People diagnosed as having Type 2 diabetes take drugs to teeter-totter the balancing act between pancreatic islet performance and liver management of glucose. Type 2 usually kicks in around 30 years of age, although it can hit much younger people. In 1992, researchers came upon a new form of the disease, which they named maturity onset diabetes of the young, Type 2 (MODY2). It turned out to be caused by genetic mutations in the glucokinase gene. MODY is a rare, mild affliction, occurring in non-obese adolescents.
Genes aside, a main cause of Type 2 diabetes is obesity, which is rapidly gaining on the world's populations. With that symptom come three other manifestations: hypertension, hyperlipidemia and coronary artery disease.
The July 18 issue of Science carries a paper titled "Allosteric [shifty enzyme] activators of glucokinase: Potential role in diabetes therapy," whose senior author, Joseph Grippo, is vice president of metabolic diseases at Hoffmann-La Roche (Nutley, New Jersey). The lead author is Joseph Grimsby, Roche's preclinical glucokinase activator project leader. "The overall message," they said in an interview with BBI's sister publication, BioWorld Today, "would be that we have made a novel discovery of an activator of the enzyme glucokinase [GK] that would represent a novel drug target for Type 2 diabetes. There are no marketed products that share this mode of action. We hope that should Hoffmann-La Roche bring GK to market, it would prove a first-in-class marketed product for Type 2 diabetes."
Grippo and Grimsby called the discovery "a major advance for the potential development of a new-model therapy for Type 2 diabetes." What's attractive about that particular approach, they said, is that it targets both insulin secretion and hepatic glucose production. "Both are defective in Type 2 diabetics. The tissue expression of glucokinase is predominantly in the beta cells of the pancreas and in the liver. So any drugs that would have an activity on GK would be controlling activity within those two organs."
As for epidemiology, they said, "we are looking at maybe 135 million anywhere up to 300 million diabetic patients. Some people may consider this epidemic proportions, what with obesity coming in earlier and earlier in children. There's an expectation that more kids will get Type 2 diabetes and not juvenile-onset, Type 1." With obesity being "a large, unmet medical need," the Roche researchers said that drug therapies in current use do not prevent further development of Type 2 diabetes. "There would be lots of room for early diagnosis, and what people in the industry feel is that there's room for new treatment modalities, to see if we can get increases in efficacy and manage the patients better."
Typically in first-line therapy, Grippo and Grimsby said a subject who is obese will be prescribed metformin. "If not obese, the drug of choice will sulfonylurea." As time goes on and the disease progresses, they said, "these treatments become ineffective and usually the second tier is a combination therapy of metformin and sulfonylurea together." As a class, all of these agents generally are not preventative of the disease. "So we in industry are looking to find unique ways of influencing a group of drugs treating diabetics," they said. "Most diabetics go from diet and exercise to oral therapy, ending up on insulin treatment. We think this is largely because we diagnosed too late to stop the progression of the disease."
So the Roche researchers asked, "Can we find better secretagogues that have unique mechanisms?" The enzyme glucokinase came up as an answer. "We have a better insulin secretagogue now that has two effects: one in the liver, one in the pancreas."
Grippo and Grimsby said they used a biochemical screen to first inactivate GK by mixing it with an inhibitory glucose kinase regulatory protein. "The complex of those two proteins together inhibits GK activity," they said. "We presented that inhibited enzyme to about 120,000 different random molecules of a particular subset from a library back in the early 1990s. We had GK down to the inhibitor's regulatory protein, and we asked the drug to increase GK activity."
The researchers noted that there is "little precedent in the industry for a small-molecule enzyme activator. It was unheard of. That's what makes this discovery so special." They added: "We found two classes of molecules: One relieved the inhibition induced by the regulatory protein, the other class of molecules directly activated GK in the absence of the regulatory protein."
Grimsby and Grippo conducted preclinical experiments with GK on rats and mice. "When we found that we could effect lowering of glucose in control animals, we asked the same question to a variety of rodents, and found that GK could lower glucose blood sugar levels in controls as well, and then we could decrease blood sugar levels in all the diabetic rats and mice." Then they gave oral glucose challenge tests to both wild-type and diabetic mouse and rat models, "and found that we could control the levels of glucose when our GK drug was on board.
"We did this in as many animal models as we could," the Roche researchers said. Eventually those studies were taken up through canine models, with similar results.