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Donnelly D 《British journal of pharmacology》2012,166(1):27-41
Glucagon-like peptide-1(7-36)amide (GLP-1) is a 30-residue peptide hormone released from intestinal L cells following nutrient consumption. It potentiates the glucose-induced secretion of insulin from pancreatic beta cells, increases insulin expression, inhibits beta-cell apoptosis, promotes beta-cell neogenesis, reduces glucagon secretion, delays gastric emptying, promotes satiety and increases peripheral glucose disposal. These multiple effects have generated a great deal of interest in the discovery of long-lasting agonists of the GLP-1 receptor (GLP-1R) in order to treat type 2 diabetes. This review article summarizes the literature regarding the discovery of GLP-1 and its physiological functions. The structure, function and sequence-activity relationships of the hormone and its natural analogue exendin-4 (Ex4) are reviewed in detail. The current knowledge of the structure of GLP-1R, a Family B GPCR, is summarized and discussed, before its known interactions with the principle peptide ligands are described and summarized. Finally, progress in discovering non-peptide ligands of GLP-1R is reviewed. GLP-1 is clearly an important hormone linking nutrient consumption with blood sugar control, and therefore knowledge of its structure, function and mechanism of action is of great importance. 相似文献
134.
Morrow L Hompesch M Guthrie H Chang D Chatterjee DJ 《Diabetes, obesity & metabolism》2011,13(1):75-80
Aim: To compare the pharmacokinetic (PK) [area under the curve (AUC0–24 h, Cmax)] and pharmacodynamic (PD) (AUCGIR 0–24 h, GIRmax) properties of single‐dose insulin detemir in the presence or absence of steady‐state liraglutide (1.8 mg dose) in subjects with type 2 diabetes to determine whether co‐administration affected the PK and PD profiles of either therapeutic agent. Methods: Following a 3‐week washout of oral antidiabetic agents (OADs) other than metformin, PK and PD assessments during three euglycaemia clamps were conducted: day 1 following a single dose of insulin detemir alone (0.5 U/kg), day 22 after 3 weeks of once‐daily liraglutide with weekly dose escalation to 1.8 mg daily, and day 36 after 2 weeks of steady‐state liraglutide maintenance at the 1.8 mg dose following co‐administration with a single dose of insulin detemir (0.5 U/kg). Results: The study population (N = 33; age 49.6 (±8.5) years) had diabetes for an average of 6.5 (±4.1) years, BMI 33 (±6.4) kg/m2, FPG 9.7 (±1.6) mmol/l and HbA1c 8.3% (±0.9). PK: The PK profiles of insulin detemir were similar with and without steady‐state liraglutide. Liraglutide did not affect AUC or Cmax of insulin detemir and vice versa. The 90% confidence intervals (CIs) for ratios of insulin detemir AUC [1.03; CI (0.97, 1.09)] and Cmax [1.05; CI (0.98, 1.13)] and liraglutide AUC [0.97; CI (0.87, 1.08)] and Cmax [1.03, CI (0.93, 1.13)] were all within the no‐effect boundary (0.80, 1.25) (bioequivalence criterion). A stable mean insulin detemir concentration with and without liraglutide was maintained at the end of the 24‐h PK sampling period. PD: The sum of AUCGIR for liraglutide (1982 mg/kg) and insulin detemir (1058 mg/kg) when given alone was similar to that obtained when the two were co‐administered (2947 mg/kg). No serious adverse events were reported and no adverse events led to study withdrawal. Conclusion: Co‐administration of liraglutide 1.8 mg at steady state and insulin detemir produces an additive glucose‐lowering effect without affecting the PK profile of either therapeutic agent suggesting that the addition of insulin detemir to patients treated with liraglutide will not require titration algorithms different from when insulin is added to OADs. The co‐administration of insulin detemir and liraglutide was well tolerated. 相似文献
135.
The safety and tolerability of GLP-1 receptor agonists in the treatment of type 2 diabetes: a review
Although several classes of pharmacotherapy are available for type 2 diabetes, glycaemic control is often hampered by medication-related adverse effects and contraindications such as renal impairment. Glucagon-like peptide-1 (GLP-1) receptor agonists provide a new pharmacotherapeutic option based on the multiple glucose-lowering effects of the human hormone GLP-1. This mechanism of action not only provides therapeutic efficacy but also suggests that GLP-1 receptor agonists have distinct safety and tolerability concerns compared with other diabetes therapies. Stimulation of pancreatic insulin secretion by GLP-1 receptor agonists is glucose dependent, conferring a lesser risk of hypoglycaemia than that seen with sulfonylureas. Individual GLP-1 receptor agonists differ in their metabolism and excretion profiles, affecting the choice of agent for patients with renal impairment. As with other protein-based therapies, GLP-1 receptor agonists may induce the formation of antibodies that may attenuate therapeutic efficacy and affect safety. Conclusions on cardiovascular safety must await outcomes studies, but at present no signal of harm has been reported, and preclinical data and effects on risk markers suggest a potential for benefit. Current data on thyroid medullary cancer in humans and pancreatic malignancy in rodents do not suggest that there is any reason to restrict the clinical use of GLP-1 analogues in most people with diabetes. It is currently difficult to ascertain the possible contributory role of GLP-1 receptor agonists in increasing the risk of pancreatitis, and vigilance for signs and symptoms is prudent. Primary tolerability issues include transient gastrointestinal symptoms, common with GLP-1 receptor agonists, which can be reduced through dose titration. 相似文献
136.
GLP-1-modulating therapies are a class of anti-diabetic drugs that improve glycemic control by stimulating glucose-dependent insulin secretion from pancreatic beta-cells. In addition, GLP-1-based therapies have a variety of extrapancreatic effects, including satiety induction and gastric mobility reduction, which extend to distinct cardiovascular actions. GLP-1 was found to reduce infarct size in the context of acute myocardial ischemia which depends on the activation of prosurvival pathways including PI3-kinase, Akt, and ERK1/2. Also, GLP-1 augments the left ventricular function in dilative and metabolic cardiomyopathy, possibly by increasing insulin independent cardiomyocyte glucose uptake. Furthermore, experimental and preliminary clinical evidence suggest vasoprotective efficacy of GLP-1 mediated by improved endothelial function and anti-inflammatory capacities leading to atheroprotection. Mechanistically, the GLP-1 receptor is relevant for glucose lowering efficacy of GLP-1. However, many of its vasoprotective actions have also been described for the GLP-1 metabolite (9-37), which does not activate the GLP-1 receptor, suggesting the presence of an additional, yet unknown, signaling pathway. Ongoing research investigates the relevance of these observations in human disease and underlying mechanisms, which are reviewed in the present article. 相似文献
137.
Subodh Verma MD Stephen C. Bain MD Tea Monk Fries MD C. David Mazer MD Michael A. Nauck MD Richard E. Pratley MD Søren Rasmussen PhD Hans A. Saevereid MD Bernard Zinman MD John B. Buse MD 《Diabetes, obesity & metabolism》2019,21(7):1745-1751
Cardiovascular risk reduction with liraglutide and semaglutide in patients with type 2 diabetes was demonstrated in the LEADER ( ClinicalTrials.gov : NCT01179048) and SUSTAIN 6 ( ClinicalTrials.gov : NCT01720446) cardiovascular outcome trials. This post hoc analysis assessed the impact of diabetes duration (<5, 5 to <15, 15 to <25 and ≥25 years at baseline) on cardiorenal efficacy of these human glucagon-like peptide-1 analogues using a Cox proportional hazards model. Proportions of patients in the LEADER trial across diabetes duration strata were 15% (<5 years, n = 1377), 50% (5 to <15 years, n = 4692), 27% (15 to <25 years, n = 2504) and 8% (≥25 years, n = 748); corresponding proportions in the SUSTAIN-6 trial were 13% (<5 years, n = 422), 48% (5 to <15 years, n = 1582), 30% (15 to <25 years, n = 977) and 10% (≥25 years, n = 316). Overall, longer diabetes duration was associated with higher age; higher prevalence of females; history of ischaemic stroke, peripheral arterial disease and insulin use; and inferior renal function. There was an increased frequency of major adverse cardiovascular events (MACE), expanded MACE and nephropathy events with increasing diabetes duration. Liraglutide and semaglutide consistently reduced the risk of cardiorenal outcomes across categories of diabetes duration (P-interaction was not significant for all endpoints analysed). 相似文献
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Marconi Abreu MD Anna Tumyan MD Ahmed Elhassan MD Katherine Peicher DO Olivia Papacostea MD Perihan Dimachkie MD Muhammad S. Siddiqui MD Laurentiu M. Pop MD Uma Gunasekaran MD Luigi F. Meneghini MD Beverley Adams-Huet MS Xilong Li PhD Ildiko Lingvay MD 《Diabetes, obesity & metabolism》2019,21(9):2133-2141
140.
Dario Giugliano MD Juris J. Meier MD Katherine Esposito MD 《Diabetes, obesity & metabolism》2019,21(5):1081-1087
An excess risk of heart failure (HF) persists in patients with type 2 diabetes (T2D) despite optimal control of an array of conventional risk factors, including hyperglycaemia. Twelve cardiovascular outcome trials (CVOTs) have been published to date, although none, with the exception of the DECLARE trial with dapagliflozin, has included HF as a primary endpoint. The four trials with dipeptidyl-peptidase inhibitors (DPP-4i) (SAVOR-TIMI 53 with saxagliptin, EXAMINE with alogliptin, TECOS with sitagliptin and CARMELINA with linagliptin) failed to show any significant effect on HF risk in patients with T2D, with the notable exception of saxagliptin which was associated with a 27% increased risk. Five completed CVOTs with the GLP-1 RAs lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), exenatide once weekly (EXSCEL) and albiglutide (HARMONY) also failed to reveal any significant effect on HF risk. The three trials with sodium glucose co-transporter-2 inhibitors (SGLT-2i) (EMPA-REG OUTCOME with empagliflozin, CANVAS with canagliflozin and DECLARE with dapagliflozin) all revealed a robust and significant reduction in the hazard ratios of hospitalization for HF, from 27% to 35%, which remained consistent, significant and of similar magnitude regardless of the presence of a history of HF or established atherosclerotic cardiovascular disease. There is no association between reductions in HF risk and haemoglobin A1c (A1C) levels, while there is a significant association between reductions in HR for MACE and A1C levels (Spearman's correlation, r = 0.695; P = 0.013). All of the 12 CVOTs completed to date have provided reassurance of the overall cardiovascular safety of the newer anti-hyperglycaemic drugs. At present, the robust, consistent and reproducible reduction of approximately 30% in the risk of HF with SGLT-2i may be considered a class effect. The beneficial effect on MACE outcome observed with the use of some GLP-1RAs and SGLT-2i must be interpreted within the frame of the single trial. 相似文献