Glucokinase activators offer a potentially promising therapeutic approach for type 2 diabetes

Summer not only signifies the end of another academic year, it also ushers in the major diabetes and endocrine annual meetings. I would like to briefly discuss an interesting and novel class of agents for treating diabetes that you will undoubtedly be hearing and reading more about — the glucokinase activators. These compounds are a potentially promising therapeutic approach for patients with type 2 diabetes.

Glucokinase is a key enzyme in glucose homeostasis and acts in the liver and pancreas. In the liver, glucokinase mediates gluconeogenesis, glucose utilization and glycogen synthesis. In the beta cells of the pancreas, glucokinase is the rate-limiting enzyme in glucose-stimulated insulin release. Glucokinase activators (GKAs) may additionally have a third effect — antagonizing apoptosis in B cells. GKAs can potentially affect the beta cells of the pancreas by improving glucose-sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring postprandial glucose uptake and storage as glycogen.

Glucokinase phosphorylates glucose to glucose 6-phosphate, the first step in glycolysis. Glucokinase is expressed mostly in metabolically active tissues: the liver, pancreas, brain and gut.

Because glucokinase has a lower affinity for glucose than other hexokinases and is not inhibited by its product, it lowers glucose levels by enhancing the capability of pancreatic islet beta cells to sense blood glucose concentrations and thus determines the threshold for insulin secretion. Therefore, glucokinase activity increases with rising postprandial glucose concentrations to elevate hepatic glucose uptake while suppressing hepatic glucose production.

Research to date

Animal studies have demonstrated that if the glucokinase gene is disrupted, mice die within days of birth from severe diabetes. Heterozygous loss-of-function mutations in the glucokinase gene can result in maturity onset diabetes of the young — type 2, which is linked to defective insulin secretion. The over-expression of glucokinase results in decreased basal blood glucose levels, as well as resistance to developing type 2 diabetes. Mutations in humans that increase enzyme activity cause hyperinsulinemic hypoglycemia.

Edward C. Chao

GKAs have reduced blood glucose in several animal models of type 2 diabetes. Ro-28-1675 was the first GKA noted to reduce blood glucose after an oral glucose tolerance test in several models of type 2 diabetes in rodents. This compound also lowered basal glucose in diet-induced obese mice, which underwent fasting for 2 hours; an accompanying rise in insulin was also noted. Ro-28-1675 attenuated endogenous glucose production and elevated hepatic glucose disposal.

Another compound was discovered, PSN-GK1, which has greater safety and metabolic stability. This agent lowered basal glucose in normal mice and improved glucose tolerance in Zucker diabetic fatty rats placed on a high-fat diet.

A double blind, placebo-controlled, randomized, multiple-ascending dose study of an agent, RO4389620, in type 2 diabetes patients examined first dose and steady state pharmacodynamics and pharmacokinetics in fasting and fed conditions. The study included 59 patients aged 40 to 69 years with diabetes for 0.7 to 29.3 years and a mean BMI of 22 to 37. Researchers compared daily dosing of 200 mg of the agent vs. twice-daily dosing (10 mg, 25 mg, 50 mg and 100 mg plus 200 mg). The study medication was administered first as a single dose, and then consecutively daily for 6 days and twice daily for 5.5 days.

Patients demonstrated a rapid, dose-dependent 24-hour glucose reduction that was secondary to declines in fasting and postprandial plasma glucose. There were no deaths or serious adverse events noted, including no serious hypoglycemia. The most common adverse event was headache; this did not bear a discernable relationship with dose. Two of eight patients on daily dosing of 200 mg experienced symptomatic hypoglycemia. Four of nine patients on the 200-mg twice-daily dose were observed to be hypoglycemic. RO4389620 appeared to be well-tolerated.

Among the findings reported in a study on ARRY-403, presented at the 2009 European Association for the Study of Diabetes meeting, dose-dependent decreases in glucose were shown in a 28-day investigation in obese mice: –30%, –49% and –62% at 3 mg/kg, 10 mg/kg and 30 mg/kg compared with vehicle. Administration of this compound yielded fasting and postprandial blood glucose readings comparable to those of normal mice.

Roche was the first pharmaceutical company to bring a GKA into clinical trials. It put two others, piragliatin (R 1440) and R 1511, into phase 2 and phase 1 studies, respectively. However, Roche’s GKAs were discontinued from further development; the reasons have not been disclosed.

AstraZeneca, OSI/Prosidion in conjunction with Eli Lilly, and Merck have been in and are continuing phase 1 and phase 2 investigations. Results of a phase 1, single ascending-dose study in healthy people, with daily and three-times daily dosing of the Merck agent, MK-0599, were presented in abstract form. Significant declines in plasma glucose were detected at doses of 50 mg three-times daily or more. Hypoglycemia, however, was observed with doses of 25 mg or more.

A single ascending-dose study of ARRY-403 in patients with type 2 diabetes, which has not yet been reported in an abstract, indicated that this agent lowered fasting and postprandial glucose, and the pharmacokinetics appeared to suggest that once-daily dosing was feasible. A multiple ascending-dose study is currently under way. Further data for the other agents have not yet been reported. Adverse effects may include significant hypoglycemia and accumulation of GKAs in hepatic fat with long-term use.

Potential significant advance

If future studies bear out from these and other early investigations, GKAs would represent a significant advance in clinical therapeutic agents for diabetes because of their unique dual mechanism of potentially acting on both the beta cells of the pancreas; improving glucose sensitive insulin secretion, as well as the liver; reducing uncontrolled glucose output; and restoring postprandial glucose uptake and storage as glycogen.

Other functions of glucokinase may be uncovered. For instance, administration of a GKA centrally could suppress hypothalamic and brainstem neuronal circuits. Consequently, appetite and energy balance might be affected, and an additional clinical application for obesity could be realized.

Although the preclinical and early phase 1 studies suggest promise for these agents, further studies will be needed to elucidate efficacy, safety and tolerability in large numbers of patients in clinical trials.

This is my best attempt at a trenchant analysis of these agents, with the preliminary information that we currently have available. What forthcoming data will show should be interesting.

Edward C. Chao, DO, is assistant clinical professor of medicine at University of California, San Diego, and staff physician at VA Medical Center, San Diego.

For more information:

• Froguel P. N Engl J Med. 1993;328:697-702.
• Fyfe MC. Diabetologia. 2007;50:1277-1287.
• Gloyn AL. Diabetes. 2003;52:2433-2440.
• Grimsby J. Science. 2003;301:370-373.
• Hinklin RJ. ARRY-403, a glucokinase activator with potent glucose-dependent anti-hyperglycemic activity in animal models of type 2 diabetes mellitus: first-in-patient clinical results. Presented at: European Association for the Study of Diabetes 45th Annual Meeting; Sept. 29-Oct. 2, 2009; Vienna, Austria.
• Migoya EM. The glucokinase (GK) activator MK-0599 lowers plasma glucose concentrations in healthy non-diabetic subjects. Presented at: American Diabetes Association 69th Scientific Sessions; June 5-9, 2009; New Orleans.
• Postic C. J Biol Chem. 1999;274:305-315.
• Zhai S. Phase I assessments of a novel glucokinase activator RO4389620 in healthy male volunteers. Presented at: European Association for the Study of Diabetes 44th Annual Meeting; Sept. 7-11, 2008; Rome.