Diabetes mellitus comes in two main persuasions - Type I (insulin-dependent) and Type II (insulin non-dependent).

People who suffer from Type I must spend their lives shooting up insulin. Those diagnosed as having Type II take drugs to teeter-totter the balancing act between pancreatic islet performance and liver management of glucose. Diabetes Type II usually kicks in around 30 years of age, though it can hit much younger people. In 1992, researchers came upon a strange 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 diabetes Type II is obesity, which is rapidly gaining on the world's populations. With that symptom come three other manifestations: hypertension (high blood pressure), hyperlipidemia (high cholesterol) and coronary artery disease (forerunner of heart failure and ischemic stroke).

Today's Science, dated July 18, 2003, carries a paper titled "Allosteric [shifty enzyme] activators of glucokinase: Potential role in diabetes therapy." Its senior author, Joseph Grippo, is vice president of metabolic diseases at Hoffmann-La Roche Inc., of Nutley, N.J. The paper's lead author is Joseph Grimsby, Roche's preclinical glucokinase activator project leader. Both men shared this interview with BioWorld Today:

"The overall message of this paper," they said, "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 II 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 II diabetes.

"This is a major advance for the potential development of a new-model therapy for Type II diabetes. And what's attractive about this particular approach is that it targets both insulin secretion and hepatic glucose production. Both are defective in Type II 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."

Type II Takes No Prisoners, Kids And All

"As for epidemiology," the two continued, "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 II diabetes and not juvenile-onset, Type I.

"From the industry's perspective, obesity is a large, unmet medical need. The drug therapies in use do not prevent further development of Type II 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, 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, these treatments become ineffective and usually the second tier is a combination therapy of both metformin and sulfonylurea together.

"In general, as a class, all of these agents are not preventative of the disease. So we in industry, big and small, are looking to find unique ways of influencing a group of drugs treating diabetics. Most diabetics go from diet and exercise to oral therapy, ending up on insulin treatment. And we think this is largely because we diagnosed too late to stop the progression of the disease.

"We asked: Can we find better secretagogues that have unique mechanisms?' When we answered that question, the enzyme glucokinase came up. It is the key natural controlling point for glucose-induced insulin secretion. We have a better insulin secretagogue now that has two effects: one in the liver, one in the pancreas."

Grippo and Grimsby described how they created their GK compound: "Using a biochemical screen," they recounted, "we first inactivated GK by mixing it with an inhibitory glucose kinase regulatory protein. The complex of those two proteins together inhibits GK activity. We presented that inhibited enzyme to about 120,000 different random molecules of a particular subset from a library back in the early '90s. This was all done in 96-well dishes. A standard biochemical assay where we had GK down to the inhibitor's regulatory protein, and we asked the drug to increase GK activity."

Unheard-Of' Pharmaceutical Discovery

"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. 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 extensive preclinical experiments with GK on diabetes-prone and wild-type rats and mice. "In a nutshell," they began, "we looked first at control animals. Then we administered the drug orally to wild-type models, and looked to see a reduction in blood glucose. 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.

"The next thing we asked was what happens if you were to give sugar or mimic a postprandial treatment, such as eating a meal? Then we 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.

"These were the main approaches we took initially, and we did this in as many animal models as we could. In addition to that we looked at insulin levels as we characterized spikes of influence in response to the drug treatment. Then we more elegantly looked at the ability of this compound to suppress hepatic glucose production," they concluded, "and eventually these studies were taken up through canine models, with similar results."