Novel action of grape skin components on postprandial hyperglycemia

葡萄皮成分对餐后高血糖的新作用

• 批准号: 8578514
• 负责人: Kequan zhou
• 金额: $ 38.28万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578514
• 关键词: Abdomen; Acarbose; Acute; Adverse effects; Affect; American; Amylases; Animals; Anthocyanins; Antidiabetic Drugs; Antioxidants; Biological; Blood Glucose; Carbohydrates; Catechin; Clinical Research; Clinical Trials; Data; Development; Diabetes Mellitus; Diabetes prevention; Diabetic mouse; Diarrhea; Diet; Dietary Intervention; Dietary Supplementation; Dietary intake; Digestion; Drug Targeting; Eating; Enzymes; Fermentation; Functional disorder; Future; Glucose; Glucosidase Inhibitor; Goals; Grapes; Hepatic; Human; Hyperglycemia; In Vitro; Individual; Inflammatory; Intake; Intervention Studies; Intestines; Large Intestine; Lead; Mediating; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obese Mice; Oral; Pharmaceutical Preparations; Pre-Clinical Model; Prediabetes syndrome; Preparation; Prevention; Public Health; Reaction; Resveratrol; Role; Safety; Skin; Specificity; Staging; Starch; Stress; Supplementation; Testing; Toxic effect; Translations; United States; Weight Gain; absorption; base; conventional therapy; cost; db/db mouse; diabetes control; diabetes management; diabetic; dietary antioxidant; dietary starch; evidence base; gastrointestinal; glucose output; glucose uptake; glucosidase; glycemic control; impaired glucose tolerance; improved; inhibitor/antagonist; insight; insulin secretion; mouse model; novel; pandemic disease; pre-clinical; prevent; public health relevance

DESCRIPTION (provided by applicant): Diabetes has become a major public health problem and is emerging as a pandemic. There is a strong need for developing novel complementary and alternative strategies for controlling diabetes. Our long-term goal is to develop a safe and effective nutritional intervention to support diabetes prevention and treatment. The objective of this application is to identify novel unique ¿-glucosidase-inhibiting components in GSE, to elucidate the role of these components in lowering postprandial hyperglycemia, and to further assess the safety and efficacy of the GSE components in preclinical models for preventing and treating type-2 diabetes. GSE is a nutritional antioxidant supplement used frequently by the American public. We have recently found that that GSE intake exerts a novel inhibitory activity on postprandial hyperglycemia in diabetic mice, which is related to its specific inhibition of intestinal ¿-glucosidases. Furthermore, we showed that dietary supplementation of GSE significantly reduced blood glucose in diet-induced obese mice independent of its effects on food intake, weight gain, or antioxidant activity. More recently, we demonstrated that oral intake of GSE significantly reduced postprandial blood glucose in humans. We therefore hypothesize that the novel inhibitory action of GSE on postprandial hyperglycemia is primarily mediated by specific inhibition of intestinal ¿-glucosidases, and GSE and its active components could be developed and used as a safe and targeted nutritional intervention to support diabetes prevention and treatment. To test our hypothesis, we will pursue three aims: Aim 1 is to identify active ¿-glucosidase-inhibiting components in GSE and further determine their inhibitory mechanisms. We will employ an activity-driven approach to isolate and identify active components in GSE. We will then determine their specificity, inhibitory mode, and possible additive/synergistic effects on specific ¿- glucosidases. Aim 2 is to determine mechanisms underlying the novel inhibitory action of GSE on postprandial hyperglycemia. We will use a type-2 diabetic model to determine whether active ¿-glucosidase-inhibiting components are responsible for lowering postprandial hyperglycemia; and whether these components primarily act on ¿-glucosidases to ameliorate postprandial hyperglycemia. Aim 3 is to determine the efficacy and safety of GSE components in preclinical models for preventing and treating type-2 diabetes. We will perform three studies: Study 1 is an acute intake study to determine the most effective GSE preparation for treating postprandial hyperglycemia in db/db mice; Study 2 is to determine whether dietary supplementation of our GSE preparation can prevent the onset of diet-induced diabetes in diet-induced obese mice; and Study 3 is to determine whether our GSE preparation, following the onset of diabetes, can improve glycemic control in db/db mice. This transitional study will provide important preclinical data regarding the antidiabetic mechanisms, biological efficacy, and safety of GSE that should facilitate eventual translation into future clinical studies to assess GSE and its components as a safe, low cost, and evidence-based nutritional intervention for diabetes.

描述（由申请人提供）：糖尿病已成为一个主要的公共卫生问题，并正在成为一种流行病。目前迫切需要开发新的补充和替代策略来控制糖尿病。我们的长期目标是开发一种安全有效的营养干预来支持糖尿病的预防和治疗。本申请的目的是鉴定GSE中新颖独特的-葡萄糖苷酶抑制成分，阐明这些成分在降低餐后高血糖中的作用，并进一步评估GSE成分在预防和治疗2型糖尿病的临床前模型中的安全性和有效性。GSE是美国公众经常使用的一种营养抗氧化剂补充剂。我们最近发现，摄入GSE对糖尿病小鼠餐后高血糖有一种新的抑制作用，这与GSE对肠道-葡萄糖苷酶的特异性抑制有关。此外，我们发现，在饮食中补充GSE可以显著降低饮食诱导的肥胖小鼠的血糖，而不受其对食物摄入、体重增加或抗氧化活性的影响。最近，我们证明口服GSE可显著降低人类餐后血糖。因此，我们假设GSE对餐后高血糖的新型抑制作用主要是通过特异性抑制肠道-葡萄糖苷酶介导的，GSE及其活性成分可以作为一种安全、有针对性的营养干预手段来支持糖尿病的预防和治疗。为了验证我们的假设，我们将追求三个目标：目标1是鉴定GSE中活性-葡萄糖苷酶抑制成分，并进一步确定其抑制机制。我们将采用活动驱动的方法来隔离和识别GSE中的活动组件。然后，我们将确定它们的特异性，抑制模式，以及对特定-葡萄糖苷酶可能的加性/协同作用。目的2是确定GSE对餐后高血糖的新型抑制作用的机制。我们将使用2型糖尿病模型来确定活性-葡萄糖苷酶抑制成分是否负责降低餐后高血糖；以及这些成分是否主要作用于-葡萄糖苷酶以改善餐后高血糖。目的3是确定GSE成分在预防和治疗2型糖尿病的临床前模型中的有效性和安全性。我们将进行三项研究：研究1是一项急性摄入研究，以确定治疗db/db小鼠餐后高血糖的最有效的GSE制剂；研究2是为了确定在饮食中添加我们的GSE制剂是否可以预防饮食性肥胖小鼠饮食性糖尿病的发生；研究3是确定我们的GSE制剂在糖尿病发病后是否可以改善db/db小鼠的血糖控制。这项过渡性研究将为GSE的抗糖尿病机制、生物学功效和安全性提供重要的临床前数据，这些数据将有助于最终转化为未来的临床研究，以评估GSE及其成分作为一种安全、低成本、循证的糖尿病营养干预措施。