Future Challenges
Endocrine Disorders
Diabetes is a scourge of western societies. Nine out of 10 diabetic patients have type 2 diabetes (also know as adult or non-insulin dependent), which is linked to obesity and aging, and occurs when body tissues become insensitive to insulin.
A research project at the Merck Frosst Centre for Therapeutic Research arose from the hypothesis that phosphatase enzymes, a class of molecules that represent one of the body's most fundamental control mechanisms, are implicated in type 2 diabetes.
Starting from scratch, the researchers made an informed guess as to which of the fifty known tyrosine phosphatases might be involved, and they were proved right. Their elucidation of the central role of protein tyrosine phosphatase 1B (PTP-1B) in activating the insulin receptor galvanized the scientific community when it was published in the journal Science in 1999.
In collaboration with researchers at McGill University in Montréal, the Merck Frosst team targeted the gene for PTP-1B and created a knockout mouse that lacked the PTP-1B enzyme. The "McGill mouse" is much more insulin sensitive that its wild-type counterpart and, surprisingly, no matter how much it eats, never becomes obese. This work was backed up by basic research at Merck Frosst demonstrating that PTP-1B was involved in dephosphorylating the insulin receptor.
The researchers' efforts are now focussed on the hunt for a PTP-1B inhibitor that sensitizes the insulin receptor in vivo, and is sufficiently potent, safe and bioavailable for use in humans. The team has a number of exciting candidates currently under investigation. Possible therapeutic applications for such a medication extend well beyond diabetes, into the treatment of obesity, the root cause of type 2 diabetes and many other chronic disorders including the most important killer of them all: cardiovascular disease.
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