Exenatide Treatment Research Articles

Exenatide preserves trabecular bone microarchitecture in experimental ovariectomized rat model.

The aim of this study is to investigate effects of exenatide (Glucagon-Like Peptide Agonist) replacement on bone mineral density (BMD) and microarchitecture in a surgical menopause-induced osteoporosis model in rats. In this study, 24 female Sprague-Dawley albino mature rats were used. Rats were assigned either to the group ovariectomized administered exenatide or to the control group. Bone Mineral Density (BMD), plasma cytokine levels and histomorphometric analysis were measured. Ovariectomized rats showed significant decrease BMD values, trabecular counts, trabecular thickness and trabecular area. Also, significant increase trabecular separation and plasma TNF-α (Tumor Necrosis Factor) and IL-6 (Interleukin) levels. Exenatide treatment reversed these changes and it showed a considerable protective effect on trabecular bone microarchitecture. Exenatide may be a candidate for use in the treatment of postmenopausal osteoporosis and anti-inflammatory properties can be attributed this effects.

Exenatide Increases IL-1RA Concentration and Induces Nrf-2‒Keap-1‒Regulated Antioxidant Enzymes: Relevance to β-Cell Function.

We previously demonstrated the anti-inflammatory and antioxidant effects of exenatide. We now hypothesized that exenatide also increases the plasma concentration of interleukin-1 receptor antagonist (IL-1RA), an endogenous anti-inflammatory protein, and modulates the nuclear factor erythroid 2‒related factor‒Kelchlike ECH-associated protein 1‒antioxidant response element (Nrf-2‒Keap-1‒ARE) system to induce key antioxidant enzymes to suppress inflammatory and oxidative stress. Twenty-four patients with obesity and type 2 diabetes receiving combined oral and insulin therapy were randomly assigned to receive either exenatide 10 μg or placebo twice a day for 12 weeks. Exenatide increased IL-1RA concentration by 61% (from 318 ± 53 to 456 ± 88 pg/mL; P < 0.05). Exenatide treatment also suppressed Keap-1 protein (P < 0.05) and increased messenger RNA expression of NQO-1, glutathione S-transferase PI, heme oxygenase-1, and p21 and increased NAD(P)H dehydrogenase [quinone] 1 protein (P < 0.05) in mononuclear cells. Because IL-1RA protects, maintains, and stimulates β-cell function in humans and Nrf-2‒Keap-1‒ARE protects β cells in animals with experimental diabetes, these actions of exenatide may contribute to a potential protective effect on β cells in diabetes.

Exenatide with Metformin Ameliorated Visceral Adiposity and Insulin Resistance

Background To study the effectiveness of exenatide with metformin and sequential treatment with exenatide and glargine added to metformin and their influence on insulin sensitivity and adipose distribution. Methods 20 newly diagnosed obese type 2 diabetic patients were enrolled, and 2-month washout treatment of metformin, 6-month exenatide treatment, and 6-month glargine treatment were administrated sequentially accompanied with previous metformin. Glucolipid metabolic parameters were compared among groups. Adipose distribution was quantified with computerized tomography according to anatomy, dividing into visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), adding up to total adipose tissue (TAT). Results The 6-month exenatide treatment dramatically ameliorated the glucose and lipid profile, improved insulin sensitivity, and mainly decreased VAT and also the ratio of VAT/SAT (RVS). The following 6-month glargine treatment increased VAT. The whole 12-month sequential treatment with exenatide and glargine added to metformin basically improved the insulin sensitivity and glucolipid control though VAT rebounded at the end, however without deteriorating the other parameters. Conclusion Exenatide is an ideal treatment for obese type 2 diabetic patients in the aspect of adipose tissue distribution. Sequential treatment of exenatide and glargine could be an alternative for low-income patients who cannot afford GLP-1 agonist for long time. This trial is registered with ChiCTR-OOC-17013679.

Exenatide treatment causes suppression of serum fasting ghrelin levels in patients with type 2 diabetes mellitus.

AimIn the present study, we investigated the long-term effects of exenatide treatment on serum fasting ghrelin levels in patients with type 2 diabetes mellitus.MethodsType 2 diabetic patients, who were using metformin with and without the other antihyperglycemic drugs on a stable dose for at least 3 months, were enrolled in the study. BMI>35 kg/m2 and HbA1c>7.0% were the additional inclusion criteria. Oral antihyperglycemic drugs, other than metformin, were stopped, and metformin treatment was continued at 2000 mg per day. Exenatide treatment was initiated at 5 µg per dose subcutaneously (sc) twice daily, and after one month, the dose of exenatide was increased to 10 µg twice daily. Changes in anthropometric variables, glycemic control, lipid parameters and total ghrelin levels were evaluated at baseline and following 12 weeks of treatment.ResultsThirty-eight patients (male/female = 7/31) entered the study. The mean age of patients was 50.5 ± 8.8 years with a mean diabetes duration of 8.5 ± 4.9 years. The mean BMI was 41.6 ± 6.3 kg/m2 and the mean HbA1c of patients was 8.9 ± 1.4%. The mean change in the weight of patients was −5.6 kg and the percentage change in weight was −5.2 ± 3.7% following 12 weeks of treatment. BMI, fasting plasma glucose and HbA1c levels of patients were decreased significantly (P < 0.001 and P < 0.001; respectively), while there was no change in lipid parameters. Serum fasting ghrelin levels were significantly suppressed following 12 weeks of exenatide treatment compared with baseline values (328.4 ± 166.8 vs 245.3 ± 164.8 pg/mL) (P = 0.024).ConclusionThese results suggest that the effects of exenatide on weight loss may be related with the suppression of serum fasting ghrelin levels, which is an orexigenic peptide.

Exenatide Improves Bone Quality in a Murine Model of Genetically Inherited Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is associated with skeletal complications, including an increased risk of fractures. Reduced blood supply and bone strength may contribute to this skeletal fragility. We hypothesized that long-term administration of Exenatide, a glucagon-like peptide-1 receptor agonist, would improve bone architecture and strength of T2DM mice by increasing blood flow to bone, thereby stimulating bone formation. In this study, we used a model of obesity and severe T2DM, the leptin receptor-deficient db/db mouse to assess alterations in bone quality and hindlimb blood flow and to examine the beneficial effects of 4 weeks administration of Exenatide. As expected, diabetic mice showed marked alterations in bone structure, remodeling and strength, and basal vascular tone compared with lean mice. Exenatide treatment improved trabecular bone mass and architecture by increasing bone formation rate, but only in diabetic mice. Although there was no effect on hindlimb perfusion at the end of this treatment, Exenatide administration acutely increased tibial blood flow. While Exenatide treatment did not restore the impaired bone strength, intrinsic properties of the matrix, such as collagen maturity, were improved. The effects of Exenatide on in vitro bone formation were further investigated in primary osteoblasts cultured under high-glucose conditions, showing that Exenatide reversed the impairment in bone formation induced by glucose. In conclusion, Exenatide improves trabecular bone mass by increasing bone formation and could protect against the development of skeletal complications associated with T2DM.

Exenatide upregulates gene expression of glucagon-like peptide-1 receptor and nerve growth factor in streptozotocin/nicotinamide-induced diabetic mice.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has modulating effects on insulin release. GLP-1 and receptors for GLP-1 are widely expressed throughout the body including the brain. The expression of GLP-1 receptors is very specific to large neurons in hippocampus, neocortex, and cerebellum. GLP-1 receptor stimulation enhances glucose-dependent insulin secretion and lowers blood glucose in type 2 diabetes mellitus. Studies on adipobiology of neurotrophins have focused on nerve growth factor (NGF) as an example of adipose-derived neurotrophins. Compromised trophic factor signaling may underlie neurodegenerative diseases ranging from Alzheimer's disease to diabetic neuropathies. Exenatide, a potent and selective agonist for the GLP-1 receptor, is currently approved for the treatment of type 2 diabetes mellitus. The aim of this study was to assess the effect of chronic exenatide treatment on the hippocampal gene expression levels of GLP-1 receptor and NGF in diabetic mice. The effects of chronic exenatide treatment (0.1 μg/kg, s.c., twice daily for 2 weeks) on GLP-1 receptor and NGF gene expression levels in the hippocampus of streptozotocin/nicotinamide (STZ-NA)-induced diabetic mice were assessed by quantitative real-time polymerase chain reaction (RT-PCR). The results of this study revealed that hippocampal gene expression of GLP-1 receptor and NGF were downregulated in diabetic mice. Importantly, a significant increase in the gene expression level of GLP-1 receptor and NGF was determined after 2 weeks of exenatide administration. Increased gene expression level of GLP-1 receptor and NGF may underlie the beneficial action of exenatide in STZ/NA-induced diabetes.

Exenatide Inhibits the KCa3.1 Channels of Aortic Vascular Smooth Muscle in Diabetic Rats.

KCa3.1 ion channels play an important role during atherosclerosis. We aimed to investigate the effect of exenatide on KCa3.1 expression in aortic vascular smooth muscle cells (VSMCs) of diabetic rats. Sprague-Dawley rats were randomly divided into normal control (NC), diabetes model (DM), and exenatide treatment (ET) groups. Hematoxylin and eosin and α-actin immunohistochemical staining were used to detect changes in rat aortic vascular smooth muscle. Quantitative RT-PCR and Western blot analysis were used to detect changes in KCa3.1 mRNA and protein levels, respectively. Aortic tissue staining in the DM group revealed an absence of smooth or integrated endothelium, increased smooth muscle cell proliferation in the media, smooth muscle hyperplasia, disorganized smooth muscle cells, and an increased number of collagen fibers, relative to the NC and ET groups. KCa3.1 mRNA expression was higher in the DM group than in the NC and ET groups. Similarly, the KCa3.1 protein level was higher in the DM group than in the NC and ET groups. The KCa3.1 protein level did not significantly differ between the ET and NC groups. Exenatide could inhibit the expression of the KCa3.1 channel in VSMCs of diabetic rats.

Effectiveness and safety of exenatide in Korean patients with type 2 diabetes inadequately controlled with oral hypoglycemic agents: an observational study in a real clinical practice

BackgroundRandomized clinical trials have shown the efficacy and safety of short-acting exenatide in patients with type 2 diabetes mellitus (T2DM). The aim of this observational study was to investigate the effectiveness and safety of exenatide twice a day in Korean patients with T2DM who are suboptimally controlled with oral hypoglycemic agents.MethodsThis study was a post hoc analysis of multi-center (71 centers), prospective, observational, single-arm, post-marketing study of short-acting exenatide 5 to 10 μg twice a day from March 2008 to March 2014 and analyzed those who finished the follow-up over 20 weeks of medication. Changes of hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and body weight values before and after exenatide treatment were analyzed. Adverse events and adverse drug reactions were estimated in patients who were treated with exenatide at least once and for whom follow-up for safety has been completed.ResultsAfter 20 weeks treatment with exenatide, mean HbA1c and body weight were significantly reduced from 8.4% to 7.7% and from 83.4 kg to 80.2 kg, respectively (both p < 0.001). Subjects with higher baseline glucose and HbA1c levels showed an independent association with a greater reduction in glucose level. In addition, short duration of diabetes less than 5 years was an independent predictor for the improvement in glucose level. The majority of study subjects showed a reduction in both body weight and glucose level (63.3%) after exenatide treatment. In terms of safety profile, exenatide treatment was generally well-tolerated and the incidence of severe adverse event was rare (0.8%). The gastrointestinal side effects were most common and hypoglycemia was reported in 1.7% of subjects.ConclusionIn real clinical practice, 20 weeks treatment with short-acting exenatide was well tolerated and showed a significant body weight and glucose reduction in Korean patients with T2D who are suboptimally controlled with oral hypoglycemic agents.Trial registrationClinicalTirals.gov, number NCT02090673, registered 14 February 2008.

Combined Treatment With Exenatide and Cyclosporine A or Parstatin 1-26 Results in Enhanced Reduction of Infarct Size in a Rabbit Model.

Exenatide and cyclosporine A have been shown to moderately protect against myocardial reperfusion injury leading to reduction of infarct size in patients. Our objective was to investigate whether the combined treatment with exenatide (glucagon-like peptide 1 receptor agonist) and cyclosporine A or parstatin 1-26 (inhibitors of mitochondrial permeability transition pore and/or inflammation) is more beneficial than either agent alone. Rabbits underwent 40 minutes of ischemia and 120 minutes of reperfusion. Intravenous bolus administration of exenatide or cyclosporine A, 10 minutes before reperfusion, reduced infarct size by 38% (P < 0.05) and 40% (P < 0.05), and cardiac troponin I (cTnI) plasma levels by 48% (P < 0.05) and 36% (P < 0.05), respectively, compared with control. The combined administration of both agents resulted in an additive decrease of infarct size by 55% (P < 0.05) and cTnI release by 61% (P < 0.05). Also, combined treatment of exenatide and parstatin 1-26 enhanced infarct size reduction (62%, P < 0.05), compared with monotherapies (41% for parstatin 1-26, P < 0.05; 43% for exenatide, P < 0.05). In contrast, the combined administration of parstatin 1-26 and cyclosporine A canceled out the cardioprotective effects observed by monotherapies. These results suggest that, for the therapy of myocardial reperfusion injury the combined administration of exenatide and cyclosporine A or parstatin 1-26 is more effective than monotherapies and may provide advantageous clinical outcome.

Short term monotherapy with exenatide is superior to metformin in weight loss, improving insulin resistance and inflammation in Chinese overweight/obese PCOS women

AimsTo evaluate the efficacy of exenatide on weight loss, insulin resistance, menstrual periods, metabolic profiles, inflammatory markers, and safety compared with metformin in Chinese overweight/obese patients with polycystic ovary syndrome. MethodsEighty-two overweight/obese (OW/OB) patients with PCOS were randomly assigned to the exenatide group (10 μg BID sc, n = 41) or metformin group (1000 mg BID po, n = 41) for 12 weeks. The main primary outcomes was mean change in body weight. ResultsSixty-three patients completed the study (31 cases in the EXE group and 32 cases in the MET group). EXE treatment was superior to MET treatment in weight loss (P = 0.009), with EXE leading to a significant mean loss of 3.1 ± 0.2 kg (P < 0.001) and MET leading to a significant mean loss of 1.2 ± 0.3 kg (P < 0.001). There was a significantly greater effect of EXE compared to metformin with respect to 2hINS, HOMA-IR, INSAUC and ISI (P < 0.001, P = 0.004, P < 0.001, P < 0.021, respectively), with both treatments leading to significant decreases in 2hINS, HOMA-IR and INSAUC (P < 0.001, P < 0.001, P < 0.001, respectively); and a significant increase in ISI (P < 0.001). FAI decreased while SHBG increased significantly with both treatments (P = 0.022, P < 0.001, respectively) with no significant difference between two groups (P > 0.05). EXE treatment was superior to MET treatment in reducing hsCRP (P = 0.016) with both treatments leading to a significant increase (P < 0.001). Menstrual periods, mFG score and Rosenfield score were not significantly different before and after treatment for either group (P > 0.05). ConclusionsShort-term exenatide treatment possesses a greater efficacy in terms of weight loss, improving insulin resistance and reducing inflammation than metformin. Large-sample and long-term clinical trials, however, are needed to assess exenatide's efficacy and safety in OW/OB women with PCOS.

Effect of exenatide after short-time intensive insulin therapy on glycaemic remission maintenance in type 2 diabetes patients: a randomized controlled trial

Early short-term intensive insulin (STII) therapy can induce drug-free glycemic remission for up to 1 year in half of newly diagnosed type 2 diabetic mellitus (T2DM) patients. Whether exenatide following STII therapy will induce higher long-term glycaemic remission is currently unknown. To assess the effect of STII+ exenatide therapy, compared with STII only, on maintenance of glycaemic remission in newly diagnosed T2DM patients. In this randomized, parallel-group, open-label, controlled trial, 129 patients (66 in STII+ exenatide group and 63 in STII only group) firstly completed 3-week STII therapy, then STII+ exenatide group was treated with exenatide for 12 weeks further. The cumulative probabilities of 1-year and 2-year glycaemic remission in STII+ exenatide group were 68.2 ± 5.7% and 53.0 ± 6.1%, which were significantly higher than STII only group (36.5 ± 6.1% and 31.8 ± 5.9%) (p-values < 0.001). Patients in STII+ exenatide group, compared with STII only group, showed significantly decreased levels of waist (82.2 (81.0, 83.5) cm v.s. 84.2 (82.7, 85.7) cm, p = 0.048) and HbA1c (5.83 (5.60, 6.06)% v.s. 6.49 (6.20, 6.77)%, p < 0.001) after 12-week exenatide treatment, but these differences disappeared after 1-year and 2-year follow-up. As conclusions, Improved effect of sequential exenatide after STII therapy on maintenance of glycaemic remission only occurred during exenatide treatment and lost upon treatment cessation.

Association between SORCS1 rs1416406 and therapeutic effect of exenatide

Objective: To study the relationship between SORCS1 gene rs1416406 and efficiency of exenatide. Methods: Between August 2010 and August 2012, a hundred and one newly diagnosed patients with type 2 diabetes mellitus (T2DM) were from CONFIDENCE study covering 25 university-affiliated hospitals in 13 provinces of China. All patients received exenatide treatment for 48 weeks. Hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), body mass index (BMI), oral glucose tolerance test (OGTT) glucose and insulin levels were measured before and after therapy. β-cell function was assessed by fasting proinsulin/insulin (PI/I), disposition index (DI) and acute insulin response (AIR). SORCS1 gene rs1416406 was genotyped by improved multiple ligase detection reaction. The relationship between rs1416406 and the glucose-lowering effect as well as β-cell function improvement of exenatide was analyzed by multiple linear regression. Results: There were statistically significant differences of HbA1c, FPG, 2 h plasma glucose (2 h PG), β-cell function (PI/I, DI and AIR) and changes of PI/I in three genotypes (GG, GA, AA) of rs1416406 between baseline and 48-week therapy of exenatide (all P<0.05). No statistically significant difference was found in changes of HbA1c, FPG, 2 h PG, DI, AIR except for PI/I, after stratifying by genotypes of rs1416406. Multiple linear regression analysis showed rs1416406 was significantly associated with the PI/I change (P<0.05) after adjustment of age, sex, baseline BMI, HbA1c and PI/I. Conclusion: SORCS1 gene rs1416406 was associated with the PI/I improvement induced by exenatide. Patients carrying GG genotype had greater reduction in PI/I after exenatide treatment as compared with those carrying allele A. The results suggests that the newly diagnosed T2DM patients with GG genotype might obtain more benefit from the early treatment of exenatide .

Exenatide treatment causes suppression of serum fasting ghrelin levels in patients with type 2 diabetes Mellitus

AIM In the present study, we investigated the long-term effects of exenatide treatment on serum fasting ghrelin levels in patients with type 2 diabetes mellitus. METHODS Type 2 diabetic patients, who were using metformin with and without the other antihyperglycemic drugs on a stable dose for at least 3 months, were enrolled in the study. BMI>35 kg/m2 and HbA1c>7.0% were the additional inclusion criteria. Oral antihyperglycemic drugs, other than metformin, were stopped, and metformin treatment was continued at 2000 mg per day. Exenatide treatment was initiated at 5 µg per dose subcutaneously (sc) twice daily, and after one month, the dose of exenatide was increased to 10 µg twice daily. Changes in anthropometric variables, glycemic control, lipid parameters and total ghrelin levels were evaluated at baseline and following 12 weeks of treatment. RESULTS Thirty-eight patients (male/female = 7/31) entered the study. The mean age of patients was 50.5 ± 8.8 years with a mean diabetes duration of 8.5 ± 4.9 years. The mean BMI was 41.6 ± 6.3 kg/m2 and the mean HbA1c of patients was 8.9 ± 1.4%. The mean change in the weight of patients was -5.6 kg and the percentage change in weight was -5.2 ± 3.7% following 12 weeks of treatment. BMI, fasting plasma glucose and HbA1c levels of patients were decreased significantly (P < 0.001 and P < 0.001; respectively), while there was no change in lipid parameters. Serum fasting ghrelin levels were significantly suppressed following 12 weeks of exenatide treatment compared with baseline values (328.4 ± 166.8 vs 245.3 ± 164.8 pg/mL) (P = 0.024). CONCLUSION These results suggest that the effects of exenatide on weight loss may be related with the suppression of serum fasting ghrelin levels, which is an orexigenic peptide.

Comparative evaluation the effects of bariatric surgery and exenatide treatment on the clinical and laboratory parameters in obese type 2 diabetic patients

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

New association of bone morphogenetic protein 4 concentrations with fat distribution in obesity and Exenatide intervention on it

BackgroundBone morphogenetic protein 4 (BMP-4) has been proven to regulate white adipogensis. We aimed to demonstrate the correlation of BMP-4 with fat distribution and Exenatide treatment on it.MethodsWe enrolled 69 obese patients. Anthropometric and metabolic indexes were collected. Fat distribution was measured by dual-energy X-ray absorptiometry. BPM-4 levels were assessed using enzyme-link immunosorbent assay kit. 30 obese patients were treated with Exenatide twice a day. Change in body weight, metabolic-related indices and BPM-4 levels were evaluated after 18 weeks.Results1) The mean(±SD) BMP-4 levels were 763.98 ± 324.11 pg/ml in the obese. BPM-4 levels were significantly positively correlated with estimated visceral adipose tissue mass in all subjects and also in females (r = 0.377, r = 0.625, respectively,all P < 0.05). BPM-4 levels were also significantly positively correlated with body mass index, hip circumference and total fat% in females (r = 0.375,r = 0.429,r = 0.493,respectively, all P < 0.05). BPM-4 levels were negatively correlated with total cholesterol(TC) in all subjects and males also (r = −0.373,r = −0.332,respectively, all P < 0.05). BPM-4 levels were also significantly positively correlated with free triiodothyronine in males (r = 0.441, P < 0.05). 3) Multivariate analyses showed that TC was risk factor of BMP-4 concentration in males and Est.VAT Area was risk factor of BMP-4 levels in females. 4) BMP-4 levels were significantly higher in the obesity with slightly increased thyroid stimulating hormone(TSH) than the obesity without slightly increased TSH (902.08 ± 354.74 pg/ml vs. 720.24 ± 306.41 pg/ml, P < 0.05). 5) Exenatide treatment leads to a significant decreased in BMP-4 from 860.05 ± 352.65 pg/ml to 649.44 + 277.49 pg/ml independent of weight loss(P < 0.05).ConclusionBMP-4 levels were associated with the visceral adipose tissue and may play a certain role in fat distribution and subclinical hypothyroidism in obesity. Exenatide treatment reduced BMP-4 levels independent of weight loss.Trial registrationClinicaltrials.gov Identifier: NCT02118376, Registered 16 April.

No cognitive-enhancing effect of GLP-1 receptor agonism in antipsychotic-treated, obese patients with schizophrenia.

Schizophrenia is associated with profound cognitive and psychosocial impairments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for diabetes and obesity treatment, and animal studies have indicated cognitive-enhancing effects. In this investigator-initiated, double-blind, randomized, placebo-controlled trial, we tested non-metabolic effects of exenatide once-weekly (Bydureon™) in obese, antipsychotic-treated patients with schizohrenia spectrum disorder. Before and after 3 months of exenatide (N = 20) or placebo (N = 20) treatment, patients were assessed with the following: Brief Assessment of Cognition in Schizophrenia (BACS), Rey-Osterreith complex figure test (REY), Short-Form Health Survey (SF-36), Personal and Social Performance Scale (PSP) and the Positive and Negative Syndrome Scale (PANSS). We used BACS composite score as the main outcome measure. Repeated measures analysis of variance on BACS composite score showed significant effect of 'Time' (P < 0.001), no effect of 'Group' (P = 0.64) and no 'Time*Group' interaction (P = 0.77). For REY, SF-36, PSP and PANSS, only significant 'Time' effects were found. The non-significant results of this first clinical trial exploring non-metabolic effects of a long-acting GLP-1RA in patients with schizophrenia could reflect a general problem of translating cognitive-enhancing effects of GLP-1RAs from animals to humans or be explained by factors specifically related to schizophrenia spectrum patients with obesity such as antipsychotic treatment.

Exenatide induces an increase in vasodilatory and a decrease in vasoconstrictive mediators.

In view of the known vasodilatory effects of glucagon-like peptide-1 and exenatide, we investigated the effects of exenatide on vasoactive factors. We analysed blood samples and mononuclear cells (MNCs) from a previous study, collected after a single dose and 12 weeks of exenatide or placebo treatment in a series of 24 patients with type 2 diabetes mellitus. After exenatide treatment, plasma concentrations of atrial natriuretic peptide, cyclic guanyl monophosphate (cGMP) and cyclic adenyl monophosphate increased significantly at 12 weeks. Plasma cGMP and adenylate cyclase expression in MNCs increased significantly after a single dose. Angiotensinogen concentration fell significantly 2 hours after a single dose and at 12 weeks, while renin and angiotensin II levels fell significantly only after a single dose and not after 12 weeks of treatment. Exenatide also suppressed the plasma concentration of transforming growth factor-β and the expression of P311 in MNCs at 12 weeks. Thus, exenatide induces an increase in a series of vasodilators, while suppressing the renin-angiotensin system. These changes may contribute to the overall vasodilatory effect of exenatide.

Add on Exenatide Treatment is Beneficial in Poorly Controlled Obese Type 2 Diabetics under Intensive Insulin Regimens.

Background: Intensive insulin treatment is bothersome in obese patients with type 2 diabetes mellitus. High insulin dosages further increase weight gain and the risk of hypoglycemia. Glucagon like peptide-1 receptor agonists decrease the insulin need, cause weight loss and reduce the risk of hypoglycemia. There is limited data about the effect of exenatide on obese diabetics under intensive insulin regimens. Methods: This retrospective case series report the clinical outcomes of 23 obese (13 morbidly obese) patients with uncontrolled type 2 diabetes mellitus (Age=59±10.44 years, body mass index 41.1±6.8 kg/m2, HbA1c 9.9±1.5%), under high dose (94.1±39.6 unit) intensive insulin. Exenatide twice daily was added for a mean follow-up period of 11.22±7.01 (3-30) months. Intensive insulin regimens were continued in 7 patients while the others were switched to basal insulin during the follow-up. Results: During the follow-up, mean HbA1c levels of the patients significantly improved (p=0.019), along with the significant decrease in body mass index and the total insulin need (p<0.001 for both). Baseline insulin dosages were significantly higher in the intensive regimen group (p=0.013) while other demographical and clinical characteristics were similar. No significant difference was present between the groups regarding the alterations of HbA1c, body mass index and the reduction in total insulin dosages. Conclusion: Add on exenatide appears to be a rational treatment modality in uncontrolled obese patients with type 2 diabetes mellitus despite intensive insulin regimens. Further prospective randomized studies with longer follow-up periods are recommended.

The protective effect of exenatide on the renal injury in diabetic rats

To investigate the protective effect of exenatide (Ex) on the renal injury in streptozotocin-induced diabetic rats. Sprague-Dawley rats were randomly divided into 2 groups:normal control group (NC group, n=8) and model group. Model group was injected with low dose of streptozotocin (30 mg·kg-1) after the rats were fed with high fat and high glucose diet for 4 weeks. Seventy-two hours later, rats of blood glucose level ≥ 16.7 mmol·L-1 were divided into diabetes mellitus group (DM, n=10) and two exenatide-treated groups (Ex groups,3 or 6μg·kg-1, n=8). Ex groups subcutaneously injected with exenatide for 12 weeks, but NC group and DM group were injected with the same volume of solvent. Changes in glycolipid metabolism and renal function such as serum creatinine (Scr), urine creatinine (Ucr), blood urea nitrogen (BUN), 24 hour urine micro-albumin (24 h UMA)in the 4 groups of rats were determined and creatinine clearance rate (Ccr) were calculated. Renal oxidative stress parameters such as superoxide dismutase (SOD), malondialdehyde(MDA), glutathione per-oxidase (GSH-Px) were measured. Hematoxylin-eosin (HE) staining was used to examine pathological morphology in the renal tissues and ELISA was performed to determine the level of advanced glycation end products(AGEs), the glycosylation end product in renal tissues. Compared to the DM group,glycolipid metabolic abnormalities in the exenatide-treated groups were significantly ameliorated with lower levels of blood glucose,HbAlc, cholesterol and triglyceride (P < 0.05). The renal function index was markedly improved (P < 0.05) with Ccr reduced, indicating a high glomerular filtration status. Meanwhile, exenatide treatment improved the diabetes-induced pathological changes in renal morphology, substantially increased the activities of SOD and GSH-Px, and reduced the levels of MDA and AGEs. Exe-natide has the renal protective effect probably by the mechanisms of inhibition of AGEs production and reduction of oxidative stress in the renal tissues of diabetic rats.

Effect of exenatide on postprandial glucose fluxes, lipolysis, and ß-cell function in non-diabetic, morbidly obese patients.

To investigate the effect of exenatide on glucose disposal, insulin secretion, ß-cell function, lipolysis and hormone concentrations in non-diabetic, morbidly obese subjects under physiological conditions. Patients were assigned to exenatide 10 µg twice daily (EXE, n = 15) or control (CT, n = 15) for 3 months. Patients received a meal test/tracer study (MTT) to measure endogenous glucose production (EGP), rate of oral glucose appearance (RaO), insulin secretion rate (ISR), ß-cell function, hepatic insulin resistance (HIR) and adipose tissue insulin resistance (AT-IR) and insulin sensitivity (IS). Post treatment, the EXE group showed a significant reduction in body weight ( P < .001). The postmeal time-course of glucose, insulin and ISR showed a lower peak between 60 and 180 minutes in phase with a reduction in RaO ( P < .01). After an initial similar suppression, EGP resumed at higher rates between 60 and 180 minutes ( P = .02) in EXE vs CT, while total RaO and EGP were similar throughout the MTT. In EXE, the postmeal glucagon, GLP1 and GIP responses were reduced ( P < .05). Fasting and postprandial lipolysis and ß-cell function were unaltered by active treatment. HIR, AT-IR and IS were all improved after exenatide treatment ( P < .05). In morbidly obese non-diabetic subjects, exenatide causes weight loss, decreased postprandial glycaemia and glucagon response without changes in ß-cell function. These effects are consequent upon delayed oral glucose appearance in the circulation. Exenatide treatment is also associated with an improvement in hepatic, adipose tissue and whole-body IS with no influence on postprandial lipolysis.