Protein kinase C is increased in the liver of humans and rats with non-insulin-dependent diabetes mellitus: an alteration not due to hyperglycemia.

Abstract

We tested the hypothesis that liver protein kinase C (PKC) is increased in non-insulin-dependent diabetes mellitus (NIDDM). To this end we examined the distribution of PKC isozymes in liver biopsies from obese individuals with and without NIDDM and in lean controls. PKC isozymes a, 13, e and g were detected by immunoblotting in both the cytosol and membrane fractions. Isozymes y and 6 were not detected. There was a significant increase in immunodetectable PKC-a (twofold), -E (threefold), and -C (twofold) in the membrane fraction isolated from obese subjects with NIDDM compared with the lean controls. In obese subjects without NIDDM, the amount of membrane PKC isozymes was not different from the other two groups. We next sought an animal model where this observation could be studied further. The Zucker diabetic fatty rat offered such a model system. Immunodetectable membrane PKC-ci, -13, -e, and -t were significantly increased when compared with both the lean and obese controls. The increase in immunodetectable PKC protein correlated with a 40% elevation in the activity of PKC at the membrane. Normalization of circulating glucose in the rat model by either insulin or phlorizin treatment did not result in a reduction in membrane PKC isozyme protein or kinase activity. Further, phlorizin treatment did not improve insulin receptor autophosphorylation nor did the treatment lower liver diacylglycerol. We conclude that liver PKC is increased in NIDDM, a change that is not secondary to hyperglycemia. It is possible that PKCmediated phosphorylation of some component in the insulin signaling cascade contributes to the insulin resistance observed in NIDDM. (J. Clin. Invest. 1995Invest. .95:2938Invest. -2944

Time-dependent effects of Prkce deletion on glucose homeostasis and hepatic lipid metabolism on dietary lipid oversupply in mice

“…The liver is therefore the most likely site of PKCε action, as previously suggested [6][7][8][9]24], and we therefore focused our investigation on this tissue.…”

“…PKCε translocation was also observed in muscles of glucose-infused rats [3], obese Zucker rats [4] and the diabetes-prone sand rat, Psammomys obesus [5]. PKCε activation has also been reported in the liver of fat-fed rats [6], while increased PKCε levels have been found in liver biopsies from obese people with type 2 diabetes [7]. Mechanisms proposed to account for the inhibitory effects of PKCε include serine/threonine phosphorylation of the insulin receptor or insulin receptor substrate 1 (IRS1) to inhibit insulin signal transduction [1].…”

TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance

“…Among the serine kinases implicated in Ser phosphorylation of the IR and the IRSs, protein kinase C (PKC) is one candidate with potential pathophysiological relevance. Numerous studies have linked excessive PKC activity to diminished insulin sensitivity, especially to that occurring together with increased lipid availability (Considine et al 1995, Qu et al 1999, Itani et al 2000. We have previously reported that IR Ser994 is an in vitro phosphorylation target for PKC (Coba et al 2003).…”

Carbon tetrachloride-induced hepatic injury through formation of oxidized diacylglycerol and activation of the PKC/NF-κB pathway

“…28 Frozen rat liver was homogenized by a Potter homogenizer in 5 ml ice-cold homogenization buffer consisting of 25 mM Tris-HCI (pH 7.4), supplemented with protease inhibitor cocktail (Sigma). The homogenate was first centrifuged at 500 g for 5 min at 4 1C to remove tissue debris, then at 100,000 g for 60 min at 4 1C.…”