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. Chloroquine has been used for many years and has been shown to decrease blood sugar in diabetics, lower cholesterol and possibly lower blood pressure. Although chloroquine has been extensivley studied, its mechanisms of action are still vague. A novel potential mechanism for chloroquine has been identified based on currently unpublished work in mice. This mechanism relates to ATM. There is compelling evidence evidece that the ATM heterozygous state produces the metabolic syndrome in mice. Chloroquine, which activates ATM, decreases blood pressure, blood glucose, and atherosclerosis in mice (unpublished data). This data suggests that ATM plays an active role in mediating the metabolic syndrome in humans. To assess this we will enroll 25 volunteers ages 18-55 that meet the criteria of the metabolic syndrome. The experiment will be conducted in 3 limbs, with subjects acting as their own controls: 1) Placebo for 3 weeks, 2) Low dose chloroquine for 3 weeks (80 to 90 mg/day based on gender), 3) Chloroquine 250 mg/day for three weeks. Each limb will be followed by an oral glucose tolerance test, insulin clamp, ambulatory blood pressure monitoring, and various lab tests for atherosclerosis markers. Monocytes will be collected for in vitro work on markers of ATM activity. Our goal is to prove that chloroquine, acting through ATM, represents a novel potential treatment pathway for the metabolic syndrome. Providing this proof of concept will allow the development of new agents that target the ATM pathway and ultimately decrease vascular risk.
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