exenatide and Diabetes-Mellitus

Diabetes is considered a new pandemic of the modern world, and the number of sufferers is steadily increasing. Sustained hyperglycemia promotes the production of free radicals and leads to persistent, low-grade inflammation. Oxidative stress causes mitochondrial destruction, which along with activation of the hexosamine pathway, nuclear factor-κB (Nf-κb), p38 mitogen-activated protein kinase (p38 MAPK), c-jun NH2 terminal kinase/stress-activated protein kinase (JNK/SAPK) or toll-like receptors (TLRs), leads to pancreatic β-cell dysfunction. However, there is also the protective mechanism that counteracts oxidative stress and inflammation in diabetes, mitophagy, which is a mitochondrial autophagy. An important part of the strategy to control diabetes is to lead a healthy lifestyle based on, among other things, regular physical activity, giving up smoking, eating a balanced diet containing ingredients with antioxidant potential, including vegetables and fruits, and using hypoglycemic pharmacotherapy. Tobacco smoke is a recognized modifiable risk factor for many diseases including diabetes, and it has been shown that the risk of the disease increases in proportion to the intensity of smoking. Physical activity as another component of therapy can effectively reduce glucose fluctuations, and high intensity interval exercise appears to have the most beneficial effect. A proper diet not only increases cellular sensitivity to insulin, but is also able to reduce inflammation and oxidative stress. Pharmacotherapy for diabetes can also affect oxidative stress and inflammation. Some oral drugs, such as metformin, pioglitazone, vildagliptin, liraglutide, and exenatide, cause a reduction in markers of oxidative stress and/or inflammation, while the new drug Imeglimin reverses pancreatic β-cell dysfunction. In studies of sitagliptin, vildagliptin and exenatide, beneficial effects on oxidative stress and inflammation were achieved by, among other things, reducing glycemic excursions. For insulin therapy, no corresponding correlation was observed. Insulin did not reduce oxidative stress parameters. There was no correlation between glucose variability and oxidative stress in patients on insulin therapy. The data used in this study were obtained by searching PubMed online databases, taking into account recent studies.

Topics: Diabetes Mellitus; Exenatide; Glucose; Humans; Inflammation; Insulin; Life Style; Oxidative Stress; Vildagliptin

Although randomized, controlled trials (RCTs) are seen as the gold standard for evidence in clinical medicine, a number of considerations are increasing the use of real-world data (RWD) to generate evidence. A series of methodological challenges must be overcome in order for such real-world evidence (RWE) to gain acceptance. In diabetes, RWE faces some particular issues that have limited its development. As the natural history of diabetes progresses, patients' disease changes over time and treatments will be modified as a result. This evolving disease and treatment pattern requires application of methods that account for such changes over time. Research developing RWE in diabetes and other conditions has sometimes been subject to important biases, and researchers should be aware of, and take steps to mitigate potential for bias in order to enhance the evidence produced.. We review a RWE study that replicated and extended evidence provided by a RCT regarding the effects of weekly exenatide relative to basal insulin (glargine or detemir) to illustrate a potential application of RWE. This study observed a 0.7% decrease in HbA1C for weekly exenatide relative to a 0.5% decrease in HbA1C for the comparator along with a 2 kg weight loss for weekly exenatide relative to a 0.25 kg weight gain, effects that were close to those from the RCT. Further, the RWE study was able to extend results to patient populations that were not well represented in the RCT.. Despite numerous challenges, RWE can be used to complement evidence from RCTs.

Topics: Diabetes Mellitus; Exenatide; Humans; Insulin Glargine

To review the evolution and advancement of GLP-1 receptor agonist (GLP-1RA) therapy, through the lens of randomised controlled trials, from differentiating characteristics, efficacy, safety, tolerability, and cardiovascular outcomes, to evidence gaps and next steps.. Clinical review of published phase 3 or later RCT data studying efficacy, safety, and outcomes of approved GLP-1 RA therapies.. Through a wealth of studies, including both placebo-controlled and active-controlled studies, GLP-1 RAs have demonstrated high glycemic efficacy and ability to facilitate weight loss, with minimal risk of hypoglycemia, potential to restore beta cell function, and evidence for improved cardiovascular outcomes in those at risk.. Over a decade of clinical studies have established the unique contributions of GLP-1 RAs in the treatment of diabetes. Individual differences between the different GLP-1 RAs, in delivery, pharmacokinetic and clinical effects, exist, allowing for tailored approaches to clinical care. The strength of evidence generated through RCTs, both short-term and long-term studies, will continue to evolve and inform our current paradigms in diabetes care.

Topics: Clinical Trials, Phase III as Topic; Diabetes Mellitus; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Treatment Outcome; Weight Loss

Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is increasingly used in obese or overweight patients with diabetes. However, its safety profile and effects on weight loss in non-diabetic obese or overweight population remain unclear. We aimed to evaluate efficacy and safety of exenatide in obese or overweight participants without diabetes.. We searched up to January 2016 in MEDLINE (Ovid SP), EMBASE (Ovid SP), Cochrane Central Register of Controlled Trials (CENTRAL), some Chinese databases and ClinicalTrials.gov for randomized controlled trials (RCTs) investigating exenatide in obese or overweight participants without diabetes. The primary outcomes included body weight and body mass index (BMI). We pooled data to calculate the mean differences (MDs) with their 95% confidence intervals (CIs). We assessed overall evidence quality of BMI reduction and weight loss according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.. Six randomized controlled trials involving 362 patients were included in the meta- analysis. The follow-up duration ranged from 12 to 24weeks. Compared with control group, a larger body weight loss (MD: -4.47kg; 95% CI: -6.67 to -2.27; P<0.0001), regardless of dosage and population, was achieved by the obese or overweight patients in exenatide group. Exenatide also elicited a greater reduction in. -0.86kg/m(2); 95% CI: -1.39 to -0.33; P=0.001) and waist circumferences (MD: -1.78cm; 95% CI: -3.13 to -0.44; P=0.009) compared with the control. No significant benefits were showed in exenatide group in terms of blood pressure and lipid profiles. Gastrointestinal adverse events were mostly common during the treatment of exenatide.. Exenatide could significantly reduce body weight in obese or overweight participants without diabetes, and might be a safe alternative GLP-1 receptor agonist for weight control in such patients. Larger randomized trials with longer follow-up duration are required to confirm the effectiveness and safety of exenatide.

Topics: Body Weight; Diabetes Mellitus; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Obesity; Overweight; Peptides; Randomized Controlled Trials as Topic; Venoms; Weight Loss

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The development and progression of DN might involve multiple factors. Connective tissue growth factor (CCN2, originally known as CTGF) is the one which plays a pivotal role. Therefore, increasing attention is being paid to CCN2 as a potential therapeutic target for DN. Up to date, there are also many drugs or agents which have been shown for their protective effects against DN via different mechanisms. In this review, we only focus on the potential renoprotective therapeutic agents which can specifically abolish CCN2 expression or nonspecifically inhibit CCN2 expression for retarding the development and progression of DN.

Topics: Animals; Anthocyanins; Antibodies, Monoclonal; Connective Tissue Growth Factor; Diabetes Mellitus; Diabetic Nephropathies; Disease Progression; Exenatide; Guanidines; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Kidney; Kidney Failure, Chronic; Mice; Mycophenolic Acid; Oligonucleotides, Antisense; ortho-Aminobenzoates; Peptides; Renin-Angiotensin System; rho-Associated Kinases; Spironolactone; Venoms

Among 12billion injections administered annually, unsafe delivery leads to >20million infections and >100million reactions. In an emerging new concept, freeze-dried plant cells (lettuce) expressing vaccine antigens/biopharmaceuticals are protected in the stomach from acids/enzymes but are released to the immune or blood circulatory system when plant cell walls are digested by microbes that colonize the gut. Vaccine antigens bioencapsulated in plant cells upon oral delivery after priming, conferred both mucosal and systemic immunity and protection against bacterial, viral or protozoan pathogens or toxin challenge. Oral delivery of autoantigens was effective against complications of type 1 diabetes and hemophilia, by developing tolerance. Oral delivery of proinsulin or exendin-4 expressed in plant cells regulated blood glucose levels similar to injections. Therefore, this new platform offers a low cost alternative to deliver different therapeutic proteins to combat infectious or inherited diseases by eliminating inactivated pathogens, expensive purification, cold storage/transportation and sterile injections.

Topics: Administration, Oral; Autoantigens; Biological Availability; Blood Glucose; Cholera Vaccines; Diabetes Mellitus; Drug Carriers; Exenatide; Factor IX; Freeze Drying; Gastrointestinal Tract; Humans; Malaria Vaccines; Peptides; Plague Vaccine; Plant Cells; Proinsulin; Proteins; Vaccines; Venoms

Recently incretin-based therapies have been developed in the clinical practice, this class includes both the dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin), and the glucagon-like peptide- 1 (GLP-1) receptor agonists [exenatide, exenatide long acting release (LAR) and liraglutide]. In particular exenatide and liraglutide have structural similarity and bind to the GLP-1 receptor, displaying a similar broad range of activities relevant to improving glycemic control, including stimulation of insulin secretion and reduction of glucagon secretion, both in a glucose-dependent manner. Furthermore, GLP-1 slows gastrointestinal motility and increases satiety, reducing the food intake; it also promotes β-cell proliferation and probably neogenesis, while reducing apoptosis in animal models. We conducted a review analyzing clinical efficacy and safety of GLP-1 receptor agonists exenatide and liraglutide, both alone and in combination with other anti-diabetic drugs, including the most important studies about them in the latest ten years. We concluded that GLP-1 receptor agonists appear to be a good choice to decrease HbA1c levels and to lower postprandial blood glucose levels. They also suppress glucagon secretion and slow gastric motility. They also have positive effects on β-cell function and they gave a significant decrease of body weight. They are not associated with hypoglycemia, but cause a relatively high frequency of gastrointestinal disturbances, with some patients experiencing one or more episodes of nausea, vomiting, or diarrhea. However, after an evaluation of the advantages and the disadvantages, we concluded that, once metformin fails to reach an adequate glycemic control, GLP-1 receptor agonists can be a valid alternative, especially in obese type 2 diabetic patients. GLP-1 receptor agonists should be considered also in patients in therapy with metformin and another agent, such as a sulfonylurea, because of the minor risk of developing hypoglycemia and the positive effect on body weight.

Topics: Animals; Diabetes Mellitus; Exenatide; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Liraglutide; Peptides; Treatment Outcome; Venoms

There is a concern on the risk of thyroid cancer associated with glucagon-like peptide-1 (GLP-1) analogs including liraglutide and exenatide. In this article, we review related experimental studies, clinical trials and observational human studies currently available. In rodents, liraglutide activated the GLP-1 receptors on C-cells, causing an increased incidence of C-cell neoplasia. Animal experiments with monkeys demonstrated no increase in calcitonin release and no C-cell proliferation after long-term liraglutide administration. Longitudinal 2-year data from clinical trials do not support any significant risk for the activation or growth of C-cell cancer in humans in response to liraglutide. However, an analysis of the FDA adverse event reporting system database suggested an increased risk for thyroid cancer associated with exenatide after its marketing. Noticeably, a recent study discovered that GLP-1 receptor could also be expressed in human papillary thyroid carcinomas (PTC), but the impact of GLP-1 analogs on PTC is not known. Therefore, GLP-1 analogs might increase the risk of thyroid C-cell pathology in rodents, but its risk in humans awaits confirmation. Since GLP-1 receptor is also expressed in PTC besides C-cells, it is important to investigate the actions of GLP-1 on different subtypes of thyroid cancer in the future.

Topics: Animals; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Disease Models, Animal; Exenatide; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Liraglutide; Macaca fascicularis; Mice; Peptides; Rats; Receptors, Glucagon; Thyroid Neoplasms; Venoms

Glucagon-like peptide 1 (GLP-1) is a small peptide component of the prohormone, proglucagon, that is produced in the gut. Exendin-4, a GLP-1 receptor agonist originally isolated from the saliva of H. suspectum or Gila monster, is a peptide that shares sequence and functional homology with GLP-1. Both peptides have been demonstrated to stimulate insulin secretion, inhibit glucagon secretion, promote satiety and slow gastric emptying. As such, GLP-1 and Exendin-4 have become attractive pharmaceutical targets as an adjunctive therapy for individuals with type II diabetes mellitus, with several products currently available clinically. Herein we summarize the cell biology leading to GLP-1 production and secretion from intestinal L-cells and the endocrine functions of this peptide and Exendin-4 in humans. Additionally, gene therapeutic applications of GLP-1 and Exendin-4 are discussed with a focus on recent work using the salivary gland as a gene therapy target organ for the treatment of diabetes mellitus.

Topics: Animals; Diabetes Mellitus; Exenatide; Gene Transfer Techniques; Genetic Therapy; Glucagon-Like Peptide 1; Humans; Organ Specificity; Peptides; Salivary Glands; Venoms

The prevalence of obesity and diabetes is epidemic. Severe insulin resistance (defined as the need for > or = 200 units of insulin per day to achieve glycemic control) is commonly seen with obesity and can complicate diabetes management. The management of patients with diabetes who have severe insulin resistance is difficult, and at times frustrating, and requires a multifaceted approach. Weight loss is the best treatment option, which can be a challenging task for patients to achieve and maintain. Medications that decrease insulin needs like metformin, thiazolidinediones, or pramlintide may help, but some patients also need high doses of insulin. This article reviews these different treatment options and provides practical advice on weight loss, use of insulin sensitizers, and use of U-500 insulin.

Topics: Amyloid; Bariatric Surgery; Diabetes Mellitus; Diet, Reducing; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Exercise; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Liraglutide; Metformin; Obesity; Peptides; Thiazolidinediones; Treatment Failure; Venoms; Weight Loss

Topics: Adamantane; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin

Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d'être is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4). A lack of secretion of incretins or an increase in their clearance are not pathogenic factors in diabetes. However, in type 2 diabetes (T2DM), GIP no longer modulates glucose-dependent insulin secretion, even at supraphysiological (pharmacological) plasma levels, and therefore GIP incompetence is detrimental to beta-cell function, especially after eating. GLP-1, on the other hand, is still insulinotropic in T2DM, and this has led to the development of compounds that activate the GLP-1 receptor with a view to improving insulin secretion. Since 2005, two new classes of drugs based on incretin action have been approved for lowering blood glucose levels in T2DM: an incretin mimetic (exenatide, which is a potent long-acting agonist of the GLP-1 receptor) and an incretin enhancer (sitagliptin, which is a DPP4 inhibitor). Exenatide is injected subcutaneously twice daily and its use leads to lower blood glucose and higher insulin levels, especially in the fed state. There is glucose-dependency to its insulin secretory capacity, making it unlikely to cause low blood sugars (hypoglycemia). DPP4 inhibitors are orally active and they increase endogenous blood levels of active incretins, thus leading to prolonged incretin action. The elevated levels of GLP-1 are thought to be the mechanism underlying their blood glucose-lowering effects.

Topics: Animals; Diabetes Mellitus; Exenatide; Glucose; Homeostasis; Humans; Hypoglycemic Agents; Incretins; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

Topics: Animals; Blood Glucose; Diabetes Mellitus; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Lizards; Obesity; Peptides; Venoms

Exenatide is the first in a new class of compounds, which possess similar activity to the naturally-occurring hormone glucagon-like peptide-1 (GLP-1). It mirrors many of the effects of GLP-1, improving glycaemic control through a combination of mechanisms, which include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduced appetite. Phase III clinical trials showed exenatide therapy for 30 weeks significantly reduced glycated haemoglobin, and fasting and postprandial plasma glucose compared with baseline when added to metformin and sulfonylureas or a combination of the two, with an average weight loss of approximately 2 kg. Exenatide can also be used in combination with thiazolidinediones and may be an alternative to insulin in patients requiring additional therapy. In patients with established Type 2 diabetes, control of both glycaemia and body weight are important to minimise the risk of future diabetes complications. Open-label extensions from these pivotal trials demonstrate that patients treated with exenatide for < or = 3 years sustained the reductions in glycaemic control achieved at 30 weeks and had a progressive reduction in body weight. Exenatide is generally well tolerated; nausea is the most commonly reported side effect, but can be significantly reduced when a target dose of exenatide is achieved in patients with gradual dose titration. Hypoglycaemia has been encountered in clinical trials of exenatide, especially on initiation of therapy with sulfonylureas (not with metformin). Exenatide may enable patients with Type 2 diabetes to improve glycaemic control and reduce or eliminate the risk of hypoglycaemia and weight gain.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Peptides; Venoms

Topics: Diabetes Mellitus; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Peptides; Venoms

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from enteroendocrine L cells in response to ingested nutrients. The first recognized and most important action of GLP-1 is the potentiation of glucose-stimulated insulin secretion in beta-cells, mediated by activation of its seven transmembrane domain G-protein-coupled receptor. In addition to its insulinotropic actions, GLP-1 exerts islet-trophic effects by stimulating replication and differentiation and by decreasing apoptosis of beta-cells. The GLP-1 receptor is expressed in a variety of other tissues important for carbohydrate metabolism, including pancreatic alpha-cells, hypothalamus and brainstem, and proximal intestinal tract. GLP-1 also appears to exert important actions in liver, muscle and fat. Thus, GLP-1 suppresses glucagon secretion, promotes satiety, delays gastric emptying and stimulates peripheral glucose uptake. The impaired GLP-1 secretion observed in type 2 diabetes suggests that GLP-1 plays a role in the pathogenesis of this disorder. Thus, because of its multiple actions, GLP-1 is an attractive therapeutic target for the treatment of type 2 diabetes, and major interest has resulted in the development of a variety of GLP-1 receptor agonists for this purpose. Ongoing clinical trials have shown promising results and the first analogs of GLP-1 are expected to be available in the near future.

Topics: Amino Acid Sequence; Animals; Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Homeostasis; Humans; Liraglutide; Maleimides; Molecular Sequence Data; Nitriles; Peptides; Protease Inhibitors; Pyrrolidines; Receptors, Glucagon; Venoms

Topics: Adiponectin; Animals; Diabetes Mellitus; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glycogen Phosphorylase; Humans; Hypoglycemic Agents; Imidazoles; Insulin; Intercellular Signaling Peptides and Proteins; Peptide Fragments; Peptides; Protein Precursors; Receptors, Glucagon; Venoms

Two major initiatives are under way to correct the beta-cell deficit of diabetes: one would generate beta-cells ex vivo that are suitable for transplantation, and the second would stimulate regeneration of beta-cells in the pancreas. Studies of ex vivo expansion suggest that beta-cells have a potential for dedifferentiation, expansion, and redifferentiation. Work with mouse and human embryonic stem (ES) cells has not yet produced cells with the phenotype of true beta-cells, but there has been recent progress in directing ES cells to endoderm. Putative islet stem/progenitor cells have been identified in mouse pancreas, and formation of new beta-cells from duct, acinar and liver cells is an active area of investigation. Peptides, including glucagon-like peptide-1/exendin-4 and the combination of epidermal growth factor and gastrin, can stimulate regeneration of beta-cells in vivo. Recent progress in the search for new sources of beta-cells has opened promising new opportunities and spawned clinical trials.

Topics: Cell Differentiation; Diabetes Mellitus; Embryo, Mammalian; Embryo, Nonmammalian; Epidermal Growth Factor; Exenatide; Gastrins; Glucagon; Glucagon-Like Peptide 1; Islets of Langerhans; Pancreas; Peptide Fragments; Peptides; Protein Precursors; Regeneration; Stem Cells; Venoms

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that promotes glucose homeostasis through the regulation of insulin and glucagon secretion, gastric emptying, and food intake. This spectrum of effects makes GLP-1 an attractive candidate for drug development. However, because GLP-1 is a small peptide with rapid metabolism in the circulation, its usefulness to treat patients is limited. However, GLP-1 mimetics that are resistant to degradation have been developed and are effective in lowering blood glucose in diabetic patients. A second strategy for harnessing GLP-1 therapeutically is to inhibit the metabolism of endogenous GLP-1; several orally available compounds are in clinical trials. These two new classes of drugs both enhance GLP-1 signaling but differ in several key characteristics that may lead to distinct roles in the treatment of diabetic patients.

Topics: Adenosine Deaminase Inhibitors; Diabetes Mellitus; Dipeptidyl Peptidase 4; Drug Design; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycoproteins; Peptides; Protease Inhibitors; Receptors, Glucagon; Signal Transduction; Venoms

Glycemic variability (GV) is an indicator of glycemic control and can be evaluated by calculating the SD of blood glucose measurements. In humans with diabetes mellitus (DM), adding a glucagon-like peptide-1 (GLP-1) analogue to conventional therapy reduces GV. In diabetic cats, the influence of GLP-1 analogues on GV is unknown.. To evaluate GV in diabetic cats receiving the GLP-1 analogue exenatide extended release (EER) and insulin.. Thirty client-owned cats with newly diagnosed spontaneous DM.. Retrospective study. Blood glucose curves from a recent prospective placebo-controlled clinical trial generated 1, 3, 6, 10, and 16 weeks after starting therapy were retrospectively evaluated for GV. Cats received either EER (200 μg/kg) or 0.9% saline SC once weekly, insulin glargine and a low-carbohydrate diet. Mean blood glucose concentrations were calculated and GV was assessed by SD. Data were analyzed using nonparametric tests.. In the EER group, GV (mean SD [95% confidence interval]) was lower at weeks 6 (1.69 mmol/L [0.9-2.48]; P = .02), 10 (1.14 mmol/L [0.66-1.62]; P = .002) and 16 (1.66 mmol/L [1.09-2.23]; P = .02) compared to week 1 (4.21 mmol/L [2.48-5.93]) and lower compared to placebo at week 6 (3.29 mmol/L [1.95-4.63]; P = .04) and week 10 (4.34 mmol/L [2.43-6.24]; P < .000). Cats achieving remission (1.21 mmol/L [0.23-2.19]) had lower GV compared to those without remission (2.96 mmol/L [1.97-3.96]; P = .01) at week 6.. The combination of EER, insulin, and a low-carbohydrate diet might be advantageous in the treatment of newly diagnosed diabetic cats.

Topics: Animals; Blood Glucose; Cat Diseases; Cats; Diabetes Mellitus; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Prospective Studies; Retrospective Studies

A commonly used therapeutic strategy for type 2 diabetes mellitus (DM) in humans involves the use of synthetic incretin hormone-based therapies including exenatide, a glucagon-like pepetide-1 hormone agonist. Glucagon-like pepetide-1 agonists can be used alone or as an ancillary therapy with other agents, including insulin and oral antihyperglycemics. Little is known about the role of these therapies for DM in cats. Therefore, the primary objective of this study was to evaluate the safety and efficacy of short-acting exenatide combined with insulin, as compared to placebo and insulin for the treatment of DM in cats. Treatment with exenatide was well tolerated; only 2 cats developed side effects requiring dose reduction. Two cats (25%) went into diabetic remission while receiving exenatide and insulin, whereas remission was not reported during placebo treatment. The average change in the daily exogenous insulin dose was significant (β = -0.56 U/kg, 95% confidence interval, -0.96 to -0.15, P = 0.007), and the dose of insulin administered was lower during exenatide treatment. The average weight loss experienced on exenatide was significantly higher than on placebo (β = 0.65 kg, 95% confidence interval, 0.09-1.21, P = 0.02). There was no significant difference in any of the hormone concentrations evaluated for cats on exenatide vs placebo treatments. Overall, the treatment of diabetic cats with insulin and a fixed dose of exenatide was found to be safe. The weight loss and decreased exogenous insulin requirement experienced with exenatide treatment could be a significant benefit for overweight diabetic cats and warrants further evaluation.

Topics: Animals; Blood Glucose; Cat Diseases; Cats; Cross-Over Studies; Diabetes Mellitus; Double-Blind Method; Drug Therapy, Combination; Exenatide; Female; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin Glargine; Male; Placebos; Random Allocation; Weight Loss

The most efficacious strategies to improve diabetes control include case management, health care team changes, patient education, and facilitated transmission of patient data to clinicians ("facilitated relay"), but these strategies have not been translated to permit general use in clinical practice.. A web-based decision support program was developed to include these features, and assessed in patients who had A1c ≥7.0% despite using metformin with/without sulfonylureas or insulin. Staff entered patients' glucose data, obtained management recommendations, reviewed the plan with a clinician, and discussed the new plan with patients.. 113 subjects were 96% male and 32% black, with average age 65.6 years and BMI 32.8. During prior primary care, A1c averaged 8.32 ± 0.16% (SEM). In all patients, baseline A1c was 8.18 ± 0.11%, and decreased to 7.54 ± 0.12%, 7.16 ± 0.13%, and 7.54 ± 0.16% at 3, 6, and 12 months, respectively, all P < .001. In 42 subjects who provided glucose data and made requested changes in medications, A1c was 8.12 ± 0.09% at baseline and fell to 7.29 ± 0.11%, 6.98 ± 0.10%, and 7.05 ± 0.10% at 3, 6, and 12 months, respectively, all P < .001. Chart review of 16 subjects followed for 12 months demonstrated that hypoglycemia (symptoms and/or glucose <70 mg/dl) averaged less than 1 episode/patient/month, and there was no severe hypoglycemia.. A novel decision support program improved A1c with little hypoglycemia. Use of this approach should allow primary care teams to keep patients well controlled, and reduce the need for specialist referrals.

Topics: Aged; Algorithms; Blood Glucose; Decision Support Systems, Clinical; Diabetes Mellitus; Double-Blind Method; Exenatide; Female; Georgia; Glycated Hemoglobin; Hospitals, Veterans; Humans; Hypoglycemic Agents; Insulin; Internet; Male; Metformin; Middle Aged; Outpatients; Patient Care Team; Patient Education as Topic; Peptides; Primary Health Care; Program Development; Research Design; Sulfonylurea Compounds; Translational Research, Biomedical; United States; Venoms; Veterans

To compare treatment satisfaction among people with type 2 diabetes receiving dulaglutide 1.5 mg and dulaglutide 0.75 mg (a once-weekly, long-acting, glucagon-like peptide-1 receptor agonist) with those receiving either exenatide or placebo (AWARD-1 study) or metformin (AWARD-3 study) over 52 weeks.. The Diabetes Treatment Satisfaction Questionnaire status version (DTSQs) and change version (DTSQc) were used to evaluate total treatment satisfaction and perceived frequency of hyperglycaemia and hypoglycaemia.. In the AWARD-1 study, significant improvements from baseline were observed in total DTSQs score for both dulaglutide doses (26 and 52 weeks) and exenatide (26 weeks). The improvement was significantly greater with both dulaglutide doses compared with placebo (26 weeks) and exenatide (26 and 52 weeks). The perceived frequency of hyperglycaemia was lower for all groups at 26 and 52 weeks compared with baseline. The improvement was greater with both dulaglutide doses and exenatide compared with placebo at 26 weeks, and was also greater with both dulaglutide doses compared with exenatide at 26 and 52 weeks. The exenatide group had an increase in perceived frequency of hypoglycaemia at 26 and 52 weeks. In the AWARD-3 study, significant improvements from baseline were observed for total DTSQs scores in all groups at 26 and 52 weeks. Perceived frequency of hyperglycaemia was lower for all groups at 26 and 52 weeks compared with baseline, and this improvement was greater with both dulaglutide doses compared with metformin at 52 weeks.. Dulaglutide was associated with improvements in treatment satisfaction and a decrease in perceived frequency of hyperglycaemia.

Topics: Adult; Diabetes Mellitus; Double-Blind Method; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptides; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Metformin; Middle Aged; Patient Satisfaction; Peptides; Recombinant Fusion Proteins; Surveys and Questionnaires; Time Factors; Venoms

Glucagon-like peptide 1 receptors (GLP-1Rs) have been found in the brain, but whether GLP-1R agonists (GLP-1RAs) influence brain glucose metabolism is currently unknown. The study aim was to evaluate the effects of a single injection of the GLP-1RA exenatide on cerebral and peripheral glucose metabolism in response to a glucose load. In 15 male subjects with HbA1c of 5.7 ± 0.1%, fasting glucose of 114 ± 3 mg/dL, and 2-h glucose of 177 ± 11 mg/dL, exenatide (5 μg) or placebo was injected in double-blind, randomized fashion subcutaneously 30 min before an oral glucose tolerance test (OGTT). The cerebral glucose metabolic rate (CMRglu) was measured by positron emission tomography after an injection of [(18)F]2-fluoro-2-deoxy-d-glucose before the OGTT, and the rate of glucose absorption (RaO) and disposal was assessed using stable isotope tracers. Exenatide reduced RaO0-60 min (4.6 ± 1.4 vs. 13.1 ± 1.7 μmol/min ⋅ kg) and decreased the rise in mean glucose0-60 min (107 ± 6 vs. 138 ± 8 mg/dL) and insulin0-60 min (17.3 ± 3.1 vs. 24.7 ± 3.8 mU/L). Exenatide increased CMRglu in areas of the brain related to glucose homeostasis, appetite, and food reward, despite lower plasma insulin concentrations, but reduced glucose uptake in the hypothalamus. Decreased RaO0-60 min after exenatide was inversely correlated to CMRglu. In conclusion, these results demonstrate, for the first time in man, a major effect of a GLP-1RA on regulation of brain glucose metabolism in the absorptive state.

Topics: Blood Glucose; Cerebrum; Cross-Over Studies; Diabetes Mellitus; Double-Blind Method; Exenatide; Glucose Tolerance Test; Glycated Hemoglobin; Homeostasis; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Prediabetic State; Venoms

Topics: Adult; ATP-Binding Cassette Transporters; Diabetes Mellitus; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Humans; Incretins; Insulin-Secreting Cells; Male; Middle Aged; Mutation; Peptides; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Receptors, Glucagon; Sulfonylurea Receptors; Venoms

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 desHis

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diet, High-Fat; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Insulin; Mice; Receptors, Glucagon

This study aims to investigate the cost-effectiveness of the add-on exenatide to conventional pharmacotherapy in patients with Parkinson's disease (PD) when considering the coexistence of diabetes mellitus (DM).. We used the Keelung and Community-based Integrated Screening databases to understand the medical utilisation in the Hoehn and Yahr stages of patients with PD. A Markov model with 1-year cycle length and 50-year time horizon was used to assess the cost-effectiveness of add-on exenatide to conventional pharmacotherapy compared to conventional pharmacotherapy alone. All costs were adjusted to the value of the new Taiwanese dollar (NT$) as of the year 2020. One-way sensitivity and probability analyses were performed to test the robustness of the results.. From a societal perspective, the add-on exenatide brought an average of 0.39 quality-adjusted life years (QALYs) gained, and a cost increment of NT$104,744 per person in a 50-year horizon compared to conventional pharmacotherapy. The incremental cost-effectiveness ratio (ICER) was NT$268,333 per QALY gained. As the ICER was less than the gross domestic product per capita (NT$839,558), the add-on exenatide was considered to be very cost-effective in the two models, according to the World Health Organization recommendation. Add-on exenatide had a 96.9% probability of being cost-effective in patients with PD, and a 100% probability of being cost-effective in patients with PD and DM.. Add-on exenatide is cost-effective in PD combined with DM. Considering that DM may be a risk factor for neurodegenerative diseases, exenatide provides both clinical benefits and cost-effectiveness when considering both PD and DM.

Topics: Cost-Benefit Analysis; Diabetes Mellitus; Exenatide; Humans; Parkinson Disease; Quality-Adjusted Life Years

To investigate the effects of exendin-4 on orthodontic tooth movement distance, root resorption, and expression levels of osteoclast-related cytokines in a mouse model.. A 10-g NiTi coil spring was placed between the anterior alveolar bone and upper left first molar of 8-week-old male C57BL/6 mice. Twenty microliters of exendin-4 solution (containing 0.2 μg, 4 μg, or 20 μg exendin-4) or phosphate-buffered saline (PBS) were injected on the buccal side of the upper left first molar at 2-day intervals (4 mice per group). Mice were sacrificed on day 12; silicone impressions were taken to record tooth movement distance. The left maxillae of the PBS and 20 μg exendin-4 groups were also excised for histological analysis and quantitative reverse transcription polymerase chain reaction analysis.. Orthodontic tooth movement distance was smaller in the 20 μg exendin-4 group than in the PBS group (P < .01). Compared with the PBS group, the 20 μg exendin-4 group showed lower osteoclast number (P < .05), odontoclast number (P < .05), and root resorption surface percentage (P < .05). Relative to maxillae with PBS injections, maxillae with 20 μg exendin-4 injections had lower receptor activator of nuclear factor kappa-B ligand (RANKL) mRNA expression (P < .05), TNF-α mRNA expression (P < .05), and RANKL/osteoprotegerin (OPG) ratio (P < .01). There were no differences in the expression of OPG mRNA.. Exendin-4 inhibits orthodontic tooth movement. Therefore, additional attention is needed for orthodontic patients who receive exendin-4 for diabetes treatment. GLP-1 receptor may be a treatment target for patients with severe root resorption.

Topics: Animals; Diabetes Mellitus; Exenatide; Humans; Male; Medicine; Mice; Mice, Inbred C57BL; Osteoclasts; RANK Ligand; Root Resorption; Tooth Movement Techniques

The oral administration route is popular with T2DM patients because they need convenience in lifelong medication. At present, oral Exenatide is not available on the market and therefore the relevant studies are valuable. Herein, we constructed a novel dual cholic acid-functionalized nanoparticle for oral delivery of Exenatide, which was based on the functionalized materials of deoxycholic acid-low molecular weight protamine and glycocholic acid-poly (ethylene glycol)-b-polysialic acid. The hydrophobic deoxycholic acid strengthened the nanoparticles and the hydrophilic glycolic acid targeted to specific transporter. We first condensed Exenatide-Zn

Topics: Administration, Oral; Delayed-Action Preparations; Deoxycholic Acid; Diabetes Mellitus; Exenatide; Glycocholic Acid; Humans; Hypoglycemic Agents; Ileum; Nanoparticles; Zinc

Pharmacological long lasting Glucagon-like peptide-1 (GLP-1) analogues, such as Exendin-4, have become widely used diabetes therapies. Chronic GLP-1R stimulation has been linked to β-cell protection and these pro-survival actions of GLP-1 are dependent on the activation of the mammalian target of rapamycin (mTOR) leading to accumulation of Hypoxia inducible factor 1 alpha (HIF-1α). Recent studies from our lab indicate that prolonged GLP-1R stimulation promotes metabolic reprograming of β-cells towards a highly glycolytic phenotype and activation of the mTOR/HIF-1α pathway was required for this action. We hypothesised that GLP-1 induced metabolic changes depend on the activation of mTOR and HIF-1α, in a cascade that occurs after triggering of a potential Insulin-like growth factor 1 receptor (IGF-1R) or the Insulin receptor (IR) autocrine loops. Loss of function of these receptors, through the use of small interfering RNA, or neutralizing antibodies directed towards their products, was undertaken in conjunction with functional assays. Neither of these strategies mitigated the effect of GLP-1 on glucose uptake, protein expression or bioenergetic flux. Our data indicates that activation of IGF-1R and/or the IR autocrine loops resulting in β-cell protection and function, involve mechanisms independent to the enhanced metabolic effects resulting from sustained GLP-1R activation.

Topics: Animals; Autocrine Communication; Diabetes Mellitus; Energy Metabolism; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Insulin-Secreting Cells; Rats; Receptor, IGF Type 1; Receptor, Insulin; TOR Serine-Threonine Kinases

Diabetes mellitus is a chronic disease in which the pancreas no longer produces enough insulin. Pancreatic alpha cell mass increases in response to insufficient insulin secretion. However, the reason for this increase is not clear. It is possible that the increased alpha-cells may stimulate compensatory insulin release in response to the insufficient insulin such as insulin resistance. In this study, we investigated whether glucagon and glucagon-like peptide-1 (GLP-1), hormones produced by alpha cells, contribute to insulin secretion in INS-1 cells, a beta cell line. We confirmed that alpha cell area in the pancreatic islets and glucagon secretion were increased in HFD-induced obese mice. Co-treatment with glucagon and exendin-4 (Ex-4), a GLP-1 receptor agonist, additively increased glucose-stimulated insulin secretion in INS-1 cells. In parallel, cAMP production was also additively increased by co-treatment with these hormones. The increase of insulin secretion by Ex-4 in the presence of high glucose was inhibited by 2'5'-dideoxyadenosine, a transmembrane adenylyl cyclase inhibitor, but not by KH-7, a soluble adenylyl cyclase inhibitor. The increase of insulin secretion by glucagon in INS-1 cells was inhibited by both 2'5'-dideoxyadenosine and KH-7. We suggest that glucagon and GLP-1 produced from alpha cells additively increase cAMP and insulin secretion in the presence of high glucose via distinct adenylyl cyclases in INS-1 cells, and this may contribute to the compensatory increase of insulin secretion by an increase of pancreatic alpha cell mass under conditions of insulin resistance.

Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Cell Line; Cyclic AMP; Diabetes Mellitus; Dideoxyadenosine; Diet, High-Fat; Exenatide; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Mice; Mice, Obese; Peptides; Venoms

Protein transduction domains (PTDs) have been shown to promote the delivery of therapeutic proteins or peptides into the living cells. In a previous study, we showed that the double mutant of TCTP-PTD 13, TCTP-PTD 13M2, was more effective in the delivery of insulin than the wild-type TCTP-PTD 13. In this study, we applied this approach to the nasal delivery of a different peptide, exendin-4, using as carriers, several modified TCTP-PTDs, such as TCTP-PTD 13M1, 13M2, and 13M3. Nasal co-administration of TCTP-PTD 13M2 with exendin-4 showed the highest exendin-4 uptake among the three analogs in normal rats, and also decreased blood glucose levels by 43.3% compared with that of exendin-4 alone and by 18.6% compared with that of exendin-4 plus TCTP-PTD 13 in diabetic mice. We also designed an additional covalently linked conjugate of TCTP-PTD 13M2 and exendin-4 and evaluated its hypoglycemic effect after subcutaneous or intranasal delivery. Subcutaneous administration of exendin-4 that its C-terminus is covalently linked to TCTP-PTD 13M2 showed hypoglycemic effect of 42.2% compared to that in untreated group, whereas intranasal delivery was not successful in diabetic mice. We conclude that a simple mixing TCTP-PTD 13M2 with peptide/protein drugs can be potentially a generally applicable approach for intranasal delivery into animals.

Topics: Administration, Intranasal; Animals; Diabetes Mellitus; Drug Delivery Systems; Exenatide; Hypoglycemic Agents; Insulin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nasal Mucosa; Rats; Rats, Wistar; Recombinant Fusion Proteins; Tumor Protein, Translationally-Controlled 1

Topics: Antiparkinson Agents; Diabetes Mellitus; Double-Blind Method; Exenatide; Humans; Hypoglycemic Agents; Parkinson Disease; Randomized Controlled Trials as Topic; Treatment Outcome

Enhancement of glucagon-like peptide-1 (GLP-1) reduces glucose levels and preserves pancreatic β-cell function, but its effect against restenosis is unknown.. We investigated the effect of subcutaneous injection of exenatide or local delivery of a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) into carotid artery, in reducing the occurrence of restenosis following balloon injury. As a control, we inserted β-galactosidase cDNA in the same vector (rAd-βGAL). Otsuka Long-Evans Tokushima rats were assigned to three groups (n = 12 each): (1) normal saline plus rAd-βGAL delivery (NS + rAd-βGAL), (2) exenatide plus rAd-βGAL delivery (Exenatide + rAd-βGAL), and (3) normal saline plus rAd-GLP-1 delivery (NS + rAd-GLP-1). Normal saline or exenatide were administered subcutaneously from 1 week before to 2 weeks after carotid injury. After 3 weeks, the NS + rAd-βGAL group showed the highest intima-media ratio (IMR; 3.73 ± 0.90), the exenatide + rAd-βGAL treatment was the next highest (2.80 ± 0.51), and NS + rAd-GLP-1 treatment showed the lowest IMR (1.58 ± 0.48, P < 0.05 vs. others). The proliferation and migration of vascular smooth muscle cells and monocyte adhesion were decreased significantly after rAd-GLP-1 treatment, showing the same overall patterns as the IMR. In injured vessels, the apoptosis was greater and MMP2 expression was less in the NS + rAd-GLP-1 than in the exenatide or rAd-βGAL groups. In vitro expressions of matrix metalloproteinases-2 and monocyte chemoattractant protein-1 and nuclear factor-kappa-B-p65 translocation were decreased more in the NS + rAd-GLP-1 group than in the other two groups (all P < 0.05).. Direct GLP-1 overexpression showed better protection against restenosis after balloon injury via suppression of vascular smooth muscle cell migration, increased apoptosis, and decreased inflammatory processes than systemic exenatide treatment. This has potential therapeutic implications for treating macrovascular complications in diabetes.

Topics: Adenoviridae; Animals; Apoptosis; Carotid Artery Injuries; Carotid Artery, External; Cell Adhesion; Cell Movement; Cell Proliferation; Cells, Cultured; Coronary Stenosis; Diabetes Mellitus; Disease Models, Animal; Exenatide; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Glucagon-Like Peptide 1; Human Umbilical Vein Endothelial Cells; Hypoglycemic Agents; Incretins; Male; Matrix Metalloproteinase 2; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Peptides; Rats, Inbred OLETF; Transcription Factor RelA; Transfection; Venoms

Topics: Benzhydryl Compounds; Congresses as Topic; Diabetes Mellitus; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptides; Glucosides; Humans; Hypoglycemic Agents; Peptides; Treatment Outcome; Venoms

Numerous studies have found that cost strongly influences patients' decision making. The objective of this study was to explore the impact of varying cost formats on patients' preferences.. Mechanical Turk workers completed a choice-based conjoint (CBC) survey. The CBC survey was designed to examine stated preferences for the use of second-line agents to treat diabetes across 5 attributes: route of administration, efficacy, risk of low blood sugar, frequency of checking blood sugar levels, and cost. We developed 7 versions of the CBC survey that were identical except for the cost attribute. We described cost in terms of: Affordability, Monthly Co-pay, Dollar Sign Rating, How Expensive, or How Cheap compared with other medications, Working Hours Equivalent (per mo) and Percent of Monthly Income. The resulting part-worth utilities were used to calculate the relative importance of cost and to estimate treatment preferences for exenatide, a sulfonylurea, and insulin.. The relative impact of cost varied significantly across the 7 formats. Cost had the greatest influence on participants' decisions when framed in terms of Affordability [mean (SD) relative importance, 37.3 (0.9)] and the lowest influence when framed in terms of How Cheap (compared with other drugs) [12.1 (0.9)]. A sulfonylurea was strongly preferred across 4 of the 7 formats. Preference for insulin, the most effective, albeit riskiest, option was low across all cost formats.. The format used to describe cost affects how the attribute impacts patients' preferences. Individuals are most cost-sensitive when cost is framed in terms of affordability and least cost-sensitive when cost is described in terms of how cheap the medication is compared with others.

Topics: Adult; Blood Glucose Self-Monitoring; Choice Behavior; Diabetes Mellitus; Drug Administration Routes; Exenatide; Fees, Pharmaceutical; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Patient Preference; Peptides; Socioeconomic Factors; Sulfonylurea Compounds; Venoms

Diminished wound healing is a major complication of diabetes mellitus and can lead to foot ulcers. However, there are limited therapeutic methods to treat this condition. Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, is known to have many beneficial effects on diabetes. In addition, mesenchymal stem cells are known to have wound healing effects. We investigated the effects of Ex-4 in combination with human adipose tissue-derived stem cells (ADSCs) on diabetic wound healing in a diabetic animal model.. Topical administration of Ex-4 or injection of ADSCs resulted in a rapid reduction of wound size in both diabetic and normoglycemic animals compared with vehicle treatment. Histological analysis also showed rapid skin reconstruction in Ex-4-treated or ADSC-injected wounds. A combination of Ex-4 and ADSCs showed a significantly better therapeutic effect over either treatment alone. In vitro angiogenesis assays showed that both Ex-4 and ADSC-conditioned media (CM) treatment improved migration, invasion and proliferation of human endothelial cells. ADSC-CM also increased migration and proliferation of human keratinocytes. In addition, both Ex-4 and ADSC-CM increased the expression of vascular endothelial growth factor. Co-culture with ADSCs increased migration and proliferation of these cells similar to that found after ADSC-CM treatment.. We suggest that Ex-4 itself is effective for the treatment of diabetic skin wounds, and a combination of topical treatment of Ex-4 and injection of ADSCs has a better therapeutic effect. Thus, a combination of Ex-4 and ADSCs might be an effective therapeutic option for the treatment of diabetic wounds, such as foot ulcers.

Topics: Adipose Tissue; Animals; Cell Movement; Cell Proliferation; Culture Media, Conditioned; Diabetes Mellitus; Exenatide; Glucose; Homeostasis; Human Umbilical Vein Endothelial Cells; Humans; Keratinocytes; Male; Mice, Inbred C57BL; Neovascularization, Physiologic; Peptides; Skin; Stem Cell Transplantation; Stem Cells; Vascular Endothelial Growth Factor A; Venoms; Wound Healing

Glucagon-like peptide-1 receptor (GLP-1R) is abundantly expressed on beta cells and may be an ideal target for the pancreas imaging. Monitoring the GLP-1R of pancreas could be benefit for understanding the pathophysiology of diabetes. In the present study, (18)F-Al labeled exendin-4 analog, (18)F-Al-NOTA-MAL-Cys(39)-exendin-4, was evaluated for PET imaging GLP-1R in the pancreas.. The targeting of (18)F-Al labeled exendin-4 analog was examined in healthy and streptozotocin induced diabetic rats. Rats were injected with (18)F-Al-NOTA-MAL-Cys(39)-exendin-4 and microPET imaging was performed at 1 h postinjection, followed by ex vivo biodistribution. GLP-1R expression in pancreas was determined through post mortern examinations.. The pancreas of healthy rats was readily visualized after administration of (18)F-Al-NOTA-MAL-Cys(39)-exendin-4, whereas the pancreas of diabetic rats, as well as those from rats co-injected with excess of unlabeled peptides, was barely visible by microPET. At 60 min postinjection, the pancreatic uptakes were 1.02 ± 0.15%ID/g and 0.23 ± 0.05%ID/g in healthy and diabetic rats respectively. Under block, the pancreatic uptakes of non-diabetic rats reduced to 0.21 ± 0.07%ID/g at the same time point. Biodistribution data and IHC staining confirmed the findings of the microPET imaging.. The favorable preclinical data indicated that (18)F-Al-NOTA-MAL-Cys(39)-exendin-4may be suitable for non-invasive monitoring functional pancreatic beta cells.

Topics: Animals; Cysteine; Diabetes Mellitus; Exenatide; Glucagon-Like Peptide-1 Receptor; Isotope Labeling; Male; Molecular Imaging; Organ Specificity; Pancreas; Peptides; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Tissue Distribution; Venoms; Whole Body Imaging

Growing evidence suggests that GLP-1 protects beta cells against various cellular injuries by modulating autophagy. In this study, we examined whether exendin-4 (Ex-4), a GLP-1 analog, had preventive effects on tacrolimus (Tac)-induced beta cell injury by improving autophagy clearance. Rats with Tac-induced diabetes mellitus exhibited increased autophagy-associated protein expression, light chain 3B levels, and autophagic vacuole numbers in pancreatic beta cells. Additionally, Tac increased autophagy in a dose- and time-dependent manner in vitro, and inhibition of autophagosome using 3-methyladenine reduced Tac-induced islet cell injury by decreasing reactive oxygen species production and apoptosis. Ex-4 treatment decreased Tac-induced hyperglycaemia, oxidative stress, and apoptosis, accompanied by decreased autophagy-associated protein expression and autophagosome numbers. In vivo and in vitro studies showed that Tac treatment impaired lysosomal function and autophagosome-lysosome fusion; these processes were improve by Ex-4 treatment. Moreover, addition of bafilomycin A1, an inhibitor of lysosomal function, abolished the protective effects of Ex-4. Our findings reveal that Tac-induced diabetes mellitus was a state of excessive burden of autophagosomes and impairment of autophagy clearance and that Ex-4 protected against Tac-induced pancreatic islet injury by reducing the burden of autophagosomes via activation of autophagosome clearance. Thus, Ex-4 had therapeutic effects on Tac-induced pancreatic beta cell injury.

Topics: Adenine; Animals; Apoptosis; Autophagy; Cell Line; Diabetes Mellitus; Exenatide; Insulin-Secreting Cells; Lysosomes; Macrolides; Male; Oxidative Stress; Peptides; Phagosomes; Protective Agents; Rats, Sprague-Dawley; Tacrolimus; Venoms

An 8-yr-old male golden lion tamarin ( Leontopithecus rosalia ) was diagnosed with diabetes mellitus based on hyperglycemia and persistent glycosuria. Initial treatment consisted of the oral antihyperglycemic medications glipizide and metformin that resulted in decreased blood glucose concentrations; however, marked glycosuria persisted. Insufficient improvement on oral antihyperglycemic therapy and poor feasibility of daily subcutaneous insulin therapy led to an investigation into an alternative therapy with extended-release exenatide, a glucagon-like peptide-1 (GLP-1) mimetic, at a dosage of 0.13 mg/kg subcutaneously once per month. Following treatment with exenatide, the persistent glycosuria resolved, the animal maintained normal blood glucose concentrations, and had lower serum fructosamine concentrations compared to pretreatment levels. Based on these findings, extended-release exenatide could be considered as a therapeutic option in nonhuman primates with diabetes mellitus that do not respond to oral antihyperglycemics and in which daily subcutaneous insulin is not feasible.

Topics: Animals; Animals, Zoo; Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus; Exenatide; Glycosuria; Hypoglycemic Agents; Leontopithecus; Male; Monkey Diseases; Peptides; Venoms

Type 2 diabetic (T2D) patients often develop early cognitive and sensorimotor impairments. The pathophysiological mechanisms behind these problems are largely unknown. Recent studies demonstrate that dysfunctional γ-aminobutyric acid (GABAergic) neurons are involved in age-related cognitive decline. We hypothesized that similar, but earlier dysfunction is taking place under T2D in the neocortex and striatum (two brain areas important for cognition and sensorimotor functions). We also hypothesized that the T2D-induced effects are pharmacologically reversible by anti-diabetic drugs targeting the glucagon-like peptide-1 receptor (GLP-1R). We determined the effect of T2D on cortical and striatal GABAergic neurons positive for glutamic acid decarboxylase-67 (GAD67), calbindin (CB), parvalbumin (PV) and calretinin (CR) by using immunohistochemistry and quantitative microscopy. Young and middle-aged T2D Goto-Kakizaki (GK) (a model of spontaneous T2D) and Wistar rats were used. Furthermore, we determined the therapeutic potential of the GLP1-R agonist exendin-4 (Ex-4) by treating middle-aged GK rats for 6 weeks with 0.1 μg/kg Ex-4 twice daily. We show that T2D reduced the density of GAD67-positive neurons in the striatum and of CB-positive neurons in both striatum and neocortex. T2D also increased the average volume of PV-positive interneurons in the striatum. Ex-4 treatment increased the density of CB-positive neurons in the striatum of GK rats. Our data demonstrate that T2D negatively affects GAD67 and CB-positive GABAergic neurons in the brain during aging, potentially identifying some of the pathophysiological mechanisms to explain the increased prevalence of neurological complications in T2D. We also show a specific, positive effect of Ex-4 on striatal CB-positive neurons, which could be exploited in therapeutic perspective.

Topics: Animals; Calbindin 2; Calbindins; Corpus Striatum; Diabetes Mellitus; Diabetes Mellitus, Experimental; Exenatide; GABAergic Neurons; gamma-Aminobutyric Acid; Glucagon-Like Peptide-1 Receptor; Glutamate Decarboxylase; Neocortex; Parvalbumins; Peptides; Rats; Rats, Wistar; Venoms

To provide selectable microRNA for intervening diabetes mellitus diseases, NOD mice's expression of microRNA in pancreas tissues and blood under the exendin-4 intervention of was observed and the difference of microRNA target gene was screened.. Forty clean NOD mice were randomly divided into four groups (in each group, n = 10): One is blank control group D which is intervened with normal saline, and the other three groups were divided into low-dose group A, middle-dose group B, and high-dose group C according to the different exendin-4 dosage 2, 4, and 8 μg/kg·d. After the 8-week intervention, these four groups were killed, and the pancreatic tissue and blood were left to prepare specimens for morphology and molecular biology analysis. The specimen with differential expression microRNA in pancreas tissue and blood should be screened out after detected with the locked nucleic acid array system (LNATM) microRNA expression profile chip. The primers should be designed, and the ABI7500 real-time fluorescent quantitative PCR should be applied to amplify, analyze, and verify according to the screen results of the microRNA chip in order to screen out the significant differentially expressed microRNA.. Histological detection showed that the pancreas of the mice in control group D was fibrosis gradually and the islet frame was relatively disordered and significantly atrophied. Groups A, B, and C have no islet hypertrophy or atrophy and the degree of fibrosis of the pancreas has reduced. According to the gene chip detection, there are four significantly differently expressed microRNAs in pancreas tissue and blood among the group A, B, and C, among which miR-19a, miR-19b, and miR-22 were downregulated expressed while the miRNA-1 was upregulated expressed. Bioinformatics analysis showed that the target genes of 4 differentially regulated microRNA genes were related to cell proliferation, apoptosis, glucose metabolism, and angiogenesis. The expression of microRNA in pancreatic tissue and blood of NOD rats was highly consistent.. MicroRNA expression file of pancreatic tissue and blood can be changed during the intervention of the NOD rat model with exendin-4. MicroRNA that indicates the differential expression may take part in the recovering process of the NOD pancreatic trauma. At the same time, the administration of exendin-4 can protect NOD mice, reduce its pancreatic tissue fibrosis, and regulate molecular markers of pancreatic cells in size and pancreatic mast cells. This may be one of the main mechanisms of pancreatic injury in diabetes prevention.

Topics: Animals; Diabetes Mellitus; Disease Models, Animal; Exenatide; Mice; Mice, Inbred NOD; MicroRNAs; Pancreas; Peptides; Rats; Venoms

Exenatide extended-release (ER) is a microencapsulated formulation of the glucagon-like peptide 1-receptor agonist exenatide. It has a protracted pharmacokinetic profile that allows a once-weekly injection with comparable efficacy to insulin with an improved safety profile in type II diabetic people. Here, we studied the pharmacology of exenatide ER in 6 healthy cats. A single subcutaneous injection of exenatide ER (0.13 mg/kg) was administered on day 0. Exenatide concentrations were measured for 12 wk. A hyperglycemic clamp (target = 225 mg/dL) was performed on days -7 (clamp I) and 21 (clamp II) with measurements of insulin and glucagon concentrations. Glucose tolerance was defined as the amount of glucose required to maintain hyperglycemia during the clamp. Continuous glucose monitoring was performed on weeks 0, 2, and 6 after injection. Plasma concentrations of exenatide peaked at 1 h and 4 wk after injection. Comparing clamp I with clamp II, fasting blood glucose decreased (mean ± standard deviation = -11 ± 8 mg/dL, P = 0.02), glucose tolerance improved (median [range] +33% [4%-138%], P = 0.04), insulin concentrations increased (+36.5% [-9.9% to 274.1%], P = 0.02), and glucagon concentrations decreased (-4.7% [0%-12.1%], P = 0.005). Compared with preinjection values on continuous glucose monitoring, glucose concentrations decreased and the frequency of readings <50 mg/dL increased at 2 and 6 wk after injection of exenatide ER. This did not correspond to clinical hypoglycemia. No other side effects were observed throughout the study. Exenatide ER was safe and effective in improving glucose tolerance 3 wk after a single injection. Further evaluation is needed to determine its safety, efficacy, and duration of action in diabetic cats.

Topics: Animals; Blood Glucose; Cat Diseases; Cats; Diabetes Mellitus; Drug Synergism; Exenatide; Fasting; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Clamp Technique; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Microspheres; Peptides; Venoms

Although mitochondrial oxidative phosphorylation (OxPhos) dysfunction is believed to be responsible for beta cell dysfunction in insulin resistance and mitochondrial diabetes, the mechanisms underlying progressive beta cell failure caused by defective mitochondrial OxPhos are largely unknown.. We examined the in vivo phenotypes of beta cell dysfunction in beta cell-specific Crif1 (also known as Gadd45gip1)-deficient mice. CR6-interacting factor-1 (CRIF1) is a mitochondrial protein essential for the synthesis and formation of the OxPhos complex in the inner mitochondrial membrane.. Crif1(beta-/-) mice exhibited impaired glucose tolerance with defective insulin secretion as early as 4 weeks of age without defects in islet structure. At 11 weeks of age, Crif1(beta-/-) mice displayed characteristic ultrastructural mitochondrial abnormalities as well as severe glucose intolerance. Furthermore, islet area and insulin content was decreased by approximately 50% compared with wild-type mice. Treatment with the glucoregulatory drug exenatide, a glucagon-like peptide-1 (GLP-1) agonist, was not sufficient to preserve beta cell function in Crif1(beta-/-) mice.. Our results indicate that mitochondrial OxPhos dysfunction triggers progressive beta cell failure that is not halted by treatment with a GLP-1 agonist. The Crif1(beta-/-) mouse is a useful model for the study of beta cell failure caused by mitochondrial OxPhos dysfunction.

Topics: Age Factors; Animals; Autophagy; Blood Glucose; Cell Cycle Proteins; Cell Line; Diabetes Mellitus; Disease Models, Animal; Disease Progression; Exenatide; Genotype; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Incretins; Insulin; Insulin-Secreting Cells; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Oxidative Phosphorylation; Peptides; Phenotype; Time Factors; Venoms

Cardiovascular complications of obesity and diabetes are major health problems. Assessing their development, their link with ectopic fat deposition and their flexibility with therapeutic intervention is essential. The aim of this study was to longitudinally investigate cardiac alterations and ectopic fat accumulation associated with diet-induced obesity using multimodal cardiovascular magnetic resonance (CMR) in mice. The second objective was to monitor cardiac response to exendin-4 (GLP-1 receptor agonist).. Male C57BL6R mice subjected to a high fat (35 %) high sucrose (34 %) (HFHSD) or a standard diet (SD) during 4 months were explored every month with multimodal CMR to determine hepatic and myocardial triglyceride content (HTGC, MTGC) using proton MR spectroscopy, cardiac function with cine cardiac MR (CMR) and myocardial perfusion with arterial spin labeling CMR. Furthermore, mice treated with exendin-4 (30 μg/kg SC BID) after 4 months of diet were explored before and 14 days post-treatment with multimodal CMR.. HFHSD mice became significantly heavier (+33 %) and displayed glucose homeostasis impairment (1-month) as compared to SD mice, and developed early increase in HTGC (1 month, +59 %) and MTGC (2-month, +63 %). After 3 months, HFHSD mice developed cardiac dysfunction with significantly higher diastolic septum wall thickness (sWtnD) (1.28 ± 0.03 mm vs. 1.12 ± 0.03 mm) and lower cardiac index (0.45 ± 0.06 mL/min/g vs. 0.68 ± 0.07 mL/min/g, p = 0.02) compared to SD mice. A significantly lower cardiac perfusion was also observed (4 months:7.5 ± 0.8 mL/g/min vs. 10.0 ± 0.7 mL/g/min, p = 0.03). Cardiac function at 4 months was negatively correlated to both HTGC and MTGC (p < 0.05). 14-day treatment with Exendin-4 (Ex-4) dramatically reversed all these alterations in comparison with placebo-treated HFHSD. Ex-4 diminished myocardial triglyceride content (-57.8 ± 4.1 %), improved cardiac index (+38.9 ± 10.9 %) and restored myocardial perfusion (+52.8 ± 16.4 %) under isoflurane anesthesia. Interestingly, increased wall thickness and hepatic steatosis reductions were independent of weight loss and glycemia decrease in multivariate analysis (p < 0.05).. CMR longitudinal follow-up of cardiac consequences of obesity and diabetes showed early accumulation of ectopic fat in mice before the occurrence of microvascular and contractile dysfunction. This study also supports a cardioprotective effect of glucagon-like peptide-1 receptor agonist.

Topics: Adiposity; Animals; Blood Glucose; Coronary Circulation; Diabetes Mellitus; Diet, High-Fat; Dietary Sucrose; Disease Models, Animal; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Heart Diseases; Liver; Magnetic Resonance Imaging, Cine; Male; Mice, Inbred C57BL; Multimodal Imaging; Multivariate Analysis; Myocardial Contraction; Myocardial Perfusion Imaging; Myocardium; Obesity; Peptides; Predictive Value of Tests; Proton Magnetic Resonance Spectroscopy; Recovery of Function; Time Factors; Triglycerides; Venoms; Ventricular Function; Weight Gain

Glucagon-like peptide 1 (GLP1) agonists are promising therapeutic agents in the treatment of diabetes mellitus. This study examines the mechanism of the protective effects of exenatide in experimental diabetes, employing four groups of ten rats each, in which two groups were streptozotocin-induced diabetic and two were control groups. One control and one diabetic group were treated with exenatide (1 μg/kg body weight (BW)) for 10 weeks. Blood plasma was taken for biochemical analyses while pancreatic tissue was taken for immunofluorescence and immunoelectron microscopy studies and real-time PCR to examine the expression of genes. The results show that exenatide improved BW gain and reduced blood glucose in diabetic rats compared with controls. Similarly, exenatide enhanced insulin release from the pancreatic fragments and improved liver and kidney functions and lipid profile in diabetic rats compared with controls. Exenatide not only induced significant increases in serum insulin level but also elevated the number of insulin-, GLP1- and exenatide-positive cells compared with untreated controls. Exenatide also elevated the number of catalase- and glutathione reductase-positive cells in diabetic rat pancreas compared with controls. Exenatide caused significant elevation in the expressions of pancreatic duodenal homeobox-1, heat shock protein-70, glutathione peroxidase, insulin receptor and GLP1 receptor genes in the pancreas of both control and diabetic rats compared with untreated animals. The results have demonstrated that exenatide can exert its beneficial and protective effects by elevating the levels of endogenous antioxidants and genes responsible for the survival, regeneration and proliferation of pancreatic β-cell.

Topics: Animals; Antioxidants; Blood Glucose; Catalase; Diabetes Mellitus; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glutathione Peroxidase; Homeodomain Proteins; Humans; Hypoglycemic Agents; Insulin; Male; Pancreas; Peptides; Rats; Rats, Wistar; Receptors, Glucagon; Trans-Activators; Venoms

To identify the glucose lowering ability and chronic treatment effects of a novel coumarin-glucagon-like peptide-1 (GLP-1) conjugate HJ07.. A receptor activation experiment was performed in HEK 293 cells and the glucose lowering ability was evaluated with hypoglycemic duration and glucose stabilizing tests. Chronic treatment was performed by daily injection of exendin-4, saline, and HJ07. Body weight and HbA1c were measured every week, and an intraperitoneal glucose tolerance test was performed before treatment and after treatment.. HJ07 showed well-preserved receptor activation efficacy. The hypoglycemic duration test showed that HJ07 possessed a long-acting, glucose-lowering effect and the glucose stabilizing test showed that the antihyperglycemic activity of HJ07 was still evident at a predetermined time (12 h) prior to the glucose challenge (0 h). The long time glucose-lowering effect of HJ07 was better than native GLP-1 and exendin-4. Furthermore, once daily injection of HJ07 to db/db mice achieved long-term beneficial effects on HbA1c lowering and glucose tolerance.. The biological activity results of HJ07 suggest that HJ07 is a potential long-acting agent for the treatment of type 2 diabetes.

Topics: Animals; Blood Glucose; Coumarins; Diabetes Mellitus; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Glycated Hemoglobin; HEK293 Cells; Humans; Hypoglycemic Agents; Male; Mice, Inbred C57BL; Mice, Knockout; Peptides; Receptors, Glucagon; Venoms

A 74-year-old man with diabetes mellitus since 64 years of age had been treated with glimepiride, metformin and alogliptin; however, his glycemic control remained poor, i.e., a casual blood glucose level of 318 mg/dl, HbA1c level of 10.6% and glycated albumin level of 24.9%. Although his blood glucose level improved with intensive insulin therapy, he exhibited dementia with an MMSE score of 9/30 and was unable to continue insulin injections by himself, thus rejecting his family's help. The extended-release form of the GLP-1 agonist exenatide (Bydureon(®)) was recently introduced in Japan. This new anti-diabetic agent enables the administration of once-weekly type 2 diabetes treatment that delivers a continuous dose of exenatide in a single weekly injection. We employed weekly exenatide therapy in combination with oral hypoglycemic agents in this case. The patient visited our outpatient clinic for injections every week, showing a remarkable improvement in his HbA1c level, from 10.7% to 7.1% in five months. Subcutaneous induration was the only side effect of weekly exenatide injection. Weekly exenatide therapy can be easily managed by other caregivers and is expected to be a useful treatment approach in elderly diabetic patients with dementia.

Topics: Aged; Dementia; Diabetes Complications; Diabetes Mellitus; Exenatide; Humans; Hypoglycemic Agents; Male; Peptides; Venoms

Despite the therapeutic potential of exendin-4 as a glucagon-like peptide-1 (GLP-1) mimetic for the treatment of type 2 diabetes, its utility has so far been limited because of the low level of patient compliance due to the requirement for frequent injections. In this study, an orally available exendin-4 was produced by conjugating it to low molecular weight chitosan (LMWC). Conjugation between the LMWC and cysteinylated exendin-4 was carried out using a cleavable linker system in order to maximize the availability of the active peptide. The LMWC-exendin-4 conjugate formed a nanoparticle structure with a mean particle size of 101 ± 41 nm through complexation between the positively charged LMWC backbone and the negatively charged exendin-4 of individual conjugate molecules. The biological activity of the LMWC-exendin-4 conjugate was evaluated in an INS-1 cell line. The LMWC-exendin-4 conjugate stimulated insulin secretion in a dose dependent manner as similar as that of native exendin-4. From the pharmacokinetic study after oral administration of the conjugate, a C(max) value of 344 pg/mL and a T(max) of 6 h were observed, and the bioavailability, relative to the subcutaneous counterpart, was found to be 6.4%. Furthermore, the absorbed exendin-4 demonstrated a significantly enhanced hypoglycemic effect. These results suggest that the LMWC-exendin-4 conjugate could be used as a potential oral anti-diabetic agent for the treatment of type 2 diabetes.

Topics: Administration, Oral; Animals; Cell Line, Tumor; Chitosan; Diabetes Mellitus; Exenatide; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Mice; Mice, Inbred C57BL; Molecular Weight; Peptides; Rats; Venoms

Topics: Adrenal Insufficiency; Diabetes Mellitus; Drug Interactions; Exenatide; Female; Humans; Hydrocortisone; Hypopituitarism; Middle Aged; Peptides; Venoms

To study a recombined chimeric peptide consisting of lysozyme N-terminal sequence and exendin-4 (shortly LYZ(N)-EX4) as a dual-action peptide for diabetes.. LYZ(N)-EX4 was recombined into plasmid pET-32a(+) and expressed in Escherichia coli. The fusion protein was separated by affinity chromatography and hydrolyzed by enterokinase to prepare LYZ(N)-EX4. The chimeric peptide was digested by thrombin and the digests were analyzed by HPLC. The secondary peptides were identified by mass spectrometry. Biological activities of the thrombin digests were determined in vitro, using NIT-1 cells for insulin promoting action and using human white blood cells (WBC) for anti-AGEs action.. The fusion protein was highly expressed in E. coli and LYZ(N)-EX4 was obtained via hydrolysis of the fusion protein. The thrombin digests of LYZ(N)-EX4 were separated by HPLC into two peaks, which were identified as LYZ(N) and EX4 by mass spectrametry. Functional studies found that the digests were able to antagonize the effects of AGEs on expression of RAGE mRNA in WBC, promote cell activity, stimulate PDX-1 mRNA expression and increase insulin secretion by NIT-1 cells, suggesting the actions of LYZ(N) and EX4 on the cells.. LYZ(N)-EX4 was sensitive to thrombin digestion, and the secondary peptides LYZ(N) and EX4 could function as anti-AGEs and insulin-promoting peptides, respectively.

Topics: Animals; Diabetes Mellitus; Escherichia coli; Exenatide; Humans; Hypoglycemic Agents; Insulin; Leukocytes; Mice; Muramidase; Peptides; Recombinant Proteins; RNA, Messenger; Thrombin; Venoms

To determine whether a Protected Graft Copolymer (PGC) containing fatty acid can be used as a stabilizing excipient for GLP-1 and whether PGC/GLP-1 given once a week can be an effective treatment for diabetes.. To create a PGC excipient, polylysine was grafted with methoxypolyethyleneglycol and fatty acid at the epsilon amino groups. We performed evaluation of the binding of excipient to GLP-1, the DPP IV sensitivity of GLP-1 formulated with PGC as the excipient, the in vitro bio-activity of excipient-formulated GLP-1, the in vivo pharmacokinetics of excipient-formulated GLP-1, and the efficacy of the excipient-formulated GLP-1 in diabetic rats.. We showed reproducible synthesis of PGC excipient, high affinity binding of PGC to GLP-1, slowed protease degradation of excipient-formulated GLP-1, and that excipient-formulated GLP-1 induced calcium influx in INS cells. Excipient-formulated GLP-1 stays in the blood for at least 4 days. When excipient-formulated GLP-1 was given subcutaneously once a week to diabetic ZDF rats, a significant reduction of HbA1c compared to control was observed. The reduction is similar to diabetic ZDF rats given exendin twice a day.. PGC can be an ideal in vivo stabilizing excipient for biologically labile peptides.

Topics: Animals; Delayed-Action Preparations; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dose-Response Relationship, Drug; Excipients; Exenatide; Fatty Acids; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Incretins; Insulin-Secreting Cells; Peptides; Polyethylene Glycols; Polylysine; Protein Stability; Rats; Rats, Sprague-Dawley; Rats, Zucker; Venoms

Albumin-binding achieved by fatty-acylation to drugs is considered to be an effective means of prolonging the circulation lifetimes of short-lived peptides. Here, exendin-4 was modified with palmitic acid, and the particle size and albumin-binding of palmitic acid-conjugated exendin-4 (Pal-Ex4) purified was investigated and visualized. Additionally, its pharmacokinetics and pharmacodynamics were evaluated in diabetic rodents. Pal-Ex4 had a greater molecular size (~125nm) and its albumin-binding was 5.6-fold that of Ex4. Molecular imaging showed that the subcutaneous absorption of Pal-Ex4 was delayed until 24h post-injection, whereas Ex4 was rapidly absorbed and distributed systemically. Pharmacokinetic and pharmacodynamic results confirmed these observations, for example, times to reach peak concentration and to achieve a blood glucose level nadir were greatly delayed versus Ex4, and the circulating half-life of Pal-Ex4 was much greater than that of Ex4. Consequently, the hypoglycemic degree of Pal-Ex4 (500 nmol/kg) was 4.2 fold greater than Ex4. Our results show that the extended hypoglycemic efficacy of Pal-Ex4 was due to (i) a delayed absorption due to micelle formation and (ii) an increased in vivo circulating half-life due to albumin-binding. We believe that this prototype of exendin-4 has considerable pharmaceutical potential as a systemic type 2 anti-diabetic treatment.

Topics: Absorption; Animals; Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus; Diabetes Mellitus, Experimental; Exenatide; Fasting; Half-Life; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Micelles; Palmitic Acid; Particle Size; Peptides; Serum Albumin; Tissue Distribution; Venoms

Inhalable deoxycholic acid-modified glycol chitosan (DOCA-GC) nanogels containing palmityl acylated exendin-4 (Ex4-C16) were prepared by self-assembly and characterized physicochemically. The lung deposition of DOCA-GC nanogels was monitored using an infrared imaging system, and the hypoglycemia caused by Ex4-C16-loaded DOCA-GC nanogels was evaluated after pulmonary administration in type 2 diabetic db/db mice. The cytotoxicities and lung histologies induced by DOCA-GC nanogels were examined in human lung epithelial cells (A549 and Calu-3) and db/db mice, respectively. Results showed that the DOCA-GC nanogels prepared were spherical and compact and had a diameter of ~220 nm. Although the incorporation of Ex4-C16 (50.9±7.8%) into DOCA-GC nanogels was significantly lower than that of Ex4 (81.4±4.9%), the Ex4-C16 release from DOCA-GC nanogels was greatly delayed vs. Ex4. DOCA-GC nanogels were deposited rapidly after pulmonary administration and remained in the lungs for ~72 h. Furthermore, the hypoglycemic duration of inhaled Ex4-C16 nanogels was much greater than that of Ex4 nanogels in db/db mice. Cytotoxicity results of DOCA-GC nanogels were considered acceptable, and the tissue histologies of mouse lungs administered nanogels did not show any significant difference vs. control lungs. The authors believe that Ex4-C16 DOCA-GC nanogels offer a long-acting inhalation delivery system for treating type 2 diabetes.

Topics: Acylation; Administration, Inhalation; Animals; Chitosan; Desoxycorticosterone; Diabetes Mellitus; Drug Carriers; Exenatide; Gels; Hypoglycemic Agents; Lung; Male; Mice; Mice, Inbred ICR; Nanostructures; Palmitic Acid; Peptides; Venoms

Our aim was to employ novel analytical methods to investigate the therapeutic treatment of the energy regulation dysfunction occurring in a Huntington disease (HD) mouse model. HD is a neurodegenerative disorder that is characterized by progressive motor impairment and cognitive alterations. Changes in neuroendocrine function, body weight, energy metabolism, euglycemia, appetite function, and gut function can also occur. It is likely that the locus of these alterations is the hypothalamus. We determined the effects of three different euglycemic agents on HD progression using standard physiological and transcriptomic signature analyses. N171-82Q HD mice were treated with insulin, Exendin-4, and the newly developed GLP-1-Tf to determine whether these agents could improve energy regulation and delay disease progression. Blood glucose, insulin, metabolic hormone levels, and pancreatic morphology were assessed. Hypothalamic gene transcription, motor coordination, and life span were also determined. The N171-82Q mice exhibited significant alterations in hypothalamic gene transcription signatures and energy metabolism that were ameliorated, to varying degrees, by the different euglycemic agents. Exendin-4 or GLP-1-Tf (but not insulin) treatment also improved pancreatic morphology, motor coordination, and increased life span. Using hypothalamic transcription signature analyses, we found that the physiological efficacy variation of the drugs was evident in the degree of reversal of the hypothalamic HD pathological signature. Euglycemic agents targeting hypothalamic and energy regulation dysfunction in HD could potentially alter disease progression and improve quality of life in HD.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Drug Design; Exenatide; Glucagon-Like Peptide 1; Huntington Disease; Hypothalamus; Insulin; Male; Mice; Mice, Transgenic; Models, Animal; Models, Neurological; Oligonucleotide Array Sequence Analysis; Pancreas; Peptides; Serotonin Plasma Membrane Transport Proteins; Transcription, Genetic; Venoms

Exenatide, a glucagon-like peptide-1 receptor agonist, is used twice daily (BID) as monotherapy or adjunctive therapy for the improvement of glycemic control in patients with type 2 diabetes mellitus. The purpose of this pooled analysis was to evaluate the safety and efficacy of exenatide BID in patients stratified by various demographic characteristics.. This post hoc analysis included data from 16 randomized controlled trials in which patients with type 2 diabetes mellitus were treated with 10-μg exenatide BID. Each patient was classified into subgroups on the basis of his or her baseline values for age (< 65 or ≥ 65 years), sex (male or female), race (white, black, Asian, or Hispanic), duration of diabetes (< 10 years or ≥ 10 years), and body mass index (BMI; ≥ 20 to < 25, ≥ 25 to < 30, ≥ 30 to < 35, or ≥ 35 kg/m(2)).. A total of 2067 patients were included. All groups experienced significant improvements in glycated hemoglobin, fasting plasma glucose levels (other than black patients, who had a relatively low baseline fasting plasma glucose level), and body weight from baseline to endpoint. Most groups had significant improvements in systolic blood pressure. All of the age, sex, and duration of diabetes groups experienced significant improvements in lipid levels (other than high-density lipoprotein cholesterol). Whites and Asians generally experienced significant improvements in lipid levels, whereas blacks and Hispanics did not. Significant improvements in lipid levels were generally seen across BMI groups. The most common adverse events overall were nausea (38.6%), hypoglycemia (28.4%), and vomiting (14.0%). Hypoglycemia was more common overall in patients who were taking a concomitant sulfonylurea than it was in patients who were not.. In this pooled analysis, exenatide BID improved glycemic control and body weight, and had generally beneficial effects on blood pressure and lipid levels in patients regardless of baseline age, sex, race, duration of diabetes, or BMI. Gastrointestinal events were the most common adverse events.. www.ClinicalTrials.gov [NCT00039026, NCT00039013, NCT00082381, NCT00035984, NCT00082407, NCT00381342, NCT00360334, NCT00375492, NCT00603239, NCT00765817, NCT00577824, NCT00434954].

Topics: Age Factors; Blood Glucose; Body Mass Index; Diabetes Mellitus; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Peptides; Racial Groups; Retrospective Studies; Sex Factors; Treatment Outcome; Venoms

A porous large poly(lactic-co-glycolic acid) (PLGA) microspheres (MS) adsorbed with palmityl-acylated exendin-4 (Ex4-C(16)) was devised as an inhalation delivery system. The porous MS was prepared by a single o/w emulsification/solvent evaporation method using extractable Pluronic F68/F127, and its fabrication and formulation conditions were carefully optimized. Results show that the prepared MS was in the appropriate size range for inhalation and contained many surfaces and internal pores meaning low aerodynamic density. Ex4-C(16) was more efficiently adsorbed onto porous PLGA MSs than native exendin-4, and an approximately 5% loading of Ex4-C(16) onto this porous MS (RG504H) was achieved. This optimized porous MS was found to be efficiently deposited throughout the entire lungs of mice including alveoli region. Furthermore, this porous MS adsorbed with Ex4-C(16) (approx. 100 μg/mouse) displayed much protracted hypoglycemic efficacy in non-fasted type 2 diabetic db/db mice. Porous PLGA MS with adsorbed Ex4-C(16) showed the dual-advantages of (i) sustained release and acceptable drug-loading due to strong hydrophobic interaction and (ii) longer in vivo pulmonary hypoglycemic duration due to albumin-binding by the palmityl group. We consider that this new prototype of porous PLGA MS has considerable pharmaceutical potential as a type 2 anti-diabetic inhalation treatment.

Topics: Adsorption; Animals; Diabetes Mellitus; Exenatide; Hydrophobic and Hydrophilic Interactions; Hypoglycemic Agents; Lactic Acid; Male; Mice; Mice, Inbred C57BL; Microspheres; Peptides; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Porosity; Venoms

We report the use of Exenatide, a GLP-1 agonist, in the management of diabetes mellitus in a 19 year-old female with Prader-Willi syndrome. The beneficial effects of Exenatide in weight reduction and appetite suppression provide a promising strategy for the treatment of obesity and diabetes mellitus in Prader-Willi syndrome.

Topics: Adult; Diabetes Mellitus; Exenatide; Female; Ghrelin; Humans; Peptides; Prader-Willi Syndrome; Venoms; Young Adult

Improved glucagon-like peptide-1 (GLP-1) receptor activation is considered one of the most effective targets for antidiabetic therapy. For this purpose, we modified the GLP-1 analog of exendin-4 using two fatty acids (FA) either lauric acid (LUA, C12) or palmitic acid (PAA, C16) at its two lysine residues, to produce; Lys(12)-FA-Exendin-4 (FA-M2), Lys(27)-FA-Exendin-4 (FA-M1), or Lys(12,27)-diBA-Exendin-4 (FA-Di). The structural, biological, and pharmaceutical characteristics of these exendin-4 analogs were then investigated. Biological activity tests demonstrated that LUA-M1 had well-preserved in vivo antidiabetic activity and in vitro insulinotropic activity with minimum GLP-1 receptor binding affinity loss as compared with exendin-4. Furthermore, pharmacokinetic studies in rats revealed that s.c. administration of LUA-M1 significantly enhanced pharmacokinetic parameters, such as, elimination half-life, mean residence time, and AUC values as compared with exendin-4. The protracted antidiabetic effects of LUA-M1 were also confirmed by prolonged normoglycemia observed in type 2 diabetic mice (20nmol/mouse single injection of exendin-4 or LUA-M1 induced normoglycemia for 6 or 24h, respectively). These findings suggest that FA conjugated exendin-4s should be considered potential candidates for the treatment of diabetes.

Topics: Animals; Antigens; Diabetes Mellitus; Diabetes Mellitus, Type 2; Exenatide; Fatty Acids; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Half-Life; Hypoglycemic Agents; Lysine; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Palmitic Acid; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Venoms

Exenatide must be administered serially by twice-daily subcutaneous (SC) injection due to its short half-life. The purpose of the present study is to develop an improved sustained-release exenatide formulation with a therapeutic efficacy comparable to serial, twice-daily injections of exenatide. A novel SR formulation of exenatide, DA-3091, was prepared by single-emulsion solvent evaporation using PLGA. It was administered by SC injection to ZDF rats in single exenatide doses of 0.1, 0.25, 0.5, 1 or 2mg/kg. On the 28th, 49th and 70th days, a 1 or 2mg/kg dose of DA-3091 was further administered to rats in dose groups of 1 or 2mg/kg. The efficacy of DA-3091 was then compared with that of serial, twice-daily SC injections of an exenatide solution for 13 weeks. NFBG and HbA1c concentrations were decreased both significantly and linearly as the exenatide dose in DA-3091 increased. In addition, food intake and body weight were suppressed both significantly and dose-dependently. In equivalent or half doses of exenatide, the efficacy of DA-3091 was comparable to that of twice-daily injections of exenatide solution for 13 weeks. In conclusion, DA-3091 has the potential to be clinically effective when administered every 3 weeks, or less frequently, which promises to significantly improve patient compliance.

Topics: Animals; Blood Glucose; Body Weight; Chemistry, Pharmaceutical; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Administration Schedule; Exenatide; Feeding Behavior; Glycated Hemoglobin; Hypoglycemic Agents; Male; Microspheres; Peptides; Rats; Rats, Zucker; Venoms

Endothelial cell senescence is an important contributor to vascular aging and is increased under diabetic conditions. Here we investigated whether the antidiabetic hormone glucagon-like peptide 1 (GLP-1) could prevent oxidative stress-induced cellular senescence in endothelial cells.. In Zucker diabetic fatty rats, a significant 2-fold higher level of vascular senescence was observed compared with control lean rats. Dipeptidyl-peptidase 4 (DPP-4) inhibition significantly increased GLP-1 levels in these animals and reduced senescence almost to lean animal levels. In vitro studies with human umbilical vein endothelial cells showed that GLP-1 had a direct protective effect on oxidative stress (H(2)O(2))-induced senescence and was able to attenuate oxidative stress-induced DNA damage and cellular senescence. The GLP-1 analogue exendin-4 provided similar results, whereas exendin fragment 9-39, a GLP-1 receptor antagonist, abolished this effect. Intracellular signaling by the phosphoinositide 3-kinase (PI3K)/Akt survival pathway did not appear to be involved. Further analysis revealed that GLP-1 activates the cAMP response element-binding (CREB) transcription factor in a cAMP/protein kinase A (PKA)-dependent manner, and inhibition of the cAMP/PKA pathway abolished the GLP-1 protective effect. Expression analysis revealed that GLP-1 can induce the oxidative defense genes HO-1 and NQO1.. Dipeptidyl-peptidase 4 inhibition protects against vascular senescence in a diabetic rat model. In vitro studies with human umbilical vein endothelial cells showed that reactive oxygen species-induced senescence was attenuated by GLP-1 in a receptor-dependent manner involving downstream PKA signaling and induction of antioxidant genes.

Topics: Adamantane; Animals; Cells, Cultured; Cellular Senescence; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; DNA Damage; Dose-Response Relationship, Drug; Endothelial Cells; Enzyme Activation; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heme Oxygenase-1; Humans; Hydrogen Peroxide; Hypoglycemic Agents; Male; NAD(P)H Dehydrogenase (Quinone); Nitriles; Oxidants; Oxidative Stress; Peptides; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyrrolidines; Rats; Rats, Zucker; Reactive Oxygen Species; Receptors, Glucagon; Signal Transduction; Venoms; Vildagliptin

Exendin-4, a glucagon-like peptide-1 (GLP-1) analogue, is reported to have modest anti-inflammatory effects in addition to that of improving beta cell survival. We therefore sought to determine whether exendin-4 decreases expression of the gene encoding chemokine (C-X-C motif) ligand (CXCL)10, which plays a role in initiating insulitis in type 1 diabetes.. The expression of CXCL10 in human islets was determined at the mRNA level by real-time RT-PCR analysis and at the protein level by western blotting. The level of CXCL10 in culture medium was measured by ELISA. Pathway-specific gene expression profiling was carried out to determine the expression of a panel of genes encoding chemokines and cytokines in human islets exposed to cytokines.. IFN-γ induced expression of CXCL10 through activation of signal transducer and activator of transcription-1 (STAT-1). A combination of cytokines (IL-1β, TNF-α and IFN-γ) showed strong synergy in the induction of numerous chemokines and cytokines through nuclear factor kappa B and STAT-1. Exendin-4 suppressed basal expression of several inflammatory mediators. In combination with phosphodiesterase inhibitors, exendin-4 also decreased IFN-γ-induced CXCL10 expression in human islets and in MIN6 cells (a mouse beta cell line), and its secretion into the culture medium. Exendin-4 action was mimicked by forskolin, an activator of adenylyl cyclase, and by dibutyryl cyclic AMP. Protein kinase A was not involved in mediating exendin-4 action on CXCL10. The mechanism of exendin-4's anti-inflammatory action involved decreases in STAT-1 levels.. These findings suggest that the GLP-1-cyclic AMP pathway decreases islet inflammation in addition to its known effects on beta cell survival.

Topics: Analysis of Variance; Anti-Inflammatory Agents; Blotting, Western; Cell Line; Cells, Cultured; Chemokine CXCL10; Cyclic AMP; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Exenatide; Humans; In Vitro Techniques; Interferon-gamma; Interleukin-1beta; Islets of Langerhans; NF-kappa B; Peptides; Phosphodiesterase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; STAT1 Transcription Factor; Tumor Necrosis Factor-alpha; Venoms

The calcium-regulated phosphatase calcineurin intersects with both calcium and cAMP-mediated signaling pathways in the pancreatic β-cell. Pharmacologic calcineurin inhibition, necessary to prevent rejection in the setting of organ transplantation, is associated with post-transplant β-cell failure. We sought to determine the effect of calcineurin inhibition on β-cell replication and survival in rodents and in isolated human islets. Further, we assessed whether the GLP-1 receptor agonist and cAMP stimulus, exendin-4 (Ex-4), could rescue β-cell replication and survival following calcineurin inhibition. Following treatment with the calcineurin inhibitor tacrolimus, human β-cell apoptosis was significantly increased. Although we detected no human β-cell replication, tacrolimus significantly decreased rodent β-cell replication. Ex-4 nearly normalized both human β-cell survival and rodent β-cell replication when co-administered with tacrolimus. We found that tacrolimus decreased Akt phosphorylation, suggesting that calcineurin could regulate replication and survival via the PI3K/Akt pathway. We identify insulin receptor substrate-2 (Irs2), a known cAMP-responsive element-binding protein target and upstream regulator of the PI3K/Akt pathway, as a novel calcineurin target in β-cells. Irs2 mRNA and protein are decreased by calcineurin inhibition in both rodent and human islets. The effect of calcineurin on Irs2 expression is mediated at least in part through the nuclear factor of activated T-cells (NFAT), as NFAT occupied the Irs2 promoter in a calcineurin-sensitive manner. Ex-4 restored Irs2 expression in tacrolimus-treated rodent and human islets nearly to baseline. These findings reveal calcineurin as a regulator of human β-cell survival in part through regulation of Irs2, with implications for the pathogenesis and treatment of diabetes following organ transplantation.

Topics: Animals; Apoptosis; Calcineurin; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclic AMP; Diabetes Mellitus; Exenatide; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin Receptor Substrate Proteins; Insulin-Secreting Cells; Mice; NFATC Transcription Factors; Organ Transplantation; Peptides; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Signal Transduction; Tacrolimus; Venoms

Topics: Bariatric Surgery; Body Mass Index; Diabetes Mellitus; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Peptides; Risk Assessment; Venoms

Not only exendin-4 but also exercise has been reported to improve glucose homeostasis by enhancing insulinotropic action, but the nature of its molecular mechanism has not been clarified. We investigated a mechanism to promote insulinotropic action by means of exendin-4 and exercise training in 90% pancreatectomized (Px) rats fed 40% energy fat diets. Px diabetic rats were divided into 4 groups: 1) exendin-4, 2) exendin-4 plus exercise, 3) saline (control), and 4) exercise. During the 8-week experimental period, rats in the exendin-4 groups were subcutaneously administered with 150 pmol/kg exendin-4 twice a day, while those in the exercise groups ran on an uphill treadmill with a 15 degree incline at 20 m/min for 30 min 5 days a week. First phase insulin secretion was elevated by both the administration of exendin-4 and exercise training during hyperglycemic clamp. However, second phase insulin secretion did not differ among the groups. Individual treatment of exendin-4 and exercise expanded beta-cell mass by increasing its proliferation and reducing its apoptosis, but the administration of exendin-4 plus exercise training did not produce any additional, positive effects. Both exendin-4 and exercise enhanced insulin receptor substrate (IRS)-2 expression through the activation of cAMP responding element binding protein in the islets, which potentiated their insulin/insulin like growth factor-1 signaling. The potentiation of the signaling increased the expression of pancreas duodenum homeobox-1, involved in beta-cell proliferation. In conclusion, exendin-4 and exercise equivalently improved glucose homeostasis due to the induction of IRS-2 in the islets of diabetic rats through a cAMP dependent common pathway.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Cell Proliferation; Diabetes Mellitus; Energy Intake; Exenatide; Gene Expression Regulation; Hypoglycemic Agents; Immunoblotting; Immunohistochemistry; Insulin; Insulin Receptor Substrate Proteins; Insulin-Like Growth Factor I; Insulin-Secreting Cells; Intracellular Signaling Peptides and Proteins; Islets of Langerhans; Male; Pancreatectomy; Peptides; Phosphoproteins; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Time Factors; Venoms

Topics: Diabetes Mellitus; Drug Interactions; Exenatide; Humans; Hypoglycemic Agents; Peptides; Venoms

The aim of this study was to investigate the in vivo and in vitro effects of exendin-4, a potent glucagon-like peptide 1 agonist, on the protection of the pancreatic beta-cells against their cell death. In in vivo experiments, we used beta-cell-specific calmodulin-overexpressing mice where massive apoptosis takes place in their beta-cells, and we examined the effects of chronic treatment with exendin-4. Chronic and s.c. administration of exendin-4 reduced hyperglycemia. The treatment caused significant increases of the insulin contents of the pancreas and islets, and retained the insulin-positive area. Dispersed transgenic islet cells lived only shortly, and several endoplasmic reticulum (ER) stress-related molecules such as immunoglobulin-binding protein (Bip), inositol-requiring enzyme-1alpha, X-box-binding protein-1 (XBP-1), RNA-activated protein kinase-like endoplasmic reticulum kinase, activating transcription factor-4, and C/EBP-homologous protein (CHOP) were more expressed in the transgenic islets. We also found that the spliced form of XBP-1, a marker of ER stress, was also increased in beta-cell-specific calmodulin-overexpressing transgenic islets. In the quantitative real-time PCR analyses, the expression levels of Bip and CHOP were reduced in the islets from the transgenic mice treated with exendin-4. These findings suggest that excess of ER stress occurs in the transgenic beta-cells, and the suppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.

Topics: Animals; Apoptosis; Biomarkers; Calmodulin; Diabetes Mellitus; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Exenatide; Heat-Shock Proteins; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Mice; Mice, Transgenic; Molecular Chaperones; Peptides; Reverse Transcriptase Polymerase Chain Reaction; Stress, Physiological; Transcription Factor CHOP; Venoms

The American Diabetes Association currently recommends an A1C goal of less than 7 percent. However, many patients are unable to achieve this goal by using oral drug combinations or diet and exercise, leaving insulin as the only treatment option. In most cases, insulin is initiated later in therapy because of its inconvenience and adverse effects (e.g., weight gain, hypoglycemia, possible role in atherogenesis). Although insulin effectively helps patients attain glucose goals, the search for new agents continues. Two injectable agents, pramlintide and exenatide, were approved in 2005 for the treatment of diabetes. Pramlintide, indicated for use in patients with type 1 and 2 diabetes, is a synthetic analogue of human amylin that acts in conjunction with insulin to delay gastric emptying and inhibit the release of glucagon. Exenatide, a glucagon-like peptide-1 mimetic, has multiple mechanisms for lowering glucose levels, including the enhancement of insulin secretion, and is indicated for use in patients with type 2 diabetes. Clinical trials have shown that both agents reduce, by a statistically significant degree, A1C levels (0.3 to 0.7 percent more than placebo), fasting plasma glucose levels, and body weight (3 to 5 lb [1.4 to 2.3 kg]). No studies have examined their effects on diabetic complications, cardiovascular disease, or overall mortality. Pramlintide and exenatide may help make glycemic goals more attainable.

Topics: Amyloid; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Peptides; Venoms

Topics: Amyloid; Anti-Ulcer Agents; Diabetes Mellitus; Exenatide; Humans; Hypoglycemic Agents; Injections; Insulin; Islet Amyloid Polypeptide; Peptides; United States; Venoms

Topics: Diabetes Mellitus; Diabetic Angiopathies; Exenatide; Heart Diseases; Humans; Hypoglycemic Agents; Metformin; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

Topics: Amyloid; Diabetes Mellitus; Exenatide; Humans; Hypoglycemic Agents; Insulin; Islet Amyloid Polypeptide; Middle Aged; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

Diabetes mellitus is a frequent comorbidity of cancer patients. The growing epidemic of diabetes is anticipated to have tremendous impact on health care. Diabetes may negatively impact both cancer risk and outcomes of treatment. Oncology nurses are ideally positioned to identify patients at risk for complications that arise from cancer treatment in the setting of pre-existing diabetes. Additionally, oncology nurses may be the first to identify underlying hyperglycemia/hidden diabetes in a patient undergoing cancer treatment. Strategies for assessment and treatment will be discussed, along with specific strategies for managing hyperglycemia, potential renal toxicity, and peripheral neuropathy. Guidelines for aggressive treatment of hyperglycemia to minimize risks of complications will be reviewed. The role of interdisciplinary care, utilizing current evidence, is crucial to supporting patients and their families as they manage the challenges of facing two life-limiting diseases. Whole-person assessment and individualized treatment plans are key to maximizing quality of life for patients with cancer and diabetes.

Topics: Ambulatory Care; Amyloid; Comorbidity; Diabetes Mellitus; Exenatide; Humans; Hypoglycemic Agents; Inpatients; Insulin; Islet Amyloid Polypeptide; Neoplasms; Peptides; Practice Guidelines as Topic; Pyrazines; Quality of Life; Risk Factors; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Venoms

When using observational data to compare the effectiveness of medications, it is essential to account parsimoniously for patients' longitudinal characteristics that lead to changes in treatments over time.. We developed a method of estimating effects of longitudinal treatments that uses subclassification on a longitudinal propensity score to compare outcomes between a new drug (exenatide) and established drugs (insulin and oral medications) assuming knowledge of the variables influencing the treatment assignment. RESEARCH DESIGN/SUBJECTS: We assembled a retrospective cohort of patients with diabetes mellitus from among a population of employed persons and their dependents.. The data, from i3Innovus, includes claims for utilization of medications and inpatient and outpatient services. We estimated a model for the longitudinal propensity score process of receiving a medication of interest. We used our methods to estimate the effect of the new versus established drugs on total health care charges and hospitalization.. We had data from 131,714 patients with diabetes filling prescriptions from June through December 2005. Within propensity score quintiles, the explanatory covariates were well-balanced. We estimated that the total health care charges per month that would have occurred if all patients had been continually on exenatide compared with if the same patients had been on insulin were minimally higher, with a mean monthly difference of $397 [95% confidence interval (CI), $218-$1054]. The odds of hospitalization were also comparable (relative odds, 1.02; 95% CI, 0.33-1.98).. We used subclassification of a longitudinal propensity score for reducing the multidimensionality of observational data, including treatments changing over time. In our example, evaluating a new diabetes drug, there were no demonstrable differences in outcomes relative to existing therapies.

Topics: Adolescent; Adult; Diabetes Mellitus; Drug Prescriptions; Drug Utilization; Exenatide; Female; Humans; Hypoglycemic Agents; Logistic Models; Longitudinal Studies; Male; Middle Aged; Models, Statistical; Observation; Patient Compliance; Peptides; Pharmacoepidemiology; Practice Patterns, Physicians'; Retrospective Studies; Treatment Outcome; Venoms

Exenatide was approved by the US Food and Drug Administration (FDA) in April 2005 as adjunctive therapy to metformin or a sulfonylurea for the treatment of type 2 diabetes mellitus (DM).. We evaluated whether use of exenatide soon after its approval was consistent with the FDA- approved indications.. We assembled a retrospective cohort of patients with DM using data from a population of employed persons and their dependents, including pharmacy claims and claims for inpatient and outpatient services, provided by i3 Innovus. The data set included patients aged between 18 and 64 years with a diagnosis of DM or a claim for a DM drug from June 1, 2004, to December 31, 2005. Laboratory data were available for a subgroup of patients tested at specific commercial laboratories from June 1, 2003, to December 31, 2005. In addition, we requested data for patients with a diagnosis of obesity, regardless of a diagnosis of DM, to assess early off-label use of this medication. Patients were categorized by DM medication use and by their first fill date for exenatide, and their clinical characteristics were described. Early use was defined as filling a prescription for exenatide in the first 3 months after its approval. For descriptive purposes, we reported the means and percentages for the variables described.. The study included data for 206,345 individuals (mean age, 51.3 years), of whom 54.0% were male. Starting in June 2005, prescriptions for exenatide were filled by 3225 (1.6%) individuals. Fifty-three percent of early users were women. Among those who filled a prescription for exenatide, 21.9% were obese, compared with 10.9% to 15.1% of those filling prescriptions for other DM medications. The proportion of patients filling a prescription for exenatide who had not received a prescription for any other DM medication in the preceding year was 14%, suggesting that exenatide was their initial therapy. A prescription for a thiazolidinedione was filled by 29.9% of patients within 60 days of filling a prescription for exenatide.. Soon after its approval, exenatide was frequently used as monotherapy or in combination with a thiazolidinedione, neither of which is an FDA- approved indication. The observation that those filling a prescription for exenatide had a higher prevalence of obesity than those receiving prescriptions for other therapies may reflect awareness of the weight-lowering effects of exenatide.

Topics: Adult; Blood Glucose; Cohort Studies; Diabetes Mellitus; Diffusion of Innovation; Drug Labeling; Drug Prescriptions; Drug Therapy, Combination; Drug Utilization Review; Exenatide; Female; Guideline Adherence; Humans; Hypoglycemic Agents; Insurance, Pharmaceutical Services; Male; Middle Aged; Obesity; Peptides; Practice Guidelines as Topic; Retrospective Studies; Treatment Outcome; United States; United States Food and Drug Administration; Venoms

Topics: Amyloid; Diabetes Mellitus; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Islet Amyloid Polypeptide; Liraglutide; Peptides; Venoms

Topics: Body Weight; Diabetes Mellitus; Exenatide; Peptides; Venoms

Topics: Adenosine Deaminase Inhibitors; Animals; Colipases; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Inhibitors; Enzyme Precursors; Exenatide; Gastric Inhibitory Polypeptide; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glycoproteins; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Liraglutide; Peptides; Protein Precursors; Societies, Medical; Taste Threshold; Venoms

Topics: Diabetes Mellitus; Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Kidney; Monosaccharide Transport Proteins; Peptides; Venoms

Activation of the glucagon-like peptide-1 (GLP-1) receptor on pancreatic beta cells by GLP-1 and exendin-4 increases insulin secretion. Exendin-4 is 39 amino acids long, unlike GLP-1 which has 30 amino acids. Because of its non-mammalian (lizard) origin and unique C-terminal sequence, exendin-4 may be immunogenic in humans. We showed previously that the C terminally truncated exendin peptide exendin (1-30) has a reduced affinity for the GLP-1 receptor and a diminished ability to increase intracellular cAMP in insulinoma cells. Here we show that daily intraperitoneal injection of exendin (1-30) (1 nmol/kg) for 20 d followed by 31 d twice daily to Lepr(db)/Lepr(db) (db/db) mice significantly reduced the amount of visceral fat relative to saline-treated controls and improved HbA1C (control 9.5 +/- 0.2% vs treated 7.9 +/- 0.2%, p = 0.001) but was not as effective as exendin-4. To examine the ability of exendin (1-30) to stimulate beta-cell growth, we injected one group of 3-mo-old Fisher rats with exendin (1-30) (1 nmol/kg) and another group with saline for 8 d. We observed no change in beta-cell area, but did see a change in the number of islets with nuclei positive for BrdU [10.7 +/- 1.8% exendin (1-30) vs 6.5 +/- 0.5% control].

Topics: Adipose Tissue; Amino Acid Sequence; Animals; Blood Glucose; Body Composition; Bromodeoxyuridine; Cell Proliferation; Diabetes Mellitus; Eating; Exenatide; Glycated Hemoglobin; Immunoenzyme Techniques; Injections, Intraperitoneal; Insulin; Islets of Langerhans; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Microscopy, Confocal; Molecular Sequence Data; Peptides; Rats; Rats, Inbred F344; Venoms; Weight Gain

The 64th scientific congress of the American Diabetes Association had a special session devoted to the presentation of the results from three clinical trials: 1) the first multicentre international trial of pancreatic islet transplantation according to the so-called Edmonton protocol with the primary endpoint of restoring insulin independence in type 1 diabetic patients; 2) three pivotal studies of 30 weeks testing both the efficacy and safety of exenatide (exendin-4), a new insulin secretagogue that is a long-acting analogue of glucagon-like peptide-1, in patients with type 2 diabetes treated with either metformin, or a sulfonylurea, or a metformin-sulfonylurea combination; and 3) the "Collaborative AtoRvastatin Diabetes Study" (CARDS), a placebo-controlled primary prevention trial of cardiovascular complications using atorvastatin 10 mg in 2 838 at risk patients with type 2 diabetes. The main results and conclusions of these trials are briefly presented as they open new perspectives in the management of patients with type 1 or type 2 diabetes mellitus.

Topics: Anticholesteremic Agents; Atorvastatin; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Exenatide; Glucagon; Glucagon-Like Peptide 1; Heptanoic Acids; Humans; Islets of Langerhans Transplantation; Peptide Fragments; Peptides; Protein Precursors; Pyrroles; Venoms

Topics: Animals; Diabetes Mellitus; Exenatide; Humans; Hypoglycemic Agents; Lizards; Peptides; Phytotherapy; Plant Preparations; Rats; Venoms

Glucagon-like peptide-1 ameliorates the symptoms of diabetes through stimulation of insulin secretion and enhancement of beta-cell mass. We have therefore investigated the effects of glucagon-like peptide-1 on the development of diabetes, using db/db mice as a model of Type II diabetes.. The potent glucagon-like peptide-1 analogue Exendin-4 or vehicle (control) was administered (i.p.; 1 nmol/kg) to obese 6-week old db/db mice daily for 14 days ( n=10).. By 8 weeks of age, control db/db mice developed hyperglycaemia (fasting: 10.4+/-0.5 mmol/l), hyperinsulinaemia and impaired glucose tolerance. However, Exendin-4 treatment prevented hyperglycaemia (fasting: 6.1+/-1.0 mmol/l, p<0.01), with reduced plasma insulin concentrations ( p<0.001) and improved glucose tolerance ( p<0.05). Peripheral insulin sensitivity was not affected. However, insulin release in vivo and in vitro from the perfused pancreas was improved by Exendin-4, as were pancreatic insulin concentrations (0.54+/-0.02 vs 0.32+/-0.01 micro g/mg protein, p<0.05). These changes occurred in conjunction with increased beta-cell mass (3.01+/-0.31 vs 2.22+/-0.22 mg, p<0.05) and proliferation (BrdU(+) beta-cells: 1.08+/-0.20 vs 0.47+/-0.11%, p<0.05), as well as decreased apoptosis (Tunel (+) beta-cells: 0.37+/-0.06 vs 1.20+/-0.21%). Western blot demonstrated increased expression of Akt1 (by fivefold, p<0.01) and p44 MAP kinase (by sixfold, p<0.01), and decreased activation of caspase-3 (by 30%, p<0.05).. Our results suggest that Ex4 treatment delays the onset of diabetes in 6-8 week old db/db mice, through a mechanism involving Akt1 and expansion of the functional beta-cell mass.

Topics: Animals; Apoptosis; Blood Glucose; Cell Division; Diabetes Mellitus; Diabetes Mellitus, Type 1; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Hyperglycemia; Insulin; Islets of Langerhans; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Peptide Fragments; Peptides; Protein Precursors; Venoms

To develop transplantable beta-cell lines for the treatment of diabetes mellitus, we have taken advantage of the property of INS-1 cells to synthesize and secrete not only insulin, but also small quantities of the insulinotropic hormone glucagon-like peptide-1 (GLP-1). In INS-1 cells over-expressing the beta-cell GLP-1 receptor (GLP-1-R), we have shown, by radioimmune assay and bioassay of conditioned medium, that an autocrine signaling mechanism of hormone action exists whereby self-secreted GLP-1 acts as a competence factor in support of insulin gene transcription. INS-1 cells also exhibit insulin gene promoter activity, as assayed in cells transfected with a rat insulin gene I promoter-luciferase construct (RIP1-Luc). The GLP-1-R agonist exendin-4 stimulates RIP1-Luc activity in a glucose-dependent manner, an effect mediated by endogenous GLP-1-Rs, and is blocked by the serine/threonine protein kinase inhibitor Ro 31-8220. Over-expression of GLP-1-R in transfected INS-1 cells reduces the threshold for exendin-4 agonist action, whereas basal RIP1-Luc activity increases 2.5-fold in the absence of added agonist. The increase of basal RIP1-Luc activity is a consequence of autocrine stimulation by self-secreted GLP-1 and is blocked by introduction of (1) an inactivating W39A mutation in the N-terminus ligand-binding domain of GLP-1-R or (2) mutations in the third cytoplasmic loop that prevent G protein coupling. No evidence for constitutive ligand-independent signaling properties of the GLP-1-R has been obtained. Over-expression of GLP-1-R increases the potency and efficacy of D-glucose as a stimulator of RIP1-Luc. Thus, INS-1 cells over-expressing the GLP-1-R recapitulate the incretin hormone effect of circulating GLP-1, thereby providing a possible strategy by which beta-cell lines may be engineered for efficient glucose-dependent insulin biosynthesis and secretion.

Topics: Animals; Autocrine Communication; Cell Line; Diabetes Mellitus; Enzyme Inhibitors; Exenatide; Gene Expression Regulation; Genetic Engineering; Glucagon; Glucagon-Like Peptide 1; Indoles; Insulin; Insulinoma; Islets of Langerhans; Islets of Langerhans Transplantation; Peptide Fragments; Peptides; Promoter Regions, Genetic; Protein Kinase C; Protein Precursors; Rats; Receptors, Peptide; Recombinant Proteins; Research Design; Second Messenger Systems; Tumor Cells, Cultured; Venoms

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus; Exenatide; Humans; Hypoglycemic Agents; Lizards; Peptides; Venoms

The present study explores the potential utility of peripheral versus central administration of glucagon-like peptide-1 (GLP-1) receptor agonists in the regulation of feeding behavior in Wistar and Zucker obese rats. Acute central (intracerebroventricular [i.c.v.]) and peripheral (subcutaneous [s.c.]) administration of both GLP-1 (7-36) amide and exendin-4 resulted in a reduction in food intake for at least 4 hours, exendin-4 being much more potent than GLP-1 (7-36) amide, especially after peripheral administration. Both Zucker obese rats (fa/fa) and their lean littermates (Fa/-) responded to acute central and peripheral administration of exendin-4. Moreover, in situ hybridization revealed specific labeling for the mRNA for GLP-1 receptors in several brain areas of both the obese and lean rats. The presence of this receptor was also detected by affinity cross-linking assays. Long-term s.c. administration of exendin-4 (1 single injection per day, 1 hour prior to the onset of the dark phase of the cycle) decreased daily food intake and practically blocked weight gain in obese rats. In contrast to previous studies, these findings show that peripheral (s.c.) administration of both GLP-1 receptor agonists also induces satiety and weight loss in rats, and suggest the potential usefulness of exendin-4 as a therapeutic tool for the treatment of diabetes and/or obesity.

Topics: Amines; Animals; Appetite; Body Weight; Brain; Diabetes Mellitus; Drinking; Eating; Exenatide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; In Situ Hybridization; Injections, Intraventricular; Injections, Subcutaneous; Male; Obesity; Peptide Fragments; Peptides; Rats; Rats, Wistar; Rats, Zucker; Receptors, Glucagon; RNA, Messenger; Venoms

Diabetes is caused by a failure of the pancreas to produce insulin in amounts sufficient to meet the body's needs. A hallmark of diabetes is an absolute (type 1) or relative (type 2) reduction in the mass of pancreatic beta-cells that produce insulin. Mature beta-cells have a lifespan of approximately 48-56 days (rat) and are replaced by the replication of preexisting beta-cells and by the differentiation and proliferation of new beta-cells (neogenesis) derived from the pancreatic ducts. Here, we show that the insulinotropic hormone glucagon-like peptide (GLP)-1, which is produced by the intestine, enhances the pancreatic expression of the homeodomain transcription factor IDX-1 that is critical for pancreas development and the transcriptional regulation of the insulin gene. Concomitantly, GLP-1 administered to diabetic mice stimulates insulin secretion and effectively lowers their blood sugar levels. GLP-1 also enhances beta-cell neogenesis and islet size. Thus, in addition to stimulating insulin secretion, GLP-1 stimulates the expression of the transcription factor IDX-1 while stimulating beta-cell neogenesis and may thereby be an effective treatment for diabetes.

Topics: Animals; Diabetes Mellitus; Exenatide; Glucagon; Glucagon-Like Peptide 1; Homeodomain Proteins; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Peptide Fragments; Peptides; Promoter Regions, Genetic; Protein Precursors; Trans-Activators; Venoms

Exendin-4 is a 39 amino acid peptide isolated from the salivary secretions of the Gila monster (Heloderma suspectum). It shows 53% sequence similarity to glucagon-like peptide (GLP)-1. Unlike GLP-1, exendin-4 has a prolonged glucose-lowering action in vivo. We compared the potency and duration of glucose-lowering effects of exendin-4 and GLP-1 in hyperglycemic db/db and ob/ob mice. Whereas reductions in plasma glucose of up to 35% vanished within 1 h with most doses of GLP-1, the same doses of exendin-4 resulted in a similar glucose-lowering effect that persisted for >4 h. Exendin-4 was 5,530-fold more potent than GLP-1 in db/db mice (effective doses, 50% [ED50s] of 0.059 microg/kg +/-0.15 log and 329 microg/kg+/-0.22 log, respectively) and was 5,480-fold more potent in ob/ob mice (ED50s of 0.136 microg/kg+/-0.10 log and 744 microg/kg+/-0.21 log, respectively) when the percentage fall in plasma glucose at 1 h was used as the indicator response. Exendin-4 dose-dependently accelerated glucose lowering in diabetic rhesus monkeys by up to 37% with an ED50 of 0.25 microg/kg +/-0.09 log. In two experiments in which diabetic fatty Zucker rats were injected subcutaneously twice daily for 5-6 weeks with doses of exendin-4 up to 100 microg x rat(-1) x day(-1) (approximately 250 microg/kg), HbA1c was reduced relative to saline-injected control rats. Exendin-4 treatment was also associated in each of these experiments with weight loss and improved insulin sensitivity, as demonstrated by increases of up to 32 and 49%, respectively, in the glucose infusion rate (GIR) in the hyperinsulinemic euglycemic clamp. ED50s for weight loss and the increase in clamp GIR were 1.0 microg/kg+/-0.15 log and 2.4 microg/kg+/-0.41 log, respectively. In conclusion, acute and chronic administration of exendin-4 has demonstrated an antidiabetic effect in several animal models of type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Dose-Response Relationship, Drug; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Kinetics; Macaca mulatta; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Peptide Fragments; Peptides; Protein Precursors; Rats; Rats, Zucker; Sequence Homology; Venoms