Mechanisms of Post-Bariatric Hypoglycemia

摘要 减肥手术越来越被认为是治疗2型糖尿病（T2 D）的有效工具， 不仅体重减轻，而且血糖快速改善， 手术后几天内的药物治疗1.然而，沿着这种代谢的成功， 一部分患者发生重度低血糖（称为减肥后低血糖; PBH）。严重 低血糖症不仅引起令人痛苦的肾上腺素能和胆碱能症状， 低血糖无意识，损害安全性并增加残疾、晕厥、心律失常、癫痫发作的风险， 昏迷和死亡虽然最初认为发生在<1%的患者中，并孤立于Roux-en-Y胃旁路术 （RYGB），最新估计表明，在RYGB和垂直袖后，约30%的患者发生 胃切除术（SG），具有相似的表现和严重程度谱。餐后肠促胰岛素增加， 胰岛素分泌、胰岛素敏感性增加和胆汁酸代谢改变都与 PBH的发病机制最近的研究还表明，RYGB减少了反调节反应， 低血糖总之，这些数据表明，就像代谢成功的机制一样， 手术后，PBH的潜在机制是多因素的。然而，PBH的一个重要特征是， 症状的时间。虽然肠促胰岛素的增加和葡萄糖稳态的改善几乎 PBH通常在术后数年立即发作。因此，有更多的PBH比 增加肠促胰岛素和胰岛素反应。该提案的目标是利用一种组合 临床前和临床研究，以确定生理和分子机制， PBH，以确定这些变化是否也有助于手术诱导的改善， 葡萄糖稳态，并确定潜在的治疗干预PBH。我们将确定是否 在减肥手术诱导的低血糖之前， 啮齿类动物外周胰岛素敏感性的改善（目标1）。我们将检验这个假设， 在有或没有肥胖症的肥胖患者中， PBH（目标2）。最后，我们发现PBH患者的FGF 19增加，我们将利用临床和免疫组化方法， 临床前策略，以回答是什么驱动了FGF 19的增加（目标3），以及是否 这是发展PBH（目标4）所必需的。

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 surgery1. 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).