The conversion of homocysteine to methionine is substantially (approximately 30%) decreased in hemodialysis patients, whereas transsulfuration is not. Decreased remethylation may explain hyperhomocysteinemia in ESRD. This stable isotope technique is applicable for developing new and effective homocysteine-lowering treatment regimens in ESRD based on pathophysiological mechanisms.

Glycogen storage disease type 1a (GSD-1a) is a metabolic disorder characterized by fasting-induced hypoglycemia, hepatic steatosis, and hyperlipidemia. The mechanisms underlying the lipid abnormalities are largely unknown. To investigate these mechanisms seven GSD-1a patients and four healthy control subjects received an infusion of [1-13 C]acetate to quantify cholesterogenesis and lipogenesis. In a subset of patients, [1-13 C]valine was given to assess lipoprotein metabolism and [2-13 C]glycerol to determine whole body lipolysis. Cholesterogenesis was 274 Ϯ 112 mg/d in controls and 641 Ϯ 201 mg/d in GSD-1a patients (p Ͻ 0.01). Plasma triglyceride-palmitate derived from de novo lipogenesis was 7.1 Ϯ 9.4 and 86.3 Ϯ 42.5 mol/h in controls and patients, respectively (p Ͻ 0.01). Production of VLDL did not show a consistent difference between the groups, but conversion of VLDL into intermediate density lipoproteins was relatively retarded in all patients (0.6 Ϯ 0.5 pools/d) compared with controls (4.3 Ϯ 1.8 pools/d). Fractional catabolic rate of intermediate density lipoproteins was lower in patients (0.8 Ϯ 0.6 pools/d) compared with controls (3.1 Ϯ 1.5 pools/d). Whole body lipolysis was similar, i.e., 4.5 Ϯ 1.9 mol/kg/ min in patients and 3.8 Ϯ 1.9 mol/kg/min in controls. Hyperlipidemia in GSD-1a is associated with strongly increased lipid production and a slower relative conversion of VLDL to LDL. (Pediatr Res 63: 702-707, 2008) G lycogen storage disease type 1a (GSD-1a, von Gierke Disease, OMIM#232200) is caused by deficiency of glucose-6-phosphatase ␣ (G6Pase-␣), which catalyzes the terminal steps in gluconeogenesis and glycogenolysis by converting glucose-6-phosphate to glucose and phosphate. G6Pase-␣ deficiency results in an inability to release glucose from liver, kidney, and possibly intestine. Phenotypical, G6Pase-␣ deficiency is characterized by growth retardation, hypoglycemia, hepatomegaly (massive hepatic steatosis) and lactic acidemia, as well as hypertriglyceridemia and hypercholesterolemia (1). Increased concentrations of cholesterol are found in both very LDL (VLDL) and LDL fractions whereas HDL cholesterol and apolipoprotein A-I concentrations are usually decreased (2,3). To control hypoglycemia in GSD-1a, patients often receive uncooked cornstarch which is accompanied by reductions in plasma lipid levels in GSD-1a (4,5). The underlying mechanisms responsible for disturbed lipid metabolism in GSD-1a are largely unknown. We have previously reported increased rates of hepatic de novo lipogenesis and cholesterogenesis in two patients with GSD-1a (6), which may drive VLDL production by the liver. Lipogenesis and cholesterogenesis have both been implicated in regulation of VLDL secretion (7-9). In addition, insulin is known to suppress hepatic VLDL production (10): prevailing low insulin concentrations in GSD-1a patients may contribute to increased VLDL production in these subjects, but quantitative data are not available. Furthermore, defective lipoprotein lipolysis might also contribute to hy...

Type 2 diabetes in humans is associated with increased de novo lipogenesis (DNL), increased fatty acid (FA) fluxes, decreased FA oxidation, and hepatic steatosis. In this condition, VLDL production is increased and resistant to suppressive effects of insulin. The relationships between hepatic FA metabolism, steatosis, and VLDL production are incompletely understood. We investigated VLDL-triglyceride and -apolipoprotein (apo)-B production in relation to DNL and insulin sensitivity in female ob/ob mice. Hepatic triglyceride (5-fold) and cholesteryl ester (15-fold) contents were increased in ob/ob mice compared with lean controls. Hepatic DNL was increased ϳ10-fold in ob/ob mice, whereas hepatic cholesterol synthesis was not affected. Basal rates of hepatic VLDL-triglyceride and -apoB100 production were similar between the groups. Hyperinsulinemic clamping reduced VLDL-triglyceride and -apoB100 production rates by ϳ60% and ϳ75%, respectively, in lean mice but only by ϳ20% and ϳ20%, respectively, in ob/ob mice. No differences in hepatic expression of genes encoding apoB and microsomal triglyceride transfer protein were found. Hepatic expression and protein phosphorylation of insulin receptor and insulin receptor substrate isoforms were reduced in ob/ob mice. Thus, strongly induced hepatic DNL is not associated with increased VLDL production in ob/ob mice, possibly related to differential hepatic zonation of apoB synthesis (periportal) and lipid accumulation (perivenous) and/or relatively low rates of cholesterogenesis. Insulin is unable to effectively suppress VLDL-triglyceride production in ob/ob mice, presumably because of impaired insulin signaling. Diabetes