Targeting a pathway that plays a major role in both hepatic glucose production and insulin sensitivity may eventually help treat type 2 diabetes, researchers reported.
In a series of experiments in mice, researchers found that inhibition of the kinase CaMKII -- or even some of its downstream components -- lowered blood glucose and insulin levels, Ira Tabas, MD, PhD, of Columbia University Medical Center in New York City, and colleagues reported online in Cell Metabolism.
The pathway is activated by glucagon signaling in the liver, and appears to have roles in both insulin resistance as well as hepatic glucose production in the liver.
In an earlier study, Tabas and colleagues showed that inhibiting the CaMKII pathway lowered hepatic glucose production by suppressing p38-mediated FoxO1 nuclear localization.
In the current study, they found CaMKII inhibition suppresses levels of the pseudo-kinase TRB3 to improve Akt-phosphorylation, thereby improving insulin sensitivity.
Thus this single pathway targets "two cardinal features of type 2 diabetes -- hyperglycemia and defective insulin signaling," the researchers wrote.
"When we realized we had one common pathway that was responsible for these two disparate processes that, in essence, comprise all of type 2 diabetes, we though it would be an ideal target for new drug therapy," Tabas told MedPage Today.
Tabas and colleagues conducted several experiments to evaluate the CaMKII pathway.
In one experiment in obese mice, they found that no matter how CaMKII was knocked out, it led to lower blood glucose levels and lower fasting plasma insulin levels in response to a glucose challenge.
The improvements also occurred when they knocked out downstream processes, including p38 and MAPK-activating protein kinase 2 (MK2).
"Thus liver p38 and MK2, like CaMKII, play an important role in the development of hyperglycemia and hyperinsulinemia in obese mice," they wrote.
In further analyses, the researchers discovered deleting or inhibiting any of these three elements ultimately improved insulin-induced Akt-phosphorylation in obese mice -- an important part of improving insulin sensitivity.
And unlike the effects on hepatic glucose production, these changes didn't occur through effects on FoxO1.
Instead, inhibiting the CaMKII pathway suppressed levels of the pseudo-kinase TRB3, which likely occurred because of suppression of ATF4 -- all of which led to an increase in Akt-phosphorylation and insulin sensitivity.
Indeed, when mice were made to overexpress TRB3, the improvement in phosphorylation disappeared, "indicating that the suppression of TRB3 by CaMKII deficiency is causally important in the improvement in insulin signaling," they wrote.
As a result, there "appear to be two separate CaMKII pathways, one involved in CaMKII-p38-FoxO1 dependent hepatic glucose production, and the other involved in defective insulin-induced p-Akt," they wrote.
The findings suggest the possibility of a drug that can target both hyperglycemia and insulin resistance in type 2 diabetes, they said.
The authors have started developing such an agent. Although kinases can act very generally, Tabas said he and colleagues are working on an allosteric version that will more specifically target MK2 by binding to a site that is unique to this enzyme.
He said this should help to avoid problems with drugs that targeted p38 but ultimately failed, with little efficacy and too many side effects.
"For reasons now known at a very detailed level, when you inhibit p38 by that mechanism, mainly by inhibiting MK2, you avoid the adverse effects," Tabas said. "When we realized all of this and had to make a choice [for further development], the obvious choice was MK2."
CaMKII inhibitors are in development for heart failure, and MK2 inhibitors are being looked at as an alternative to p38 inhibitors for inflammatory diseases.
Tabas also said the drug may be valuable in treating prediabetes, since early data have suggested that CaMKII is generally overactive in obese patients who have not yet progressed to full blown diabetes but is not overactive in lean people.
"One of the areas we're most excited about in potential clinical use is in obese people before they get diabetic," Tabas told MedPage Today. "There are hundreds of millions of people who are obese but not yet diabetic even though they have the hallmarks that they're going to get diabetes."
Tabas noted that his group's early human data "suggest that our pathway is turned on in prediabetes. If we can block that pathway before people get diabetes, it would even be better."
The study was supported by the NIH, the American Heart Association, the German Center for Cardiovascular Research, the German Ministry of Education and Research, and the European Union.
Tabas and a co-author are among the founders of Tabomedex Biosciences, which is developing MK2 inhibitors.