Mezza Teresa, Wewer Albrechtsen Nicolai J, Di Giuseppe Gianfranco, Ferraro Pietro Manuel, Soldovieri Laura, Ciccarelli Gea, Brunetti Michela, Quero Giuseppe, Alfieri Sergio, Nista Enrico Celestino, Gasbarrini Antonio, Tondolo Vincenzo, Mari Andrea, Pontecorvi Alfredo, Giaccari Andrea, Holst Jens J
Pancreas Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Roma, Italy; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Roma, Italy.
Department of Clinical Biochemistry, Copenhagen University Hospital - Bispebjerg, Copenhagen, Denmark.
Metabolism. 2025 Feb;163:156087. doi: 10.1016/j.metabol.2024.156087. Epub 2024 Dec 1.
A number of studies have suggested that pancreatic α cells produce intact GLP-1, thereby constituting a gut-independent paracrine incretin system. However, the debate on whether human α cells contain intact GLP-1 and whether this relates to the presence of diabetes is still ongoing. This study aimed to determine the presence of proglucagon-derived peptides, including GLP-1 isoforms, in pancreas biopsies obtained during partial pancreatectomy from metabolically profiled human donors, stratified according to pre-surgery glucose tolerance.
We enrolled 61 individuals with no known history of type 2 diabetes (31F/30M, age 64.6 ± 10.6 yrs., BMI 24.2 ± 3.68 kg/m) scheduled for partial pancreatectomy for periampullary neoplasm. Differences in glucose tolerance and insulin secretion/sensitivity were assessed using preoperative 2 h OGTT, 4 h-Mixed Meal Test and Hyperinsulinemic Euglycemic Clamp. Subjects were subsequently classified as normal glucose tolerant (NGT, n = 19), impaired glucose tolerant (IGT, n = 20) or newly diagnosed diabetes (DM) (n = 22). We measured total GLP-1, intact GLP-1, glucagon, insulin, and C-peptide in pancreas biopsies and plasma from these subjects and correlated the results with their secretory and metabolic parameters.
Extractable levels of total GLP-1 were 23.9 ± 2.66 pmol/g, while intact GLP-1 levels were 1.15 ± 0.18 pmol/g. When we examined proglucagon derived peptides (adjusted for glucagon levels), in subjects classified according to glucose tolerance, we observed similar levels of total GLP-1, however, intact GLP-1 was significantly increased in IGT and DM groups and inversely associated with beta cell glucose sensitivity and insulin secretion in vivo.
Our data show that development of glucose intolerance and beta cell dysfunction are significantly associated with increased levels of intra-islet intact GLP-1, a potentially beneficial adaptation of the paracrine regulation of insulin secretion in type 2 diabetes.
多项研究表明，胰腺α细胞可产生完整的胰高血糖素样肽-1（GLP-1），从而构成一个不依赖肠道的旁分泌肠促胰岛素系统。然而，关于人类α细胞是否含有完整的GLP-1以及这是否与糖尿病的存在有关的争论仍在继续。本研究旨在确定在对具有代谢特征的人类供体进行部分胰腺切除术中获取的胰腺活检组织中胰高血糖素原衍生肽（包括GLP-1异构体）的存在情况，并根据术前糖耐量进行分层。
我们纳入了61例无2型糖尿病病史的个体（31名女性/30名男性，年龄64.6±10.6岁，体重指数24.2±3.68kg/m²），他们因壶腹周围肿瘤计划进行部分胰腺切除术。使用术前2小时口服葡萄糖耐量试验（OGTT）、四小时混合餐试验和高胰岛素正常血糖钳夹技术评估糖耐量和胰岛素分泌/敏感性的差异。随后，受试者被分类为糖耐量正常（NGT，n = 19）、糖耐量受损（IGT，n = 20）或新诊断糖尿病（DM）（n = 22）。我们测量了这些受试者胰腺活检组织和血浆中的总GLP-1、完整GLP-1、胰高血糖素、胰岛素和C肽，并将结果与其分泌和代谢参数进行关联。
可提取的总GLP-1水平为23.9±2.66pmol/g，而完整GLP-1水平为1.15±0.18pmol/g。当我们根据糖耐量对受试者进行分类并检查胰高血糖素原衍生肽（根据胰高血糖素水平进行调整）时，我们观察到总GLP-1水平相似，然而，完整GLP-1在IGT和DM组中显著增加，并且与体内β细胞葡萄糖敏感性和胰岛素分泌呈负相关。
我们的数据表明，糖耐量异常和β细胞功能障碍的发生与胰岛内完整GLP-1水平的升高显著相关，这是2型糖尿病中胰岛素分泌旁分泌调节的一种潜在有益适应性变化。
