Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
Diabetes Modelling Group, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
J Clin Endocrinol Metab. 2019 Feb 1;104(2):359-368. doi: 10.1210/jc.2018-01176.
Glucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear.
To determine the mechanisms of postprandial lipid and glucose control with lixisenatide (GLP-1 analog) in type 2 diabetes.
Randomized, double-blind, cross-over study.
Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom.
Eight obese men with type 2 diabetes [age, 57.3 ± 1.9 years; body mass index, 30.3 ± 1.0 kg/m2; glycosylated hemoglobin, 66.5 ± 2.6 mmol/mol (8.2% ± 0.3%)].
Two metabolic studies, 4 weeks after lixisenatide or placebo, with cross-over and repetition of studies.
Study one: very-low-density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with an IV bolus of [2H5]glycerol in a 12-hour study, with hourly feeding. Oral [13C]triolein, in a single meal, labeled enterally derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable IV [6,6-2H2]glucose infusion.
Study one: CM-TAG (but not VLDL-TAG) pool-size was lower with lixisenatide (P = 0.046). Lixisenatide reduced CM [13C]oleate area under the curve (AUC)60-480min concentration (P = 0.048) and increased CM-TAG clearance, with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC0-240min were reduced with lixisenatide (P = 0.0051; P < 0.05). Total glucose production (P = 0.015), rate of glucose appearance from the meal (P = 0.0098), and acetaminophen AUC0-360min (P = 0.006) were lower with lixisenatide than with placebo.
Lixisenatide reduced [13C]oleate concentrations, derived from a single meal in CM-TAG and glucose rate of appearance from the meal through delayed gastric emptying. However, day-long CM production, measured with repeated meal feeding, was not reduced by lixisenatide and decreased CM-TAG concentration resulted from increased CM-TAG clearance.
胰高血糖素样肽-1（GLP-1）激动剂可控制 2 型糖尿病患者的餐后血糖和血脂波动，但具体机制尚不清楚。
研究利西那肽（GLP-1 类似物）控制 2 型糖尿病患者餐后血脂和血糖的机制。
随机、双盲、交叉研究。
英国吉尔福德皇家萨里郡医院糖尿病、内分泌和研究中心。
8 名肥胖的 2 型糖尿病男性[年龄，57.3±1.9 岁；体重指数，30.3±1.0 kg/m2；糖化血红蛋白，66.5±2.6 mmol/mol（8.2%±0.3%）]。
在接受利西那肽或安慰剂治疗 4 周后进行两项代谢研究，交叉重复进行研究。
研究一：通过静脉内给予[2H5]甘油 12 小时研究和每小时进食，测量极低密度脂蛋白（VLDL）和乳糜微粒（CM）三酰甘油（TAG）动力学，口服[13C]三油酸甘油酯，标记肠内来源的 TAG。研究二：通过混合餐（加扑热息痛以测量胃排空）和可变静脉内[6,6-2H2]葡萄糖输注，用[U-13C]葡萄糖测量葡萄糖动力学。
研究一：利西那肽组 CM-TAG（而非 VLDL-TAG）池大小较低（P=0.046）。利西那肽降低了 CM[13C]油酸 AUC60-480min 浓度（P=0.048），增加了 CM-TAG 清除率，但对 CM-TAG 生成率无影响。研究二：利西那肽降低了餐后血糖和胰岛素 AUC0-240min（P=0.0051；P<0.05）。利西那肽组总葡萄糖生成（P=0.015）、来自进餐的葡萄糖出现率（P=0.0098）和扑热息痛 AUC0-360min（P=0.006）均低于安慰剂组。
利西那肽通过延迟胃排空，降低了源自 CM-TAG 中单餐的[13C]油酸浓度和来自进餐的葡萄糖出现率。然而，通过重复餐食喂养测量的全天 CM 生成并未被利西那肽减少，CM-TAG 浓度降低是由于 CM-TAG 清除率增加所致。
