胆汁酸与减肥手术治疗2型糖尿病的关系

研究人员报告称，一种涉及到胆汁酸生成的通路或许在2型糖尿病缓解过程中起作用，这种作用通常会在减肥手术后被观察到。

宾夕法尼亚州丹维 尔市格伊辛格医疗系统的George Argyropoulos博士及其同事对来自两项队列研究的数据进行了分析，他们发现，在接受Roux-en-Y式胃肠旁路手术(RYGB)的患者中，与 术后病情未能缓解的糖尿病患者以及非糖尿病患者相比，术后病情发生缓解的糖尿病患者具有最高的成纤维细胞生长因子19(FGF19)和总胆酸水平(P值均 小于0.001)。

他们的发现被发表在了《糖尿病治疗》杂志上并被收录到美国糖尿病学会会议的糖尿病治疗论文集中

“处于缓解期的患者在FGF19和胆汁酸水平上发生了最为显著的改变，” Argyropoulos说，“我们推测，胆汁酸在FGF19中起了至关重要的作用，这或许改变了患者对胰岛素的敏感程度。”

RYGB手术使大部分糖尿病患者的病情发生了缓解，但其机制并不完全清楚。已知FGF19与肝脏分泌胆汁酸的调节有关，于是研究人员推测，该机制或许在病情缓解中发挥了某些作用。

Argyropoulos 及其同事所评估的数据来自两组接受减肥手术患者的队列：其中一组涉及了66名糖尿病患者和54名非糖尿病患者；另一组涉及了115名糖尿病患者和71名非 糖尿病患者。他们将队列分为三组：非糖尿病的RYGB患者，RYGB术后病情至少缓解了12个月的糖尿病患者和RYGB术后病情无缓解的糖尿病患者。

术前，与非糖尿病患者相比，糖尿病患者具有更低的FGF19水平和更高的胆汁酸水平，“这提示，在糖尿病状态下，肝肠的FGF19-胆汁酸（BA）通路或许存在某种损伤。”研究人员写道。

通过溯源分析发现，在糖尿病患者，较低水平的FGF19与较高水平的肝脏胆固醇7α-羟化酶(CYP7A1，一种胆汁酸生成的调节酶)相关，而在非糖尿病患者中不存在该相关性(P<0.048)。

综上，研究人员发现，在接受减肥手术的各组患者中，绝大多数患者的血清FGF19水平出现了升高，其中，术后病情发生缓解的糖尿病患者该指标增幅最大(P<0.001)。

他 们发现，术后病情缓解的糖尿病患者在总胆酸方面也具有最大的增幅(P<0.001)。特别值得注意的是，在该组患者中还观察到了最大的胆酸和脱氧胆 酸的升高，此外，虽然在各组中都观察到鹅脱氧胆酸(CDCA)水平的增高，但糖尿病出现缓解的患者具有最大的增幅(P值均小于0.01)。

研究人员注意到，胆酸已被证实与胰岛素抵抗呈负相关，这就提示它可能在减肥手术后糖尿病缓解中起到了关键作用。

Argyropoulos 说，可能的机制或许是，随着手术的完成，胆汁酸分泌进入空的十二指肠并直接转运至远端的小肠，与回肠更加接近，而后者正是FGF19产生的部位。不与食物 相接触的胆汁酸可能更具生物活性，其或许可以改变肝脏葡萄糖氧化并刺激FGF19的产生。他补充说，这或许可以使肝脏重建对FGF19的敏感并继而促进体 内葡萄糖水平的稳定。

没有参与此项研究的纽约莱诺克斯山医院的Mitchell Roslin博士表示，该研究“非常有效”的证明了已知的观点，即胆汁酸在减肥手术中“是平衡的重要组成部分”。

Roslin说：“我并不认为这是胆汁酸或FGF19本身的作用，但我觉得它们是允许细菌或抗炎药物进入患者机体的乘客。”

他补充说，其他炎症性疾病也显示可以通过减肥手术获得缓解，其中包括牛皮癣和类风湿性关节炎。他说：“它们获得了明显的好转，我觉得这是相同的机制参与的结果。”

（丁香园：zf057)

ADA: Bile Acids Affect T2D After Bariatric Tx

A pathway involved in the production of bile acids may play a role in the remission of type 2 diabetes often seen after bariatric surgery, researchers reported here.

In an analysis of data from two cohort studies, diabetic patients who went into remission following Roux-en-Y gastric bypass (RYGB) surgery had the greatest increases in levels of fibroblast growth factor 19 (FGF19) and the greatest increases in total bile acids compared with diabetics who did not go into remission and with non-diabetic patients who had surgery (P<0.001 for both), according to George Argyropoulos, PhD, of Geisinger Health System in Danville, Pa., and colleagues.

They reported their findings in Diabetes Care and in the Diabetes Care symposium at the American Diabetes Association meeting.

"Patients in remission experienced the biggest changes in FGF19 and bile acids," Argyropoulos said. "We hypothesize that bile acids play a major role in FGF19, which ... may sensitize patients to insulin."

RYGB surgery leads to remission of diabetes in a large proportion of patients, but the mechanism behind this relationship isn't well understood. FGF19 has been associated with the regulation of hepatic bile acid production, so the researchers speculated that this pathway may play a role in that remission.

Argyropoulos and colleagues assessed data from two cohorts of bariatric surgery patients: one with 66 patients with diabetes and 54 patients without the disease; a second with 115 diabetic and 71 non-diabetic patients.

They split the cohort into three groups: RYGB patients without diabetes, RYGB with diabetes who had remission for at least 12 months after surgery, and RYGB patients with diabetes who didn't have remission of diabetes after surgery.

Pre-operatively, patients with diabetes had lower levels of FGF19 and higher bile acid levels than non-diabetic patients, "suggesting the possible presence of an impairment in the enterohepatic FGF19-[bile acid, (BA)] pathway in the diabetic state," the researchers wrote.

In genetic analyses, lower levels of FGF19 correlated with higher hepatic cholesterol 7 alpha-hydroxylase (CYP7A1) -- a modulator of bile acid production -- in diabetic patients, but not in non-diabetic patients (P<0.048).

Overall, the researchers found that serum FGF19 levels increased for the majority of all groups of patients following bariatric surgery, but diabetic patients who went into remission had the greatest increases of all three groups (P<0.001).

Diabetic patients in remission also had the greatest increases in total bile acids, they found (P<0.001). Specifically, the greatest increases in cholic and deoxycholic acids were seen in this group, and although all groups saw increases in chenodeoxycholic acid (CDCA), gains were greatest among those in remission from diabetes (P<0.01 for all).

The researchers noted that cholic acid has been inversely related with insulin resistance, suggesting it could play a key role in remission of diabetes after bariatric surgery.

Argyropoulos said the likely mechanism could be that with surgery, bile acids get secreted into an empty duodenum and travel directly to the distal small intestine, which is closer to the ileum, where FGF19 is produced.

These bile acids may be more bioactive since they don't come in contact with food, and may be able alter hepatic glucose oxidation and stimulate FGF19 production, he said, adding that this may re-sensitize the liver to FGF19 and promote glucose homeostasis.

Mitchell Roslin, MD, of Lenox Hill Hospital in New York City, who was not involved in the study, said the research is "very valid" given that it's been known that bile acids "are an important part of the equation" in bariatric surgery.

"I don't think it's the bile acids or FGF19 themselves, but I think they are passengers that allow bacteria or inflammatory agents to get into a patient's system," Roslin said.

He added that other inflammatory diseases also appear to be mediated by bariatric surgery, including psoriasis and rheumatoid arthritis.

"They get markedly better," he said, "and I think the same pathway is involved."

原文链接：http://www.medpagetoday.com/MeetingCoverage/ADA/40043

编辑： belinda_1231    来源：丁香园