CMPF could offer a new target for diabetes

A potential culprit for diabetes in pregnancy (gestational diabetes) and type 2 diabetes has been identified in a recent study published in Cell Metabolism.

Gestational diabetes can affect up to 5% of pregnant women, at least in the UK, and can develop in the absence of any previous history of intolerance to glucose. Women with this condition have higher than normal levels of glucose in their blood, usually because their bodies do not produce enough insulin to transport glucose into the cells. The mechanism underlying the development of this condition has remained a mystery, although it has been linked with a decline in the function of pancreatic β cells, the cells that produce insulin.

An imbalance of metabolites

When the authors screened the blood plasma of women with gestational diabetes, they found a significant change in metabolites compared with women without this disease, in particular in the levels of a range of fatty acids. Among this was the furan fatty acid metabolite CMPF, which was greatly increased in those with gestational diabetes. Interestingly, levels of CMPF were also increased in patients with type 2 diabetes compared with controls, and in both cases this was independent of BMI or age.

Experiments in mice and mouse cells then showed that treatment with CMPF results in reduced insulin secretion in response to the presence of glucose. 

So how is this achieved? The authors carried out a range of experiments to determine the mechanism by which CMPF blocks glucose-stimulated secretion, and found that CMPF enters β cells  through a transporter known as OAT3 (organic anion transporter 3). This results in oxidative stress and the production of reactive oxygen species, blocking a signalling pathway involving the molecules AKT and GSK3β, and ultimately interfering with the production and processing of insulin.

Importantly, blocking the OAT3 transporter, and thus CMPF entry into the cell, prevented the negative effects of CMPF on insulin synthesis and, consequently, the impaired glucose-stimulated insulin secretion. 

Could targeting CMPF offer a new therapeutic avenue for gestational and type 2 diabetes? Further work is obviously required at this point, but given that oxidative stress have in fact previously been implicated in the pathology of type 2 diabetes, this is certainly something that needs to be explored further.