scholarly journals Incretins today: multiple effects and therapeutic potential

2019 ◽  
Vol 22 (1) ◽  
pp. 70-78
Author(s):  
Oksana V. Tsygankova ◽  
Varvara V. Veretyuk ◽  
Alexander S. Ametov
Keyword(s):  
Therapeutic Potential ◽  
Incretin Hormones ◽  
Alcoholic Fatty Liver ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The 1960S ◽  
Insulinotropic Peptide

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.

Co-Purification of Recombinant Modified Glucagon-Like and Glucose-Dependent Insulinotropic Peptide to Create a Two-Component Drug for the Treatment of Type 2 Diabetes Mellitus and Obesity

2021 ◽  
Vol 37 (6) ◽  
pp. 74-83
Author(s):  
A.Yu. Gorbunova ◽  
E.P. Sannikova ◽  
I.I. Gubaidullin ◽  
O.M. Ignatova ◽  
M.Yu. Kopaeva ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Mouse Model ◽  
Specific Activity ◽  
Two Component ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Insulinotropic Peptide

In addition to the previously developed recombinant modified human glucagon-like peptide 1 (rmglp1, Glypin), a recombinant modified human glucose-dependent insulinotropic peptide (RMGIP) has been obtained. A new universal reverse-phase HPLC technique has been proposed allowing quantitative analysis of rmGlp1 and rmGip separately and as part of a two-component preparation. The data show that the design of recombinant human rmGip according to the Glypine formula makes it possible to produce one-component and two-component preparations containing various rmGip and rmGlp1 protein ratios ranging from 1:0 to 20:1, using cell biomass samples mixed in predetermined proportions. Studies of human rmGip activity in a mouse model revealed reduced specific activity and signs of weak antagonistic effects. In this regard, there is a need for further study of human rmGip activity in a mouse model, including the use of alternative mouse or rat rmGip. type 2 diabetes mellitus; two-component drug, glucose-dependent insulinotropic peptide, glucagon-like peptide-1 The work was supported by the Internal Grant from National Research Center Kurchatov Institute.

Subcutaneous glucagon-like peptide-1 (7-36) amide is insulinotropic and can cause hypoglycaemia in fasted healthy subjects

1998 ◽  
Vol 95 (6) ◽  
pp. 719-724 ◽  
Author(s):  
C. Mark B. EDWARDS ◽  
Jeannie F. TODD ◽  
Mohammad A. GHATEI ◽  
Stephen R. BLOOM
Keyword(s):  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Plasma Glucose ◽  
Healthy Subjects ◽  
Therapeutic Potential ◽  
Double Blind ◽  
Gut Hormone ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

1. Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone released postprandially that stimulates insulin secretion, suppresses glucagon secretion and delays gastric emptying. The insulinotropic action of GLP-1 is more potent under hyperglycaemic conditions. Several published studies have indicated the therapeutic potential of subcutaneous GLP-1 in non-insulin-dependent (Type 2) diabetes mellitus. 2. We investigated whether subcutaneous GLP-1, at a dose shown to improve glycaemic control in early Type 2 diabetes, is insulinotropic at normal fasting glucose concentrations. A double-blind, randomized, crossover study of 10 healthy subjects injected with GLP-1 or saline subcutaneously after a 16 h fast was performed. The effect on cardiovascular parameters was also examined. 3. GLP-1 caused a near 5-fold rise in plasma insulin concentration. After treatment with GLP-1, circulating plasma glucose concentrations fell below the normal range in all subjects. One subject had symptoms of hypoglycaemia after GLP-1. A rise in pulse rate was found which correlated with the fall in plasma glucose concentration. An increase in blood pressure occurred with GLP-1 injection which was seen at the same time as the rise in plasma GLP-1 concentrations. 4. This study indicates that subcutaneous GLP-1 can override the normal homoeostatic mechanism maintaining fasting plasma glucose in man, and is also associated with an increase in blood pressure.

scholarly journals How glucagon-like peptide 1 receptor agonists work

2021 ◽  
Author(s):  
Christine Rode Andreasen ◽  
Andreas Andersen ◽  
Filip Krag Knop ◽  
Tina Vilsbøll
Keyword(s):  
Body Weight ◽  
Therapeutic Potential ◽  
Clinical Effects ◽  
Glucose Lowering ◽  
Receptor Agonists ◽  
Reduce Body Weight ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Clinical Utilisation

Recent years, glucagon-like peptide 1 receptor agonists (GLP-1RAs) have become central in the treatment of type 2 diabetes (T2D). In addition to their glucose-lowering properties with low risk of hypoglycaemia, GLP-1RAs reduce body weight and show promising results in reducing cardiovascular risk and renal complications in high-risk individuals with T2D. These findings have changed guidelines on T2D management over the last years, and GLP-1RAs are now widely used in overweight patients with T2D as well as in patients with T2D and cardiovascular disease regardless of glycaemic control. The currently available GLP-1RAs have different pharmacokinetic profiles and differ in their ability to improve glycaemia, reduce body weight and in their cardio- and renal protective potentials. Understanding how these agents work, including insights into their pleiotropic effects on T2D pathophysiology, may improve their clinical utilisation and be useful for exploring other indications such as non-alcoholic steatohepatitis and neurodegenerative disorders. In this review, we provide an overview of approved GLP-1RAs, their clinical effects and mode of actions, and we offer insights into the potential of GLP-1RAs for other indications than T2D. Finally, we will discuss the emerging data and therapeutic potential of using GLP-1RAs in combinations with other receptor agonists.

scholarly journals Cardiovascular effects of glucagon-like peptide 1 receptor agonists: from mechanistic studies in humans to clinical outcomes

2019 ◽  
Vol 116 (5) ◽  
pp. 916-930 ◽  
Author(s):  
Valerie D Heuvelman ◽  
Daniël H Van Raalte ◽  
Mark M Smits
Keyword(s):  
Cardiovascular Disease ◽  
Blood Glucose ◽  
Cardiovascular Effects ◽  
Lifestyle Changes ◽  
Mechanistic Studies ◽  
Receptor Agonists ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Type 2 diabetes mellitus (T2DM) is currently one of the most prevalent diseases, with as many as 415 million patients worldwide. T2DM is characterized by elevated blood glucose levels and is often accompanied by several comorbidities, such as cardiovascular disease. Treatment of T2DM is focused on reducing glucose levels by either lifestyle changes or medical treatment. One treatment option for T2DM is based on the gut-derived hormone glucagon-like peptide 1 (GLP-1). GLP-1 reduces blood glucose levels by stimulating insulin secretion, however, it is rapidly degraded, and thereby losing its glycaemic effect. GLP-1 receptor agonists (GLP-1RAs) are immune to degradation, prolonging the glycaemic effect. Lately, GLP-1RAs have spiked the interest of researchers and clinicians due to their beneficial effects on cardiovascular disease. Preclinical and clinical data have demonstrated that GLP-1 receptors are abundantly present in the heart and that stimulation of these receptors by GLP-1 has several effects. In this review, we will discuss the effects of GLP-1RA on heart rate, blood pressure, microvascular function, lipids, and inflammation, as measured in human mechanistic studies, and suggest how these effects may translate into the improved cardiovascular outcomes as demonstrated in several trials.

scholarly journals Predictors of Effectiveness of Glucagon-Like Peptide-1 Receptor Agonist Therapy in Patients with Type 2 Diabetes and Obesity

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Alina Yu. Babenko ◽  
Daria A. Savitskaya ◽  
Yulia A. Kononova ◽  
Aleksandra Yu. Trofimova ◽  
Anna V. Simanenkova ◽  
...  
Keyword(s):  
Lipid Profile ◽  
Response To Treatment ◽  
Glucose And Lipid Metabolism ◽  
Lower Baseline ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Insulinotropic Peptide ◽  
Diabetes And Obesity ◽  
Hba1c Levels

Rationale. It is well known that diabetes mellitus (DM) exacerbates the mechanisms underlying atherosclerosis. Currently, glucagon-like peptide-1 receptor agonists (aGLP-1) have one of the most prominent cardioprotective effects among the antidiabetic agents. However, the treatment with aGLP-1 is effective only in 50-70% of the cases. Taking into account the high cost of these medications, discovery of the predictors of optimal response to treatment is required. Purpose. To identify the predictors of the greater impact of aGLP-1 on HbA1c levels, weight reduction, and improvement in lipid profile. Methods. The study group consisted of 40 patients with type 2 DM (T2DM) and obesity who were treated with aGLP-1. The follow-up period was 24 weeks. Patients’ evaluation was conducted at baseline and after 24 weeks. In addition, it included the assessment of the hormones involved in glucose and lipid metabolism and appetite regulation. Results. Patients who have initially higher BMI (body mass index), glycemia, and triglycerides (TG) had better improvement in these parameters undergoing aGLP-1 treatment. In patients with a BMI loss≥5%, GLP-1 and fasting ghrelin levels were higher and ghrelin level in postnutritional status was lower. The HbA1c levels decreased more intensively in participants with higher GLP-1 levels. TG responders had lower baseline fasting glucose-dependent insulinotropic peptide (GIP) and postprandial ghrelin levels. Conclusion. The evaluation of the glycemic control, lipid profile, and GLP-1, GIP, and ghrelin levels are useable for estimating the expected efficacy of aGLP-1.

Pharmacophore modeling and molecular docking studies of acridines as potential DPP-IV inhibitors

2015 ◽  
Vol 93 (7) ◽  
pp. 721-729
Author(s):  
R. Abu Khalaf ◽  
Z. Jarekji ◽  
T. Al-Qirim ◽  
D. Sabbah ◽  
G. Shattat
Keyword(s):  
Type 2 Diabetes ◽  
Gastric Inhibitory Polypeptide ◽  
Pharmacophore Modeling ◽  
Docking Studies ◽  
Glucose Levels ◽  
Dpp Iv ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Circulating Levels

Inhibition of dipeptidyl peptidase-IV (DPP-IV) prevents the inactivation of gastric inhibitory polypeptide (GIP) and glucagon-like peptide–1 (GLP-1). This increases circulating levels of active GLP-1 and GIP and stimulates insulin secretion, which results in lowering of glucose levels and improvement of the glycemic control in patients with type 2 diabetes. In this study, pharmacophore modeling and docking experiments were carried out and a series of eight novel 2-ethoxy-6,9-disubstituted acridines (13, 15, and 17a–17f) have been designed and synthesized. Then, these compounds were evaluated for their ability to inhibit DPP-IV. Most of the synthesized compounds were proven to have anti-DPP-IV activity where compound 17b displayed the best activity of 43.8% inhibition at 30 μmol/L concentration. Results of this work might be helpful for further optimization to develop more potent DPP-IV inhibitors.

scholarly journals Glucose-Responsive Microneedle Patches for Diabetes Treatment

2018 ◽  
Vol 13 (1) ◽  
pp. 41-48 ◽  
Author(s):  
Guojun Chen ◽  
Jicheng Yu ◽  
Zhen Gu
Keyword(s):  
Drug Delivery ◽  
Blood Glucose ◽  
Release Kinetics ◽  
Blood Glucose Control ◽  
Diabetes Therapy ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Treatment Of Diabetes ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Antidiabetic therapeutics, including insulin as well as glucagon-like peptide 1 (GLP-1) and its analogs, are essential for people with diabetes to regulate their blood glucose levels. Nevertheless, conventional treatments based on hypodermic administration is commonly associated with poor blood glucose control, a lack of patient compliance, and a high risk of hypoglycemia. Closed-loop drug delivery strategies, also known as self-regulated administration, which can intelligently govern the drug release kinetics in response to the fluctuation in blood glucose levels, show tremendous promise in diabetes therapy. In the meantime, the advances in the development and use of microneedle (MN)-array patches for transdermal drug delivery offer an alternative method to conventional hypodermic administration. Hence, glucose-responsive MN-array patches for the treatment of diabetes have attracted increasing attentions in recent years. This review summarizes recent advances in glucose-responsive MN-array patch systems. Their opportunities and challenges for clinical translation are also discussed.

scholarly journals The effect of dapagliflozin on alanine aminotransferase as a marker of liver inflammation: updated results from the ABCD dapagliflozin audit

2020 ◽  
Vol 20 (1) ◽  
pp. 19-24
Author(s):  
Thomas SJ Crabtree ◽  
Mahender Yadagiri ◽  
Ian Gallen ◽  
Suzanne Phillips ◽  
Alison Evans ◽  
...  
Keyword(s):  
Alanine Aminotransferase ◽  
Liver Inflammation ◽  
Audit Tool ◽  
Baseline Hba1c ◽  
Alcoholic Fatty Liver ◽  
Increased Risk ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Alcoholic Fatty Liver Disease

Introduction: People with type 2 diabetes are known to be at increased risk of non-alcoholic fatty liver disease (NAFLD). There is increasing evidence of diabetes treatments with benefits of also improving NAFLD. Although mostly focused on glucagon-like peptide 1 agonists, sodium-glucose linked transporter 2 inhibitors may also have some promise in improving markers of NAFLD.Method: Data were extracted from the ABCD nationwide dapagliflozin audit tool. Alanine aminotransferase (ALT) was available in these data and was used as a marker of liver inflammation. Patients were stratified based on baseline ALT levels to see if this predicted response to treatment.Results: 1,873 patients were included for analysis (mean±SD age 58.7±10 years, 60.8% male, median duration of diabetes 3.5 years (IQR 1.5–9)) and were followed up in this study for an average of 11.4 months. Where known (n=280), 60.8% of these were Caucasian. Baseline HbA1c was 78±17.2 mmol/mol, weight 102.1±22.5 kg and body mass index (BMI) 34.2±7.6 kg/m2. Median ALT reduction overall was 4 U/L (95% CI 3 to 4; p<0.001). Reductions in weight (3.2 kg; 95% CI 2.9 to 3.5), BMI (0.9 kg/m2, 95% CI 0.6 to 1.2) and HbA1c (10.8 mmol/mol, 95% CI 10.1 to 11.5) (0.9%, 95% CI 0.8% to 1.0%) were all significant (p<0.001). Where ALT was elevated at baseline (>19 U/L female; >30 U/L male), the median reduction in ALT was 5 U/L in women (95% CI 4 to 6; p<0.0001) and 10 U/L in men (95% CI 8 to 11; p<0.0001). Stratified into three groups by ALT using the male reference range and twice this, there were reductions in ALT in all groups, which was greatest (24 U/L 95% CI 20 to 27) in the subgroup with baseline ALT >59 U/L.Conclusion: Our observational data suggest significant reductions in ALT as a possible marker of liver inflammation in those taking dapagliflozin. This appears to be greatest in those with the most elevated levels at baseline.

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