GLP-1及其类似物对2型糖尿病β细胞功能及量的影响

胰岛β细胞功能障碍是2型糖尿病的重要发病机制之一,而β细胞量减少是β细胞功能障碍的物质基础,这两个因素在2型糖尿病治疗领域越来越受到重视.目前的研究发现,胰高血糖素样肽(GLP-1)及其长效类似物利拉鲁肽在改善β细胞功能障碍、逆转β细胞量的减少方面有显著的效应.     

2型糖尿病治疗的现状与挑战——肠促胰岛素治疗的前景

传统的2型糖尿病治疗措施不能有效地控制和维持血糖稳定,此点已被β细胞功能随时间进行性下降和相应的血糖水平升高所证实.诊断为2型糖尿病时β细胞功能一般丧失了50%,所以迫切需要早诊断和早治疗,以避免β细胞功能下降过快.本文阐述了β细胞在正常糖代谢和2型糖尿病中的作用,总结了目前2型糖尿病的治疗,展望了肠促胰岛素特别是胰高血糖素样肽(GLP)-1类似物的治疗应用前景.GLP-1类似物可带来血糖控制以外的益处,有利于降低体重,并且通过对β细胞的保护可能改变糖尿病的自然进程.     

人骨髓间充质干细胞体外诱导分化为胰岛素分泌细胞的实验研究

目的探讨联合应用高糖和胰升血糖素样肽-I（GLP-1）、活化素A、尼克酰胺和B细胞调节素（BTC）刺激体外能否诱导人骨髓间充质干细胞向胰岛样细胞分化。方法分别用放射免疫法、RT-PCR和免疫细胞化学方法检测胰岛素浓度、胰岛素mRNA表达以及相关蛋白的表达。结果（1）刺激后各组可分泌胰岛素量增加。（2）RT-PCR发现GLP-1组、活化素A组、尼克酰胺组、共同刺激组和BTC组等均可产生约300bp的目的片段,即胰岛素原基因的mRNA表达。（3）免疫细胞化学证实除了对照组外,各刺激组均有胰岛素表达;各刺激组均未表达胰升血糖素;除协同作用组有生长抑素的弱阳性表达外,其他各刺激组均未表达生长抑素;尼克酰胺组和协同作用组可见到巢蛋白的弱阳性表达。（4）高糖刺激胰岛素释放实验结果显示,经联合高糖和GLP-1、活化素A、BTC、尼克酰胺和共同刺激诱导分化后,骨髓间充质干细胞（BM—SCs）对高葡萄糖刺激有反应,能相应增加胰岛素的分泌量。结论联合高糖、GLP-1、活化素A、尼克酰胺和BTC等因子可以在体外诱导人BMSCs分化为胰岛素分泌细胞,但胰岛素分泌水平较低。     

2型糖尿病治疗新策略:基于肠促胰素的治疗

基于肠促胰素特别是胰高血糖素样肽(GLP)-1类似物的治疗方法,针对2型糖尿病的多个病理生理靶点,单药治疗和联合用药均显示出良好的疗效,并且能够避免低血精、体重增加等不良反应,有望成为2型糖尿病治疗的新选择.     

Glucagon-like peptide-1 in type 2 diabetes: the β-cell and beyond

Many traditional treatments for type 2 diabetes fail to achieve and maintain effective glycaemic control, witnessed by a progressive decline in β-cell functionality and a corresponding rise in blood glucose levels over time. The routine loss of 50% of β-cell function at diagnosis lends new urgency that both diagnosis and treatment initiation take place as early as possible in the course of the disease, before β-cell decline proceeds too far. This review describes the role of the β-cell and glucagon-like peptide-1 (GLP-1) in both normal metabolism and type 2 diabetes, highlights available and anticipated therapies and explores the prospect that certain incretin-derived therapies, which seek to harness the therapeutic potential of native GLP-1, may offer more than glycaemic control alone: they may also facilitate weight loss, improve the cardiovascular profile and, ideally, treat the β-cell in such a way as to modify the natural history of the disease itself.     

Efficacy and safety of high-dose glucagon-like peptide-1, glucagon-like peptide-1/glucose-dependent insulinotropic peptide,and glucagon-like peptide-1/glucagon receptor agonists in type 2 diabetes

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become agents of choice for people with type 2 diabetes (T2D) with established cardiovascular disease or in high-risk individuals. With currently available GLP-1 RAs, 51%-79% of subjects achieve an HbA1c target of less than 7.0% and 4%-27% lose 10% of body weight, illustrating the need for more potent agents. Three databases (PubMed, Cochrane, Web of Science) were searched using the MESH terms ‘glucagon-like peptide-1 receptor agonist’, ‘glucagon receptor agonist’, ‘glucose-dependent insulinotropic peptide’, ‘dual or co-agonist’, and ‘tirzepatide’. Quality of papers was scored using PRISMA guidelines. Risk of bias was evaluated using the Cochrane assessment tool. An HbA1c target of less than 7.0% was attained by up to 80% with high-dose GLP-1 RAs and up to 97% with tirzepatide, with even up to 62% of people with T2D reaching an HbA1c of less than 5.7%. A body weight loss of 10% or greater was obtained by up to 50% and up to 69% with high-dose GLP-1 RAs or tirzepatide, respectively. The glucose- and weight-lowering effects of the GLP-1/glucagon RA cotadutide equal those of liraglutide 1.8 mg. Gastrointestinal side effects of high-dose GLP-1 RAs and co-agonists occurred in 30%-70% of patients, mostly arising within the first 2 weeks of the first dose, being mild or moderate in severity, and transient. The development of high-dose GLP-1 RAs and the dual GLP-1/glucose-dependent insulinotropic peptide RA tirzepatide resulted in increasing numbers of people reaching HbA1c and body weight targets, with up to 62% attaining normoglycaemia with 15-mg tirzepatide. Whether this will also translate to better cardiovascular outcomes and affect treatment guidelines remains to be studied.     

Function of a long-term, GLP-1-treated, insulin-secreting cell line is improved by preventing DPP IV-mediated degradation of GLP-1

Glucagon-like peptide-1 (GLP-1) is an important insulinotropic hormone with potential in the treatment of type 2 diabetes. However, the short biological half-life of the peptide after cleavage by dipeptidylpeptidase IV (DPP IV) is a major limitation. Inhibition of DPP IV activity and the development of resistant GLP-1 analogues is the subject of ongoing research. In this study, we determined cell growth, insulin content, insulin accumulation and insulin secretory function of a insulin-secreting cell line cultured for 3 days with either GLP-1, GLP-1 plus the DPP IV inhibitor diprotin A (DPA) or stable N-acetyl-GLP-1. Native GLP-1 was rapidly degraded by DPP IV during culture with accumulation of the inactive metabolite GLP-1(9-36)amide. Inclusion of DPA or use of the DPP IV-resistant analogue, N-acetyl-GLP-1, improved cellular function compared to exposure to GLP-1 alone. Most notably, basal and accumulated insulin secretion was enhanced, and glucose responsiveness was improved. However, prolonged GLP-1 treatment resulted in GLP-1 receptor desensitization regardless of DPP IV status. The results indicate that prevention of DPP IV action is necessary for beneficial effects of GLP-1 on pancreatic beta cells and that prolonged exposure to GLP-1(9-36)amide may be detrimental to insulin secretory function. These observations also support the ongoing development of DPP-IV-resistant forms of GLP-1, such as N-acetyl-GLP-1.     

GLP-1受体激动剂对糖尿病患者肾功能的影响

作为一种新型的降糖药物,胰高血糖素样肽(GLP)-1受体激动剂可有效降低血糖、减轻体重.此外,该药可能还具有改善糖尿病患者肾功能,调节水、盐排泄、降低血压等作用.并且,这一保护作用可能是通过其抗炎、抗氧化应激、改善内皮细胞功能实现的.但是,该药物不适用于严重肾脏病变的患者,因此,它是否可以用于预防和治疗糖尿病肾病,目前尚无定论.     

GLP-1对胰岛β细胞保护作用的研究进展

胰升糖素样肽-1（GLP-1）是一种肠促胰岛素，它通过复杂的机制降低餐后血糖。β细胞凋亡在胰腺的正常生理、糖尿病的发病机理及胰岛移植存活方面都起着重要的作用。新近的研究发现GLP-1不但能刺激β细胞增殖和分化，而且还可抑制凋亡从而起到保护β细胞的作用。GLP-1受体激动剂或类似物及二肽基肽酶Ⅳ抑制剂在治疗糖尿病和改善胰岛移植方面均有良好的应用前景。研究GLP-1对胰岛β细胞的保护作用及其机制，为开发用于治疗糖尿病及胰岛移植的新药提供了理论依据。     

New Injectable Agents for the Treatment of Type 2 Diabetes Part 2—Glucagon-Like Peptide-1 (GLP-1) Agonists

The US Food and Drug Administration has recently approved several new glucagon-like peptide-1 (GLP-1) agonists alone and in combination with various insulin products. The second of 2 articles in a series, this review will describe the potential advantages and disadvantages of the GLP-1 agonist class of products.     

2型糖尿病治疗的现状与挑战—肠促胰岛素治疗的前景

传统的2型糖尿病治疗措施不能有效地控制和维持血糖稳定,此点已被β细胞功能随时间进行性下降和相应的血糖水平升高所证实。诊断为2型糖尿病时β细胞功能一般丧失了50％,所以迫切需要早诊断和早治疗,以避免β细胞功能下降过快。本文阐述了β细胞在正常糖代谢和2型糖尿病中的作用,总结了目前2型糖尿病的治疗,展望了肠促胰岛素特别是胰高血糖素样肽（GLP）-1类似物的治疗应用前景。GLP-1类似物可带来血糖控制以外的益处,有利于降低体重,并且通过对β细胞的保护可能改变糖尿病的自然进程。     

Body weight and eGFR during dulaglutide treatment in type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7)

In patients with type 2 dibetes and moderate-to-severe chronic kidney disease, dulaglutide treatment led to body weight (BW) loss and lesser eGFR decline compared to insulin glargine. As BW may affect muscle mass, creatinine-based eGFR can be altered independently of kidney function. Cystatin C-based eGFR is not affected by muscle mass. The objective of this post-hoc analysis was to determine whether the lesser eGFR decline with dulaglutide was related to BW loss. Baseline characteristics were similar between treatments ([mean ± SD] age, 64.6 ± 8.6 years; women, 48%; BW, 89.1 ± 17.7 kg; eGFR [CKD-EPI-cystatin C] 38 ± 14 mL/min/1.73m²). BW decreased with dulaglutide 1.5 and 0.75 mg and increased with insulin glargine ([LSM change (SE)], −2.66 [0.47] kg and −1.71 [0.45] vs 1.57 [0.43] kg; P < 0.001). Changes in eGFR were not significant with dulaglutide 1.5 and 0.75 mg, but eGFR significantly decreased with insulin glargine (eGFR-CKD-EPI-cystatin C [LSM change (95%CI)], −0.7 [−2.5, 1.0] and −0.7 [−2.4, 1.1] vs −3.3 [−5.1, −1.6] mL/min/1.73 m²; P ≤ 0.037 vs glargine). Changes in BW did not correlate with changes in eGFR-CKD-EPI-cystatin C (r = −0.041; n = 471; P = 0.379) or eGFR-CKD-EPI-creatinine (r = −0.074; n = 473; P = 0.106). In conclusion, the lesser decline in eGFR observed with dulaglutide was not influenced by BW loss.     

Cardiovascular effects of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: The P value and beyond

Despite growing awareness of the dangers of a dichotomous interpretation of trial results based on the ‘statistical significance’ of a treatment effect, the uptake of new approaches has been slow in diabetes medicine. We showcase a number of ways to interpret the evidence for a treatment effect applied to the cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT-2is): the P value function (or confidence curves), which depicts the treatment effect across the whole spectrum of confidence levels; the counternull value, which is the hazard ratio (i.e. treatment effect size) supported by the same amount of evidence as the null value (i.e. no treatment effect); and the S value, which quantifies the strength of the evidence against the null hypothesis in terms of the number of coin tosses yielding the same side. We show how this approach identifies potential treatment effects, highlights similarities among trials straddling the threshold of statistical significance, and quantifies differences in the strength of the evidence from trials reporting statistically significant results. For example, while REWIND, CANVAS and CREDENCE failed to reach statistical significance at the .05 level for all-cause mortality, their counternull values indicate that reduced death rates by 19%, 24% and 31%, respectively, are supported by the same amount of evidence as that indicating no treatment effect. Moreover, similarities among results emerge in trials of GLP-1RAs (REWIND, EXSCEL and LEADER) lying closely around the threshold of ‘statistical significance’. Lastly, several S values, such as for the primary outcome in HARMONY Outcomes (S value 10.9) and all-cause death in EMPAREG-OUTCOME (S value 15.0), stand out compared with values for other outcomes and other trials, suggesting much larger differences in the evidence between these studies and several others that cluster around the .05 significance threshold. P value functions, counternull values and S values should complement the standard reporting of the treatment effect to help interpret clinical trials and make decisions among competing glucose-lowering medications.     

The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to “isoglycaemic” intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and—in the long run—body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH₂) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs.     

Addition of glucagon-like peptide-1 receptor agonist therapy to insulin in C-peptide-positive patients with type 1 diabetes

We aimed to test the hypothesis that addition of glucagon-like peptide-1 receptor agonists (GLP-1RAs) to insulin in C-peptide-positive patients with type 1 diabetes (T1D) will result in a reduction in glycated haemoglobin (HbA1c) with reduced insulin requirements and a rise in C-peptide concentrations. We conducted a retrospective analysis of 11 normal-weight patients with T1D consecutively treated with a GLP-1RA in addition to insulin. Paired t tests were used to compare the changes in HbA1c, insulin doses, body weight, body mass index, and C-peptide concentrations prior to and 12 ± 1 weeks after GLP-1RA therapy. At the end of 12 ± 1 weeks of GLP-1RA therapy, HbA1c fell from 10.74 ± 0.96% (95 ± 10.5 mmol/mol) to 7.4 ± 0.58% (58 ± 6.3mmol/mol) (P < 0.01), body weight fell from 71 ± 2.0 to 69 ± 2 kg (P = 0.06), and total insulin dose was reduced by 64% from 33 ± 6 to 11 ± 5 units (P < 0.01). Five out of 10 patients did not require any insulin. C-peptide concentrations increased significantly from 0.43 ± 0.09 ng/ml (0.14 ± 0.02 nmol/L) to 1.42 ± 0.42ng/ml (0.47 ± 0.13 nmol/L) (P = 0.01). Addition of GLP-1RA therapy to insulin in normal-weight patients with T1D led to a reduction in HbA1c with reduced insulin requirements, a 3.5-fold increase in C-peptide concentrations and freedom from insulin therapy in 50% of patients who tolerated the GLP-1RA therapy over a period of 12 ± 1 weeks.