A DOUBLE-BLIND STUDY TO EXPLORE EFFECTS OF LAF237 ON GLUCOSE DURING OVERNIGHT

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。目的：本研究的主要目的是确定单剂量LAF237对2型糖尿病患者吸收后夜间内源性葡萄糖（RaE）出现率的影响。次要目标将决定：(1)葡萄糖在一夜吸收后的消失率；(2)对空腹血糖浓度的影响；(3)对胰岛素分泌率、胰高血糖素水平和葡萄糖从胃肠道进入率的影响；(4)胰岛素和胰高血糖素分泌的改变是否影响血浆游离脂肪酸水平；(5) LAF237对胰岛素原/胰岛素比值的急性影响。研究计划/方法：这是一项随机、交叉比较研究，研究LAF237和安慰剂对内源性葡萄糖产生的影响。LAF237是一种实验性药物，可阻断二肽基肽酶- iv。这种酶，DPP-4，负责快速降解胰高血糖素样肽-1 (GLP-1)，当它在饭后释放到肠道中时。GLP-1抑制胰高血糖素释放，抑制肝脏葡萄糖输出。因此，预计LAF237会导致GLP-1水平升高，胰高血糖素分泌减少，血糖降低。这可以改善糖尿病患者的葡萄糖稳态。研究人员将研究年龄在18-75岁的2型糖尿病患者，其他健康状况良好，HbA1c在7-11%，空腹血糖160-280，饮食或口服降糖药控制糖尿病，BMS为22 - 45。受试者将在GCRC上看到四次。在第二次和第三次访问期间，患者将接受膳食耐受性测试，包括煮鸡蛋，帕玛森奶酪和含有c14标记葡萄糖的橙子味水。此外，他们将接受h3标记葡萄糖的输注，并接受葡萄糖药代动力学的连续血液样本（总样本高达882毫升）。目的是确定c14标记和h3标记的葡萄糖的药代动力学。临床意义：LAF是一种新型口服降糖药，通过抑制DDP-IV，抑制胰高血糖素分泌，刺激胰岛素分泌。它可以作为单一疗法或与目前批准的抗糖尿病药物联合使用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: The primary objective of this study is to determine the effect of a single dose of LAF237 on the rate of appearance of endogenous glucose (RaE) during the overnight post-absorptive period in type 2 diabetics. Secondary objectives will determine: (1) the rate of disappearance eof glucose during the overnight post-absorptive period; (2) the effect on fasting plasma glucose concentration; (3) effects on insulin secretion rates, glucagon levels, and rate of glucose entry from the GI tract; (4) if alterations in insulin and glucagon secretion affect plasma free fatty acid levels; and (5) the acute effects of LAF237 on the proinsulin/insulin ratio. RESEARCH PLAN/METHODS: This is a randomized, cross-over comparison study of the effect of LAF237 and placebo on endogenous glucose production. LAF237 is an investigational agent that blocks the enzyme dipeptidyl-peptidase-IV. This enzyme, DPP-4, is responsible for rapidly degrading glucagons-like peptide-1 (GLP-1) upon its release in the intestine after a meal. GLP-1 suppresses glucagons release, suppressing hepatic glucose output. Thus, if is expected that LAF237 should lead to increased GLP-1 levels, decreased glucagons production, and lower blood sugars. This translates into an improved glucose homeostasis for diabetics. Investigators will study adults ages 18-75 with type 2 diabetes, otherwise in good health, HbA1c at 7-11%, fasting blood sugar 160-280, diet- or oral hypoglycemic agent-controlled diabetes, and BMS 22 to 45. Subjects will be seen on the GCRC four times. During the second and third visits, patients will receive a meal-tolerance test consisting of a boiled egg, parmesan cheese, and orange-flavored water with C14-labeled glucose. In addition, they will receive an infusion of H3-labeled glucose, and serial blood samples for glucose pharmacokinetics (total samples up to 882 ml). The goal is to determine the pharmacokinetics of both the C14-labeled and H3-labeled glucose. CLINICAL RELEVANCE: LAF is a new oral antidiabetic agent that works by inhibiting DDP-IV, leading to inhibition of glucagon secretion and stimulation of insulin secretion. It can be used as monotherapy or in combination with currently approved antidiabetic agents.