Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
Diabetologia. 2017 Jul;60(7):1197-1206. doi: 10.1007/s00125-017-4271-x. Epub 2017 Apr 7.
AIMS/HYPOTHESIS: Diabetic ketoacidosis (DKA) is often caused by concomitant systemic inflammation and lack of insulin. Here we used an experimental human model to test whether and how metabolic responses to insulin are impaired in the early phases of DKA with a specific focus on skeletal muscle metabolism.
Nine individuals with type 1 diabetes from a previously published cohort were investigated twice at Aarhus University Hospital using a 120 min infusion of insulin (3.0/1.5 mU kg min) after an overnight fast under: (1) euglycaemic conditions (CTR) or (2) hyperglycaemic ketotic conditions (KET) induced by an i.v. bolus of lipopolysaccharide and 85% reduction in insulin dosage. The primary outcome was insulin resistance in skeletal muscle. Participants were randomly assigned to one of the two arms at the time of screening using www.randomizer.org . The study was not blinded.
All nine volunteers completed the 2 days and are included in the analysis. Circulating concentrations of glucose and 3-hydroxybutyrate increased during KET (mean ± SEM 17.7 ± 0.6 mmol/l and 1.6 ± 0.2 mmol/l, respectively), then decreased after insulin treatment (6.6 ± 0.7 mmol/l and 0.1 ± 0.07 mmol/l, respectively). Prior to insulin infusion (KET vs CTR) isotopically determined endogenous glucose production rates were 17 ± 1.7 μmol kg min vs 8 ± 1.3 μmol kg min (p = 0.003), whole body phenylalanine fluxes were 2.9 ± 0.5 μmol kg min vs 3.1 ± 0.4 μmol kg min (p = 0.77) and urea excretion rates were 16.9 ± 2.4 g/day vs 7.3 ± 1.7 g/day (p = 0.01). Insulin failed to stimulate forearm glucose uptake and glucose oxidation in KET compared with CTR (p < 0.05). Glycogen synthase phosphorylation was impaired in skeletal muscle.
CONCLUSIONS/INTERPRETATION: In KET, hyperglycaemia is primarily driven by increased endogenous glucose production. Insulin stimulation during early phases of DKA is associated with reduced glucose disposal in skeletal muscle, impaired glycogen synthase function and lower glucose oxidation. This underscores the presence of muscle insulin resistance in the pathogenesis of DKA. Trial registration www.clinicaltrials.gov (ID number: NCT02157155). Funding This work was funded by the Danish Council for Strategic Research (grant no. 0603-00479B).
目的/假设：糖尿病酮症酸中毒（DKA）通常由伴随的全身炎症和缺乏胰岛素引起。在这里，我们使用一个实验性的人类模型来测试在 DKA 的早期阶段，胰岛素对代谢的反应是否受到影响，以及受到怎样的影响，特别关注骨骼肌代谢。
在奥胡斯大学医院，对之前发表的队列中的 9 名 1 型糖尿病患者进行了两次研究，在一夜禁食后，通过静脉内给予脂多糖和胰岛素剂量减少 85%，分别在以下两种情况下输注胰岛素（3.0/1.5 mU kg min）：（1）正常血糖（对照）或（2）高血糖酮症条件（KET）。主要结局是骨骼肌胰岛素抵抗。参与者在筛选时使用 www.randomizer.org 随机分配到两个臂之一。该研究未设盲。
所有 9 名志愿者均完成了 2 天的研究，并纳入分析。KET 期间循环葡萄糖和 3-羟丁酸浓度升高（平均 ± SEM 分别为 17.7 ± 0.6 mmol/L 和 1.6 ± 0.2 mmol/L），然后在胰岛素治疗后降低（6.6 ± 0.7 mmol/L 和 0.1 ± 0.07 mmol/L）。在胰岛素输注之前（KET 与 CTR），同位素测定的内源性葡萄糖生成率分别为 17 ± 1.7 μmol kg min 和 8 ± 1.3 μmol kg min（p = 0.003），全身苯丙氨酸通量分别为 2.9 ± 0.5 μmol kg min 和 3.1 ± 0.4 μmol kg min（p = 0.77），尿素排泄率分别为 16.9 ± 2.4 g/天和 7.3 ± 1.7 g/天（p = 0.01）。与 CTR 相比，KET 中胰岛素未能刺激前臂葡萄糖摄取和葡萄糖氧化（p < 0.05）。骨骼肌中糖原合酶磷酸化受损。
结论/解释：在 KET 中，高血糖主要是由内源性葡萄糖生成增加引起的。DKA 早期阶段胰岛素刺激与骨骼肌葡萄糖摄取减少、糖原合酶功能受损和葡萄糖氧化降低有关。这表明 DKA 发病机制中存在肌肉胰岛素抵抗。试验注册 www.clinicaltrials.gov（注册号：NCT02157155）。资金本工作由丹麦战略研究理事会（grant no. 0603-00479B）资助。
