We have investigated the mechanism by which high concentrations of glucose inhibit insulin stimulation of glycogen synthase. In NIH-3T3-L1 adipocytes cultured in low glucose (LG; 2.5 mM), the half-maximal activation concentration (A 0 Glycogen synthase, which incorporates activated glucose into glycogen, is a major gatekeeper of carbohydrate metabolism. The enzyme is highly regulated, both allosterically and by several kinases and phosphatases (1, 2). Phosphorylation inactivates the enzyme. The process is complex, since there are nine phosphorylation sites, targeted by several kinases, each with different effects on enzyme activity (3-5). The inactivation of glycogen synthase can be overcome by allosteric interaction with glucose 6-phosphate (G6P) 1 (6). Insulin stimulates glycogen synthase primarily through the phosphatidylinositol 3-kinase/Akt pathway, resulting in inhibition of glycogen synthase kinase-3 and dephosphorylation of the enzyme by protein phosphatase 1 (1,7,8). Protein phosphatase 1 is itself regulated by stimulation and by specific targeting to glycogen (9 -11). With activation by insulin, glycogen synthase becomes more sensitive to G6P, and basal, G6P-independent activity is increased. In type 2 diabetes mellitus there is resistance to the stimulation of glycogen synthase by insulin and a reduction of glycogen synthase activity (12)(13)(14). How this insulin resistance is triggered is not known. Work from Marshall's laboratory originally suggested that insulin resistance could be mediated by an increase in carbohydrate flux through the hexosamine biosynthesis pathway (HBP) (15). Consistent with that hypothesis, acute infusions of glucosamine or transgenic overexpression in muscle and fat of the rate-limiting enzyme in the HBP, glutamine:fructose-6-phosphate amidotransferase, result in insulin resistance (16,17)..The terminal metabolites of the hexosamine pathway are UDP-hexosamines. UDP-N-acetylglucosamine is a substrate for the cytosolic UDP-N-acetylglucosamine:peptide glycosyltransferase (OGT), which glycosylates nuclear and cytosolic proteins with a single N-acetylglucosamine moiety on serine and threonine residues (O-GlcNAc) (18,19). This recently described protein modification is in many ways analogous to phosphorylation; it is dynamic and has been shown to occur exclusively on phosphoproteins. Additionally, it has been shown to often have a reciprocal relationship with the degree of phosphorylation of a protein (20,21). Recent studies have suggested possible links between the O-GlcNAc modification on proteins and the pathogenesis of diabetes and insulin resistance. For example, insulin resistance of endothelial nitric-oxide synthase stimulation results when the Akt phosphorylation site of endothelial nitric-oxide synthase is modified by O-GlcNAc (22). Transgenic overexpression of OGT in skeletal muscle and fat results in the development of insulin resistance in mice, mimicking the effects of increased hexosamine flux (23).We have previously demonstrated that treatment of fibroblasts with h...
Carnitine-acylcarnitine translocase (CACT) deficiency is a rare disorder of long chain fatty acid oxidation with a very high mortality rate due to cardiomyopathy or multiorgan failure. We present the course of a very premature infant with early onset CACT deficiency complicated by multiple episodes of necrotizing enterocolitis, sepsis, and liver insufficiency, followed by eventual demise. The complications of prematurity, potentiated by the overlay of CACT deficiency, contributed to the difficulty of reaching the ultimate diagnosis of CACT deficiency.
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