Changes in markers of hepatic steatosis and fibrosis in patients with type 2 diabetes during treatment with glucagon-like peptide-1 receptor agonists. A multicenter retrospective longitudinal study

AimsMetabolic dysfunction-associated fatty liver disease (MAFLD) is common in people with type 2 diabetes (T2D) and can progress to advanced fibrosis and cirrhosis. In this retrospective study, we explored the longitudinal changes in markers of hepatic steatosis and fibrosis during T2D treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs).MethodsWe analysed observational data from six diabetes outpatient clinics. In the whole T2D population, we calculated the hepatic steatosis index (HSI), which we previously validated against liver ultrasonography, and the Fibrosis (Fib)-4 index. We then identified patients who initiated a GLP-1RA from 2010 to 2018 and for whom data were available to evaluate changes in both HSI and Fib-4 scores over 24 months.ResultsFrom 83,116 outpatients with T2D, 41,302 (49.7%) had complete data for calculating HSI and Fib-4. Most of these T2D patients (∼70%) had MAFLD (defined as HSI>36), 9.7% of whom had advanced fibrosis based on Fib-4 thresholds. Patients with low compared to high risk of advanced fibrosis were 5-times more likely to be treated with GLP-1RA. In 535 patients who initiated a GLP-1RA, the prevalence of MAFLD based on HSI declined significantly at 6 and 24 months, but Fib-4 categories did not. HSI improved significantly only in patients receiving human-based but not exendin-based GLP-1RA, while patients concomitantly receiving metformin had less worsening in Fib-4 categories.ConclusionsMAFLD is very common among outpatients with T2D (∼70%) and the estimated prevalence of advanced fibrosis was ∼10%. Treatment with GLP-1RAs significantly improved MAFLD, but not MAFLD-associated advanced fibrosis.     

Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

Aims/hypothesis The incretin hormone glucagon-like peptide 1 (GLP-1) has antihyperglycaemic effects, but its therapeutic usefulness is limited by its metabolic instability. Dipeptidyl peptidase IV (DPP-IV) is established as the primary inactivating enzyme, but the roles of other enzymes remain unclear.Methods The effect of candoxatril, a selective inhibitor of neutral endopeptidase (NEP) 24.11, on GLP-1 pharmacokinetics/pharmacodynamics with or without DPP-IV inhibition was examined in anaesthetised pigs.Results During GLP-1 infusion, candoxatril doubled C-terminal immunoreactivity, improving the pharmacokinetics (t_&frac; 2.3±0.1 to 8.8±1.2 min; metabolic clearance rate [MCR] 20.4±3.4 to 4.8±0.4 ml·kg^–1· min^–1; p<0.01), but had no effect upon intact GLP-1 (t_&frac; 1.4±0.1 to 1.6±0.1 min; MCR 47.9±8.0 to 38.8±5.0 ml·kg^–1·min^–1). Insulin responses to intravenous glucose were unaffected by candoxatril, but glucose tolerance was improved (AUC_{min 27–87} 118±5 to 74±14 min·mmol·l^–1; glucose elimination rate [k] 6.6±0.5 to 8.6±0.5%; p<0.05). When candoxatril was co-administered with valine pyrrolidide (a DPP-IV inhibitor), changes in C-terminal GLP-1 pharmacokinetics mirrored those seen when candoxatril alone was administered (t_&frac; 2.7±0.3 and 7.7±0.8 min; MCR 17.3±2.6 and 6.5±0.8 ml·kg^–1·min^–1 for valine pyrrolidide without and with candoxatril, respectively). However, intact GLP-1 pharmacokinetics were improved (t_&frac; 2.8±0.3 and 7.5±0.6 min; MCR 18.3±0.6 and 9.4±0.9 ml·kg^–1·min^–1; p<0.02), potentiating the antihyperglycaemic/insulinotropic effects of GLP-1 (glucose AUC_{min 27– 87} 103±8 to 62±14 min·mmol·l^–1; k 6.8±0.4 to 11.4±1.4%; insulin AUC_{min 27–87} 3,680±738 to 7,201±1,183 min·pmol·l^–1; p<0.05).Conclusions/interpretation This study confirms a role for NEP-24.11 in GLP-1 metabolism in vivo, suggesting that up to 50% of GLP-1 entering the circulation may be degraded by NEP-24.11. Furthermore, combined inhibition of DPP-IV and NEP-24.11 is superior to DPP-IV inhibition alone in preserving intact GLP-1, which raises the possibility that the combination has therapeutic potential.     

肠促胰素与糖尿病性骨质疏松症的研究进展

糖尿病（Diabetes,DM）、骨质疏松症（Osteoporosis,OP）是两种常见的慢性病,在DM患者中存在的代谢紊乱可致OP发生的风险机率大大增加,严重影响患者的生活质量,而由此导致的OP称为糖尿病性骨质疏松症(Diabetic osteoporosis,DOP),主要指糖尿病所致骨量减少,骨组织微结构破坏,骨脆性增加,易于骨折的一种全身性代谢性疾病 。对DOP的治疗首先要控制血糖,血糖是基础,而肠促胰素（Incretin）作为一种降糖药物已应用于临床,在减重及降糖方面效果突出,但最近研究显示肠促胰素在降糖的同时对OP有一定的改善,本文将简单阐述肠促胰素对DOP的影响。     

Pharmacological control of blood sugar

Diabetes is a chronic and progressive metabolic disorder characterized by hyperglycaemia. The two main types of diabetes are type 1 diabetes (T1DM) where there is complete lack of insulin and type 2 diabetes (T2DM) which may be due to a combination of insulin resistance and relative insulin deficiency due to impaired β-cell function. Good control of blood glucose near physiological limits is vital to reduce long-term microvascular and macrovascular complications of diabetes. Insulin replacement is a life-saving measure in individuals with T1DM whereas the mainstay of therapy in T2DM includes oral agents, non-insulin injectables (incretin mimetics) and insulin. In T2DM, the incretin mimetics have revolutionized recent treatment options by reducing blood glucose, promoting weight loss and improving β-cell function. Moreover, the emergence of a new class of drugs such as the sodium–glucose transporter inhibitors for patients with T2DM holds much promise. Despite the availability of several drugs to treat this chronic debilitating condition, the management of hyperglycaemia remains challenging. The role of diet, lifestyle changes and patient education is of paramount importance and should be pursued aggressively. This review will look at drugs currently used to optimize blood glucose control and briefly discuss the role of newer therapeutic agents.     

DPP-4 inhibition and COVID-19: From initial concerns to recent expectations

Dipeptidyl peptidase-4 inhibitors (DPP-4is) have gained a key place in the management of type 2 diabetes mellitus (T2DM) essentially because of their good safety profile even in the frail population. DPP-4, originally known as ‘T-cell antigen CD26’, is expressed in many immune cells and regulates their functions, so the initial concern over the use of DPP-4is was the possible increased susceptibility to infections. Furthermore, because of the high affinity between human DPP-4 and the spike (S) receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it was suspected that this virus, responsible for coronavirus disease 2019 (COVID-19), might be able to use the DPP-4 enzyme as a functional receptor to gain entry into the host. However, DPP-4is also exert anti-inflammatory effects, which could be beneficial in patients exposed to cytokine storms due to COVID-19. Yet, when observational (mostly retrospective) studies compared clinical outcomes in DPP-4i users vs non-users among diabetes patients with COVID-19, the overall results regarding the risk of progression towards more severe forms of the disease and mortality were heterogeneous, thereby precluding any definite conclusions. Nevertheless, new expectations have arisen following recent reports of significant reductions in admissions to intensive care units and mortality in DPP-4i users. However, given the limitations inherent in such observational studies, any available results should be considered, at best, as hypothetical and only suggestive of potentially substantial benefits with DPP-4is in diabetes patients with COVID-19. While the safe use of DPP-4is in COVID-19 patients appears to be an acceptable hypothesis, all such positive findings still need to be confirmed in randomized controlled trials (a few of which are currently ongoing) before any recommendations can be made for clinical practice.     

Insulinotropic actions of intravenous glucagon-like peptide-1 (GLP-1) [7–36 amide] in the fasting state in healthy subjects

GLP-1 (7–36 amide) stimulates insulin and suppresses glucagon secretion in normal subjects and may, in pharmacological doses, normalize hyperglycaemia in type 2 diabetic patients. It is not known whether such pharmacological doses can actually lower blood glucose to hypoglycaemic levels. Therefore, in seven normal fasting subjects, GLP-1 (7–36 amide) was infused intravenously at 0.3, 0.9 and 2.7 pmol/kg per min for 30 min each. The plasma concentration of GLP-1 (7–36 amide) increased dose-dependently, but insulin secretion (insulin, C-peptide) was stimulated only marginally. Glucagon was slightly suppressed, and plasma glucose was reduced, but not into the hypoglycaemic range. In conclusion, when plasma glucose concentrations are in the normal fasting range, GLP-1 (7–36 amide) is not able to stimulate insulin secretion to a degree that causes hypoglycaemia. This should limit the risk of hypoglycaemic responses when GLP-1 (7–36 amide) is administered in pharmacological doses to reduce hyperglycaemia in type 2 diabetic patients.     

肠促胰素在血糖稳态调节和2型糖尿病治疗中的作用

肠促胰素(incretin)是一类在食物营养物质刺激下,由肠道内分泌细胞合成分泌的激素,具有葡萄糖依赖性促胰岛素分泌的特性,可通过促进β细胞的胰岛素分泌、抑制α细胞不适当的胰升糖素分泌、延缓胃排空及抑制食欲等多个途径参与机体血糖稳态调节.同时,肠促胰素还可促进β细胞增殖、抑制β细胞凋亡,增加胰岛素合成、改善β细胞功能,从而延缓甚至逆转2型糖尿病病程的进展.以肠促胰素为基础的治疗方案,包括胰升糖素样肽-1(GLP-1)类似物和二肽基肽酶-4(DPP-4)抑制剂将为2型糖尿病的治疗开辟一条新的途径.