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"Fasting pathway" points the way to new class of diabetes drugs

Reuben Shaw and Maria Mihaylova

Reuben Shaw and Maria Mihaylova

After a meal, insulin instructs muscle cells to squirrel away glucose for later use and turns off sugar production in the liver, ensuring that blood sugar levels don't rise too high. Conversely, the fasting hormone glucagon signals liver cells to flip on glucose production when supplies run low.

In many patients with type 2 diabetes, however, the body turns a deaf ear to insulin's urgent message, and as a result, the liver acts like a sugar factory on overtime, churning out glucose throughout the day, even when blood sugar levels are high. The most widely used drug to control blood glucose levels in type 2 diabetics is currently metformin.

A uniquely collaborative study led by researchers in the lab of Reuben J. Shaw recently uncovered a novel mechanism that turns up glucose production in the liver when blood sugar levels drop, pointing toward a new class of drugs for the treatment of metabolic disease. The findings, published in Cell, have revealed a crucial role for a group of enzymes called histone deacetylases (HDACs).

A few years ago, Shaw had discovered how metformin helps insulin control glucose levels: it binds to a "metabolic master switch" known as AMPK that blocks glucose production in the liver. Trying to identify novel targets of AMPK that might be relevant to diabetes, Maria Mihaylova, a graduate student in Shaw's laboratory, focused her efforts on a family of enzymes known as class II HDACs. Working closely with Ronald M. Evans, Mihaylova found that inhibiting class II HDACs shut down genes encoding enzymes needed to synthesize glucose in the liver. In collaboration with colleagues in Marc Montminy's lab, she also discovered that HDACs themselves associated with the DNA regulatory elements controlling the expression of the glucose-synthesizing enzymes, but only after she had treated cells with the fasting hormone glucagon. In response, chemical modifications on class II HDACs are removed, and they can translocate into the nucleus, where they bind to a key metabolic regulator that is shut down by insulin.

Recently, many drug companies have been developing HDAC inhibitors as anti-cancer drugs, so Shaw speculates that some of these compounds, which may or may not be useful for cancer, could have therapeutic potential for the treatment of insulin resistance and diabetes.