持续血糖监测与血糖监测对儿童、青少年和年轻1型糖尿病患者严重低血糖和糖尿病酮症酸

1

Agrp-negative arcuate NPY neurons drive feeding under positive energy balance via altering leptin responsiveness in POMC neurons

Agrp阴性的弓形NPY神经元通过改变POMC神经元的瘦素反应来驱动正能量平衡下的摄食

Neuropeptide Y (NPY) in the arcuate nucleus (ARC) is known as one of the most critical regulators of feeding. However, how NPY promotes feeding under obese conditions is unclear. Here, we show that positive energy balance, induced by high-fat diet (HFD) or in genetically obese leptin-receptor-deficient mice, leads to elevated Npy2r expression especially on proopiomelanocortin (POMC) neurons, which also alters leptin responsiveness. Circuit mapping identified a subset of ARC agouti-related peptide (Agrp)-negative NPY neurons that control these Npy2r expressing POMC neurons. Chemogenetic activation of this newly discovered circuitry strongly drives feeding, while optogenetic inhibition reduces feeding. Consistent with that, lack of Npy2r on POMC neurons leads to reduced food intake and fat mass. This suggests that under energy surplus conditions, when ARC NPY levels generally drop, high-affinity NPY2R on POMC neurons is still able to drive food intake and enhance obesity development via NPY released predominantly from Agrp-negative NPY neurons.

弓形核（ARC）中的神经肽Y （NPY）被认为是最重要的摄食调节因子之一。然而，NPY如何促进肥胖条件下的喂养尚不清楚。在这里，我们发现，高脂肪饮食（HFD）或遗传性肥胖瘦素受体缺陷小鼠诱导的正能量平衡，导致Npy2r表达升高，特别是在propropiomanocortin （POMC）神经元上，这也改变了瘦素反应性。电路图谱鉴定出一个ARC agouti相关肽（Agrp）阴性的NPY神经元亚群，控制这些表达Npy2r的POMC神经元。这种新发现的电路的化学发生激活强烈地驱动摄食，而光遗传抑制则减少摄食。与此一致的是，POMC神经元上缺乏Npy2r会导致食物摄入量减少和脂肪量减少。这表明在能量过剩条件下，当ARC NPY水平普遍下降时，POMC神经元上的高亲和力NPY2R仍然能够通过主要由Agrp -阴性NPY神经元释放的NPY驱动食物摄入并促进肥胖发展。

2

Vitamin D: 100 years of discoveries, yet controversy continues

维生素D: 100年来的发现，但争议仍在继续

Over the past 100 years, many major breakthroughs and discoveries have occurred in relation to vitamin D research. These developments include the cure of rickets in 1919, the discovery of vitamin D compounds, advances in vitamin D molecular biology, and improvements in our understanding of endocrine control of vitamin D metabolism. Furthermore, recommended daily allowances for vitamin D have been established and large clinical trials of vitamin D, aimed at clarifying the effect of Vitamin D in the prevention of multiple diseases, have been completed. However, disappointingly, these clinical trials have not fulfilled the expectations many had 10 years ago. In almost every trial, various doses and routes of administration did not show efficacy of vitamin D in preventing fractures, falls, cancer, cardiovascular diseases, type 2 diabetes, asthma, and respiratory infections. Although concerns about side-effects of long-term high-dose treatments, such as hypercalcaemia and nephrocalcinosis, have been around for four decades, some trials from the past 5 years have had new and unexpected adverse events. These adverse events include increased fractures, falls, and hospitalisations in older people (aged >65 years). Several of these clinical trials were powered appropriately for a primary outcome but did not include dose response studies and were underpowered for secondary analyses. Furthermore, more attention should be paid to the safety of high doses of vitamin D supplementation, particularly in older people. In addition, despite universal recommendations by osteoporosis societies for combining calcium supplements with vitamin D there remains insufficient data about their efficacy and effect on fracture risk in the highest risk groups. More trials are needed for people with severe vitamin D deficiency (ie, serum 25-hydroxyvitamin D <25nmol/L [10ng/mL]). In this Personal View, we summarise and discuss some of the major discoveries and controversies in the field of vitamin D.

在过去的100年里，在维生素D研究方面出现了许多重大突破和发现。这些发展包括1919年佝偻病的治愈，维生素D化合物的发现，维生素D分子生物学的进展，以及我们对维生素D代谢的内分泌控制的理解的改进。此外，还制定了维生素D的每日推荐摄入量，并完成了维生素D的大型临床试验，目的是阐明维生素D在预防多种疾病方面的作用。然而，令人失望的是，这些临床试验并没有达到许多人10年前的期望。在几乎所有的试验中，各种剂量和给药途径都没有显示维生素D在预防骨折、跌倒、癌症、心血管疾病、2型糖尿病、哮喘和呼吸道感染方面的功效。尽管对长期高剂量治疗的副作用（如高钙血症和肾钙质沉着症）的担忧已经存在了40年，但过去5年的一些试验出现了新的和意想不到的不良事件。这些不良事件包括老年人（>65岁）骨折、跌倒和住院的增加。这些临床试验中有几个对主要结果有适当的支持，但没有包括剂量反应研究，并且对次要分析的支持不足。此外，应更多地注意高剂量补充维生素D的安全性，特别是老年人。此外，尽管骨质疏松症协会普遍建议将钙补充剂与维生素D结合使用，但关于其对高危人群骨折风险的疗效和影响的数据仍然不足。需要对严重维生素D缺乏症患者（即血清25-羟基维生素D <25nmol/L [10ng/mL]）进行更多的试验。在这篇个人观点中，我们总结和讨论了维生素D领域的一些重大发现和争议。

3

Continuous glucose monitoring versus blood glucose monitoring for risk of severe hypoglycaemia and diabetic ketoacidosis in children, adolescents, and young adults with type 1 diabetes

持续血糖监测与血糖监测对儿童、青少年和年轻1型糖尿病患者严重低血糖和糖尿病酮症酸中毒风险的影响

Background

The effect of continuous glucose monitoring on the risk of severe hypoglycaemia and ketoacidosis in patients with diabetes is unclear. We investigated whether rates of acute diabetes complications are lower with continuous glucose monitoring, compared with blood glucose monitoring, and which metrics predict its risk in young patients with type 1 diabetes.

Methods

In this population-based cohort study, patients were identified from 511 diabetes centres across Austria, Germany, Luxembourg, and Switzerland participating in the Diabetes Prospective Follow-up initiative. We included people with type 1 diabetes aged 1·5–25·0 years, with a diabetes duration of more than 1 year, who had been treated between Jan 1, 2014, and June 30, 2021, and had an observation time of longer than 120 days in the most recent treatment year. Severe hypoglycaemia and ketoacidosis rates during the most recent treatment year were examined in people using continuous glucose monitoring and in those using blood glucose monitoring. Adjustments of statistical models included age, sex, diabetes duration, migration background, insulin therapy (pump or injections), and treatment period. Rates of severe hypoglycaemia and diabetic ketoacidosis were evaluated by several continuous glucose monitoring metrics, including percentage of time below target glucose range (<3·9 mmol/L), glycaemic variability (measured as the coefficient of variation), and mean sensor glucose.

背景

持续血糖监测对糖尿病患者发生严重低血糖和酮症酸中毒风险的影响尚不清楚。我们调查了与血糖监测相比，持续血糖监测是否降低了急性糖尿病并发症的发生率，以及哪些指标可以预测年轻1型糖尿病患者的并发症风险。

方法

在这项以人群为基础的队列研究中，患者来自奥地利、德国、卢森堡和瑞士的511个糖尿病中心，参与了糖尿病前瞻性随访计划。我们纳入了2014年1月1日至2021年6月30日期间接受治疗的1型糖尿病患者，年龄1.5 - 25.0岁，糖尿病病程1年以上，最近治疗年度观察时间超过120天的患者。在最近的治疗年度中，对使用连续血糖监测的人和使用血糖监测的人进行了严重低血糖和酮症酸中毒率的检查。统计模型的调整包括年龄、性别、糖尿病病程、移民背景、胰岛素治疗（泵或注射）和治疗时间。通过几个连续血糖监测指标评估严重低血糖和糖尿病酮症酸中毒的发生率，包括低于目标血糖范围（< 3.9 mmol/L）的时间百分比、血糖变异性（以变异系数测量）和平均传感器葡萄糖。