Augmented Insulinotropic Action of Arachidonic Acid through the Lipoxygenase Pathway in the Obese Zucker Rat

Abstract

Objective: The metabolism of arachidonic acid (AA) has been shown to be altered in severe insulin resistance that is present in obese (fa/fa) Zucker rats. We examined the effects and mechanism of action of AA on basal and glucose‐stimulated insulin secretion in pancreatic islets isolated from obese (fa/fa) Zucker rats and their homozygous lean (Fa/Fa) littermates. Research Methods and Procedures: Islets were isolated from 10‐ to 12‐week‐old rats and incubated for 45 minutes in glucose concentrations ranging from 3.3 to 16.7 mM with or without inhibitors of the cyclooxygenase or lipoxygenase pathways. Medium insulin concentrations were measured by radioimmunoassay, and islet production of the 12‐lipoxygenase metabolite, 12‐hydroxyeicosatetraenoic acid (12‐HETE), was measured by enzyme immunoassay. Results: In islets from lean animals, AA stimulated insulin secretion at submaximally stimulatory glucose levels (< 11.1 mM) but not at 16.7 mM glucose. In contrast, in islets derived from obese rats, AA potentiated insulin secretion at all glucose concentrations. AA‐induced insulin secretion was augmented in islets from obese compared with lean rats at high concentrations of AA in the presence of 3.3 mM glucose. Furthermore, the inhibitor of 12‐lipoxygenase, esculetin (0.5 μM), inhibited AA‐stimulated insulin secretion in islets from obese but not lean rats. Finally, the islet production of the 12‐HETE was markedly enhanced in islets from obese rats, both in response to 16.7 mM glucose and to AA. Discussion: The insulin secretory response to AA is augmented in islets from obese Zucker rats by a mechanism related to enhanced activity of the 12‐lipoxygenase pathway. Therefore, augmented action of AA may be a mechanism underlying the adaptation of insulin secretion to the increased demand caused by insulin resistance in these animals.

Activation of 12-lipoxygenase in proinflammatory cytokine-mediated beta cell toxicity

“…12LO expression has been shown to be upregulated in islets and beta cells by the proinflammatory cytokine IL-1β [18], and metabolic stresses [14,16,17]. Targeted deletion of leucocyte 12LO also yields protection from low-dose STZ-induced diabetes in the mouse [19].…”

“…12LO message expression is induced under hyperglycaemic conditions in rat islets [14] along with cyclooxygenase. In diabetic Zucker Fatty rats, elevated 12LO expression is associated with deficits in insulin secretion and beta cell decompensation [15][16][17]. 12LO message, protein and activity can be induced by the proinflammatory cytokine IL-1β in rat islets and insulin-secreting beta cells [18].…”

Dietary polyunsaturated fatty acids and their metabolites: Implications for diabetes pathophysiology, prevention, and treatment

“…Remarkably, 12-LOX knockout mice are protected from developing insulin resistance and β-cell destruction when fed a high-fat diet [98]. 12-LOX gene expression and 12-HETE production is upregulated in adipose tissue and islets from the Zucker diabetic rat, linking this pathway to the progression and development of insulin resistance in type 2 diabetes [99, 100]. Moreover, it was shown that rat islets treated with exogenous 11-HETE, 15-HETE, LTB 4 , and LTC 4 all inhibited insulin secretion [92].…”

The role of phospholipase A2-derived mediators in obesity

“…1) (17;17–19). Thus, it is important to understand the regulatory role of PLA 2 as the products of their hydrolytic activity have been implicated in the regulation of metabolic disorders (14;20–22). …”