Biologists at UC San Diego have discovered a chemical that offers a completely new and promising direction for the development of drugs to treat metabolic disorders such as type 2 diabetes — a major public health concern in the United States due to the current obesity epidemic.
Now Kay and his team have discovered a small molecule — one that can be easily developed into a drug — that controls the intricate molecular cogs or timekeeping mechanisms of cryptochrome in such a manner that it can repress the production of glucose by the liver. Like mice and other animals, humans have evolved biochemical mechanisms to keep a steady supply of glucose flowing to the brain at night, when we’re not eating or otherwise active.
“At the end of the night, our hormones signal that we’re in a fasting state,” said Kay. “And during the day, when we’re active, our biological clock shuts down those fasting signals that tell our liver to make more glucose because that’s when we’re eating.”
Diabetes is caused by an accumulation of glucose in the blood, which can lead to heart disease, strokes, kidney failure and blindness. In type 1 diabetes, destruction of insulin producing cells in the pancreas results in the high blood sugar. In type 2 diabetes, which makes up 90 percent of the cases, gradual resistance to insulin because of obesity or other problems, leads to high blood sugar.
What he and his team found in their most recent discovery was that a much smaller molecule, dubbed “KL001” (for the first such compound from the Kay Lab), can regulate that activity as well. It slowed down the biological clock by stabilizing the cryptochrome protein — that is, it essentially prevented crypotochrome from being sent to the cellular garbage can, the proteasomes.
Continuing his search, Hirota resumed his efforts to acquisition added chemicals that diffuse or slowed bottomward circadian rhythms, enabling the scientists to accept added about the intricate actinic and abiogenetic accouterment of the biological clock. He and his colleagues in Kay’s lab did this by screening bags of compounds from a actinic library with animal beef in alone micro-titer wells in which a luciferase gene from fireflies is absorbed to the biological alarm machinery, enabling the scientists to ascertain a afterglow whenever the biological alarm is activated. Their atomic fishing campaign came up with a cardinal of added compounds, one of which was KL001.
“In abrasion alarmist cells,” said Kay, “we showed that KL001 inhibited gene announcement for gluconeogenesis that is induced back apparent to the hormone glucagon, which promotes glucose assembly by the liver. It’s a hormone we all aftermath in abnegation states. And our compound, in a dosage abased way, inhibits hepatic gluconeogenesis, the absolute assembly of glucose by those alarmist cells.”
Kay said the abutting footfall for the analysis accumulation is to accept how KL001 and agnate molecules that affect cryptochrome action in active systems, such has class mice. The scientists additionally plan to delving how such compounds affect added processes besides the alarmist that may tie the biological alarm to metabolic diseases. “As with any abruptness discovery,” he notes, “this opens the aperture to added opportunities for atypical analysis than we can currently imagine.”