Insulin and GLP-1 analog combinations in type 2 diabetes mellitus: a critical review

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists have been used in clinical management of type 2 diabetes since 2005. Currently approved agents were initially developed and approved for combination therapy with oral antidiabetic drugs (OADs). The potential for combined use with insulin has garnered increasing attention due to the potential to reduce side effects associated with insulin therapy and improve glycemic control.

Areas covered: We reviewed published and other publicly released data from controlled and uncontrolled studies that included subjects treated with insulin/GLP-1 analog combination therapy. The currently available guidance for clinical practice when combining insulin and GLP-1 analogs was also summarized.

Expert opinion: Limited data currently available from placebo-controlled trials support the use of exenatide twice daily or liraglutide once daily in combination with basal insulin and metformin in subjects with type 2 diabetes unable to attain treatment goals. Several randomized controlled trials are currently studying combinations of insulin with various GLP-1 analogs. Additional guidance on the clinical use of these combinations will likely be forthcoming once these studies are reported. Insulin/GLP-1 analog combinations will require optimization of blood glucose monitoring strategies and delivery systems to decrease the risk of administration errors and reduce the potential complexity of these regimens.     

脊柱手术模拟系统的设计与研发

手术模拟系统是近年来发展迅速的一个领域,显示了良好的应用前景.为能使医生更好地开展脊柱疾患术前诊断、手术计划及模拟,并选择合理的手术方案指导手术,节约手术的时间、降低手术风险.本文从开发的必要性、系统功能设计及初步实现的功能进行阐述,探讨脊柱手术模拟系统的设计与开发.     

Systemic cytokines, clinical and physiological changes in patients hospitalized for exacerbation of COPD

BACKGROUND: Systemic inflammation in patients with COPD may worsen during exacerbations, but there is limited information relating levels of systemic inflammatory markers with symptoms and physiologic changes during an exacerbation METHODS: We measured dyspnea using the visual analog scale, pulmonary function tests, hemograms, and plasma levels for interleukin (IL)-6, IL-8, leukotriene B(4) (LTB4), tumor necrosis factor-alpha, and secretory leukocyte protease inhibitor (SLPI) in 20 patients on admission to a hospital for exacerbation of COPD (ECOPD), 48 h later (interim), and 8 weeks after hospital discharge (recovery). RESULTS: Dyspnea was present in all patients. Inspiratory capacity improved faster than FEV(1). Compared to recovery, there was a significant increase in the mean (+/- SD) hospital admission plasma levels of IL-6 (6.38 +/- 0.72 to 2.80 +/- 0.79 pg/mL; p = 0.0001), IL-8 (8.18 +/- 0.85 to 3.72 +/- 0.85 pg/mL; p = 0.002), and LTB4 (8,675 +/- 1,652 to 2,534 +/- 1,813 pg/mL; p = 0.003), and the percentages of segmented neutrophils (79 to 69%; p < 0.02) and band forms (7.3 to 1.0%; p < 0.01) in peripheral blood, with no changes in TNF-alpha and SLPI. There were significant correlations between changes in IL-6 (r = 0.61; p = 0.01) and IL-8 (r = 0.56; p = 0.04) with changes in dyspnea and levels of IL-6 (r = -0.51; p = 0.04) and TNF-alpha (r = -0.71; p < 0.02) with changes in FEV(1.) CONCLUSIONS: Hospitalized patients with ECOPDs experience significant changes in systemic cytokine levels that correlate with symptoms and lung function. An ECOPD represents not only a worsening of airflow obstruction but also increased systemic demand in a host with limited ventilatory reserve.     

From the Cover: Zyklophin,a systemically active selective kappa opioid receptor peptide antagonist with short duration of action

The cyclic peptide zyklophin {[N-benzylTyr¹,cyclo(D-Asp⁵,Dap⁸)-dynorphin A-(1–11)NH₂, Patkar KA, et al. (2005) J Med Chem 48: 4500–4503} is a selective peptide kappa opioid receptor (KOR) antagonist that shows activity following systemic administration. Systemic (1–3 mg/kg s.c.) as well as central (0.3–3 nmol intracerebroventricular, i.c.v.) administration of this peptide dose-dependently antagonizes the antinociception induced by the selective KOR agonist U50,488 in C57BL/6J mice tested in the 55 °C warm water tail withdrawal assay. Zyklophin administration had no effect on morphine- or SNC-80-mediated antinociception, suggesting that zyklophin selectively antagonizes KOR in vivo. Additionally, the antagonism of antinociception induced by centrally (i.c.v.) administered U50,488 following peripheral administration of zyklophin strongly suggests that the peptide crosses the blood-brain barrier to antagonize KOR in the CNS. Most importantly, the antagonist activity of zyklophin (3 mg/kg s.c.) lasts less than 12 h, which contrasts sharply with the exceptionally long duration of antagonism reported for the established small-molecule selective KOR antagonists such as nor-binaltorphimine (nor-BNI) that last weeks after a single administration. Systemically administered zyklophin (3 mg/kg s.c.) also prevented stress-induced reinstatement of cocaine-seeking behavior in a conditioned place preference assay. In conclusion, the peptide zyklophin is a KOR-selective antagonist that exhibits the desired shorter duration of action, and represents a significant advance in the development of KOR-selective antagonists.     

Exenatide类似物对2型糖尿病大鼠降糖作用研究

目的：研究Exenatide类似物对2型糖尿病（type 2 diabetes mellitus, T2DM）大鼠血糖的作用。方法：采用链脲佐菌素（streptozotocin, STZ）加高糖高脂饲养诱导新生大鼠产生T2DM,同时连续皮下注射给予Exenatide类似物8周,测定其对大鼠体重、血糖、糖耐量及血脂的影响。实验结束后,分离胰腺进行胰岛素免疫组化观察。结果：Exenatide类似物可以降低T2DM大鼠的空腹血糖（fasting blood glucose,FPG）,改善大鼠的糖耐量,降低血脂,控制高脂饲养大鼠体重的增长。Exenatide类似物干预后,大鼠胰岛结构完整,胰岛素阳性染色明显增加。结论：Exenatide类似物对T2DM大鼠有显著的降血糖作用。     

具有抗癌活性的新型三氮唑核苷类似物的研究进展

核苷类似物是一类重要的抗癌药物。通过在非天然核苷的三氮唑碱基中引入芳香基团,笔者发展了一系列1,2,4-三氮唑核苷类似物。该文简要综述这些三氮唑核苷类似物的分子设计、化学合成及其抗癌活性测试的研究成果。     

Effects of glucagon-like peptide 1 analogs in combination with insulin on myocardial infarct size in rats with type 2 diabetes mellitus

AIM To evaluate the effects of glucagon-like peptide-1 analogs(GLP-1 a) combined with insulin on myocardial ischemiareperfusion injury in diabetic rats.METHODS Type 2 diabetes mellitus(T2 DM) was induced in maleWistar rats with streptozotocin(65 mg/kg) and verified using an oral glucose tolerance test. After anesthesia, the left coronary artery was occluded for 40 min followed by 80 min reperfusion. Blood glucose level was measured during surgery. Rats were randomized into six groups as follows:(1) control rats;(2) insulin(0.1 U/kg) treated rats prior to ischemia;(3) insulin(0.1 U/kg) treated rats at reperfusion;(4) GLP-1 a(140 mg/kg) treated rats prior to ischemia;(5) GLP-1 a(140 mg/kg) treated rats at reperfusion; and(6) rats treated with GLP-1 a(140 mg/kg) prior to ischemia plus insulin(0.1 U/kg) at reperfusion. Myocardial area at risk and infarct size was measured planimetrically using Evans blue and triphenyltetrazolium chloride staining, respectively.RESULTS There was no significant difference in the myocardial area at risk among groups. Insulin treatment before ischemia resulted in a significant increase in infarct size(34.7% ± 3.4% vs 18.6% ± 3.1% in the control rats, P 0.05). Post-ischemic administration of insulin or GLP-1 a had no effect on infarct size. However, pre-ischemic administration of GLP-1 a reduced infarct size to 12% ± 2.2%(P 0.05). The maximal infarct size reduction was observed in the group treated with GLP-1 a prior to ischemia and insulin at reperfusion(8% ± 1.6%, P 0.05 vs the control and GLP-1 a alone treated groups).CONCLUSION GLP-1 a pre-administration results in myocardial infarct size reduction in rats with T2 DM. These effects are maximal in rats treated with GLP-1 a pre-ischemia plus insulin at reperfusion.     

慢性乙型肝炎抗病毒治疗进展

慢性乙型肝炎的抗病毒治疗仍是国内外所面临的一大难题,近年来虽已取得显著成果,但目前临床的抗病毒治疗只能抑制病毒的复制,尚不能彻底清除体内乙型肝炎病毒。病毒的耐药变异仍然是影响CHB抗病毒疗效的重要原因之一,现国际国内仍在探讨新的抗病毒治疗方法,特别是新的免疫治疗策略以期获得持久的病毒学和血清学应答,达到CHB的永久性治愈。本文就慢性乙型肝炎的抗病毒治疗最新进展进行综述。