Metabolic effects of 3-hydroxybutyrate infusion in individuals with type 1 diabetes compared with healthy control participants: a randomised crossover trial showing intact feedback suppression of lipolysis.

The ketone body 3-hydroxybutyrate (3-OHB) inhibits lipolysis in healthy individuals.

酮体3-羟基丁酸（3-OHB）在健康个体中抑制脂解作用。

The current study aimed to test whether this feedback suppression of lipolysis by 3-OHB is disrupted in individuals with type 1 diabetes.

当前研究旨在检验3-OHB对脂解作用的反馈抑制是否在1型糖尿病患者中受到破坏。

Methods

We used a single-blind, randomised, crossover design to study ten men diagnosed with type 1 diabetes and ten healthy control participants.

我们采用单盲、随机、交叉设计，研究了十名被诊断为1型糖尿病的男性患者和十名健康对照参与者。

Eligibility criteria were male sex, age ≥18 years, BMI of 19-26 kg/m2 and no severe comorbidities/diseases.

纳入标准为男性，年龄≥18岁，BMI在19-26 kg/m2之间，且无严重合并症/疾病。

Following an overnight fast, each participant received two 3 h i.v. infusions: (i) sodium-D/L-3-OHB and (ii) iso-osmolar saline (NaCl), separated by a 1 h washout period.

经过一夜的禁食，每位参与者接受了两次3小时的静脉输注：(i)钠-D/L-3-OHB和(ii)等渗盐水（NaCl），两次输注之间相隔1小时的洗脱期。

The order of the two interventions was assigned by randomisation for each participant.

每位参与者的两次干预顺序通过随机分配确定。

Participants were blinded to the allocation throughout the study day, but investigators were aware of the assigned intervention order.

在研究当天，参与者对分配的干预顺序不知情，但研究人员知晓所分配的干预顺序。

We evaluated the lipolytic rate and glucose turnover using [9,10-3H]palmitate and [3-3H]glucose tracers.

我们使用[9,10-3H]棕榈酸和[3-3H]葡萄糖示踪剂评估了脂解速率和葡萄糖周转。

Additionally, adipose tissue signalling was quantified using western blotting techniques in subcutaneous abdominal adipose tissue biopsies.

此外，使用西方印迹技术对皮下腹部脂肪组织活检样本中的脂肪组织信号进行了定量。

The primary endpoint measure was palmitate flux (lipolytic rate).

主要终点测量指标是棕榈酸通量（脂解速率）。

Results

During the infusion of 3-OHB, the D/L-3-OHB blood concentrations increased to 3.3 ± 0.7 mmol/l in participants with type 1 diabetes compared with 2.9 ± 0.5 mmol/l in control participants (p=0.03).

在3-OHB输注期间，1型糖尿病患者的D/L-3-OHB血液浓度增加到3.3 ± 0.7 mmol/l，而对照组参与者的浓度为2.9 ± 0.5 mmol/l（p=0.03）。

The infusion effectively suppressed the lipolytic rates by more than 50% (p<0.001) and reduced circulating NEFA by approximately 0.5 mmol/l (p<0.001) compared with NaCl in both participants with type 1 diabetes and control participants.

输注有效抑制了脂解率超过50%（p<0.001），并使1型糖尿病患者和对照组参与者的循环游离脂肪酸（NEFA）水平降低了约0.5毫摩/升（p<0.001）相比NaCl。

In adipose tissue, 3-OHB reduced protein kinase A phosphorylation of perilipin (p<0.001) and hormone-sensitive lipase phosphorylation at Ser660 (p<0.001) and Ser563 (p<0.01) similarly in participants with type 1 diabetes and control participants.

在脂肪组织中，3-OHB降低了蛋白激酶A对 perilipin 的磷酸化（p<0.001）以及对激素敏感脂肪酶在 Ser660（p<0.001）和 Ser563（p<0.01）位点的磷酸化，这种效果在1型糖尿病患者和对照组参与者中相似。

Indices of glucose metabolism remained unaffected throughout in both groups.

两组的葡萄糖代谢指标在整个过程中均未受影响。

conclusions/interpretation

Our findings indicate that, in individuals with type 1 diabetes, the suppression of lipolysis, blood NEFA concentrations and adipose tissue signalling activity in response to 3-OHB remains intact compared with healthy control participants.

我们的研究结果表明，在1型糖尿病患者中，与健康对照组相比，3-OHB对脂解作用、血浆游离脂肪酸(NEFA)浓度和脂肪组织信号活动的抑制作用仍然保持完好。

These findings imply that derailment of receptor signalling by 3-OHB is unlikely to be involved in the development of diabetic ketoacidosis.

这些发现暗示，3-OHB对受体信号传导的干扰不太可能参与糖尿病酮症酸中毒的发展。

trial_registration

ClinicalTrials.gov NCT04656236 FUNDING: Open access funding provided by Aarhus Universitet.

ClinicalTrials.gov NCT04656236 资助信息：由奥胡斯大学提供的开放获取资金。

This study was supported by the Novo Nordisk Foundation (NNF19OC0058872) and the Health Research Foundation of Central Denmark Region.

本研究由诺和诺德基金会（NNF19OC0058872）和中丹麦地区卫生研究基金会支持。