1型糖尿病的非胰岛素辅助降糖治疗

1型糖尿病（T1DM）是一种自身免疫介导的以胰岛素分泌减少或胰岛素绝对缺乏为特征的疾病,胰岛素治疗是 其主要的治疗方式。胰岛素治疗存在着增加体重和低血糖风险的缺点。与此同时,胰岛素治疗不能延缓或阻止胰岛 功能的进行性破坏,因此T1DM患者病程中晚期多出现脆性糖尿病。文章总结了近些年有关T1DM非胰岛素辅助治 疗的最新研究进展,详细阐述了口服降糖药、注射类药物、免疫治疗等作为胰岛素的辅助治疗带来的新作用,为改善 T1DM患者生活质量带来新思路与新展望。     

Glucagon-like peptide-1 receptor agonists and microvascular outcomes in type 2 diabetes: A systematic review and meta-analysis

We conducted a systematic review and meta-analysis of randomized controlled trials to assess the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on microvascular endpoints in adult patients with type 2 diabetes. We included 60 studies with 60 077 patients. GLP-1 RAs marginally reduced urinary albumin-to-creatinine ratio compared with placebo or other antidiabetic agents (weighted mean difference − 2.55 mg/g; 95% confidence interval [CI] −4.37 to −0.73 and −5.52; −10.89 to −0.16, respectively) and had no clinically relevant effect on change in estimated glomerular filtration rate. Treatment with GLP-1 RAs did not increase incidence of diabetic retinopathy, macular oedema, retinal detachment and retinal haemorrhage, irrespective of comparator. Nevertheless, incidence of vitreous haemorrhage was higher in subjects treated with GLP-1 RAs compared with placebo (odds ratios 1.93; 95% CI 1.09 to 3.42). In conclusion, GLP-1 RAs are safe regarding nephropathy- and retinopathy-related outcomes. Caution may be warranted for incidence of vitreous haemorrhage. The low overall quality of evidence highlights the need for consistent assessment and reporting of microvascular endpoints in future trials.     

Bariatric surgery: unstressing or boosting the β-cell?

Bariatric surgery is the most effective therapy for severe obesity in terms of reduction of morbidity and mortality and quality of life improvement. Different bariatric procedures distinctly differ with regard to their effectiveness to reduce body weight and to improve morbidities, such as type 2 diabetes. In this regard, the most effective procedures are bilio-pancreatic diversion (BPD) and duodenal switch procedure curing 98.9% of the diabetes patients, followed by Roux-en-Y gastric bypass (RYGB) with 83.7% success rate, by gastroplasty with 71.6% and by gastric banding with 47.9%. Interestingly, a net improvement up to resolution of type 2 diabetes has been consistently reported few days after RYGB and BPD. RYGB promotes incretin secretion which, in turn, stimulates insulin secretion while insulin sensitivity is slightly improved. Rarely, the long-term effect of incretin hypersecretion might result in hypertrophy and hyperplasia of the islets of Langerhans, otherwise known as nesidioblastosis, associated with hyperinsulinaemia and severe postprandial hypoglycaemia. In contrast, BDP improves insulin resistance to a greater extent and results, in the long run, in supra-normal values of insulin sensitivity with subsequent reduction of insulin secretion. The mechanism allowing diabetes resolution after surgical intestinal manipulation is extremely interesting but only partially understood.     

Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control

Type 2 diabetes mellitus is a well-established risk factor for cardiovascular disease (CVD). New therapeutic approaches have been developed recently based on the incretin phenomenon, such as the degradation-resistant incretin mimetic exenatide and the glucagon-like peptide-1 (GLP-1) analogue liraglutide, as well as the dipeptidyl dipeptidase (DPP)-4 inhibitors, such as sitagliptin, vildagliptin, saxagliptin, which increase the circulating bioactive GLP-1. GLP-1 exerts its glucose-regulatory action via stimulation of insulin secretion and glucagon suppression by a glucose-dependent way, as well as by weight loss via inhibition of gastric emptying and reduction of appetite and food intake. These actions are mediated through GLP-1 receptors (GLP-1Rs), although GLP-1R-independent pathways have been reported. Except for the pancreatic islets, GLP-1Rs are also present in several other tissues including central and peripheral nervous systems, gastrointestinal tract, heart and vasculature, suggesting a pleiotropic activity of GLP-1. Indeed, accumulating data from both animal and human studies suggest a beneficial effect of GLP-1 and its metabolites on myocardium, endothelium and vasculature, as well as potential anti-inflammatory and antiatherogenic actions. Growing lines of evidence have also confirmed these actions for exenatide and to a lesser extent for liraglutide and DPP-4 inhibitors compared with placebo or standard diabetes therapies. This suggests a potential cardioprotective effect beyond glucose control and weight loss. Whether these agents actually decrease CVD outcomes remains to be confirmed by large randomized placebo-controlled trials. This review discusses the role of GLP-1 on the cardiovascular system and addresses the impact of GLP-1-based therapies on CVD outcomes.     

The cardiovascular safety trials of DPP-4 inhibitors,GLP-1 agonists,and SGLT2 inhibitors

In this paper, we review the results of large, double-blind, placebo-controlled randomized trials mandated by the US Food and Drug Administration to examine the cardiovascular safety of newly-approved antihyperglycemic agents in patients with type 2 diabetes. The cardiovascular effects of dipeptidyl peptidase-4 (DPP-4) inhibitors remain controversial: while these drugs did not reduce or increase the risk of primary, pre-specified composite cardiovascular outcomes, one DPP-4 inhibitor (saxagliptin) increased the risk of hospitalization for heart failure in the overall population; another (alogliptin) demonstrated inconsistent effects on heart failure hospitalization across subgroups of patients, and a third (sitagliptin) demonstrated no effect on heart failure. Evidence for cardiovascular benefits of glucagon-like peptide-1 (GLP-1) agonists has been similarly heterogeneous, with liraglutide and semaglutide reducing the risk of composite cardiovascular outcomes, but lixisenatide having no reduction or increase in cardiovascular risk. The effect of GLP-1 agonists on retinopathy remains a potential concern. In the only completed trial to date to assess a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin reduced the risk of composite cardiovascular endpoints, predominantly through its impact on cardiovascular mortality and heart failure hospitalization.     

Polyarthropathy in type 2 diabetes patients treated with DPP4 inhibitors

Dipeptidyl peptidase-4 inhibitors (DPP-4Is) inhibit the inactivation of incretin hormones while also affecting the immune system, since CD26/DPP-4 is involved in immune regulation. The current study shows that the use of DPP-4Is as therapy for type 2 diabetes patients may induce joint symptoms with decrease in plasma SDF-1α level.     

Sirtuins and β-cell function

Over the past century, there have been major advances in medicine, diet and living conditions that have substantially extended the health span of people in the developed world. Over the past decade or so, the science of ageing has made great strides in providing an understanding of the underlying causes of ageing and how diet and genes play into the ageing process. In this essay, we will review some of the recent advances made in the science of sirtuins and β-cell biology, and discuss how we will apply this knowledge to further the progress of humankind in healthy ageing.     

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.     

胰升糖素样肽-1对高游离脂肪酸诱导的胰岛β细胞凋亡作用的研究

目的探讨胰升糖素样肽（GLP-1）对高浓度游离脂肪酸（FFA）诱导的胰岛细胞凋亡的保护作用。方法细胞采用小鼠胰岛素瘤细胞株betaNIT-1,试验分为4组：（1）对照组;（2）GLP-1组;（3）FFA组;（4）FFA＋GLP-1组。干预24小时以后,TUNEL法和Annexin-V/PI双标流式测定法测定各组细胞凋亡率,W estern b lot测定凋亡相关蛋白Bc l-2及Caspase-3的蛋白量。结果（1）1mM FFA可以诱导出明显的细胞凋亡（与对照组比较,P〈0.05）;（2）Annexin-v/PI流式测定及TUNEL法测定均表明GLP-1能抑制FFA诱导的细胞凋亡（FFA组与FFA＋GLP-1组比较,P〈0.05）;（3）W erstern b lot测定显示,FFA能使Bc l-2表达下降（FFA组与对照组比较,P〈0.05）,GLP-1能抑制这种改变（FFA＋GLP-1组与FFA组比较,P〈0.05;与对照组比较,P〉0.05）;Caspase-3在FFA组与对照组间无明显差异,但在GLP-1＋FFA组中,尽管与FFA组比较P〉0.05,但有下降趋势。结论GLP-1能够抑制高浓度游离脂肪酸诱导的NIT-1细胞凋亡,并且可能是通过改变凋亡蛋白的表达来实现这一功能的。     

β-cell hyperexcitability: from hyperinsulinism to diabetes

Nutrient oxidation in β cells generates a rise in [ATP]:[ADP] ratio. This reduces K_ATP channel activity, leading to depolarization, activation of voltage-dependent Ca²⁺ channels, Ca²⁺ entry and insulin secretion. Consistent with this paradigm, loss-of-function mutations in the genes ( KCNJ11 and ABCC8 ) that encode the two subunits (Kir6.2 and SUR1, respectively) of the ATP-sensitive K⁺ (K_ATP) channel underlie hyperinsulinism in humans, a genetic disorder characterized by dysregulated insulin secretion. In mice with genetic suppression of K_ATP channel subunit expression, partial loss of K_ATP channel conductance also causes hypersecretion, but unexpectedly, complete loss results in an undersecreting, mildly glucose-intolerant phenotype. When challenged by a high-fat diet, normal mice and mice with reduced K_ATP channel density respond with hypersecretion, but mice with more significant or complete loss of K_ATP channels cross over, or progress further, to an undersecreting, diabetic phenotype. It is our contention that in mice, and perhaps in humans, there is an inverse U-shaped response to hyperexcitabilty, leading first to hypersecretion but with further exacerbation to undersecretion and diabetes. The causes of the overcompensation and diabetic susceptibility are poorly understood but may have broader implications for the progression of hyperinsulinism and type 2 diabetes in humans.     

Additive hypoglycaemic effect of nateglinide and exogenous glucagon-like peptide-1 in type 2 diabetes

We examined the postprandial glucose regulators nateglinide and GLP-1, separately and in combination, in people with type 2 diabetes. Nateglinide inhibited DPP-4 activity, reduced GLP-1 degradation and enhanced its insulinotropic and blood glucose lowering effect. Combining nateglinide and GLP-1 derivatives may effectively control postprandial glycaemia.     

Atrial fibrillation and type 2 diabetes: Prevalence,etiology, pathophysiology and effect of anti-diabetic therapies

New-onset atrial fibrillation (NAF) is increased in the type 2 diabetic patient because of the presence of the metaboli syndrome and increased sympathetic activity. This results in inflammation, endothelial dysfunction and myocardial steatosis which, in turn, lead to atrial fibrosis and dilatation. The end result is the development of structural and electrical atrial remodeling. Drugs that lower insulin resistance, particularly pioglitazone, decrease the incidence of NAF while drugs that, through hypoglycaemia, stimulate the sympathetic nervous system, insulin and secretagogues, increase the incidence of NAF. Currently there is no evidence that GLP-1 agonists, SGLT2 inhibitors and DPP-4 inhibitors either accelerate or decelerate the development of NAF.     

Genetic and biochemical pathways of β-cell failure in type 2 diabetes

We review mechanisms of β-cell failure in type 2 diabetes. A wealth of information indicates that it is caused by impaired insulin secretion and decreased β-cell mass. Interestingly, there appears to be a link between these two mechanisms. The earliest reaction to peripheral insulin resistance is an increase in insulin production, owing primarily to increased secretion, and to a lesser extent to decreased clearance. Experimental animal models indicate that hyperinsulinaemia promotes an increase in β-cell mass, largely via increased β-cell replication. In contrast, following the onset of overt diabetes, there is a slowly progressive loss of β-cell function and mass, both in animal models and in diabetic humans. It is of great interest that most diabetes-associated genes identified in genome-wide association studies appear to be enriched in the β-cell and to have the potential to regulate mass and/or function. Here, we review evidence derived from experimental animal models to unravel the mechanisms underlying β-cell dysfunction. We focus primarily on signalling pathways, as opposed to nutrient sensing, and specifically on the notion that insulin and growth factor signalling via Foxo1 in pancreatic β-cells links insulin secretion with cellular proliferation and survival.     

Gender difference in cardiovascular outcomes with SGLT-2 inhibitors and GLP-1 receptor agonist in type 2 diabetes: A systematic review and meta-analysis of cardio-vascular outcome trials

Background and aimsType 2 diabetes confers a differential risk of cardiovascular (CV) disease according to the gender. Whether newly approved anti-diabetic drugs like sodium-glucose co-transport-2 inhibitors (SGLT-2Is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) that have shown a significant reduction in the CV end-points in CV outcome trials (CVOTs) also have a differential impact gender-wise, is still not clearly known.MethodsWe systematically searched the medical database up to December 31, 2019 and retrieved all the dedicated CVOTs conducted with SGLT-2Is and GLP-1RAs that explicitly reported the outcome of major adverse cardiac events (MACE). Subsequently, we pooled the hazard ratio (HR) of MACE in both sexes separately and meta-analyzed the result gender-wise.ResultsThe meta-analysis of three CVOTs conducted with SGLT-2Is (N = 34,322), demonstrated a significant reduction in MACE in men but not in women (Men - HR, 0.90; 95% CI, 0.83 to 0.97; P = 0.006; Women - HR, 0.88; 95% CI, 0.77 to 1.00; P = 0.06) compared to placebo. The meta-analysis of seven CVOTs conducted with GLP-1RAs (N = 56,004) demonstrated a significant reduction in MACE in both sex (Men - HR, 0.88; 95% CI, 0.82 to 0.93; P < 0.0001; Women - HR, 0.88; 95% CI, 0.79 to 0.99; P = 0.03), against the placebo.ConclusionsThe reduction in MACE with SGLT-2Is appears to be significantly less in women with diabetes vs men, while GLP-1RAs confers a similar reduction in MACE, irrespective of the gender. Whether these results are related to inadequate statistical power (underrepresentation of women) in CVOT, or it reflects a true gender difference, still remains to be established.