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T2DM is of epidemic proportions in the western hemisphere, having doubledin incidence in the past two decades. According to an article in the New YorkTimes on May 16, 2006, diabetes is the only disease in the U.S. with a deathrate that is still rising, accounting for over 225,000 deaths per year. It isestimated that there are at least 20 million diabetics in the USA, with athird still undiagnosed. In addition to the direct morbidity and mortalitydue to diabetes, elevated fasting blood glucose levels, even levels below thethreshold for a diabetes diagnosis, have been associated with a significantlyincreased risk of heart attack and stroke. The American Diabetes Associationhas estimated that $92 billion was spent in 2002 on diabetes care. Of that,$20 billion was for the diabetes drug market, accounting for over 12% oftotal pharmaceutical sales.
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Through its proprietary screening platform, MTI has identified multiplesmall molecule chemotypes that potently activate AMPK directly in vitro aswell as in cultured cells. MTI is in the process of applying for patentprotection on these novel core structures and simultaneously initiatingpreclinical studies on these lead series. MTI has also identified a number ofsmall molecules that stimulate AMPK activity indirectly in a variety ofmouse, rat and human cell lines. Of these cellular actives, MTI has been ableto demonstrate that this activity in cell culture corresponds to an effectin-vivo, inducing the accelerated clearance of elevated blood glucose levelsin mouse models. These assays were performed in two ways. In the first model,normal lean mice were challenged with a large dose of glucose and weretreated 20 minutes later with an AMPK activator. Mice that were treated witha known AMPK activator or with the MTI compounds showed an accelerated rateof clearance of blood glucose levels within 30 to 90 minutes of treatment,compared to mice who only received glucose.
AMPK plays a key role in maintaining cellular and whole body energybalance. It is found in all cells and tissues, but most importantly inskeletal muscle, liver, and adipose tissue. AMPK activation shifts bothintracellular and whole body metabolism away from cholesterol, fatty acid andtriglyceride synthesis (fat storage) and toward �²-oxidation (fat breakdown,energy production). Because exercise has similar metabolic effects inskeletal muscle to AMPK activation, AMPK has lightly been referred to as"exercise in a bottle" or the "jogging pill." There are several isoforms ofeach of the 3 subunits that comprise the AMPK protein, with AMPK�±2 beingthought of as the most appropriate target in skeletal muscle, while AMPK�±1is the predominant isoform in liver, which is thought to be activatedindirectly by a number of anti-diabetic drugs. AMPK activity is alsoupregulated by hormones secreted from the GI tract and from adipose tissue,including ghrelin, leptin, and adiponectin, and is inhibited by increases inamino acids, glucose, or insulin.
In T2DM
