Mechanisms of Post-Bariatric Hypoglycemia

摘要 减肥手术日益被认为是治疗2型糖尿病(T2D)的有效工具， 不仅体重减轻，而且血糖迅速改善，使糖尿病相关疾病得以停止 手术后数日内用药1。然而，伴随着这种新陈代谢的成功， 部分患者的严重低血糖(称为减肥后低血糖；PBH)的发生率。严重者 低血糖不仅会引起令人痛苦的肾上腺素能和胆碱能症状，还会导致神经性低血糖和 无意识低血糖，损害安全性，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，并被隔离到Roux-en-Y胃分流术 (RYGB)，最新估计表明，在RYGB和垂直袖子之后，大约30%的患者会发生这种情况 胃切除术(SG)，具有相似的症状和严重程度。增加餐后胰岛素和 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减少了对 低血糖症。总而言之，这些数据表明，就像支持新陈代谢成功的机制一样 手术后，PBH的发病机制(S)是多因素的。然而，PBH的一个重要特征是 症状出现的时间。而胰岛素的增加和血糖稳态的改善几乎发生在 通常，PBH的发病通常发生在术后数年。因此，PBH有更多的东西 增加了胰岛素，从而增加了胰岛素的反应。这项提议的目标是利用 临床前和临床研究，以确定生理和分子机制的基础 以确定这些变化是否也有助于手术诱导的改善 血糖动态平衡，并确定潜在的治疗措施的PBH。我们将确定是否 减肥手术前对低血糖的反调节激素反应减少 改善啮齿动物的外周胰岛素敏感性(目标1)。我们将检验这一假设 减肥后患者对低血糖的反调节激素反应受损，无论是否有 PBH(目标2)。最后，我们看到PBH患者的FGF19增加，我们将利用临床和 临床前策略，以回答关键问题，即是什么推动了FGF19的增加(目标3)，以及 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).