Peter W. Stacpoole

Metabolic Effects of Dichloroacetate in Patients with Diabetes Mellitus and Hyperlipoproteinemia

Dichloroacetate is known to reduce plasma glucose and triglycerides in diabetic and starved animals and to lower plasma lactate under various experimental conditions. To investigate its metabolic effects in man, we administered oral doses (3 to 4 g) of dichloroacetate as the sodium salt to patients with diabetes mellitus or hyperlipoproteinemia or both for six to seven days. Dichloroacetate significantly reduced fasting hyperglycemia an average of 24 per cent (P less than 0.01) from base line and produced marked, concomitant falls in plasma lactate (73 per cent; P less than 0.05 to less than 0.01) and alanine (82 per cent; P less than 0.01 to less than 0.001). In addition, it significantly decreased plasma cholesterol (22 per cent; P less than 0.01 to less than 0.001) and triglyceride (61 per cent; P less than 0.01) levels while increasing (71 per cent; P less than 0.01) plasma ketone-body concentrations. Plasma insulin, free fatty acid and glycerol levels were not affected. Serum uric acid rose, whereas excretion and renal clearance fell. Some patients experienced mild sedation, but no other laboratory or clinical evidence of adverse effects was noted during or immediately after the treatment phase.

Reduction of serum cholesterol in two patients with homozygous familial hypercholesterolemia by dichloroacetate.

Dichloroacetate is known to reduce plasma cholesterol and triglyceride in patients with Fredrickson Types IIb or IV hyperlipoproteinemia. We now report the effects of chronic, oral dichloroacetate administration (as the sodium salt) in two patients with severe homozygous familial hypercholesterolemia. Dichloroacetate markedly reduced serum total and low density lipoprotein cholesterol levels and lowered the low density lipoprotein to high density lipoprotein cholesterol ratio. One patient developed a polyneuropathy while receiving dichloroacetate which resolved following discontinuation of the drug. Because of its apparent toxicity, dichloroacetate cannot be recommended for chronic oral use. Investigation of the mechanism of its lipid-lowering effect, however, may provide insight into the pathogenesis and treatment of hypercholesterolemic disorders.

Effect of dichloroacetate on gluconeogenesis in isolated rat hepatocytes

The effect of dichloroacetate on rates of gluconeogenesis was studied in isolated parenchymal cells obtained from the livers of normal fasted rats. Dichloroacetate significantly inhibited glucose formation from endogenous substrates and from added precursors (e.g., lactate, pyruvate, or glycerate) which enter the gluconeogenic pathway prior to the level of glyceraldehyde-3-phosphate dehydrogenase (GPDH). In contrast, dichloroacetate did not significantly affect glucose synthesis from precursors (e.g., fructose, or glycerol) which enter beyond the GPDH-catalyzed step. Lactate production from fructose of glycerol was unaffected by dichloroacetate. Inhibition of gluconeogenesis occurred regardless of the apparent effects of dichloroacetate on the redox state of the cytosol. Dichloroacetate produced variable effects on the lactate-pyruvate substate pair, while it consistently produced a more oxidized state in the beta-hydroxybutyrate--acetoacetate couple. Unlike uncoupling agents, dichloroacetate reduced glucose synthesis without stimulating respiration or altering total adenine nucleotide levels or ATP/ADP ratios. Dichloroacetate did not affect the metabolism of lactate or pyruvate to CO2 or glycogen. It did, however, significantly inhibit conversion by the cells of added lactate to pyruvate and glucose or of added pyruvate to lactate and glucose.

Elevated cholesterol and bile acid synthesis in an adult patient with homozygous familial hypercholesterolemia. Reduction by a high glucose diet.

Elevated levels of cholesterol synthesis are reported for several young children with homozygous familial hypercholesterolemia (HFH) and are considered to contribute directly to their hypercholesterolemia. In contrast, increased cholesterol production has not previously been found in adult patients with HFH. Using the fecal steroid balance technique, we studied rates of cholesterol and bile acid synthesis in a 24-yr-old man who had severe hypercholesterolemia typical of HFH and who lacked skin fibroblast low density lipoprotein (LDL) receptor activity. On an average diet (45% carbohydrate, 40% fat, 15% protein) mean +/- SEM cholesterol (24.8 +/- 1.4 mg/kg per d) and bile acid (11.1 +/- 1.6 mg/kg per d) excretion were approximately threefold higher than normal. When an isocaloric high carbohydrate, low fat diet (90.5% glucose oligosaccharides, 1.3% safflower oil, 8.2% crystalline amino acids was substituted, mean cholesterol (13.0 +/- 0.5 mg/kg per d) and bile acid (8.6 +/- 0.4 mg/kg per d) fell markedly. The decline in fecal steroid excretion was accompanied by modest reductions in plasma total and LDL cholesterol concentrations and by a softening of cutaneous xanthomata. Although the patient phenotypically and biochemically resembled the HFH state, his family pedigree was not noteable for hypercholesterolemia. While the patients father had premature cardiovascular disease, his mother had no evidence of heart disease, had normal plasma total and LDL cholesterol levels, and had normal fibroblast LDL receptor activity. Likewise, the plasma cholesterol levels of three other members of the patients family were normal. Despite the unusual genotypic background of this individual, however, the fecal balance data shows that elevated cholesterol and bile acid synthesis may occur in adult, as well as juvenile, patients with HFH and may be responsive to dietary control.

Morphologic abnormalities of erythrocytes from patients with homozygous familial hypercholesterolemia.

Erythrocytes from patients with various disorders of lipoprotein metabolism have been found to have abnormal morphology. We report morphologic abnormalities of erythrocytes from two patients with homozygous familial hypercholesterolemia (HFH), in which knisocytes, stomatocytes and crenated cells were observed. The membrane lipid and phospholipid fatty acid composition of HFH erythrocytes was not significantly different from controls. HFH erythrocytes incubated in HFH patient plasma and a lipoprotein-rich fraction of HFH plasma appeared morphologically similar to erythrocytes from HFH patients. These studies support the concept that serum lipids exert an important role in the regulation of erythrocyte morphology in the normal state, as well as in patients with disorders of lipoprotein metabolism.

Stimulation of rat liver 3-hydroxy-3-methylglutaryl-coenzyme a reductase activity by o,p′-DDD

To investigate the mechanism by which op-DDD (2,2-bis [2-chlorphenyl-4-chlorophenyl]-1,1-dichloroethane; Mitotane) produces hypercholesterolemia in man, we studied the effect of the drug on hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity in reverse light-cycled rats. o,p-DDD markedly stimulated reductase activity in vivo and in vitro in a dose-dependent manner. This effect was not associated with demonstrable adrenocortical toxicity or changes in plasma corticosterone concentrations. Thus o,p-DDD may elevate circulating cholesterol levels in man by increasing endogenous cholesterol synthesis. In addition, the o,p-DDD may elevate circulating cholesterol levels in man by increasing endogenous cholesterol synthesis. In addition, the o,p-DDD-treated rat may serve as a useful model for testing other agents for the ability to suppress endogenous cholesterol synthesis and lower circulating cholesterol levels.

Cholesterol reduction by a high-glucose diet in a patient with homozygous familial hypercholesterolemia: A preliminary report

Homozygous familial hypercholesterolemia is refractory to standard dietary or drug therapy. Recent studies, however, suggest that a high-carbohydrate/low-fat diet may reduce circulation cholesterol levels in normal or hyperlipidemic subjects. In this regard, we treated a nine year old boy with homozygous familial hypercholesterolemia with a liquid formula diet containing 82 to 90 percent of total calories as glucose. The diet was given as a constant nasogastric infusion or as intermittent daytime drinks followed by a nighttime infusion. Plasma total and low-density lipoprotein cholesterol fell from basal levels of 719 mg/dl and 676 mg/dl to 456 mg/dl and 434 mg/dl, respectively, after one week of therapy. After approximately 14 weeks of treatment, plasma total and low-density lipoprotein cholesterol levels were 311 mg/dl and 277 mg/dl, each representing approximately a 58 percent decrease from basal levels. The fall in circulating cholesterol levels was accompanied by a regression of xanthomatous skin lesions, a rise in plasma insulin levels and no change in plasma glucose or glucagon concentrations. No adverse effects of therapy occurred. We conclude that high-carbohydrate diets may be a safe and effective adjunct in the treatment of homozygous familial hypercholesterolemia.

Role of vitamin C in infectious disease and allergic reactions

Summary Vitamin C exerts significant anti-microbial and anti-histaminic effects under both in vitro and in vivo conditions. It is proposed that such actions are mediated by free radicals generated during ascorbic acid metabolism. These effects appear to be optimal under conditions in which the dietary intake of vitamin C far exceeds the amount necessary to prevent scurvy.