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
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.
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
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
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
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, Roches 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.
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,
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
- 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.