Cystic Fibrosis Centre Copenhagen, Department of Infectious Diseases, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
Centre for Physical Activity Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
Front Endocrinol (Lausanne). 2023 Aug 31;14:1249876. doi: 10.3389/fendo.2023.1249876. eCollection 2023.
The purpose of the study was to further elucidate the pathophysiology of cystic fibrosis (CF)-related diabetes (CFRD) and potential drivers of hypoglycaemia. Hence, we aimed to describe and compare beta cell function (insulin and proinsulin) and alpha cell function (glucagon) in relation to glucose tolerance in adults with CF and to study whether hypoglycaemia following oral glucose challenge may represent an early sign of islet cell impairment.
Adults with CF (≥18 years) were included in a cross-sectional study using an extended (-10, -1, 10, 20, 30, 45, 60, 90, 120, 150, and 180 min) or a standard (-1, 30, 60, and 120 min) oral glucose tolerance test (OGTT). Participants were classified according to glucose tolerance status and hypoglycaemia was defined as 3-hour glucose <3.9 mmol/L in those with normal glucose tolerance (NGT) and early glucose intolerance (EGI).
Among 93 participants, 67 underwent an extended OGTT. In addition to worsening in insulin secretion, the progression to CFRD was associated with signs of beta cell stress, as the fasting proinsulin-to-insulin ratio incrementally increased (p-value for trend=0.013). The maximum proinsulin level (pmol/L) was positively associated with the nadir glucagon, as nadir glucagon increased 6.2% (95% confidence interval: 1.4-11.3%) for each unit increase in proinsulin. Those with hypoglycaemia had higher 60-min glucose, 120-min C-peptide, and 180-min glucagon levels (27.8% [11.3-46.7%], 42.9% [5.9-92.85%], and 80.3% [14.9-182.9%], respectively) and unaltered proinsulin-to-insulin ratio compared to those without hypoglycaemia.
The maximum proinsulin concentration was positively associated with nadir glucagon during the OGTT, suggesting that beta cell stress is associated with abnormal alpha cell function in adults with CF. In addition, hypoglycaemia seemed to be explained by a temporal mismatch between glucose and insulin levels rather than by an impaired glucagon response.
本研究旨在进一步阐明囊性纤维化（CF）相关糖尿病（CFRD）的病理生理学和低血糖的潜在驱动因素。因此，我们旨在描述和比较 CF 成人中与葡萄糖耐量相关的胰岛β细胞功能（胰岛素和胰岛素原）和胰岛α细胞功能（胰高血糖素），并研究口服葡萄糖耐量试验（OGTT）后是否可能存在低血糖代表胰岛细胞损伤的早期迹象。
本横断面研究纳入了≥18 岁的 CF 成人，采用延长（-10、-1、10、20、30、45、60、90、120、150 和 180 分钟）或标准（-1、30 和 60 分钟）OGTT。根据葡萄糖耐量状态对参与者进行分类，对于正常葡萄糖耐量（NGT）和早期葡萄糖耐量受损（EGI）者，定义低血糖为 3 小时血糖<3.9mmol/L。
在 93 名参与者中，有 67 名进行了延长 OGTT。除了胰岛素分泌恶化外，向 CFRD 的进展与β细胞应激的迹象有关，因为空腹胰岛素原与胰岛素的比值逐渐增加（趋势检验的 p 值=0.013）。最大胰岛素原水平（pmol/L）与胰高血糖素的最低值呈正相关，因为胰高血糖素的最低值增加了 6.2%（95%置信区间：1.4-11.3%），而胰岛素原增加了一个单位。与无低血糖者相比，有低血糖者的 60 分钟血糖、120 分钟 C 肽和 180 分钟胰高血糖素水平更高（27.8%[11.3-46.7%]、42.9%[5.9-92.85%]和 80.3%[14.9-182.9%]），而胰岛素原与胰岛素的比值无差异。
最大胰岛素原浓度与 OGTT 时的胰高血糖素最低值呈正相关，表明 CF 成人中β细胞应激与异常的α细胞功能有关。此外，低血糖似乎是由于葡萄糖和胰岛素水平之间的时间不匹配引起的，而不是由于胰高血糖素反应受损引起的。
