Pioglitazone Therapy for Endocrine and Exocrine Disease in Alcoholic Pancreatitis

描述（申请人提供）：作为GI部和糖尿病中心的成员，我的研究方向是内分泌和外分泌胰腺疾病，对糖尿病或胰岛素抵抗与胰腺外分泌减少和/或慢性胰腺炎（CP）的关系感兴趣。我们打算通过评估PPAR-3激动剂对CP的内分泌功能和外分泌功能及结构的治疗效果，将啮齿动物研究的数据转化为人类。与M.A. Anderson博士和临床GI胰腺组以及糖尿病研究中心主任W.H. Herman博士合作，这项研究的数据将用于竞争校外资金，以开展更大的、多中心的研究（并引导胰腺项目）。胰岛素能使餐后和促分泌剂刺激的胰腺外分泌增加约5倍。在疾病中，胰腺内分泌和外分泌紊乱经常共存于假定的原发性内分泌或外分泌紊乱；胰岛素抵抗和2细胞功能障碍发生在CP中，胰岛素缺乏和胰岛素抵抗发生胰腺外分泌受损。在轻中度CP患者中，外分泌和内分泌功能障碍之间的关系尚在研究中，但大多数患者出现胰岛素抵抗。具有治疗意义的是，在大鼠模型中，胰岛素致敏PPAR-3激动剂可以改善炎症和纤维化，甚至可以中止已建立的CP。此外，我们发现胰岛素抵抗模型（内皮NO合成酶（eNOS）基因缺失小鼠）CCK引起的胰腺外分泌减少50%，PPAR-3激动剂治疗可恢复胰岛素敏感性和胰腺外分泌。eNOS（-/-）小鼠的发现与CP相关，因为CP的主要危险因素是酒精和吸烟，两者都使eNOS与NO的产生分离。因此，对于共存的内分泌和外分泌胰腺疾病，一种疾病的成功治疗可能需要同时治疗两种疾病。我们的第一个假设是，在轻度-中度酒精性CP患者中，内分泌和外分泌功能障碍是可逆的。其次，我们假设吡格列酮通过改善内分泌功能障碍，改善胰腺外分泌功能、结构和生活质量，减轻疼痛。为了开始验证这些假设，我们将在轻度-中度酒精性CP患者中进行一项前瞻性随机对照研究，以确定吡格列酮与安慰剂是否能通过口服葡萄糖耐量试验改善胰腺内分泌功能，2)胰腺外分泌和结构，以及3)健康相关的生活质量。CP是一种进行性临床疾病，涉及胰腺内分泌和外分泌功能障碍，引起衰弱性腹痛。包括CP在内的“良性”胰腺疾病在美国影响着500万至2400万人，每年造成的损失高达25亿美元。CP的触发、阈值、免疫反应和细胞机制尚不清楚，治疗方法尚未得到证实。本研究可能有助于了解糖尿病、胰岛素抵抗和CP之间的内分泌和外分泌相互作用，并阐明胰岛素抵抗治疗是否可以逆转CP的自然史，延缓/中止糖尿病、吸收不良、钙化和疼痛。

DESCRIPTION (provided by applicant): As a member of the GI Division and Diabetes Center, my research focuses on endocrine and exocrine pancreatic diseases, with interest in the relationship between diabetes mellitus or insulin resistance and reduced pancreatic exocrine secretion and/or chronic pancreatitis (CP). We intend to translate data from rodent studies to humans by evaluating the therapeutic effect of PPAR-3 agonists on endocrine function & exocrine function & structure of CP. In collaboration with the Dr. M.A. Anderson and the clinical GI pancreas group, and Dr. W.H. Herman, Director of the Diabetes Research Center, data from this study will be used to compete for extramural funding to carry out a larger, multi- centered study (and lead toward a pancreas program project) In health, insulin potentiates postprandial and secretagogue stimulated pancreatic exocrine secretion by ~5-fold. In disease, pancreatic endocrine and exocrine disorders frequently coexist in presumed primary endocrine or exocrine disorders; insulin resistance and 2-cell dysfunction occur in CP and impaired exocrine pancreatic secretion occurs with insulinopenia and insulin resistance. In patients with mild- moderate CP, the relationship between exocrine and endocrine dysfunction is under- investigated, but the majority develop insulin resistance. Of therapeutic importance, it is established that insulin sensitizing PPAR-3 agonists ameliorate inflammation and fibrosis and even abort established CP in rat models. Further, we showed that an established model of insulin resistance (endothelial NO synthase (eNOS) gene deleted mice) has a 50% reduction in pancreatic exocrine secretion evoked by CCK and that treatment with a PPAR-3 agonist restores insulin sensitivity and exocrine pancreatic secretion. Findings in eNOS (-/-) mice are relevant to CP because the major risk factors for CP are alcohol and smoking, and both uncouple eNOS from NO production. Hence, with coexisting endocrine and exocrine pancreas disorders, successful treatment of one disorder may require treatment of both. Our first hypothesis is that endocrine and exocrine dysfunction are reversible in patients with mild-moderate alcoholic CP. Secondly, we hypothesize that pioglitazone, by improving endocrine dysfunction, will improve pancreatic exocrine function and structure and quality of life and reduce pain. To begin to test these hypotheses we will perform a prospective, randomized controlled study in patients with mild-moderate alcoholic CP to determine whether pioglitazone vs. placebo improves 1) pancreatic endocrine function by oral glucose tolerance testing, 2) pancreatic exocrine secretion & structure and 3) health related quality of life. PROJECT NARRATIVE CP is a progressive clinical disease involving endocrine and exocrine pancreas dysfunction and causing debilitating abdominal pain. "Benign" pancreatic diseases, including CP, affect 5-24 million in the U.S. and cost up to $2.5 billion annually. The triggers, thresholds, immunologic response and cellular mechanisms of CP are unclear and therapies remain unproven. This study may provide insight into endocrine & exocrine pancreas interactions found in diabetes mellitus, insulin resistance and CP and clarify whether therapies for insulin resistance can reverse the natural history of CP and delay/abort diabetes, malabsorption, calcification and pain.