Inhibition Of Glucagon Release Research Articles

Retinopathy risk factors in patients with type 2 diabetes on liraglutide.

Liraglutide, a glucagon-like peptide 1 receptor agonist, effectively treats type 2 diabetes(T2D) by lowering glucose levels, suppressing glucagon release, and promoting insulin secretion. Liraglutide has been shown to reduce body weight and glycated hemoglobin (HbA1c) levels and improve cardiovascular outcomes. However, evidence regarding the association between liraglutide and diabetic retinopathy in the Middle East is insufficient. Therefore, this study aimed to investigate the characteristics and risk factors of diabetic retinopathy in patients with T2D treated with liraglutide in Saudi Arabia. This retrospective cohort study was conducted on patients (≥14 years) with T2D treated with liraglutide between 2015 and 2021, who had a documented retinopathy assessment at baseline before liraglutide initiation and during follow-up, at King Abdulaziz Medical City (KAMC), Riyadh. Data collection included demographic information, retinopathy status, body mass index (BMI), and HbA1c level at baseline and follow-up after liraglutide use. The study included 181 patients with a mean age of 58.2 (9.8) years. Of these, 72.9% were females. At baseline, the median weight (interquartile range) was 88 (77-100) kg, diabetes duration was 19 (13-23.5) years, and HbA1c level was 9% (8-10%). Total of 69.6% were on insulin, 22.7% were on oral hypoglycemic agents, and 7.7% were on no other medications in addition to liraglutide. After a median of 2 years follow-up, both HbA1c level and weight decreased significantly (P < .001). Seventy-one of the 87 patients (81.6%) without retinopathy at baseline continued to show no retinopathy. Among patients with retinopathy at baseline, 25.5% showed improvement and 44.7% showed no change. In the multivariate binary mixed effect analysis, factors significantly associated with retinopathy were: use of insulin (odds ratio [OR]:2.68; 95% confidence interval [CI]: 1.18-6.09, P = .019), older age (OR:1.03; 95% CI: 1.00-1.06; P = .022), higher HbA1c level (OR:1.17; 95% CI: 1.02-1.34; P = .024), Hypertension (OR:2.56; 95% CI: 1.13-5.76; P=<.0001) and longer diabetes duration (OR:1.04; 95% CI: 1.00-1.08; P = .024). In conclusion, liraglutide use caused significant reductions in the HbA1c level and weight of patients with T2D. Most patients showed no change in retinopathy status after liraglutide use.

Teneligliptin hydrobromide hydrate mouth dissolving strip: Formulation and evaluation

Oral route is considered as one of the most convenient route for administration of various pharmaceutical dosage form like tablet, capsule, syrup, suspension and emulsion. Fast Dissolving Drug Delivery systems have developed various fast disintegrating preparations like Oral disintegrating film, ODF. Oral disintegrating film is the solid oral drug delivery system, in which water soluble polymer involve to disintegrate film into mouth fastly. Oral disintegrating film is superior as compare to orally disintegrating tablet as the cost of production is low. The present research was undertaken to develop oral disintegrating film of tteneligliptin hydrobromide hydrate to have rapid onset of action. of tteneligliptin hydrobromide hydrate which is an anti-diabetic. The mechanism action of Teneligliptin is to increase incretin levels (GLP-1 and GIP), which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.The concept of formulating fast disintegrating film Teneligliptin containing offers a suitable and practical approach in serving desired objective of faster disintegration and dissolution characteristics with increased bioavailability. ODF of Teneligliptin were prepared by solvent casting method and evaluated physicochemical parameters like thickness, weight variation, moisture content, folding endurance, drug content, etc. All the formulations of Teneligliptin ODF displayed optimum folding endurance, which indicates the formulation prepared can withstand handling and transportation. From the results obtained, it was concluded that the formulation of oral disintegrating film has better physical chemical properties with good disintegration property.

Urocortin 3 contributes to paracrine inhibition of islet alpha cells in mice.

Pancreatic alpha cell activity and glucagon secretion lower as glucose levels increase. While part of the decrease is regulated by glucose itself, paracrine signaling by their neighboring beta and delta cells also plays an important role. Somatostatin from delta cells is an important local inhibitor of alpha cells at high glucose. Additionally, urocortin 3 (UCN3) is a hormone that is co-released from beta cells with insulin and acts locally to potentiate somatostatin secretion from delta cells. UCN3 thus inhibits insulin secretion via a negative feedback loop with delta cells, but its role with respect to alpha cells and glucagon secretion is not understood. We hypothesize that the somatostatin-driven glucagon inhibition at high glucose is regulated in part by UCN3 from beta cells. Here, we use a combination of live functional Ca2+ and cAMP imaging as well as direct glucagon secretion measurement, all from alpha cells in intact mouse islets, to determine the contributions of UCN3 to alpha cell behavior. Exogenous UCN3 treatment decreased alpha cell Ca2+ and cAMP levels and inhibited glucagon release. Blocking endogenous UCN3 signaling increased alpha cell Ca2+ by 26.8 ± 7.6%, but this did not result in increased glucagon release at high glucose. Furthermore, constitutive deletion of Ucn3 did not increase Ca2+ activity or glucagon secretion relative to controls. UCN3 is thus capable of inhibiting mouse alpha cells, but, given the subtle effects of endogenous UCN3 signaling on alpha cells, we propose that UCN3-driven somatostatin may serve to regulate local paracrine glucagon levels in the islet instead of inhibiting gross systemic glucagon release.

New insights into nanomedicines for oral delivery of glucagon-like peptide-1 analogs.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that arises when the body cannot respond fully to insulin, leading to impaired glucose tolerance. Currently, the treatment embraces non-pharmacological actions (e.g., diet and exercise) co-associated with the administration of antidiabetic drugs. Metformin is the first-line treatment for T2DM; nevertheless, alternative therapeutic strategies involving glucagon-like peptide-1 (GLP-1) analogs have been explored for managing the disease. GLP-1 analogs trigger insulin secretion and suppress glucagon release in a glucose-dependent manner thereby, reducing the risk of hyperglycemia. Additionally, GLP-1 analogs have an extended plasma half-life compared to the endogenous peptide due to their high resistance to degradation by dipeptidyl peptidase-4. However, GLP-1 analogs are mainly administered via subcutaneous route, which can be inconvenient for the patients. Even considering an oral delivery approach, GLP-1 analogs are exposed to the harsh conditions of the gastrointestinal tract (GIT) and the intestinal barriers (mucus and epithelium). Hereupon, there is an unmet need to develop non-invasive oral transmucosal drug delivery strategies, such as the incorporation of GLP-1 analogs into nanoplatforms, to overcome the GIT barriers. Nanotechnology has the potential to shield antidiabetic peptides against the acidic pH and enzymatic activity of the stomach. In addition, the nanoparticles can be coated and/or surface-conjugated with mucodiffusive polymers and target intestinal ligands to improve their transport through the intestinal mucus and epithelium. This review focuses on the main hurdles associated with the oral administration of GLP-1 and GLP-1 analogs, and the nanosystems developed to improve the oral bioavailability of the antidiabetic peptides. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

80-LB: Evaluation of the Pharmacokinetics of Glucagon-Like-Peptide-1 (GLP-1) Receptor Agonist Delivered through the BIOJET Oral Biotherapeutic Delivery Platform in Porcine Model

Glucagon-like-peptide-1 (GLP-1) receptor agonists stimulate insulin secretion and suppress glucagon release. Semaglutide is a GLP-1 agonist currently injected subcutaneously or taken orally to treat type 2 diabetes and for weight management. However, oral administration of protein/peptide therapeutics has proven difficult due to the harsh conditions of the upper gastrointestinal tract (GIT) and poor absorption rates in the small intestine. The BIOJET™ oral biotherapeutic delivery platform is an ingestible drug-device combination developed to increase drug bioavailability via needleless jet injection in the proximal small intestine following oral administration. Previous testing of an earlier, autonomously triggered version of the device in animal models was presented at ACG 2022. In this study we evaluated the pharmacokinetics (PK) of semaglutide delivered through the BIOJET device in a porcine model. Due to prolonged and variable gastric residence times in the porcine model, devices filled with semaglutide (~1mg) were administered by intraduodenal (ID) endoscopic placement and activated in the proximal small intestine of Yucatan swine. PK blood sampling was performed from 0 to 240 hours post-dose to evaluate systemic exposure of semaglutide. Seven of eight (7/8) devices were successfully placed and activated in the duodenum. All seven animals showed detectable drug levels up to ten days post-dosing and had an oral bioavailability average of 37% ± 15% (CV: 40%), ranging from 19%-60% compared to IV control. No significant clinical signs were observed in the animals. This study demonstrated that administration of the BIOJET device has the potential to achieve a magnitude greater bioavailability than the currently marketed oral semaglutide (&amp;lt; 1%). The BIOJET device could provide an alternative for the oral administration of large molecules and may improve patient compliance. Disclosure S. N. Lee: Employee; Biora Therapeutics. C. A. Stork: Employee; Biora Therapeutics. R. O. Valenzuela-rivas: Employee; Biora Therapeutics. M. Walker: Employee; Biora Therapeutics. B. J. Smith: Employee; Biora Therapeutics. J. A. Smith: None. N. Quintana: None. C. Wahl: Employee; Biora Therapeutics. S. Singh: None.

Glucagon and Insulin Overview: An Odd Couple's History and Physiology.

Glucagon is a peptide hormone that is produced primarily by the alpha cells in the islet of Langerhans in the pancreas, but also in intestinal enteroendocrine cells and in some neurons. Approximately 100 years ago several research groups discovered that pancreatic extracts would cause a brief rise blood glucose before they observed the decrease in glucose attributed to insulin. An overall description of the regulation of glucagon secretion requires inclusion of its sibling insulin because they both are made primarily by the islet and they both regulate each other in different ways. For example, glucagon stimulates insulin secretion, whereas insulin suppresses glucagon secretion. The mechanism of action of glucagon on insulin secretion has been identified as a trimeric guanine nucleotide-binding protein (G-protein)-mediated event. The manner in which insulin suppresses glucagon release from the alpha cell is thought to be highly dependent on the peri-portal circulation of the islet through which blood flows downstream from beta cells to alpha cells. In this scenario, it is via the circulation that insulin is thought to suppresses the release of glucagon. However, high levels of glucose also have been shown to suppress glucagon secretion. Consequently, the glucose lowering effect of insulin may be additive to the direct effects of insulin to suppress alpha cell function, so that in vivo both the discontinuation of the insulin signal and the condition of low glucose jointly are responsible for induction of glucagon secretion.

Small molecule glucagon release inhibitors with activity in human islets.

Type 1 diabetes (T1D) accounts for an estimated 5% of all diabetes in the United States, afflicting over 1.25 million individuals. Maintaining long-term blood glucose control is the major goal for individuals with T1D. In T1D, insulin-secreting pancreatic islet β-cells are destroyed by the immune system, but glucagon-secreting islet α-cells survive. These remaining α-cells no longer respond properly to fluctuating blood glucose concentrations. Dysregulated α-cell function contributes to hyper- and hypoglycemia which can lead to macrovascular and microvascular complications. To this end, we sought to discover small molecules that suppress α-cell function for their potential as preclinical candidate compounds. Prior high-throughput screening identified a set of glucagon-suppressing compounds using a rodent α-cell line model, but these compounds were not validated in human systems. Here, we dissociated and replated primary human islet cells and exposed them to 24 h treatment with this set of candidate glucagon-suppressing compounds. Glucagon accumulation in the medium was measured and we determined that compounds SW049164 and SW088799 exhibited significant activity. Candidate compounds were also counter-screened in our InsGLuc-MIN6 β-cell insulin secretion reporter assay. SW049164 and SW088799 had minimal impact on insulin release after a 24 h exposure. To further validate these hits, we treated intact human islets with a selection of the top candidates for 24 h. SW049164 and SW088799 significantly inhibited glucagon release into the medium without significantly altering whole islet glucagon or insulin content. In concentration-response curves SW088799 exhibited significant inhibition of glucagon release with an IC50 of 1.26 µM. Given the set of tested candidates were all top hits from the primary screen in rodent α-cells, this suggests some conservation of mechanism of action between human and rodents, at least for SW088799. Future structure-activity relationship studies of SW088799 may aid in elucidating its protein target(s) or enable its use as a tool compound to suppress α-cell activity in vitro.

Imaging the effects of GLP-1 on the developing pancreas

GLP-1 (Glucagon-like peptide 1) is an incretin (a metabolic hormone modulating glucose metabolism) known to lower blood glucose by stimulating insulin release and inhibiting glucagon release. The effects of GLP-1 are well documented in adults, but little is known about the role of GLP-1 during development. The hypothesis of this project is that GLP-1 assists the pancreas in development, differentiation, and proliferation. To test this hypothesis, Glucagon-like peptide 1 receptor knockout mice (GLP-1R KO) were compared to control mice to block the mechanism of GLP-1. Sections of the pancreas were taken from both GLP-1R KO and control mice and were stained for insulin, glucagon, and proliferation. The data from the experiment suggests that GLP-1R KO mice have less islet cell mass (both α and β) and proliferation compared to controls. Further studies could investigate the role of GLP-1 during pancreatic organogenesis.

The Glucagon-Like Peptide-1 Analogues therapy in the non-diabetic patients

Glucagon like peptide-1 (GLP-1) receptor agonists are a group of hypoglycemic drugs that are used primarily to treat type 2 diabetes both as monotherapy and in combination with other antidiabetic drugs. In contrast to most hypoglycemic drugs, GLP-1 receptor agonists not only do not cause weight gain, but can even lead to weight reduction. This is why they are recently also increasingly used in the treatment of obesity in patients without type 2 diabetes. Current research indicate that liraglutide and semaglutide are effective and safe methods of treatment for overweight and obesity in patients without diabetes. GLP-1 receptor agonists’ mechanism of action is related to the incretin system. They lowers glucose concentrations by increasing insulin secretion and suppressing glucagon release. Moreover, they cause a retardation of gastric emptying and affect the central nervous system, resulting in a decrease in appetite and stimulation of satiety. In addition, a rising number of research studies show that GLP-1 receptor agonists may also have beneficial effects in the treatment of other conditions, such as nervous and cardiovascular diseases, metabolic diseases or endocrine disorders. Due to the new findings, even more research should be carried out to further investigate and describe the multidirectional effects of these drugs.

Alpha cells as targets for incretin therapy

Abstract The pivotal role of alpha cells in glucose homeostasis, primarily through glucagon secretion, necessitates a deeper understanding of their potential as therapeutic targets in diabetes management. This narrative review explores the emerging paradigm of incretin-based therapies targeting alpha cells to ameliorate hyperglycemia associated with diabetes. Amidst the prevailing focus on beta cells, this review accentuates the lesser-explored potential of alpha cells in modulating glucose levels. Incretin hormones, notably glucagon-like peptide-1 (GLP-1), not only augment insulin secretion but also inhibit glucagon release, thereby acting as a dual mechanism for glucose control. Contemporary pharmaceutical agents like GLP-1 receptor agonists and DPP-4 inhibitors exhibit promise in modulating alpha-cell function, with evidence suggesting their efficacy in reducing postprandial glucagon and improving glycemic control. Clinical trials evince a favorable safety profile with minimal hypoglycemia risk. Moreover, DPP-4 inhibitors demonstrate a unique potential in reducing glycemic variability by nuanced modulation of alpha-cell activity. This review underscores the imperative for further research to elucidate the molecular pathways underpinning alpha-cell dysfunction in diabetes and to explore combinatory regimens for optimizing glycemic control. The insights garnered could pave the way for novel therapeutic strategies, enriching the armamentarium against diabetes through a more holistic approach targeting both alpha and beta cells.

PSUN241 A Case of Dulaglutide-Induced Acute Pancreatitis in a Diabetic Patient – A Case Report

Abstract Introduction Dulaglutide is a glucagon-like peptide-1 (GLP-1 RA) receptor agonist that was approved by the FDA as a pharmacological treatment of diabetes management over the last decade. It is available in an injectable form that is dosed weekly which increases patients’ adherence and improves outcomes. The mechanism of action of GLP-1 RA is through regulation of blood glucose levels through glucose-dependent stimulation of insulin secretion and inhibition of glucagon release. Also, their effect on GLP-1 receptors in the CNS and the gastrointestinal tract leads to delay in gastric emptying and induces satiety. Such mechanism of action decreases the risk of hypoglycemia and facilitates weight loss. All these features make GLP-1 RA of great interest among new diabetes pharmacological options.The most frequently reported adverse effects from GLP-1 RA are gastrointestinal symptoms and injection-site pruritus. Acute pancreatitis is a rare but serious complication of GLP-1 RA use. We present a case of Dulaglutide-induced acute pancreatitis in a diabetic patient. Case presentation 77-year-old type II diabetic male on Dulaglutide 1.5 mg weekly which was increased to 3 mg weekly 2 weeks prior to a presentation presented with epigastric pain, nausea, and vomiting for 2 days. The patient denied any previous episodes, history of gallstones or alcohol use or recent endoscopic retrograde cholangiogram. An abdominal exam revealed epigastric tenderness. Laboratory workup was remarkable for Lipase of 953, otherwise, Calcium, triglycerides, liver enzymes were within normal limit. Computed tomography scan of the abdomen confirmed pancreatitis. Right upper quadrant ultrasound showed no evidence of gallstones or biliary system dilation. Holding Dulaglutide with standard treatment for pancreatitis resulted in symptom resolution. Discussion GLP-1 RA-induced pancreatitis is a very serious adverse event, yet this association has not been well established in humans, especially that baseline rate of pancreatitis in diabetic patients (most population studied using GLP-1 agonist) is higher compared to the general population. Until now most available data are driven from studies on animals, case reports, and a few observed cases on studies.Pathophysiologyis not well understood. One theory is thought to be due to GLP-1 RA effect on decreasing gut motility including biliary and gallbladder, which increases the risk of gallstone formation. However, not all reported cases had history of gallstones. This leads us to the other suggested mechanism through effect of GLP-1 RA on exocrine pancreas through ductal proliferation and metaplasia which if severe, can lead to hemorrhagic pancreatitis.Hence, the GLP-1 RA use should be judicious in patients with high risk of pancreatitis, such as severe hypertriglyceridemia, alcohol intake, or prior pancreatitis history. Conclusion Diabetes and hypertriglyceridemia are independent risk factors of acute pancreatitis. Future studies are warranted to assess GLP-1 RA-induced pancreatitis in non-diabetic patients and to investigate its dose-dependence relationship. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Surfactin Mitigates a High-Fat Diet and Streptozotocin-Induced Type 2 Diabetes through Improving Pancreatic Dysfunction and Inhibiting Inflammatory Response.

Surfactin from Bacillus amyloliquefaciens fmb50 was utilized to treat mice with type 2 diabetes (T2DM) induced by a high-fat diet/streptozotocin (HFD/STZ). Our group’s earlier research indicated that surfactin could lower blood glucose and mitigate liver dysfunction to further improve HFD/STZ-induced T2DM through modulating intestinal microbiota. Thus, we further investigated the effects of surfactin on the pancreas and colon in mice with T2DM to elucidate the detailed mechanism. In the present study, mice with HFD/STZ-induced T2DM had their pancreatic and colon inflammation, oxidative stress, and endoplasmic reticulum stress (ERS) reduced when given oral surfactin at a dose of 80 mg/kg body weight. According to further research, surfactin also improved glucose metabolism by activating the phosphatidylinositol kinase (PI3K)/protein kinase B (Akt) signaling pathway, further protecting islets β-cell, promoting insulin secretion, inhibiting glucagon release and mitigating pancreas dysfunction. Additionally, after surfactin treatment, the colon levels of the tight junction proteins Occludin and Claudin-1 of T2DM mice were considerably increased by 130.64% and by 36.40%, respectively. These findings revealed that surfactin not only ameliorated HFD/STZ-induced pancreas inflammation and dysfunction and preserved intestinal barrier dysfunction and gut microbiota homeostasis but also enhanced insulin sensitivity and glucose homeostasis in T2DM mice. Finally, in the further experiment, we were able to demonstrate that early surfactin intervention might delay the development of T2DM caused by HFD/STZ, according to critical biochemical parameters in serum.

Post-transplant Diabetes Mellitus: What Physicians Need to Know.

Post-transplant diabetes mellitus (PTDM) is a common problem among solid organ transplant recipients contributing to morbidity and affecting patient as well as graft survival adversely. It can occur at any period following transplantation, but maximum incidence is observed in the first few months, with a second peak after a few years after transplantation. The pathogenesis is complex and poorly understood, however, it is associated with both dysfunctional beta-cells and insulin resistance. Both nonpharmacologic and antidiabetic therapies are important for adequate glycemic control. This point of view article provides a short review on PTDM in solid organ transplantation (SOT) recipients from a general physician's perspective.

Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation

Aims/hypothesisType 2 diabetes is characterised by hyperglucagonaemia and perturbed function of pancreatic glucagon-secreting alpha cells but the molecular mechanisms contributing to these phenotypes are poorly understood. Insulin-degrading enzyme (IDE) is present within all islet cells, mostly in alpha cells, in both mice and humans. Furthermore, IDE can degrade glucagon as well as insulin, suggesting that IDE may play an important role in alpha cell function in vivo.MethodsWe have generated and characterised a novel mouse model with alpha cell-specific deletion of Ide, the A-IDE-KO mouse line. Glucose metabolism and glucagon secretion in vivo was characterised; isolated islets were tested for glucagon and insulin secretion; alpha cell mass, alpha cell proliferation and α-synuclein levels were determined in pancreas sections by immunostaining.ResultsTargeted deletion of Ide exclusively in alpha cells triggers hyperglucagonaemia and alpha cell hyperplasia, resulting in elevated constitutive glucagon secretion. The hyperglucagonaemia is attributable in part to dysregulation of glucagon secretion, specifically an impaired ability of IDE-deficient alpha cells to suppress glucagon release in the presence of high glucose or insulin. IDE deficiency also leads to α-synuclein aggregation in alpha cells, which may contribute to impaired glucagon secretion via cytoskeletal dysfunction. We showed further that IDE deficiency triggers impairments in cilia formation, inducing alpha cell hyperplasia and possibly also contributing to dysregulated glucagon secretion and hyperglucagonaemia.Conclusions/interpretationWe propose that loss of IDE function in alpha cells contributes to hyperglucagonaemia in type 2 diabetes.Graphical abstract

Abstract #1182965: Remarkable 161.8lbs weight loss with Liraglutide in a non-diabetic morbidly obese patient

Glucagon like peptide-1 (GLP-1) is a hormone produced by the enteroendocrine L cells of the gut and is released subsequent to food intake. It stimulates insulin secretion, inhibits glucagon release, delays gastric emptying, and decreases food intake through increased satiety, thus decreasing blood sugar with the ultimate result of promoting weight loss. We present a case of a morbidly obese patient on Liraglutide, one such GLP-1 receptor agonist which led to a remarkable weight loss over the course of 3 years.

Metabolic effects of combined glucagon receptor antagonism and glucagon-like peptide-1 receptor agonism in high fat fed mice

Ablation of glucagon receptor (GCGR) signalling is a potential treatment option for diabetes, whilst glucagon-like peptide-1 (GLP-1) receptor agonists are clinically approved for both obesity and diabetes. There is a suggestion that GCGR blockade enhances GLP-1 secretion and action, whilst GLP-1 receptor activation is known to inhibit glucagon release, implying potential for positive interactions between both therapeutic avenues. The present study has examined the ability of sustained GCGR antagonism, using desHis1Pro4Glu9-glucagon, to augment the established benefits of the GLP-1 mimetic, exendin-4, in high fat fed (HFF) mice. Twice-daily injection of desHis1Pro4Glu9-glucagon, exendin-4 or a combination of both peptides to groups of HFF mice for 10 days had no impact on body weight or energy intake. Circulating blood glucose and glucagon concentrations were significantly (P < 0.05–0.01) decreased by all treatment regimens, with plasma insulin levels elevated (P < 0.001) when compared to lean control mice. Intraperitoneal and oral glucose tolerance were improved (P < 0.05–0.01) by all treatments, despite lack of enhanced glucose-stimulated insulin secretion. Following exogenous glucagon administration, all HFF treatment groups displayed reduced (P < 0.05–0.001) glucose and insulin levels compared to HFF saline controls, although peripheral insulin sensitivity was largely unchanged across all animals. Interestingly, all treatments had tendency to increase pancreatic insulin content with pancreatic glucagon content significantly elevated (P < 0.05) by all interventions. These studies highlight the capacity of peptide-based GCGR inhibition, or GLP-1 receptor activation, to significantly improve metabolism in HFF mice but suggest no obvious additive benefits of combined therapy.

Gap junction coupling and islet delta-cell function in health and disease

The pancreatic islets contain beta-cells and alpha-cells, which are responsible for secreting two principal gluco-regulatory hormones; insulin and glucagon, respectively. However, they also contain delta-cells, a relatively sparse cell type that secretes somatostatin (SST). These cells have a complex morphology allowing them to establish an extensive communication network throughout the islet, despite their scarcity. Delta-cells are electrically excitable cells, and SST secretion is released in a glucose- and KATP-dependent manner. SST hyperpolarises the alpha-cell membrane and suppresses exocytosis. In this way, islet SST potently inhibits glucagon release. Recent studies investigating the activity of delta-cells have revealed they are electrically coupled to beta-cells via gap junctions, suggesting the delta-cell is more than just a paracrine inhibitor. In this Review, we summarize delta-cell morphology, function, and the role of SST signalling for regulating islet hormonal output. A distinguishing feature of this Review is that we attempt to use the discovery of this gap junction pathway, together with what is already known about delta-cells, to reframe the role of these cells in both health and disease. In particular, we argue that the discovery of gap junction communication between delta-cells and beta-cells provides new insights into the contribution of delta-cells to the islet hormonal defects observed in both type 1 and type 2 diabetes. This reappraisal of the delta-cell is important as it may offer novel insights into how the physiology of this cell can be utilised to restore islet function in diabetes.

The Effects of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptydilpeptidase-4 Inhibitors on Blood Pressure and Cardiovascular Complications in Diabetes.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are a class of newly introduced antidiabetic medications that potentially lower blood glucose by several molecular pathways. DPP-4 inhibitors are the other type of novel antidiabetic medications which act by preventing GLP-1 inactivation and thereby increasing the activity levels of GLP-1, leading to more glucose-induced insulin release from islet β-cells and suppression of glucagon release. Most patients with diabetes have concurrent hypertension and cardiovascular disorder. If antihyperglycemic agents can attenuate the risk of hypertension and cardiovascular disease, they will amplify their overall beneficial effects. There is conflicting evidence on the cardiovascular benefits of GLP-1R induction in laboratory studies and clinical trials. In this study, we have reviewed the main molecular mechanisms by which GLP-1R induction may modulate the cardiovascular function and the results of cardiovascular outcome clinical trials.

A 2021 Update on the Use of Liraglutide in the Modern Treatment of 'Diabesity': A Narrative Review.

Obesity and type 2 diabetes mellitus have become a significant public health problem in the past decades. Their prevalence is increasing worldwide each year, greatly impacting the economic and personal aspects, mainly because they frequently coexist, where the term “diabesity” may be used. The drug class of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) is one of the most modern therapy options in managing these metabolic disorders. This review focuses on the effects of liraglutide, a long-acting GLP-1 RA, in diabesity and non-diabetic excess weight. This drug class improves glycemic control by enhancing insulin secretion from the beta-pancreatic cells and inhibiting glucagon release. Furthermore, other effects include slowing gastric emptying, increasing postprandial satiety, and reducing the appetite and food consumption by influencing the central nervous system, with weight reduction effects. It also reduces cardiovascular events and has positive effects on blood pressure and lipid profile. A lower-dose liraglutide (1.2 or 1.8 mg/day) is used in patients with diabetes, while the higher dose (3.0 mg/day) is approved as an anti-obesity drug. In this review, we have summarized the role of liraglutide in clinical practice, highlighting its safety and efficacy as a glucose-lowering agent and a weight-reduction drug in patients with and without diabetes.

A review of GLP-1 receptor agonists in type 2 diabetes: A focus on the mechanism of action of once-weekly agents.

What is known and objectiveGlucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) are one of the preferred approved treatment options for people with type 2 diabetes (T2D) and inadequate glycaemic control. The objective of this review is to provide a general clinical overview of the similarities and differences in the mechanisms of action (MoA) of the once‐weekly GLP‐1 RA class of medications, highlighting the role of pharmacists in providing optimal medication management, education and care for people with diabetes.MethodsThis is a narrative review of the published literature regarding the MoA of the currently available once‐weekly GLP‐1 RAs in T2D.Results and discussionGLP‐1 RAs have an established efficacy and safety profile. Their benefits derive from their blood glucose‐lowering effects, which include pancreatic beta‐cell‐mediated glucose‐dependent insulin secretion and suppressed glucagon release, and their ability to slow gastric emptying and promote satiety. GLP‐1 RAs may also exert beneficial effects on multiple organ systems in which GLP‐1 receptors are present, including the cardiovascular and renal systems. Differences between individual GLP‐1 RAs with regard to their molecular size, structure and duration of action (short or longer acting) have led to differing pharmacodynamics and clinical effects such as degree of glycaemic control, weight loss abilities, cardiovascular effects and tolerability profiles.What is new and conclusionFrom the literature, this appears to be the first review of the evidence base supporting the MoA of once‐weekly GLP‐1 RAs in T2D aimed at pharmacists, with a particular emphasis on the expanding role of pharmacists in team‐based diabetes management. As a class, GLP‐1 RAs are an effective treatment option for people with T2D, shown to achieve multi‐factorial clinical benefits. The results suggest that when selecting or advising about treatments, pharmacists should consider how the different once‐weekly GLP‐1 RAs and their MoA affect clinical outcomes in order to ensure optimal treatment for individuals.