Bottomline: Linoleic acid Increases glucose production in a dose-dependent manner, which may be a key mechanism in the progression of Type II diabetes in obese people.  Am J Physiol Cell Physiol 295: C1518-C1527, 2008Am J Physiol Cell Physiol 295: C1518-C1527, 2008.

Background: Free fatty acid levels are often increased in obese individuals and have been implicated in the progression of obesity to type II diabetes. The liver plays a major role in regulating glucose levels by making, storing and releasing glucose in the blood.   Fatty acids have been proposed to directly influence gluconeogenesis in the liver, independent of hormones.  But the components of the signaling cascade have not been systemically investigated and until this study, remained largely unknown. Linoleic acid is the most abundant polyunsaturated fatty acid in the diet.

Study:  Scientists evaluated the effect of fatty acids on specific enzymes and transcription factors effecting glucose metabolism in liver cells.  Linoleic acid increased glucose production in a dose dependent manner, through its effect on several pathways.  There was an increase of the enzymes COX-2, cytosolic phospholipase A2 (cPLA2) and an increase in transcription factors.  The researchers proposed the following mechanism, illustrated below, whereby linoleic acid triggers a  calcium influx and cPLA₂, which stimulates arachidonic release, COX-2 activation, and PGE₂ production.  Linoleic acid also activates transcription factors, which subsequently increase gluconeogenic enzymes, ultimately increasing glucose production:

Study Quote: “Linoleic acid also acts through membrane lipids, as ligands for receptors and transcription factors that regulate gene expression, as precursor for eicosanoids, in cellular communication, and through direct interactions with proteins.”

Comment: This study adds another layer of concern about eating excessive omega-6 fats; because linoleic  acid was shown to directly trigger many biological responses.  One of the key concerns of eating excessive linoleic acid has been that it competes with the enzymes needed to make the potent omega-3 fatty acids, (EPA and DHA), which is akin to a biological game of musical chairs.  Except rather than grabbing for limited chairs, the omega-6 and omega-3 fatty acids vie for limited enzymes. When linoleic acid “wins” it uses the enzymes to make arachidonic acid, which is a key player in many inflammatory responses leading to chronic diseases from cancer to heart disease.

Link to Study:
Han Na Suh, Huang Thi Huong, Chang Hun Song, Jang Hern Lee, and Ho Jae Han.
Linoleic acid stimulates gluconeogenesis via Ca²⁺/PLC, cPLA₂, and PPAR pathways through GPR40 in primary cultured chicken hepatocytes .Am J Physiol Cell Physiol 295: C1518-C1527, 2008Am J Physiol Cell Physiol 295: C1518-C1527, 2008. First published doi:10.1152/ajpcell.00368.2008