胰高血糖素样肽-1 受体激动剂减轻小鼠体质量的作用机制研究#br#

目的 探讨胰高血糖素样多肽-1 受体激动剂（GLP-1Ra）减轻小鼠体质量的作用机制。方法 正常对照（N）组 8 只小鼠以普通饲料喂养, 高脂饮食（HF）组 32 只以高脂饲料喂养, 造模成功后的小鼠分为单纯 HF 组（HF）组、 处死前寒冷刺激（CS）组和 200 、 400 μg/kg GLP-1 Ra 干预[Lira（200）、 Lira（400） ]组, 喂养 8 周。观察各组小鼠的体质量、 血糖及三酰苷油 （TG） 的水平变化。HE 染色观察小鼠不同部位白色脂肪 （WAT） 形态学改变; 免疫组织荧光 染色、 Real-time PCR 方法观察利拉鲁肽对棕色脂肪（BAT）特异因子 UCP-1 表达的影响;Western blot 方法观察UCP-1 表达的调节因子 PPAR-γ共激活因子 1α （PGC-1α） 表达的影响。结果 Lira （200） 组和 Lira （400） 组平均体质量低于 HF 组 （P＜0.05）。HF 组较 N 组血糖和 TG 水平均升高, Lira （200） 组和 Lira （400） 组血糖和 TG 水平较 HF 组降低 （P＜0.05）。Lira（200）组及 Lira（400）组肾周与腹股沟皮下脂肪组织部分转变为含有微小脂滴的棕色样脂肪细胞, UCP-1 蛋白和基因、 PGC-1α蛋白表达水平较 HF 组均有不同程度的增加, Lira（400）组均强于 Lira（200）组（P <0.05）。结论 GLP-1Ra能明显减轻小鼠体质量, 其机制可能与增加 UCP-1 表达, 促进白色脂肪发生棕色样变有关。     

Is liraglutide or exenatide better in type 2 diabetes?

Background: Subjects with type 2 diabetes have high circulating levels of glucose. Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that has a major role in glucose homeostasis. Exenatide and liraglutide are both agonists at the GLP-1 receptor, and are effective at reducing circulating glucose levels (measured as Hb_A1c levels), but they have not been compared. Objectives/methods: This evaluation is of a clinical trial comparing liraglutide once a day with exenatide twice a day in subjects with type 2 diabetes. Results: In the Liraglutide Effect and Action in Diabetes (LEAD)-6 trial, subcutaneous liraglutide 1.8 mg once a day was compared with exenatide 10 μg twice a day. The primary efficacy outcome was change in Hb_A1c levels, and this was significantly greater with liraglutide (1.12%) than with exenatide (0.79%). Liraglutide and exenatide had similar small abilities to reduce body weight, blood pressure and LDL-cholesterol. Conclusions: Liraglutide was more effective than exenatide for overall glycaemic control in subjects with type 2 diabetes. However, this is only true for the preparations and doses tested, that is liraglutide 1.8 mg once weekly and exenatide 10 μg b.i.d., and may not apply when the comparison is undertaken with the new longer-lasting preparation of exenatide once weekly.     

降糖药利拉鲁肽及其临床评价

利拉鲁肽(Iiraglutide)是新一代以肠促胰素为基础的降糖药,具有良好的降糖效果,无论单独应用还是与其他口服降糖药联用,均能迅速、高效地降低血糖和糖化血红蛋白(HbA1c)水平.其降糖作用依赖于葡萄糖浓度,即仅在血糖水平升高时刺激胰岛素释放达到治疗效果,因此发生低血糖的概率非常低.此外,利拉鲁肽能改善B细胞功能,降低血压,延缓糖尿病进展,减低糖尿病心血管并发症危险.与其他大多数降糖药相比,利拉鲁肽能帮助患者减轻体重.利拉鲁肽具有超越现有糖尿病治疗药物的多种特点.     

Dipeptide-modified nanoparticles to facilitate oral docetaxel delivery: new insights into PepT1-mediated targeting strategy

Oligopeptide transporter 1 (PepT1) has been a striking prodrug-designing target. However, the underlying mechanism of PepT1 as a target to facilitate the oral absorption of nanoparticles (NPs) remains unclear. Herein, we modify Poly (lactic-co-glycolic acid) (PLGA) NPs with the conjugates of dipeptides (L-valine-valine, L-valine-phenylalanine) and polyoxyethylene (PEG Mw: 1000, 2000) stearate to facilitate oral delivery of docetaxel (DTX) to investigate the oral absorption mechanism and regulatory effects on PepT1 of the dipeptide-modified NPs. The cellular uptake of the dipeptide-modified NPs is more efficient than that of the unmodified NPs in the stably transfected hPepT1- Hela cells and Caco-2 cells, suggesting the involvement of PepT1 in the endocytosis of NPs. The internalization of the dipeptide-modified NPs is proved to be a proton-dependent process. Moreover, the L-valine-valine modified NPs with shorter PEG chain exhibit distinct advantages in terms of intestinal permeability and oral absorption, resulting in significantly improved oral bioavailability of DTX. In summary, PepT1 could serve as a desirable target for oral nanoparticulate drug delivery and the dipeptide-modified NPs represent a promising nanoplatform to facilitate oral delivery of hydrophobic drugs with low bioavailability.     

Fixed-ratio combination therapy with GLP-1 receptor agonist liraglutide and insulin degludec in people with type 2 diabetes

Introduction: A fixed combination of basal insulin degludec and glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide (IDegLira; 50 units degludec/1.8 mg liraglutide) has been developed as a once daily injection for the treatment of type 2 diabetes (T2D). In the phase 3a trial programme ‘Dual action of liraglutide and insulin degludec in type 2 diabetes’ (DUAL?), five trials of 26 weeks duration and one trial of 32 weeks duration have evaluated the efficacy and safety of IDegLira compared with administration of insulin degludec, insulin glargine, liraglutide alone or placebo.

Areas covered: Combination therapy with IDegLira reduces HbA1c more than monotherapy with a GLP-1RA (liraglutide) or insulin (degludec or glargine). Combination therapy leads also to weight loss, or a stable body weight, with no increase in hypoglycaemia. Rates of adverse events did not differ between treatment groups; however, gastrointestinal side effects were fewer with IDegLira compared with liraglutide treatment alone. A limitation of the DUAL? development programme is that patients receiving basal insulin doses in excess of 50 units were excluded from the studies.

Expert commentary: In conclusion, IDegLira combines the clinical advantages of basal insulin and GLP-1RA treatment, and is a treatment strategy that could improve the management of patients with T2D.     

The efficacy and safety of exenatide once weekly in patients with type 2 diabetes

Introduction: Exenatide once weekly (QW) is a glucagon-like peptide 1 receptor agonist (GLP-1RA) that was approved in 2012 in Europe and the U.S.A. for the treatment of type 2 diabetes (T2D).

Areas covered: This review provides an overview of the safety and efficacy of exenatide QW for the treatment of T2D and evaluates the benefit–risk ratio compared to other available long-acting GLP-1RAs. In addition, the authors provide an outline of the novel formulations and delivery methods of exenatide.

Expert opinion: Exenatide QW is an efficacious and safe treatment for T2D. However, head-to-head trials have demonstrated exenatide QW to be inferior to liraglutide and semaglutide with respect to effects on fasting plasma glucose, glycated hemoglobin A1c, and bodyweight. In addition, exenatide QW appears inferior to liraglutide and semaglutide in terms of cardiovascular risk reduction. Currently, the overall risk-benefit profiles for the range of GLP-1RAs point to liraglutide and semaglutide as first-choice for the management of T2D, which has been confirmed by a recently published consensus report on the treatment of T2D from the American Diabetes Association and the European Association for the Study of Diabetes. The pricing of exenatide QW will most likely be a key determinant for its place in the future management of T2D.     

Liraglutide: clinical pharmacology and considerations for therapy

Liraglutide is a United States Food and Drug Administration (FDA)-approved glucagon-like peptide-1 (GLP-1) analog that is 97% homologous to native human GLP-1. The additional 16-carbon fatty acid chain causes noncovalent binding to albumin, which slows absorption from the injection site and protects the molecule from degradation by the enzyme dipeptidyl peptidase-4, allowing for protraction of action. Albumin binding and an elimination half-life of 13 hours combine to allow for once-daily dosing. Liraglutide 1.2 and 1.8 mg/day given as monotherapy for up to 52 weeks produced mean reductions in hemoglobin A1c (A1C) of 0.6-1.6%; combination therapy of liraglutide with oral antidiabetic agents demonstrated mean A1C reductions up to 1.5%. The satiety effect of GLP-1 receptor agonists and documented weight loss as great as 3.38 kg in clinical trials may make liraglutide ideal for obese patients with type 2 diabetes mellitus. Like other incretin-based agents, preliminary studies suggest liraglutide may also increase β-cell mass and function. Hypoglycemia is rare with liraglutide and tends to occur when used in combination with sulfonylureas; liraglutide in combination with insulin is not yet FDA approved. The pharmacokinetic parameters of liraglutide are unaffected by age, sex, race, or ethnicity, and no special recommendations for altered dosing of liraglutide need apply to populations with hepatic or renal impairment. Results from clinical trials have not shown an increased risk of medullary thyroid cancer, pancreatitis, or poor cardiovascular outcomes with liraglutide treatment. Ongoing, long-term monitoring studies continue to evaluate the safety of liraglutide treatment in these outcomes.     

Treatment with liraglutide--a once-daily GLP-1 analog--does not reduce the bioavailability of ethinyl estradiol/levonorgestrel taken as an oral combination contraceptive drug

Liraglutide is a once-daily human GLP-1 analog for treatment of type 2 diabetes. Like other GLP-1 analogs, liraglutide delays gastric emptying, which could potentially affect absorption of concomitantly administered oral drugs. This study investigated the effect of liraglutide on the pharmacokinetics of the components of an oral contraceptive (ethinyl estradiol/levonorgestrel). Postmeno-pausal healthy women (n = 21) were included. A single dose of this contraceptive was administered. Blood samples for ethinyl estradiol/levonorgestrel measurements were drawn until 74 hours post dosing of the contraceptive during liraglutide and placebo treatments. The 90% confidence interval (CI) of the ratio of the area under the curve (AUC) (1.06; 90% CI, 0.99-1.13) for ethinyl estradiol (during liraglutide and placebo) was within defined limits, demonstrating equivalence. The 90% CI for the ratio of AUC for levonorgestrel was not fully contained within the limits (1.18; 90% CI, 1.04-1.34) (levonorgestrel AUC was 18% greater with liraglutide vs placebo). However, equivalence was demonstrated for levonorgestrel AUC(0-t) (1.15; 90% CI, 1.06-1.24). Equivalence was not demonstrated for maximum concentration (C(max)); values for ethinyl estradiol and levonorgestrel C(max) were 12% and 13% lower with liraglutide versus placebo, respectively. Both reached C(max) ~1.5 hours later with liraglutide. No clinically relevant reduction in bioavailability of ethinyl estradiol/levonorgestrel occurred.     

口服胰高血糖素样肽-1受体激动剂研究进展及非临床评价的考虑

胰高血糖素样肽-1（Glucagon-like Peptide-1,GLP-1）是一种由肠道L细胞分泌的肠促胰素 （Incretin）,根据人体血糖水平调控胰岛素和胰高血糖素分泌,维持血糖稳定。胰高血糖素样肽-l受体激动剂（GLP-1 Receptor Agonists,GLP-1RA）是近年来开发的新型降糖药,通过模拟天然GLP-1而激活GLP-1受体,达到控制血糖的目的,同时GLP-1RA还具有控制体质量和改善非酒精性脂肪肝等多重临床获益,正逐步成为治疗糖尿病的第一大处方药物。目前已上市的GLP-1RA主要为注射用药,而与注射给药相比,口服制剂给药方便、治疗痛苦小,患者依从性更好。口服GLP-1RA药物已成为新的糖尿病治疗药物的重要研发方向之一。本文梳理了目前在研GLP-1RA口服小分子和肽类降糖药的研发现状,分析该靶点药物研究应用进展,并从非临床有效性和安全性方面提供评价策略,以期为同类药物的研发和应用提供参考。     

In vivo testing of mucus-permeating nanoparticles for oral insulin delivery using Caenorhabditis elegans as a model under hyperglycemic conditions

The aim was to evaluate the potential of mucus-permeating nanoparticles for the oral administration of insulin. These nanocarriers, based on the coating of zein nanoparticles with a polymer conjugate containing PEG, displayed a size of 260 nm with a negative surface charge and an insulin payload of 77 μg/mg. In intestinal pig mucus, the diffusivity of these nanoparticles (PPA-NPs) was found to be 20-fold higher than bare nanoparticles (NPs). These results were in line with the biodistribution study in rats, in which NPs remained trapped in the mucus, whereas PPA-NPs were able to cross this layer and reach the epithelium surface. The therapeutic efficacy was evaluated in Caenorhabditis elegans grown under high glucose conditions. In this model, worms treated with insulin-loaded in PPA-NPs displayed a longer lifespan than those treated with insulin free or nanoencapsulated in NPs. This finding was associated with a significant reduction in the formation of reactive oxygen species (ROS) as well as an important decrease in the glucose and fat content in worms. These effects would be related with the mucus-permeating ability of PPA-NPs that would facilitate the passage through the intestinal peritrophic-like dense layer of worms (similar to mucus) and, thus, the absorption of insulin.KEY WORDS: Nanoparticles, Oral delivery, Mucus-permeating, Biodistribution, Insulin, Caenorhabditis elegans, ROS, Lifespan, Zein, Epithelium     

The design and discovery of lixisenatide for the treatment of type 2 diabetes mellitus

Introduction: Lixisenatide is a once-daily short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) used in the treatment of type 2 diabetes mellitus (T2DM). It is used in combination with oral antidiabetics and/or basal insulin in patients inadequately controlled on these medications and who are undergoing diet and lifestyle modification. GLP-1RAs glucose-dependently increase insulin secretion, decrease glucagon secretion, and slow gastric emptying, thereby improving glycemic control. GLP-1RAs are associated with body weight benefits and low rates of hypoglycemia which are welcome in patients with T2DM.

Areas covered: The authors describe the identification of GLP-1RAs as suitable targets for modification with structure-inducing probe technology to improve stability and resistance to proteolytic degradation. Clinical studies have assessed lixisenatide across > 5000 patients as a monotherapy or add-on to a variety of commonly used antidiabetic medications. These studies highlighted the effects of lixisenatide on gastric emptying, explaining its particular improvements in postprandial plasma glucose (PPG) excursions and underscoring its efficacy in combination with insulin glargine. Lixisenatide was well tolerated, with nausea and vomiting being the most frequently reported adverse events.

Expert opinion: The once-daily administration of lixisenatide as well as its substantial sustained effect on gastric emptying and, hence, PPG excursions are all important features compared with the other GLP-1RAs. The combination of two injectables, such as basal insulin to lower fasting plasma glucose and a GLP-1RA that curtails PPG excursions, is clinically valuable and could differentiate lixisenatide from other GLP-1RAs, especially from those continuously acting GLP-1RAs with little effect on gastric emptying and PPG excursions.     

Insulin and GLP-1 analog combinations in type 2 diabetes mellitus: a critical review

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists have been used in clinical management of type 2 diabetes since 2005. Currently approved agents were initially developed and approved for combination therapy with oral antidiabetic drugs (OADs). The potential for combined use with insulin has garnered increasing attention due to the potential to reduce side effects associated with insulin therapy and improve glycemic control. Areas covered: We reviewed published and other publicly released data from controlled and uncontrolled studies that included subjects treated with insulin/GLP-1 analog combination therapy. The currently available guidance for clinical practice when combining insulin and GLP-1 analogs was also summarized. Expert opinion: Limited data currently available from placebo-controlled trials support the use of exenatide twice daily or liraglutide once daily in combination with basal insulin and metformin in subjects with type 2 diabetes unable to attain treatment goals. Several randomized controlled trials are currently studying combinations of insulin with various GLP-1 analogs. Additional guidance on the clinical use of these combinations will likely be forthcoming once these studies are reported. Insulin/GLP-1 analog combinations will require optimization of blood glucose monitoring strategies and delivery systems to decrease the risk of administration errors and reduce the potential complexity of these regimens.     

Tolerability, pharmacokinetics and pharmacodynamics of the once-daily human GLP-1 analog liraglutide in Japanese healthy subjects: a randomized, double-blind, placebo-controlled dose-escalation study

OBJECTIVES: Liraglutide is a once-daily human GLP-1 analog being developed as a Type 2 diabetes therapy. A dose-finding study in Japanese patients with Type 2 diabetes showed liraglutide to produce dose-dependent decreases in HbA(1C). Studies have also shown that, with stepped dose titration, liraglutide is well tolerated. This double-blind trial in 24 healthy Japanese men assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of once-daily subcutaneous (s.c.) liraglutide using doses exceeding those previously studied, and using the stepped titration approach. MATERIALS AND METHODS: Subjects were randomized to three groups in each of which 6 received liraglutide, and 2 placebo for 35 consecutive days. The daily dose of liraglutide was stepped from 5 microg/kg (s.c. abdomen, morning) to 10 and then 15 microg/kg at 7-day intervals. One group remained at this dose, the others titrating further to 20 and 25 microg/kg, respectively. Subjects remained at the study site from Day 21 until the end of the trial, with standard meals served during inhouse periods. RESULTS: No safety issues, hypoglycemia, gastrointestinal or any other adverse events were observed. Liraglutide showed dose-dependent increases in the pharmacokinetic parameters of AUC0-24 h, C(max) and C(trough), while t(max), t(1/2) and V(d/F) were constant. Mean plasma glucose concentrations were similar across all treatment groups at baseline, but dose-dependent decreases in mean and postprandial plasma glucose were seen with liraglutide, although all values remained within normal ranges. There was a tendency for weight to decrease with liraglutide in comparison to placebo. CONCLUSIONS: Liraglutide appears to be well tolerated at doses of up to 25 microg/kg in Japanese subjects. Despite clear pharmacodynamic effects in this euglycemic cohort, a low risk for hypoglycemia was suggested together with good gastrointestinal tolerability.     

利拉鲁肽和门冬胰岛素30对肥胖2型糖尿病患者疗效和β细胞功能影响的比较

目的比较利拉鲁肽和门冬胰岛素30分别与二甲双胍联合对肥胖2型糖尿病患者的疗效和β细胞功能的影响。方法将65例新诊断以及口服降糖药物效果欠佳的肥胖2型糖尿病患者,分为利拉鲁肽组[利拉鲁肽联合二甲双胍（n=30）]和门冬胰岛素30组[门冬胰岛素30联合二甲双胍治疗（n=35）],均治疗12周。分别测定所有对象治疗前后的体重（BW）、体重指数（BMI）、空腹血糖（FPG）、餐后2 h血糖（PPG）、糖化血红蛋白（Hb A1c）、糖化白蛋白（GA）、血清总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白-胆固醇（LDL-C）、高密度脂蛋白-胆固醇（HDL-C）、血清空腹C肽（FCP）、餐后2 h C肽（PCP）等指标,并计算β细胞功能指数（HOMA-β）和胰岛素抵抗指数（HOMA-IR）。比较各组治疗前后及两组间各项指标变化情况。结果利拉鲁肽组治疗12周后BW及BMI均较治疗前下降（P〈0.01）,与门冬胰岛素30组相比差异具有统计学意义（P〈0.01）。两组治疗后FPG、PPG、Hb A1c和GA均较治疗前下降（P〈0.01）。利拉鲁肽组治疗后FCP、PCP和HOMA-IR较治疗前下降（P〈0.05）,HOMA-β上升（P〈0.01）;而门冬胰岛素30组治疗后FCP和PCP较治疗前上升（P〈0.05）,HOMA-β上升（P〈0.01）。两组治疗后HOMA-IR下降差异具有统计学意义（P〈0.05）。利拉鲁肽组治疗后TC、TG及LDL-C较治疗前下降（P〈0.05）;而门冬胰岛素30组治疗后TC和LDL-C较治疗前下降（P〈0.05）。结论利拉鲁肽或门冬胰岛素30联合二甲双胍治疗对肥胖2型糖尿病患者的血糖指标控制均有效,并均可改善其β细胞功能。但在控制体重及改善胰岛素抵抗方面,利拉鲁肽更优于门冬胰岛素30。     

利拉鲁肽的药理及临床研究进展

 利拉鲁肽是一种酰化胰高血糖素样肽-1（GLP-1）类似物,通过激活GLP-1受体,以葡萄糖依赖性刺激胰岛素分泌并抑制胰高血糖素分泌,临床用于2型糖尿病的二线治疗,可与其他口服降糖药联合使用,但不用于1型糖尿病的治疗。文中通过Medline对利拉鲁肽进行文献检索,并对其药理作用、药动学、临床研究、安全性和药物相互作用等进行综述。     

The novel use of GLP-1 analogue and insulin combination in type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global public health problem. Due to the progressive nature of the disease, a combination(s) of two or more drugs acting on different pathophysiological process is often necessary to achieve early and sustained achievement of individualized glycemic targets. At the same time, choosing the safest option to avoid hypoglycemia is of paramount importance. GLP-1 analogues are a relatively recent class of anti-diabetic drugs, and are highly effective with an acceptable safety profile. Attempts have been made to combine GLP-1 analogues with basal insulin for management of T2DM. Presently GLP-1 analogues like exenatide/long acting exenatide and liraglutide have been co-administered with basal insulin like glargine and detemir respectively, and are approved by regulatory agencies. Currently a fixed dose combination (FDC) of insulin degludec and liraglutide is under development. GLP-1 analogue and insulin as FDC or by co-administration, is a rational method of controlling fasting and postprandial glucose effectively. The efficacy and safety of this combination has been studied in a wide population with promising outcomes. Innovative use of GLP-1 analogues beyond diabetes is also being attempted, and a variety of patents are filed or granted for the same. This review summarizes the current status of GLP-1 and insulin combination in the management of T2DM and highlights the new frontiers in research involving GLP-1. Patents on combination of GLP-1 and insulin which were granted earlier, and the ones which have been applied for, are also discussed.     

Effect of titanium dioxide nanoparticles on glucose homeostasis after oral administration

As food additives, titanium dioxide nanoparticles (TiO₂ NPs) have been widely used in various products that are usually simultaneously consumed with a high content of sugar, thus necessitating research on the effect of TiO₂ NPs on glucose homeostasis. We conducted an animal study to explore the effect of orally administrated TiO₂ NPs on glucose absorption and metabolism in rats at 0, 2, 10 and 50 mg kg^–1 body weight day^–1 for 30 and 90 days. The results showed that oral exposure to TiO₂ NPs caused a slight and temporary hypoglycemic effect in rats at 30 days post‐exposure but recovered at 90 days post‐exposure. Decreased levels of intestinal glucose absorption and increased levels of hepatic glucose metabolism may be responsible for the hypoglycemic effect. Remodeling of the villi in the small intestine that decreased the surface area available for glucose absorption and increased levels of hepatic glucose uptake, utilization and storage related to hepatocellular injury are supposed to be the mechanisms. Our results demonstrated that dietary intake of TiO₂ NPs as food additives could affect the absorption and metabolism of glucose.     

利拉鲁肽对急性心肌梗死早期心脏功能的影响研究

目的 探讨利拉鲁肽对急性心肌梗死(AMI)早期心脏功能是否具有保护作用,并阐明其可能机制.方法 45只Wistar大鼠,其中37只通过结扎冠状动脉左前降支制作AMI模型,术后存活16只,随机分为AMI组8只、利拉鲁肽组(Lira组,8只),剩余8只作为假手术组(Sham组,8只),术后24 h给予Lira组利拉鲁肽10...     

The value of short- and long-acting glucagon-like peptide-1 agonists in the management of type 2 diabetes mellitus: experience with exenatide

Background:

Only about half of patients with type 2 diabetes treated with antihyperglycemic drugs achieve glycemic control (HbA1c <7%), most commonly due to poor treatment adherence. Glucagon-like peptide-1 (GLP-1) receptor agonists act on multiple targets involved in glucose homeostasis and have a low risk of causing hypoglycemia. While GLP-1 receptor (GLP-1R) agonists share the same mechanism of action, clinical profiles of individual agents differ, particularly between short- and long-acting agents. In this article, recent findings regarding the pharmacology of GLP-1 agonists are reviewed, and the clinical effects of short- versus long-acting agents are compared.

Data sources:

Relevant articles were identified through a search of PubMed using the keywords glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor agonist, GLP-1R agonist, and exenatide for publications up to 22 May 2015. Supporting data were obtained from additional searches for albiglutide, dulaglutide, liraglutide and lixisenatide as well as from the bibliographies of key articles.

Findings:

Short-acting GLP-1R agonists produce greater reductions in postprandial glucose levels by slowing gastric emptying, whereas long-acting GLP-1R agonists produce greater reductions in fasting blood glucose by stimulating insulin secretion from the pancreas. These characteristics can be exploited to provide individualized treatment to patients. A large body of evidence supports the benefits of short- and long-acting exenatide as add-on therapy in patients with inadequate glycemic control despite maximum tolerated doses of metformin and/or sulfonylurea. Exenatide is generally well tolerated and no new safety concerns were identified during long-term follow-up of up to 5 years. A limitation of this review of short-and long-acting GLP-1 receptor agonists is that it focuses on exenatide rather than all the drugs in this class. However, the focus on a single molecule helps to avoid any confusion that may be introduced as a result of differences in molecular structure and size.

Conclusions:

Short-acting GLP-1R agonists including exenatide are well suited to patients with type 2 diabetes with exaggerated postprandial glucose excursions and for co-administration with basal insulin therapy. Long-acting GLP-1R agonists including once weekly exenatide offer greater convenience and are well suited to patients who require specific control of fasting hyperglycemia.     

Efficiency of cell-penetrating peptides on the nasal and intestinal absorption of therapeutic peptides and proteins

The purpose of our study was to investigate the potential of cell-penetrating peptides; penetratin as novel delivery vector, on the systemic absorption of therapeutic peptides and proteins across different mucosal administration sites. The absorption-enhancing feasibility of l- and d-penetratin (0.5 mM) was used for glucagon-like peptide-1 (GLP-1), and exendin-4 as novel antidiabetic therapy, in addition to interferon-β (IFN-β) as protein biotherapeutic model from nasal and intestinal route of administration was evaluated as first time in rats. Nasal route is the most feasible for the delivery of therapeutic peptides coadministered with penetratin whereas the intestinal route appears to be more restricted. The absolute bioavailability (BA (%)) values depend on the physichochemical characters of drugs, stereoisomer character of penetratin, and site of administration. Penetratin significantly increased the nasal more than intestinal absorption of GLP-1 and exendin-4, as the BA for nasal and intestinal administration of GLP-1 was 15.9% and 5%, and for exendin-4 were 7.7% and 1.8%, respectively. Moreover, the BA of IFN-β coadministered with penetratin was 11.1% and 0.17% for nasal and intestinal administration, respectively. From these findings, penetratin is a promising carrier for transmucosal delivery of therapeutic peptides and macromolecules as an alternative to conventional parenteral routes.