Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy.

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Mookerjea, S. & Yung, J. W. M. (1974). A Study on the Effect of Lysolecithin and Phospholipase A on Membrane-Bound Galactosyltransferase. Can. 1. Biochem. 52, Addition of lysolecithin caused very marked activation of UDP-ga1actose:glycoprotein galactosyltransferase in rat liver microsomes and in Golgi-rich membranes. Lysolecithin activated galactosyltransferase when the enzyme was assayed both with endogenous acceptor and with exogenous proteins or monosaccharides as acceptors. Lactose synthetase activity in presence of a-lactalbumin was also stimulated by lysolecithin. Lecithin, lysophosphatidylethanolamine, lysophosphatidic acid, and glycerophosphorylcholine did not activate the enzyme, suggesting that both fatty acyl and phosphorylcholine groups of the lysolecithin molecule are required for the observed activation. The degree of activation was about the same when myristoyl-, palmitoyl-, oleoyl-, or stearoyllysolecithin were tested. The activation by lysolecithin was observed well within the physiological concentration of the lipid in the liver cell. Saturating amounts of Triton masked the effect of lysolecithin.Brief preincubation with phospholipase A activated the enzyme and generated lysolecithin in the membranes. Triton and lysolecithin activated the enzyme without any lag time, whereas phospholipase A activation was dependent on preincubation and also on an alkaline pH favorable for the hydrolysis of phospholipid. EDTA blocked the activation effect of phospholipase A but had no effect on activation by lysolecithin. Albumin and cholesterol opposed the effects of lysolecithin and phospholipase A on the enzyme. Two successive incubations of the microsomes with lysolecithin caused considerable release of the enzyme into the solrtble fraction. The role of lysolecithin in the activation of the enzyme is probably related to the solubilization of the membrane and consequent enhanced interaction of the enzyme with substrate. Lysolecithin also activated N-acetylglucosaminyland sialyltransferase activities in microsomes. A possible role of lysolecithin is indicated in the regulation of glycosylation reactions in mammalian system. Mookerjea, S. & Yung, J. W. M. (1974). A Study on the Effect of Eysolecithin and Phospholipase A on Membrane-Bound Galactosyltransferase. Can. 1. Bioche~n. 52, 1053-1666L9addition de 1ysolCcithine active de fagon trks marquke l'UBP-galactose:glycoprotCine galactosyltransfkrase dans les microsornes de foie de rat et dans les membranes golgiennes riches. La lysolkcithine active la galactosyltransfCrase, que la mesure de l'activitk soit faite avec un accepteur endogkne et avec des protkines exogknes ou des monosaccharides comme accepteurs. La lysslCcithine stimule aussi l'activitk de la lactose synthktase en prksence d'a-lactalbumine. La lkcithine, la lysophosphatidylkthanolamine, l'acide lysophosphatidique et la glyckrophosphorylcholine n'activent pas l'enzyme, ce qui suggkre que les groupes acyl gras et phosphoaylcholine de la molkcule de lysolkcithine sont requis pour l'activation observke....

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Oxidative stress caused by the exposure of pancreatic ß-cells to high levels of fatty acids impairs insulin secretion. This lipotoxicity is thought to play an important role in ß-cell failure in type 2 diabetes and can be prevented by antioxidants. Gamma-hydroxybutyrate (GHB), an endogenous antioxidant and energy source, has previously been shown to protect mice from streptozotocin and alloxan-induced diabetes; both compounds are generators of oxidative stress and yield models of type-1 diabetes. We sought to determine whether GHB could protect mouse islets from lipotoxicity caused by palmitate, a model relevant to type 2 diabetes. We found that GHB prevented the generation of palmitate-induced reactive oxygen species and the associated lipotoxic inhibition of glucose-stimulated insulin secretion while increasing the NADPH/NADP+ ratio. GHB may owe its antioxidant and insulin secretory effects to the formation of NADPH.

In obesity, chronically elevated circulating free fatty acids (FFA) potentially cause ß-cell dysfunction which leads to type 2 diabetes (T2D). In vitro data have identified various cellular mechanisms leading to FFA-induced ß-cell dysfunction including activation of inflammatory kinase c-Jun N-terminal kinase (JNK). In the ß-cell, JNK1 responds to oxidative stress or ER stress, which can both be caused by FFA. Previous in vitro studies from our group have demonstrated that islets of JNK1-null mice are protected from the effect of palmitate but not oleate on inducing ß-cell dysfunction, suggesting that activation of JNK1 is specific to saturated FFA. Thus, we hypothesized that saturated FFA-induced ß-cell dysfunction is mediated in part by JNK. Due to its detergent effects, palmitate cannot be infused directly into circulation. Thus, ethylpalmitate was used, as the ethyl group reduces the toxic effect. Mice can hydrolyze the ethyl group in circulation, producing palmitate and ethanol. JNK1-null (KO) mice and their littermate controls (WT) were infused with ethylpalmitate or ethanol vehicle for 48 hours, after which their pancreatic islets were isolated for ex vivo determination of insulin secretion. We confirmed that ethylpalmitate infusion does significantly increase plasma FFA as compared to vehicle infusion. We found that WT mice infused with ethylpalmitate demonstrated significantly decreased insulin secretion as compared with WT mice infused with vehicle, whereas JNK1-null mice infused with ethylpalmitate had similar insulin secretion as controls. These data suggest that JNK1 plays a causal role in saturated FFA-induced ß-cell dysfunction in vivo. Disclosure J. Yung: None. L. Yeung: None. A. Nahle: None. K. Koulajian: None. A. Giacca: Research Support; Self; Jazz Pharmaceuticals. Funding Canadian Institutes of Health Research