Mechanisms of Post-Bariatric Hypoglycemia

减肥后低血糖的机制

• 批准号: 10159247
• 负责人: Mary E Patti
• 金额: $ 70.83万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-26 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159247
• 关键词: Acute; Adrenergic Agents; Arrhythmia; Bariatrics; Bile Acids; Body Weight decreased; Brain; Catecholamines; Cessation of life; Clinical; Clinical Research; Closure by clamp; Coma; Data; Development; Diabetes Mellitus; Distress; Exercise; FGF19 gene; Fasting; Gastrectomy; Gastric Bypass; Glucagon; Glucocorticoids; Goals; Health Benefit; Hepatic; Hormonal; Hormones; Hydrocortisone; Hypoglycemia; Impairment; Incidence; Individual; Injections; Insulin; Intestines; Link; Measures; Metabolic; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Orthologous Gene; Pathogenesis; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Physiological; Plasma; Play; Postoperative Period; Pre-Clinical Model; Reactive hypoglycemia; Rodent; Rodent Model; Role; Safety; Seizures; Severities; Signal Transduction; Somatotropin; Source; Symptoms; Syncope; Testing; Therapeutic Intervention; Time; Work; bariatric surgery; bile acid metabolism; blood glucose regulation; cholinergic; counterregulation; disability risk; experience; experimental study; glucagon-like peptide 1; glucose disposal; hypoglycemia unawareness; insulin secretion; insulin sensitivity; microbiome; obesity treatment; patient subsets; pre-clinical; preclinical study; response; success; tool

Abstract Bariatric surgery is increasingly recognized as a potent tool for the treatment of type 2 diabetes (T2D), yielding not only weight loss but also rapid improvements in glycemia allowing discontinuation of diabetes-related medication within days after surgery 1. However, along with this metabolic success comes an increased incidence of severe hypoglycemia (termed post-bariatric hypoglycemia; PBH) for a subset of patients. Severe hypoglycemia causes not only distressing adrenergic and cholinergic symptoms but also neuroglycopenia and hypoglycemia unawareness, impairing safety and increasing risk for disability, syncope, arrhythmias, seizures, coma, and death. Although initially thought to occur in <1% of patients and isolated to roux-en-Y gastric bypass (RYGB), latest estimates suggest that it occurs in ~30% of patients, after both RYGB and vertical sleeve gastrectomy (SG), with similar presentation and spectrum of severity. Increased postprandial incretin and insulin secretion, increased insulin sensitivity, and altered bile acid metabolism have all been implicated in the pathogenesis of PBH. Recent work also suggests that RYGB reduces counterregulatory responses to hypoglycemia. Together, these data suggest that, like the mechanisms that underlie the metabolic success of surgery, the mechanism(s) that underlie PBH are multi-factorial. However, an important feature of PBH is the timing of symptoms. While increases in incretins and improvements in glucose homeostasis occur almost immediately, the onset of PBH typically occurs years postoperatively. Thus, there is more to PBH than increased incretin and consequently insulin responses. The goal of this proposal is to utilize a combination of preclinical and clinical studies to identify physiological and molecular mechanisms that underlie PBH, to determine whether these changes also contribute to surgery-induced improvements in glucose homeostasis, and to define potential therapeutic interventions for PBH. We will determine if decreases in the counterregulatory hormonal responses to hypoglycemia precede bariatric surgery-induced improvements in peripheral insulin sensitivity in rodents (Aim 1). We will test the hypothesis that counterregulatory hormonal responses to hypoglycemia are impaired in post-bariatric patients with or without PBH (Aim 2). Finally, we see that FGF19 is increased in patients with PBH and we will utilize both clinical and preclinical strategies to answer the critical questions of what drives this increase in FGF19 (Aim 3) and whether it is required for the development of PBH (Aim 4).

抽象的 减肥手术越来越被认为是治疗2型糖尿病（T2D）的有效工具，产生 不仅体重减轻，还可以快速改善血症，允许停用与糖尿病有关 手术后几天内药物。但是，随着这种代谢成功的增加 一部分患者的严重低血糖（称为碳脂性低血糖； PBH）的发生率。严重 低血糖不仅引起令人痛苦的肾上腺素和胆碱能症状，还引起神经胶质细胞减少症和 低血糖不认识，障碍安全性和降低残疾的风险，晕厥，心律不齐，癫痫发作，癫痫发作， 昏迷和死亡。尽管最初被认为发生在<1％的患者中，并分离为roux-en-y胃旁路 （RYGB），最新估计表明，在RYGB和垂直套筒之后，它发生在约30％的患者中 胃切除术（SG），具有相似的表现和严重程度。增加餐后肠毒素和 胰岛素分泌，胰岛素敏感性提高和胆汁酸代谢改变均与 PBH的发病机理。最近的工作还表明，RYGB减少了对 低血糖。这些数据一起表明，就像是基于代谢成功的机制 手术，PBH基础的机制是多因素的。但是，PBH的一个重要特征是 症状的时间。虽然降量降凝剂和葡萄糖稳态的改善几乎发生了 立即，PBH的发作通常在术后几年发生。因此，PBH比 降量降和剂增加，因此增加了胰岛素反应。该提议的目的是利用一个组合 临床前和临床研究，以鉴定基于的生理和分子机制 PBH，确定这些变化是否也有助于手术引起的改善 葡萄糖稳态，并定义PBH的潜在治疗干预措施。我们将确定是否 在减肥手术诱导之前，对低血糖的反调节激素反应减少 啮齿动物中周围胰岛素敏感性的改善（AIM 1）。我们将检验以下假设 在有或没有 PBH（目标2）。最后，我们看到PBH患者的FGF19增加了，我们将同时使用临床和 临床前策略要回答促使FGF19增加的关键问题（AIM 3）以及是否是否 这是PBH开发所必需的（AIM 4）。