. These complications result from metabolic abnormalities, including hyperglycemia, elevated levels of free fatty acids, and insulin resistance. Multiple mechanisms have been proposed to mediate the adverse effects of these metabolic disorders on vascular tissues, including stimulation of protein kinase C signaling and activation of the polyol pathway by oxidative stress and inflammation. Additionally, the loss of tissue-specific insulin signaling induced by hyperglycemia and toxic metabolites can induce cellular dysfunction and both macro- and microvascular complications characteristic of diabetes. Despite these insights, few therapeutic methods are available for the management of diabetic complications. Recently, incretin-based therapeutic agents, such as glucagon-like peptide-1 and dipeptidyl peptidase-4 inhibitors, have been reported to elicit vasotropic actions, suggesting a potential for effecting an actual reduction in diabetic vascular complications. The present review will summarize the relationship between multiple adverse biological mechanisms in diabetes and putative incretin-based therapeutic interventions intended to prevent diabetic vascular complications.

scholarly journals Animal models of diabetes-associated vascular diseases: An update on available models and experimental analysis

2020 ◽  
Author(s):  
Judy Choi ◽  
Judy de Haan ◽  
Arpeeta Sharma
Keyword(s):  
Animal Models ◽  
Experimental Analysis ◽  
Microvascular Complications ◽  
Vascular Complications ◽  
Vascular Diseases ◽  
Therapeutic Interventions ◽  
Molecular Pathways ◽  
Mortality And Morbidity ◽  
Diabetic Vascular Complications ◽  
Artery Disease

Diabetes is a chronic metabolic disorder associated with the accelerated development of macrovascular (atherosclerosis, coronary artery disease) and microvascular complications (nephropathy, retinopathy and neuropathy), which remain the principal cause of mortality and morbidity in this population. Current understanding of cellular and molecular pathways of diabetes-driven vascular complications as well as therapeutic interventions have arisen from studying disease pathogenesis in animal models. Diabetes-associated vascular complications are multi-faceted, involving the interaction between various cellular and molecular pathways. Thus, the choice of an appropriate animal model to study vascular pathogenesis is important in our quest to identify innovative and mechanism-based targeted therapies to reduce the burden of diabetic complications. Herein, we provide up-to-date information on available mouse models of both Type 1 and Type 2 diabetic vascular complications as well as experimental analysis and research outputs.

Deciphering the Neuroprotective Role of Glucagon-like peptide-1 Agonists in Diabetic Neuropathy: Current Perspective and Future Directions

2020 ◽  
Vol 21 ◽  
Author(s):  
Keshav Mehta ◽  
Tapan Behl ◽  
Arun Kumar ◽  
Md Sahab Uddin ◽  
Gokhan Zengin ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Neuropathy ◽  
Metabolic Pathways ◽  
Polyol Pathway ◽  
Dipeptidyl Peptidase 4 ◽  
Hexosamine Pathway ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Incretin Therapy ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract:: Diabetic neuropathy is referred as subsequential and debilitating complication belonging to type 1 and type 2 diabetes mellitus. It is a heterogeneous group of disorder with particularly complex pathophysiology and also includes multiple forms, ranging from normal discomfort to death. The evaluation of diabetic neuropathy is associated with hyperglycemic responses, resulting in alteration in various metabolic pathways including protein kinase C pathway, polyol pathway and hexosamine pathway in sachwann and glial cells of neurons. The essential source of neuronal destruction is analogous to these respective metabolic pathways, thus identified as potential therapeutic targets. These pathways regulating therapeutic medications may be used for diabetic neuropathy, however, only target specific drugs could have partial therapeutic activity. Various antidiabetic medications have been approved and marketed, which possess therapeutic ability to control hyperglycemia and ameliorate the prevalence of diabetic neuropathy. Among all antidiabetic medications, incretin therapy, including Glucagon- like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, are the most favorable medications for the management of diabetes mellitus and associated peripheral neuropathic complications. Besides enhancing glucose-evoked insulin release from pancreatic β–cells, these therapeutic agents also play a vital role to facilitate neurite outgrowth and nerve conduction velocity in dorsal root ganglion. Furthermore, incretin therapy also activates cAMP and ERK signalling pathways, resulting in nerve regeneration and repairing. These effects are evidently supported by a series of preclinical data and investigations associated with these medications. However, the literature lacks an adequate clinical trials outcome related to these novel antidiabetic medications. The manuscript emphasizes on the pathogenesis, current pharmacological approaches and vivid description of preclinical and clinical data for the effective management of diabetic neuropathy.

scholarly journals Diabetes Microvascular Complications: An Overview of Epigenetic Modifications

2020 ◽  
Author(s):  
Neerja Aggarwal ◽  
Pawan Kumar Kare
Keyword(s):  
Association Studies ◽  
Microvascular Complications ◽  
Vascular Complications ◽  
Polyol Pathway ◽  
Epigenetic Modifications ◽  
Epigenetic Mechanisms ◽  
Diabetic Vascular Complications ◽  
Current Scenario ◽  
History Of ◽  
Diabetic Microvascular Complications

Diabetic nephropathy (DN) and diabetic retinopathy (DR) are two serious and long-standing microvascular complications of type 2 diabetes mellitus (T2DM) whose burden is increasing worldwide due to increasing burden of T2DM. Several factors which may predispose to the development of DN and DR are persistent hyperglycemia and its consequences such as formation of advanced glycation end products (AGEs), activation of hexosamine pathway, polyol pathway, uncontrolled blood pressure, increased oxidative stress, age, family history of kidney disease or hypertension, ethnic background etc. However, the pathophysiological mechanisms of these complications are complicated and not completely understood yet. Hence it is the demand to discover newer approaches to treat these devastating complications completely. Recently, various epigenetic modifications, which are the transmissible alterations in the expressions of a gene, are being studied to understand the pathophysiology of diabetic vascular complications. Metabolic and environmental factors may lead to dysregulated epigenetic mechanisms which might further affect the chromatin structure and related expressions of a gene, which may lead to diabetes-associated complications. Therefore, it is the need to explore its role in vascular complications in the current scenario. In this chapter, various epigenetic studies with regard to DN and DR, epigenome-wide association studies (EWAS) approach, and starting clinical material for such studies have been discussed. We have also summarized the better understanding of epigenetic alterations and their role in microvascular complications of diabetes through this chapter. The better understanding of epigenetic mechanisms and their role in diabetic microvascular complications could be used in clinical management of DN as well as DR or could be helpful to improve the available therapies for these complications.

Combination of SGLT-2 Inhibitors and GLP-1 Receptor Agonists: Potential Benefits in Surrogate and Hard Endpoints

2018 ◽  
Vol 24 (17) ◽  
pp. 1879-1886 ◽  
Author(s):  
Michael Doumas ◽  
Κonstantinos Imprialos ◽  
Konstantinos Stavropoulos ◽  
Andromachi Reklou ◽  
Alexandros Sachinidis ◽  
...  
Keyword(s):  
Microvascular Complications ◽  
Total Mortality ◽  
Cardiac Risk ◽  
Cvd Risk ◽  
Mortality And Morbidity ◽  
Receptor Agonists ◽  
Risk Patients ◽  
Glucagon Like Peptide 1 ◽  
Glycemic Targets ◽  
Cvd Mortality

Background: The treatment of type 2 diabetes mellitus (T2DM) is complex; only a few patients successfully attain glycemic targets with monotherapy, most requiring drug combination therapy. Methods: The goal of this review was to identify in PubMed the complimentary ways of action leading to clinical benefit (in lowering HbA1c, body weight, renal, and cardiac risk factors and events) of the combination of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA). Results: SGLT2i, an emerging class of antidiabetic agents with an insulin-independent mechanism of action, are suitable for use in combination with any other class of antidiabetics, including insulin. The use of SGLT2i causes a reduction in Cardiovascular Disease (CVD) morbidity (mainly heart failure-HF) as well as total and CVD mortality. Besides insulin, SGLT2i may also be combined with incretin-based therapies, such as GLP-1 RA. The latter appears to reduce the rate or the progression of both macrovascular (mainly myocardial infarction-MI and stroke) and microvascular complications of DM, having a beneficial effect on all-cause mortality and CVD mortality, as well as CVD events. SGLT2i and GLP-1 RA may have a synergic effect on glucose reduction, weight reduction, renal impairment (both an independent lethal disease and a CVD risk factor) improvement, and cardiac event reduction, because the first reduces HF and related events and the second decreases CVD risk (mainly MI and stroke). Both also reduce total mortality, especially when combined with a statin. Conclusion: The combination of metformin with SGLT2i, GLP-1 RA, and a potent statin, in high CVD risk patients with DM, is expected to substantially reduce CVD mortality and morbidity, improving the quality of life of patients with DM at the same time. Prospective studies are needed to confirm this finding.

scholarly journals The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror

2021 ◽  
Vol 22 (17) ◽  
pp. 9504
Author(s):  
María Sofía Martínez ◽  
Alexander Manzano ◽  
Luis Carlos Olivar ◽  
Manuel Nava ◽  
Juan Salazar ◽  
...  
Keyword(s):  
Cell Function ◽  
Cell Mass ◽  
Glucagon Secretion ◽  
Endocrine Regulation ◽  
Β Cell ◽  
Cell Hyperplasia ◽  
Dipeptidyl Peptidase 4 ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Glucagon Like Peptide 1 ◽  
Chronic Hyperglycaemia

Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon’s secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans’ islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (β) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to β cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.

scholarly journals Association Between Diabetes Medications and the Risk of Parkinson's Disease: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaocui Qin ◽  
Xia Zhang ◽  
Pinyu Li ◽  
Min Wang ◽  
Li Yan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Meta Analysis ◽  
Limited Data ◽  
Dipeptidyl Peptidase 4 ◽  
Single Study ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Glucagon Like Peptide 1

Background: Diabetes mellitus (DM) increases the risk of Parkinson's disease (PD). However, whether DM medications play a part on that increased PD risk is unclear. We designed this meta-analysis to assess the influence of different oral DM medications on the PD risk in patients with DM.Methods: We searched PubMed, Embase, and CENTRAL databases for relevant studies up until January 2021. We pooled adjusted outcomes to assess the PD risk in patients using different DM medications including sulfonylurea, metformin, glitazones (GTZ), dipeptidyl peptidase-4 inhibitors (DPP4i), and glucagon-like peptide-1 agonists (GLP1a).Results: We included 10 studies in our analysis. Our results indicate a lack of significant association between the PD risk and the use of sulfonylureas (three studies; HR, 1.26; 95% CI, 0.95 to 1.66; I2, 70%; p = 0.11), DPP4i (three studies; HR, 0.69; 95% CI, 0.35 to 1.38; I2, 88%; p = 0.30), metformin (five studies; HR, 1.23; 95% CI, 0.98 to 1.78; I2, 84%; p = 0.13), and GTZ (six studies; HR, 0.88; 95% CI, 0.66 to 1.16; I2, 92%; p = 0.35). After exclusion of a single study in the GTZ analysis, our results indicate a significantly reduced PD risk with GTZ use (HR, 0.78; 95% CI, 0.65 to 0.93; I2, 59%; p = 0.06). Similarly, after the exclusion of a single study, our results indicate a significantly increased PD risk with the use of metformin (HR, 1.50; 95% CI, 1.11 to 2.02; I2, 80%; p = 0.008). We also found a significantly reduced PD risk with the use of GLP1a (two studies; HR, 0.41; 95% CI, 0.19 to 0.87; I2, 0%; p = 0.02).Conclusion: The role of different DM medications on the PD risk remains unclear, and the quality of studies is low. While our analysis suggests a lack of association between the use of metformin, GTZ, DPP4i, and sulfonylureas and the PD risk, metformin (to a higher degree) and GTZ may still increase the risk. Limited data suggest a protective effect of GLP1a on the PD risk.

scholarly journals Glycemic Variability and Vascular Complications in Patients with Type 2 Diabetes Mellitus

Folia Medica ◽  
2017 ◽  
Vol 59 (3) ◽  
pp. 270-278 ◽  
Author(s):  
Martin Caprnda ◽  
Dasa Mesarosova ◽  
Pablo Fabuel Ortega ◽  
Boris Krahulec ◽  
Emmanuel Egom ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Microvascular Complications ◽  
Vascular Complications ◽  
Glycemic Variability ◽  
Cerebral Stroke ◽  
Chronic Hyperglycemia ◽  
Type 2 Dm ◽  
Artery Disease ◽  
Index Value

AbstractBackground:Presence of macro- and microvascular complications in patients with diabetes mellitus (DM) is not only related to chronic hyperglycemia represented by glycated hemoglobin (HbA1c) but also to acute glycemic fluctuations (glycemic variability, GV). The association between GV and DM complications is not completely clear. Aim of our study was to evaluate GV by MAGE index in patients with type 2 DM and to verify association of MAGE index with presence of macro- and microvascular DM complications.Methods:99 patients with type 2 DM were included in the study. Every patient had done big glycemic profile, from which MAGE index was calculated. Anthropometric measurements, evaluation of HbA1c and fasting plasma glucose (FPG) and assessment for macrovascular (coronary artery disease – CAD; peripheral artery disease – PAD; cerebral stroke – CS) and microvascular (diabetic retinopathy – DR; nephropathy – DN; peripheral neuropathy – DPPN) DM complications were done.Results:Average MAGE index value was 5.15 ± 2.88 mmol/l. We found no significant differences in MAGE index values in subgroups according to presence of neither CAD, CS, PAD nor DR, DN, DPPN. MAGE index value significantly positively correlated with FPG (p < 0.01) and HbA1c (p < 0.001) and negatively with weight (p < 0.05).Conclusion:In our study we failed to show association of MAGE index with presence of macrovascular and microvascular complications in patients with type 2 DM. However, this negative result does not necessarily disprove importance of glycemic variability in pathogenesis of diabetic complications.

New Herbal Approaches for the Treatment of Diabetic Kidney Diseases and Its Therapeutic Implications

2016 ◽  
pp. 368-406
Author(s):  
Durgavati Yadav ◽  
Vivek Pandey ◽  
Shivani Srivastava ◽  
Yamini Bhusan Tripathi
Keyword(s):  
Oxidative Stress ◽  
Kidney Diseases ◽  
Polyol Pathway ◽  
Herbal Drugs ◽  
Diabetic Kidney ◽  
Dipeptidyl Peptidase 4 ◽  
Therapeutic Implications ◽  
Dpp Iv ◽  
Dipeptidyl Peptidase 4 Inhibitors

Diabetic Kidney Diseases (DKD) is a very serious complication of diabetes. There is recent steep rise in the prevalence of metabolic syndrome and DKD worldwide. Factors responsible for intraglomerular hypertension include activation of various vasoactive systems, polyol pathway, oxidative stress, inflammation and protein kinase C. Sodium-Dependent Glucose Co-Transporter (SGLT-2) inhibitors, DPP-IV (Dipeptidyl peptidase-4) inhibitors are being develop to manage the hyperglycemia and oxidative stress induced inflammatory cascade. Herbal drugs have gained increasing popularity; are complex mixtures of polyphenols and phytochemicals from any raw or processed part of a plant, including leaves. Herbal drugs in this modern era are preferred due to its lesser side effects. Various preparations are presently used for ameliorating the effect of DKD. Since, medicinal plants have been reported to affect various metabolic receptors, enzymes and signaling cascade. Above book chapter explains the involvement of different phytochemicals in biological pathway associated with the kidney damage.

The Old and the New in the Treatment of Type 2 Diabetes: Focus on the Combination Therapy with Dipeptidyl Peptidase-4 Inhibitors and Metformin

2010 ◽  
Vol 2 ◽  
pp. CMT.S3420 ◽  
Author(s):  
Giovanni Anfossi ◽  
Isabella Russo ◽  
Katia Bonomo ◽  
Mariella Trovati
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Microvascular Complications ◽  
Chronic Complications ◽  
Dipeptidyl Peptidase 4 ◽  
Chronic Hyperglycemia ◽  
Oral Agents ◽  
Dipeptidyl Peptidase 4 Inhibitors

Type 2 diabetes mellitus (T2DM) is a complex multifactorial disease which affects the length and quality of life by severe chronic complications. Chronic hyperglycemia, which is the main alteration in T2DM, is strictly related to microvascular complications (such as retinopathy and nephropathy) and neuropathy, whereas large vessel atherosclerosis is also dependent on lipid and hemostasis abnormalities, arterial hypertension and other known cardiovascular risk factors. An early intervention to control hyperglycemia and to prevent deterioration of β-cell function is considered mandatory in patients with T2DM to minimize the risk of chronic complications. Recently, the availability of new pharmacological agents with different targets, including the activation of the incretin system has allowed the proposal of more effective strategies for early treatment of metabolic alterations in patients with T2DM. This commentary will focus on the role of new oral agents influencing the incretin system and the putative advantages of their co-administration with metformin, an old, effective anti-hyperglycemic agent also able to exert beneficial actions on arterial vessels, reducing the risk of macrovascular-related events. The vasoprotective role of metformin is largely independent of its hypoglycemic action, and has been ascribed to pleiotropic effects.

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