Darleen Sandoval  美国辛辛那提大学

　　<International Circulation> ：Please talk about the possible mechanisms behind the positive metabolic effects of bariatric surgery on improving blood sugar and blood lipids.
Prof. Sandoval：We know much more about what isn’t a mechanism than what are the mechanisms for bariatric surgery. First， these surgeries are often categorized based on their physical description. For example， if the surgery makes the stomach smaller then it is categorized as a restrictive surgery， if the intestine is rearranged it is malaborptive， if both manipulations occur then it is a combined surgery. ?We focus on two particular bariatric surgeries: ?Roux-en Y gastric bypass (RYGB) which involves gastric size reduction and intestinal re-arrangement such that ingested food bypasses ?95% of the stomach， the entire duodenum， and a short portion of the jejunum and the vertical sleeve gastrectomy (VSG) which involves removing ~80% of the stomach along the greater curvature with no intestinal rearrangement. Despite the very different physical aspects of these surgeries， their effects on body weight and glucose metabolism are very similar in humans and in our rodent models of the surgeries. Neither surgery causes sufficient caloric loss due to malabsorption to account for the weight lost. Moreover， our data indicate that although the animals take in smaller more frequent meals， they can ingest larger meals， they just choose not to. Another very interesting aspect of these surgeries that we see in animal models and is supported in the clinical literature， is that they change food preference; meaning that， if given the choice， the animals choose the lower caloric density to the higher caloric density foods. Thus， our data do not support the idea that these surgeries work because they restrict meal size or because they prevent the gut from absorbing food. Instead we believe that many of these surgeries (for example roux en Y gastric bypass & vertical sleeve gastrectomy) work by changing gut-derived signals to the brain and other organs that regulate glucose.

　　《国际循环》：请您谈一下减重手术具有改善血糖及血脂等积极代谢效应的可能机制。
Sandoval教授：对减重手术而言，与哪些是其机制相比，我们目前知道更多的是哪些不是其机制。首先，这些手术通常根据其物理描述来进行分类。例如，如果手术使胃变小，则会被归类为限制性手术；如果肠道被重新排列，则被称为吸收不良手术；如果两种情况都有，则被称为混合型手术。我们关注的是两种特殊的减重手术即Roux-en Y胃旁路术（RYGB）和袖状胃切除术（VSG）。前者包括胃体积的减小以及肠道的重排，可使摄取的食物并不流经约95%的胃、整个十二指肠以及空肠的一小部分；后者会沿着胃大弯切除近80%的胃但不伴有肠道的重排。尽管这些不同手术方式的物理性质不同，但在人类及啮齿类动物模型中对体重及血糖代谢的影响却具有相似的效应。但两种手术方式均无法通过吸收不良引起足够的热量损失以达到减重的目的。而且，我们的数据表明，尽管动物通常每次进食更少更频繁，但它们能够一餐摄取更多食物，只是不这样做罢了。我们在动物模型中发现了这些手术的另一个非常有趣的方面——其能改变对食物的喜好，并得到了临床文献的支持。这意味着，如果有选择的话，动物可以选择低能量密度食物来替代高能量密度食物。因此，我们的数据并不支这些手术是因为其限制了食物的大小或者因为他们能够阻止肠道对食物的吸收而发挥作用。相反，我们认为，很多手术如Roux-en Y胃旁路术及袖状胃切除手术都是通过改变到达大脑及其他器官的、可调节血糖的肠源性信号来发挥作用的。

　　<International Circulation> ： What role does GLP-1 play in the positive metabolic effects of bariatric surgery?
Prof. Sandoval：It is widely reported that GLP-1 response to a meal is extraordinarily higher after bariatric surgery. Our animal models of bariatric surgery also demonstrate this increase. However， critical questions remain about how this increase in GLP-1 occurs and if it is necessary for the benefits of bariatric surgery. We see that gastric emptying rate is extremely rapid after both RYGB and VSG and one possibility is that the nutrients are simply reaching the distal part of the gut where the cells that make GLP-1 are located in the greatest abundance. However， our new data demonstrate that if you control the rate of nutrient entry into the intestine， the animals that had VSG still have significantly elevated GLP-1 levels compared to sham surgery animals. Thus， we believe there are gut adaptations to this rapid nutrient entry that lead to increased nutrient sensing and thus persistent increases in nutrient-induced GLP-1 after surgery. What we need to know is what those adaptations are. However， we have performed bariatric surgery on genetic mouse models that do not have the receptor for GLP-1 and what is really interesting， and quite to the contrary of our hypothesis is that these mice respond quite well to the surgery. This suggests that these receptors are not necessary for the surgery to cause weight loss and improve glucose. It could be that the impact of surgery is multifactorial and that removing one signal is not going to be sufficient to block the effects of the surgery.

　　《国际循环》：GLP-1在减重手术的积极代谢效应中发挥了怎样的作用？
Sandoval教授：众所周知，减重手术后GLP-1对进餐的反应尤其高。我们在减重手术的动物模型也发现了这种情况。但是GLP-1是如何增加以及其是否是减重获益所必需的等关键问题都仍未解决。我们知道在RYGB及VSG后胃排空率会极速增加。其中一种可能就是，营养物质只是简单地到达了存在大量能生成GLP-1的细胞的肠道末端。然而，我们的最新数据表明，如果您能够控制营养物质进入肠道的比率，与假手术组相比，行VSG的动物其GLP-1的水平仍显著增高。因此，我们认为，肠道对营养物质的快速摄入具有适应性，可以增加营养感应，从而使术后营养素诱导的GLP-1分泌持续增加。我们需要知道的是，这些适应到底是什么。但是，我们对不表达GLP-1受体的基因小鼠模型进行了减重手术，与我们的假设恰恰相反，其结果显示，这些小鼠手术后的反应非常好。这提示，GLP-1受体并不是手术减重及改善血糖所必需的。手术可能是通过多种因素发挥作用的，阻断其中一个信号并不足以阻断其疗效。

<International Circulation> ：What positive effect(s) does bariatric surgery have on blood pressure， and why?
Prof. Sandoval：We have just begun to study the impact of bariatric on blood pressure in our animal models but our preliminary data suggest that， specifically VSG， reduces both resting systolic and diastolic blood pressure， but not heart rate in rats. Our preliminary data suggest that this decrease is related to regulation of the renin-angiotensin system.

　　《国际循环》：减重手术对血压有何积极的影响，其机制如何？
Sandoval教授：我们刚刚开始在动物模型中研究减重手术对血压的影响。初步数据表明，减重手术尤其是VSG，能够降低大鼠的静息收缩压及舒张压，但并不影响其心率。这提示，上述降压效应可能与其对肾素-血管紧张素系统的调节作用有关。