This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: The purpose of this study is to ascertain if the dietary supplement Ginkgo biloba extract has beneficial effects on selected cardiovascular risk factors such as plasma cholesterol levels and coagulation factors. It is hypothesized that Ginkgo biloba extract will improve lipid profile, decreasing total and LDL-cholesterol and increasing HDL cholesterol while reducing LDL oxidizability; that the extract will reduce platelet peroxidation, aggregability and blood hypercoagulability; and that it will improve renal function by reducing urinary platelet-activating factor and albumin excretion. A cluster of diseases are associated with insulin resistance, including the risks for cardiovascular disease. This study will attempt to demonstrate a compound whose biological activities may explain the associations found in the insulin resistance syndrome. RESEARCH PLAN: Herbal remedy is popular among those with chronic diseases, who may already be taking several prescription medications, thereby increasing the risk of drug-herb interactions. Ginkgo biloba extract is a popular dietary supplement that is ingested by the general population to enhance mental focus and by the elderly to delay onset of age-acquired loss of cognitive function. In subjects with non-insulin dependent diabetes (NIDDM), ingestion of Ginkgo biloba significantly increases pancreatic beta-cell function. The increased plasma C-peptide levels in response to glucose loading is accompanied by decreased plasma insulin levels and no significant changes in plasma glucose levels. The central hypothesis of this application is that ingestion of Ginkgo biloba produces the dissimilar plasma C-peptide/insulin ratios by increasing the metabolic clearance rates of insulin and the antidiabetic medications. The underlying mechanism may involve the alteration of drug pharmacokinetics resulting in decreased efficacy of the hypoglycemic agents and increased whole body insulin resistance. The primary objective of this study is to determine the mechanism by which Ginkgo biloba may accelerate pancreatic function and reduce glucose metabolism.
The specific aims of this project are to determine (a) the effect of ingesting Ginkgo biloba on the pharmacokinetics of glipizide, pioglitazone and metformin and (b) how the interaction between Ginkgo biloba and the three hypoglycemic agents affect the three homeostatic variables that control blood glucose levels: insulin synthesis, insulin action and hepatic glucose production. Background and Aims: We have previously shown that ingestion of Ginkgo biloba Extract (EGb 761) may increase pancreatic b-cell function in both healthy subjects as well as patients with Type 2 Diabetes mellitus (T2DM), especially T2DM patients with pancreatic exhaustion. Since hyperinsulinemia is a hallmark of T2DM, it is important to verify that an increase in insulin production is not the result of increased whole body insulin resistance. Method: Normal glucose tolerant (NGT) subjects (n=10; age, 44.2 +- 13.9 years old; BMI, 28.8 +- 5.7 kg/m2), impaired glucose tolerance (IGT) (n=6; age 51.3 +- 6.6 years old; BMI 33.2 +- 6.4 kg/m2) and T2DM subjects (n=8, 51.6 +- 15.2 years old; BMI, 29.5 +- 7.3 kg/m2) completed a randomized, double-blind, placebo-controlled crossover study. After blindly ingesting either EGb 761 (120 mg/day as a single dose) or placebo during each 3-month arm, a 2-step euglycemic insulin clamp was performed. CLINICAL
Because aging is a significant risk factor for the development of NIDDM as a result of a progressive decline in pancreatic function, and because the elderly chronically take multiple prescription medications, the increased use of Ginkgo biloba in this population may increase drug-herb interactions. Therefore, we shall examine the effect of Ginkgo biloba on the pancreatic function in the elderly to determine whether it may produce pancreatic dysfunction and a potential for the development of insulinopenia. The results of this study, when taken together should provide very important information on balancing the risk of accelerating pancreatic beta-cell dysfunction, with its beneficial effects on delaying the onset of cognitive function. The results of this study should also provide valuable information for designing new therapeutic strategies for the treatment of diseases in the insulin resistance syndrome.
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