Novel Therapies for Metabolic Complications in Patients with Lipodystrophies

描述(申请人提供)：脂肪营养不良患者易患胰岛素抵抗及其代谢并发症，包括糖尿病、血脂异常和肝脏脂肪变性。这些疾病的治疗是一个巨大的挑战，因为现有的传统疗法并不是非常有效。最近的人重组瘦素治疗重度低血症性脂营养不良患者的临床试验显示了有希望的结果，但瘦素是否对轻度低血症者同样有效尚不清楚。因此，我们建议研究新的治疗方法，如极低脂饮食、瘦素、胆酸和吡格列酮(一种PPAR伽玛激动剂)。该项目有以下目标：1)比较极低脂肪(占总能量的10%)和中等脂肪(占总能量的35%)饮食的可接受性和代谢影响，2)比较瘦素治疗轻度或重度低血糖伴家族性部分脂营养不良患者的疗效和安全性，3)评估胆酸治疗肝脏脂肪变性的有效性和安全性，以及4)评估吡格列酮的安全性和代谢影响。为了实现这些目标，我们将在随机、交叉(目标1、3和4)和随机、平行设计研究(目标2)中招募约72名具有各种类型的全身性和部分性脂营养不良(不包括HIV感染患者)的代谢并发症患者。我们将通过人体测量、双能X射线吸收测量和磁共振成像来研究体脂分布，用1-H磁共振波谱测量肝脏甘油三酯浓度，用正常血糖、高胰岛素钳夹技术测量胰岛素敏感性，还将测量血浆脂蛋白、血糖、血红蛋白A1c和胰岛素。我们的结果可能有助于设计治疗脂肪营养不良患者代谢并发症的方法。此外，这些发现可能适用于肥胖症和2型糖尿病患者代谢并发症的治疗。

DESCRIPTION (provided by applicant): Patients with lipodystrophies are predisposed to insulin resistance and its metabolic complications including diabetes mellitus, dyslipidemia and hepatic steatosis. Treatment of these conditions poses a significant challenge as available conventional therapies are not very effective. Recent clinical trials of human recombinant leptin in severely hypoleptinemic patients with lipodystrophies have shown promising results but whether leptin will be equally efficacious in those with mild hypoleptinemia is unclear. Therefore, we propose to investigate novel therapeutic approaches such as extremely low fat diets, leptin, cholic acid and pioglitazone (a PPAR gamma agonist) for patients with lipodystrophies. The project has the following aims: 1) to compare the acceptability and metabolic effects of extremely low fat (<10% of total energy) and moderate fat (35% of total energy) diets, 2) compare the efficacy and safety of leptin therapy in mildly or severely hypoleptinemic patients with familial partial lipodystrophies, 3) to evaluate the efficacy and safety of cholic acid therapy in treating hepatic steatosis and 4) to evaluate the safety and metabolic effects of pioglitaznoe. To accomplish these aims, we will enroll ~ 72 patients with various types of generalized and partial lipodystrophies (excluding HIV-infected patients) with metabolic complications in randomized, crossover (aims 1,3 and 4) and randomized, parallel design studies(aim 2). We will study body fat distribution by anthropometry, dual energy X-ray absorptiometry and magnetic resonance imaging, will measure hepatic triglyceride concentration using 1-H magnetic resonance spectroscopy, insulin sensitivity by euglycemic, hyperinsulinemic clamp technique and also measure plasma lipoproteins, glucose, hemoglobin A1c and insulin. Our results may help in designing therapeutic approaches to metabolic complications in patients with lipodystrophies. Additionally, the findings may be applicable to treating metabolic complications in patients with obesity and type 2 diabetes.