Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.
Departments of Medicine and Pediatrics-Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Illinois, USA.
J Clin Invest. 2019 Jan 2;129(1):246-251. doi: 10.1172/JCI121994. Epub 2018 Dec 3.
Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.
采用综合方法对一名 33 岁、患 17 年 1 型糖尿病（T1D）的患者的胰腺组织和分离的胰岛进行分析，我们发现供体胰岛中β细胞无胰岛炎，但尽管对 cAMP 诱导的刺激有正常的胰岛素反应，但缺乏葡萄糖刺激的胰岛素分泌。对于 T1D，我们对供体 DNA 进行了测序，发现编码肝细胞核因子-1α（HNF1A）的基因存在致病性杂合变异体。在与最常见的单基因糖尿病相关的具有致病 HNF1A 变异体的人类胰腺胰岛的首批研究之一中，我们发现 HNF1A 功能障碍通过影响葡萄糖刺激的胰岛素分泌的关键调节过程导致胰岛素不足的糖尿病，类似于 T1D，并提示了一种替代当前治疗的治疗方法的合理依据。
