Novel approaches to obesity: modulation of intestinal glucose absorption

治疗肥胖的新方法：调节肠道葡萄糖吸收

• 批准号: 7967534
• 负责人: MARK A LEVINE
• 金额: $ 17.62万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7967534
• 关键词: Address; Affect; Apical; Ascorbic Acid; Behavior; Canned Foods; Carbohydrates; Catabolism; Cell model; Cells; Clinical Research; Clinical Trials; Complex; Data; Databases; Diabetes Mellitus; Dietary intake; Enzymes; Fatty acid glycerol esters; Flavonoids; Food; Foundations; Fructose; GLUT2 gene; Glucose; Glucose Transporter; Health; Human; Incubated; Ingestion; Intestinal Absorption; Intestines; Learning; Location; Mediating; Nutrient; Obesity; Oocytes; Pathway interactions; Plasma; Preparation; Prevention; Quercetin; Research Personnel; Sodium; Specificity; Structure; System; Testing; Uncertainty; Vesicle; Xenopus laevis; Xenopus oocyte; absorption; base; brush border membrane; cholesterol absorption; fruits and vegetables; glucose transport; glucose uptake; glycosylation; in vivo; inhibitor/antagonist; novel; novel strategies; overexpression; polyphenol; research study; sugar

Explanation Diabetes and obesity are emerging worldwide health problems. New prevention and treatment options for both conditions could be based on strategies to dampen or inhibit nutrient absorption. Similar strategies are the basis of agents currently used clinically to inhibit fat absorption, cholesterol absorption, and intestinal catabolism of complex carbohydrates. A new class of agents that delayed or inhibited glucose absorption could have substantial impact in managing diabetes and obesity. Emerging evidence indicates that apical, or luminal facing, GLUT2 is a major pathway of sugar absorption, and is therefore an attractive target of such potential agents. Flavonoids are polyphenols that are widely distributed in foods, especially fruits and vegetables. Nutritive functions of flavonoids are unknown. Quercetin is a commonly ingested flavonoid, and 20-100 mg daily is ingested by dietary intake. Peak plasma concentrations of flavonoids such as quercetin do not exceed 1-2 umoles per liter after ingestion, but intestinal luminal concentrations are believed to be approximately 50 fold higher. Based on these high intraluminal concentrations, we proposed that a novel action of intraluminal flavonoids may be to dampen, re-distribute, or frankly inhibit intestinal absorption of candidate nutrients. Flavonoids either as food components or co-administered with foods could potentially have these actions, and such actions would not require flavonoids themselves to be absorbed. Partial support for this proposal was provided by data showing that some flavonoids found in foods inhibited vitamin C and glucose intestinal transport and absorption. The findings suggested that quercetin, the dominant flavonoid ingested by humans, may modulate glucose intestinal absorption by the sodium-independent facilitative glucose transporter GLUT2. Although these findings are promising, a number of uncertainties remain. Some investigators suggested that flavonoids decreased glucose uptake by a sodium-dependent pathway, via the sodium-dependent glucose transporter SGLT1. This conclusion was based on experiments using intestinal cells, brush border membrane vesicles, or Xenopus laevis oocytes expressing SGLT1. In cell and vesicle preparations it is difficult to distinguish which transporter(s) are inhibited, and the concentrations of substrates and flavonoids used in all of these experiments were not relevant to in vivo conditions. In systems where SGLT1 was either overexpressed in cells or in Xenopus oocytes, flavonoid effects on glucose transport were either modest or not directly tested. Other investigators suggested that flavonoids could be non-specific inhibitors, based on their behavior in isolated enzyme systems. It is uncertain which intestinal glucose transporters are inhibited by different flavonoids, which flavonoids are the most potent inhibitors of glucose transport, whether there is selectivity for inhibition of transport of different substrates, whether flavonoids must first be deglycosylated or transported for inhibition to occur, and whether the appropriate transporters are in the same location as the inhibitory concentrations of flavonoids. Addressing these issues would provide a clear data base of flavonoid action that could serve as the foundation of a pilot clinical study of flavonoid effects on sugar absorption. To test transporter specificity, we studied oocytes that were injected with cRNAs to express specific intestinal sugar transporters, and incubated these oocytes with a variety of flavonoids to determine potency. To learn whether flavonoid inhibition of sugar transport was specific for glucose transporters expressed only in oocytes, cell systems were also studied. Flavonoids, flavonoid concentrations, and sugar substrate concentrations were all selected to have in vivo relevance. We showed that several flavonoids were potent inhibitors of GLUT2-mediated glucose and fructose transport but had no effect on other major intestinal sugar transporters; that flavonoid structure and glycosylation affected inhibition; that GLUT2 overexpressed in cells and present in an intestinal cell model was inhibited by the relevant flavonoids; that GLUT2 was present in the proper location to be inhibited by luminal flavonoids; and that the potent inhibitor, quercetin, was not itself transported by GLUT2. Our findings provide the essential foundation for a pilot clinical study to move forward, and this can now proceed.

解释 糖尿病和肥胖症是全球性的健康问题。这两种疾病的新的预防和治疗方案可以基于抑制或抑制营养吸收的策略。类似的策略是目前临床上用于抑制脂肪吸收、胆固醇吸收和复合碳水化合物的肠内分解的药剂的基础。一类新的延迟或抑制葡萄糖吸收的药物可能对糖尿病和肥胖症的治疗产生重大影响。新出现的证据表明，顶端或腔面GLUT 2是糖吸收的主要途径，因此是此类潜在药物的有吸引力的靶点。 黄酮类化合物是多酚类物质，广泛分布于食品中，尤其是水果和蔬菜中。类黄酮的营养功能尚不清楚。槲皮素是一种常见的类黄酮，每天通过饮食摄入20-100 mg。类黄酮如槲皮素的血浆峰浓度在摄入后不超过1-2微摩尔/升，但肠腔浓度被认为高出约50倍。基于这些高的管腔内浓度，我们提出管腔内类黄酮的新作用可能是抑制、重新分布或直接抑制候选营养素的肠道吸收。 作为食物成分或与食物共同施用的黄酮类化合物可能具有这些作用，并且这些作用不需要黄酮类化合物本身被吸收。数据显示，食物中发现的一些类黄酮抑制维生素C和葡萄糖的肠道转运和吸收，这为这一提议提供了部分支持。研究结果表明，槲皮素，占主导地位的黄酮类化合物摄入的人类，可以调节葡萄糖肠道吸收的钠非依赖性促进葡萄糖转运蛋白GLUT 2。 虽然这些研究结果令人鼓舞，但仍存在一些不确定性。一些研究者认为，类黄酮通过钠依赖性葡萄糖转运蛋白SGLT 1通过钠依赖性途径降低葡萄糖摄取。这一结论是基于使用肠细胞、刷状缘膜囊泡或表达SGLT 1的非洲爪蟾卵母细胞的实验得出的。在细胞和囊泡制剂中，很难区分哪些转运蛋白被抑制，并且在所有这些实验中使用的底物和类黄酮的浓度与体内条件无关。在SGLT 1在细胞或非洲爪蟾卵母细胞中过表达的系统中，类黄酮对葡萄糖转运的影响是适度的或未直接测试。 其他研究人员认为，黄酮类化合物可能是非特异性抑制剂，基于它们在分离的酶系统中的行为。目前还不确定哪些肠道葡萄糖转运蛋白被不同的类黄酮抑制，哪些类黄酮是葡萄糖转运的最有效的抑制剂，是否存在对不同底物转运抑制的选择性，类黄酮是否必须首先去糖基化或转运抑制发生，以及合适的转运蛋白是否与类黄酮的抑制浓度处于相同的位置。 解决这些问题将提供一个明确的数据基础，类黄酮的行动，可以作为基础的试点临床研究类黄酮对糖的吸收的影响。为了测试转运蛋白特异性，我们研究了注射cRNA以表达特定肠糖转运蛋白的卵母细胞，并将这些卵母细胞与各种黄酮类化合物孵育以确定效力。为了了解类黄酮对糖转运的抑制是否对仅在卵母细胞中表达的葡萄糖转运蛋白具有特异性，还研究了细胞系统。 黄酮类化合物、黄酮类化合物浓度和糖底物浓度均被选择为具有体内相关性。我们发现，几种黄酮类化合物是GLUT 2介导的葡萄糖和果糖转运的有效抑制剂，但对其他主要的肠道糖转运蛋白没有影响;黄酮类化合物结构和糖基化影响抑制; GLUT 2在细胞中过表达并存在于肠细胞模型中被相关的黄酮类化合物抑制; GLUT 2存在于适当的位置被鲁米那黄酮类化合物抑制;而有效的抑制剂槲皮素本身并不通过GLUT 2转运。我们的研究结果为试点临床研究提供了必要的基础，现在可以继续进行。