Andersen Dana K
Department of Surgery, Johns Hopkins University Medical School, and Johns Hopkins Bayview Medical Center, Baltimore, MD 21224, USA.
Pancreas. 2007 Jul;35(1):1-15. doi: 10.1097/mpa.0b013e31805d01b0.
Exocrine and endocrine abnormalities in chronic pancreatitis contribute to the morbidity and mortality risks of the disease. Complications of exocrine insufficiency include malabsorption, vitamin deficiency syndromes, and weight loss. Oral enzyme replacement therapy is usually effective if attention is paid to factors that affect the bioavailability of enzyme preparations. Complications of endocrine insufficiency can be more difficult to treat due in part to an incomplete knowledge of their etiology.
This review focuses on the endocrine aspects of chronic pancreatitis and highlights the observations of our laboratory on the pathogenesis of the metabolic complications of the disease.
In addition to decreased insulin secretory capacity, pancreatogenic (or apancreatic) diabetes is characterized by decreased or absent glucagon and pancreatic polypeptide (PP) secretion, a loss of hepatic insulin receptor (IR) expression/availability, and an impairment in hepatic IR function (phosphorylation and endocytosis). Diminished hepatic IR expression in chronic pancreatitis appears to be because of PP deficiency; laboratory animals and patients with PP deficiency demonstrate decreased hepatic IR availability that is reversed by prolonged (8-hour) PP administration. The impairment in hepatic IR function appears independent of PP deficiency but is reversed by prolonged (28-day) treatment with the insulinotropic/insulinomimetic hormone glucagon-like peptide 1. The endocytosis of hepatic IR is linked to the endocytosis of the glucose transporter 2 from the hepatocyte plasma membrane, and studies suggest that the 2 plasma membrane-bound proteins are complexed noncovalently to function and translocate as a unit after insulin binding to the hepatic IR. The process appears vigorous and sensitive enough to account for a significant reduction in hepatic glucose output and may represent a major mechanism for insulin regulation of hepatic glucose production.
The regulatory mechanisms of PP-mediated hepatic IR expression and combined IR and GLUT2 endocytosis after insulin binding are defective in chronic pancreatitis and contribute to the apancreatic diabetes, which characterizes this disease.
慢性胰腺炎中的外分泌和内分泌异常会增加该疾病的发病和死亡风险。外分泌功能不全的并发症包括吸收不良、维生素缺乏综合征和体重减轻。如果注意到影响酶制剂生物利用度的因素，口服酶替代疗法通常是有效的。内分泌功能不全的并发症可能更难治疗，部分原因是对其病因了解不全面。
本综述聚焦于慢性胰腺炎的内分泌方面，并着重介绍我们实验室对该疾病代谢并发症发病机制的观察结果。
除了胰岛素分泌能力下降外，胰腺源性（或无胰腺性）糖尿病的特征还包括胰高血糖素和胰多肽（PP）分泌减少或缺乏、肝胰岛素受体（IR）表达/可利用性丧失以及肝IR功能受损（磷酸化和内吞作用）。慢性胰腺炎中肝IR表达降低似乎是由于PP缺乏；缺乏PP的实验动物和患者显示肝IR可利用性降低，而长期（8小时）给予PP可使其恢复。肝IR功能受损似乎与PP缺乏无关，但用促胰岛素/胰岛素模拟激素胰高血糖素样肽1进行长期（28天）治疗可使其恢复。肝IR的内吞作用与葡萄糖转运蛋白2从肝细胞膜的内吞作用相关，研究表明这两种细胞膜结合蛋白在胰岛素与肝IR结合后非共价结合，作为一个单位发挥功能并转运。该过程似乎足够活跃和敏感，足以导致肝葡萄糖输出显著减少，可能代表胰岛素调节肝葡萄糖生成的主要机制。
在慢性胰腺炎中，PP介导的肝IR表达以及胰岛素结合后IR和GLUT2联合内吞作用的调节机制存在缺陷，这导致了无胰腺性糖尿病，这也是该疾病的特征。
