Dipeptidyl Peptidase-4 Inhibitors,Peripheral Arterial Disease,and Lower Extremity Amputation Risk in Diabetic Patients

Background

Recent studies have elucidated the vascular protective effects of dipeptidyl peptidase-4 (DPP-4) inhibitors. However, to date, no large-scale studies have been carried out to determine the impact of DPP-4 inhibitors on the occurrence of peripheral arterial disease, and lower extremity amputation risk in patients with type 2 diabetes mellitus.

Dipeptidyl peptidase-4 inhibitor use and risk of diabetic retinopathy: A population-based study

Aims

This study examined whether dipeptidyl peptidase (DPP)-4 inhibitor use is beneficial or harmful to diabetic retinopathy (DR) compared with other glucose-lowering agents in patients with type 2 diabetes (T2D).

DPP-4抑制剂的抗炎作用及其在糖尿病治疗中的应用

二肽基肽酶-4（DPP-4）抑制剂作为一类新型口服降糖药物,其在2型糖尿病治疗中独特的降糖效果及良好的安全性已在大量研究中得到证实.随着糖尿病研究的深入,“炎性反应”在糖尿病发生、发展中的作用已得到广泛关注.研究发现,DPP-4抑制剂可通过抑制免疫细胞的活化,调节Toll样受体4（TLR4）及cAMP/蛋白激酶A（PKA）等信号通路达到抗炎效果.尽管目前其抗炎机制尚未明确,但已成为改善糖尿病慢性炎性反应状态新的研究热点,并为糖尿病及其并发症的防治提供了新的希望.     

2型糖尿病胰岛功能障碍与基于肠促胰素的治疗

多项研究显示,胰岛细胞功能障碍(α细胞及β细胞)对2型糖尿病的发生发展起决定性作用.β细胞功能障碍主要表现为胰岛素分泌的缺陷,α细胞功能障碍则主要是进餐后胰升糖素的分泌未得到有效抑制.因此,胰岛功能障碍是2型糖尿病治疗的重要靶点.研究显示,基于肠促胰素的药物,包括胰升糖素样肽1( GLP-1)受体激动剂及二肽基肽酶4(DPP-4)抑制剂能恢复胰岛细胞对葡萄糖的敏感性,有效改善血糖控制.期待此类药物对胰岛功能改善的更多研究.     

Challenges in achieving optimal glycemic control in type 2 diabetes patients with declining renal function: The Southeast Asia perspective

It is well recognised that Asia is at the epicenter of the global type 2 diabetes epidemic. Driven by socioeconomic changes involving industrialization, urbanization and adoption of Western lifestyles, the unprecedented increases in the prevalence of diabetes are particularly evident in Southeast Asia. The impact of diabetes is immense, and despite evidence of the benefit of optimal glucose control in reducing the risk of disease progression and development of macrovascular and microvascular complications, many individuals in this region remain poorly controlled. Chronic kidney disease (CKD) is an increasingly common diabetes‐associated complication in Asian patients. Furthermore, Southeast Asia has one of the highest rates of end‐stage renal disease (ESRD) in the world. Consequently, CKD in diabetes is associated with considerable morbidity and cardiovascular‐related mortality, highlighting the need to screen and assess patients early in the course of the disease. The management of type 2 diabetes patients with declining renal function represents a significant challenge. Many of the older antidiabetic agents, such as metformin and sulfonylureas, are limited in their utility in CKD as a result of contraindications or hypoglycemic episodes. In contrast, dipeptidyl‐peptidase IV inhibitors have provided a welcome addition to the therapeutic armamentarium for achieving glycemic control in these special populations. With comparable efficacy to and more favorable pharmacokinetic and side‐effect profiles than traditional therapies, agents in this drug class, such as linagliptin, offer a more tailored approach to disease control in type 2 diabetes patients with declining renal function.     

DPP-4抑制剂在2型糖尿病治疗中的应用

胰升糖素样肽1(GLP-1)可通过多个途径参与机体血糖稳态调节、改善胰岛功能、延缓甚至逆转2型糖尿病病程的进展.但内源性GLP-1在分泌释放入血后快速被二肽基肽酶4(DPP-4)裂解而失去活性.DPP-4抑制剂可选择性抑制DPP-4的酶活性,阻止GLP-1裂解失活,提高活性GLP-1的血浆水平,增强其生理作用,降低2型糖尿病患者的HbA1.、空腹血糖和餐后血糖水平.DPP-4抑制剂作为一类新型口服降糖药物,在2型糖尿病治疗中对血糖控制的有效性、良好的安全性和耐受性已经在大量的临床试验和实际应用中得到了证实.

Abstract：

Glucagon-like peptide-1 (GLP-1) can maintain glucose homeostasis, improve islet function,delay and even reverse deterioration of type 2 diabetes by several pathways.But shortly after secreting and releasing into the blood, endogenous intact GLP-1 is cleavaged by dipeptidyl peptidase-4 (DPP-4) into inactive forms.DPP4 inhibitors prevent the inactivation and enhance the physiological effects of GLP-1 through selectively suppressing the enzymic activity of DPP-4, resulting in reduction of HbA1C, fasting and postprandial plasma glucose in type 2diabetes mellitus.The favorable efficacy, safety, and tolerability of DPP-4 inhibitors, which have been well verified in numerous clinical trials and clinical practice for type 2 diabetes mellitus, render them a novel type of oral antidiabetic drugs.     

Different role of zinc transporter 8 between type 1 diabetes mellitus and type 2 diabetes mellitus

Diabetes can be simply classified into type 1 diabetes mellitus and type 2 diabetes mellitus. Zinc transporter 8 (ZnT8), a novel islet autoantigen, is specifically expressed in insulin‐containing secretory granules of β‐cells. Genetic studies show that the genotypes of SLC30A8 can determine either protective or diabetogenic response depending on environmental and lifestyle factors. The ZnT8 protein expression, as well as zinc content in β‐cells, was decreased in diabetic mice. Thus, ZnT8 might participate in insulin biosynthesis and release, and subsequently involved deteriorated β‐cell function through direct or indirect mechanisms in type 1 diabetes mellitus and type 2 diabetes mellitus. From a clinical feature standpoint, the prevalence of ZnT8A is gradiently increased in type 2 diabetes mellitus, latent autoimmune diabetes in adults and type 1 diabetes mellitus. The frequency and epitopes of ZnT8‐specific T cells and cytokine release by ZnT8‐specific T cells are also different in diabetic patients and healthy controls. Additionally, the response to ZnT8 administration is also different in type 1 diabetes mellitus and type 2 diabetes mellitus. In the present review, we summarize the literature about clinical aspects of ZnT8 in the pathogenesis of diabetes, and suggest that ZnT8 might play a different role between type 1 diabetes mellitus and type 2 diabetes mellitus.     

Efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus

Aim

To confirm the efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus inadequately controlled with pioglitazone monotherapy.

Materials and Methods

In an initial 12‐week, double‐blind, placebo controlled, parallel‐group study, patients (n = 204) were randomized to teneligliptin 20 mg or placebo once daily added to their stable pioglitazone therapy. This was followed by a 40‐week, open‐label period during which all patients received teneligliptin once daily. The primary end‐point was the change in hemoglobin A1c (HbA_1c) from baseline to week 12.

Results

Patients in the teneligliptin group showed significantly greater reductions in HbA_1c compared with the placebo group at week 12 (P < 0.001). The changes in HbA_1c from baseline to week 12 were −0.9 ± 0.0% (least‐squares mean ± standard error) in the teneligliptin group and −0.2 ± 0.0% in the placebo group. The change in fasting plasma glucose from baseline to week 12 was greater in the teneligliptin group than in the placebo group (P < 0.001). The blood glucose lowering effects of teneligliptin were sustained throughout the 40‐week open‐label period. Adverse events and adverse drug reactions occurred slightly more frequently in the teneligliptin group than in the placebo group, although the incidence of hypoglycemia was low. Bodyweight was unchanged in the double‐blind period, but was slightly increased in the open‐label period.

Conclusions

Add‐on therapy with teneligliptin was effective and generally well tolerated throughout the study period in Japanese patients with type 2 diabetes mellitus inadequately controlled with pioglitazone monotherapy. This trial was registered with ClinicalTrials.gov (no. NCT01026194).     

二肽基肽酶-4抑制剂对2型糖尿病心血管系统的影响

2型糖尿病(T2DM)与包括冠心病、慢性心力衰竭在内的心血管疾病危险增加有关.某些传统降糖药物可引起心血管疾病的不良后果.新型降糖药物二肽基肽酶-4(DPP-4)抑制剂对T2DM总体心血管事件、心肌梗死面积、心功能的影响仍存在争议.但近期大量临床及动物实验发现,DPP-4抑制剂具有降糖作用以外的抗炎、抗氧化应激、保护内皮等多重心血管益处.同时对高血脂、高血压等心血管危险因素表现出有益作用.短期临床观察未显示出DPP-4抑制剂对心血管系统的不良影响.     

DPP-4抑制剂的作用机制及在2型糖尿病治疗中的应用

α及母细胞功能障碍在2型糖尿病的发生中发挥重要作用.二肽基肽酶4( DPP-4)抑制剂是一类基于肠促胰素的新型的口服降糖药物,通过增加内源性活性胰升糖素样肽-1( GLP-1)及葡萄糖依赖性促胰岛素分泌多肽(GIP)水平改善α及β细胞功能障碍,表现为α及β细胞对葡萄糖的敏感性增加,葡萄糖依赖性地促进胰岛素分泌并抑制胰升糖素分泌.同时还具有增加胰岛素敏感性及调节血脂代谢等胰腺外作用.并具有较少发生低血糖,对体重的影响中性,不影响胃排空等特点.临床研究证实其无论单药还是与其他药物联合使用均具有较高的有效性及良好的安全性和耐受性.     

维格列汀在2型糖尿病治疗中的应用

维格列汀是一种强效的特异性二肽基肽酶4抑制剂,通过抑制二肽基肽酶4对胰升糖素样肽l和葡萄糖依赖性促胰岛素分泌多肽的降解作用发挥效应.维格列汀为口服制剂,已经被批准治疗2型糖尿病.单药使用维格列汀或联合其他药物可以有效降低患者HbA1C水平.此外由于维格列汀降糖作用是血糖依赖性的所以低血糖发生率低,其不良反应如胃肠道反应和水肿发生率低,因此绝大多数患者对该药耐受良好.所以,维格列汀是2型糖尿病患者新的选择,良好的血糖控制可让患者减少远期并发症.     

DPP-4抑制剂对糖尿病肾病的保护作用

高血糖是糖尿病肾病发病的重要原因之一.二肽基肽酶-4（DPP-4）抑制剂可减少胰高血糖素样肽-1（GLP-1）降解,改善机体高血糖状态,从而延缓糖尿病肾病病程的进展.此外,DPP-4抑制剂还可影响其他与糖尿病肾病相关的非GLP-1底物,如基质细胞衍生因子-1α、脑钠尿肽及金属内肽酶的表达,继而发挥GLP-1非依赖性的肾脏保护作用.研究DPP-4抑制剂对糖尿病患者肾脏的保护作用及其机制,将为其在糖尿病肾病治疗中的应用提供新的认识.     

Wound healing effects of dipeptidyl peptidase-4 inhibitors: An emerging concept in management of diabetic foot ulcer—A review

ObjectiveDipeptidyl peptidase-4 (DPP-4) inhibitors have a well-known effect on glycaemic control in patients with diabetes but little is known on their wound healing role in this group of population. This paper reviews the effects of DPP-4 inhibitors on wound healing of diabetic foot ulcers.MethodsPublished data on effects and mechanism of DDP-4 inhibitors on wound healing were derived from Medline, PubMed and Google Scholar search of English language literature from 1994 to 2014 using the key words such as “DPP-4 inhibitors”, “endothelial healing” “diabetes” and “chronic ulcers”.ResultsDPP-4 inhibitors show a potential benefit in processes of wound healing in diabetic chronic foot ulcers. The enzyme inhibitors promote recruitment of endothelial progenitor cells and allow the final scaffolding of wounds. Furthermore DPP-4 inhibitors augment angiogenesis and have widespread effects on optimising the immune response to persistent hypoxia in chronic diabetes wounds.ConclusionDPP-4 inhibitors show promise in the local wound healing of diabetic foot ulcers in addition to its already established glycaemic control. In the light of high rate of amputations due to non-healing ulcers with profound psychological and economical liability, more investigations on the usefulness of DPP-4 inhibitors in the high risk diabetes population are needed.