Elevated Blood Pyruvate Research Articles

Perturbed glucose metabolism: insights into multiple sclerosis pathogenesis.

Multiple sclerosis (MS) is a complex debilitating disease of the central nervous system (CNS) perceived to result from the autoimmune effect of T cells in damaging myelin sheath. However, the exact pathogenesis of the disease remains elusive. Initial studies describing the possibility of defective pyruvate metabolism in MS were performed in 1950s. The group observed elevated blood pyruvate level in both fasting and postprandial times in MS patients with relapse. Similarly, other investigators also reported increased fasting pyruvate level in this disease. These reports hint to a possible abnormality of pyruvate metabolism in MS patients. In addition, increase in levels of Krebs cycle acids like alpha-ketoglutarate in fasting and citrate after glucose intake in MS patients further strengthened the connection of disturbed pyruvate metabolism with MS progression. These studies led the investigators to explore the role of disturbed glucose metabolism in pathophysiological brain function. Under normal circumstances, complex molecules are metabolized into simpler molecules through their respective pathways. Differential expression of genes encoding enzymes of the glucose metabolic pathway in CNS may result in neurological deficits. In this review article, we discuss the studies related to disturbed carbohydrate metabolism in MS and other neurodegenerative diseases. These observations open new perspectives for the understanding of metabolic dynamics in MS yet many puzzling aspects and critical questions need to be addressed. Much more research is required to fully unravel the disease mechanism, and a proper understanding of the disease could eventually lead to new treatments.

Elevated blood pyruvate levels and decreased retention of thiamin in rats mildly depleted of vitamin B 12

Nine-moth-old rats that were mildly depleted of vitamin B 12 and their controls were subjected to 26 days of thiamin deficiency. All rats had been equilibrated with the control level of thiamin (500 μg/ 100 g diet) for the previous 8 months. The four subgroups (11 rats/ subgroup) included: controls (CC), vitamin B 12-depleted (BD), thiamin deficient (TD) and vitamin B 12 depleted rats made thiamin deficient (BD+TD). At the initiation of the thiamin deficiency period, BD-rats were excreting 3 times more methylmalonic acid than their controls. This was indicative of a significant, although mild, depletion of vitamin B 12. The mild depletion of vitamin B 12 (BD) led to a 49% increased loss of thiamin in urine, whereas 26 days of thiamin deficiency (TD and BD+TD) was accompanied by decreased losses of thiamin in urine. Urinary losses of thiamin were equivalent to 24% of ingested thiamin for controls (CC), but these losses of thiamin were doubled (46%) in rats depleted of vitamin B 12 (BD). Because of their reduced intakes of food, BD-rats received only 78% as much thiamin as the controls (CC), and they retained a similar relative amount (69%) of thiamin in their liver. Thiamin deficient rats (TD) retained only 7% as much thiamin in their liver. The least amount of thiamin was retained in liver when rats had a thiamin deficiency combined with the mild depletion of vitamin B 12 (BD+TD). The mild depletion of vitamin B 12 (BD) and thiamin deficiency (TD) promoted equivalent increases in blood pyruvate. Rats mildly depleted of vitamin B 12 have an inhibited ability to retain absorbed thiamin, and the resulting depletion of thiamin leads to major increases in blood pyruvate.

Glucoregulatory and metabolic responses to heat exposure in rats.

To determine the possible role of altered secretion and effects of insulin in fuel homeostasis during heat exposure, the hormonal and metabolic milieu of three groups of rats were studied. The first was placed at 35 degrees C for 12 days (HE), the second was pair-fed (PF) to the first but maintained at 23 degrees C, and the third was allowed to eat ad libitum at 23 degrees C (C). Plasma insulin, glucagon, glucose, and free fatty acids (FFA), and blood lactate, pyruvate, 3-hydroxybutyrate, and individual amino acids were determined. To further characterize glucoregulation, an intraperitoneal glucose tolerance test (1 mg/g body wt) and isotopic glucose turnover (primed infusion of [3-3H]glucose) were performed. In HE rats, weight was constant for the last third of the period, and metabolic state 4 h after food removal was characterized by euglycemia but hypoinsulinemia, elevated blood pyruvate and FFA, and normal 3-hydroxybutyrate compared with C. Lowered levels of branched-chain amino acids and arginine were found. Fourteen hours after food removal glucose turnover was decreased. However, glucose intolerance accompanied by hyperinsulinemia was also found. Many of these changes were also seen in PF, including constant weight, fasting euglycemia, hypoinsulinemia, elevated FFA, and lowered valine and isoleucine. In contrast, pyruvate concentrations were normal, that of 3-hydroxybutyrate was elevated, and the decrement in glucose turnover was smaller than in HE rats. The glucose tolerance was similar to that of HE but accompanied by hypoinsulinemia. The results in HE suggest decreased energy metabolism, insulin secretion altered in a complex manner, and altered insulin action.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of Severe Lactic Acidosis with Dichloroacetate

Four patients with severe lactic acidosis associated with septic shock were treated with sodium dichloroacetate (DCA) (50 mg/kg body wt), an activator of pyruvate dehydrogenase. All patients were in a group with an expected mortality rate of 90-100%, based on previous studies. In one patient, treatment with DCA was associated with a decrease in blood lactate levels from 11.2 mM before treatment to 0.8 mM 16 h later. Markedly elevated blood pyruvate and alanine levels also decreased to normal. After treatment, the arterial blood pH rose to 7.53, and vasopressor agents were no longer needed to support blood pressure. Some degree of biochemical improvement was also noted in the other cases in whom the blood lactate levels before treatment were 15, 17, and 31 mM. However, all three patients eventually died of refractory acidosis.

Deficiency of Dihydrolipoyl Dehydrogenase (a Component of the Pyruvate and α-Ketoglutarate Dehydrogenase Complexes): A Cause of Congenital Chronic Lactic Acidosis in Infancy

A male child died at 7 months of age with progressive neurologic deterioration and persistent metabolic acidosis. Investigations during life showed this child to have elevated blood pyruvate, lactate, and alpha-ketoglutarate as well as elevation of branched chain amino acids and occasional hypoglycemia. Cofactor therapy using either thiamine-HCl (2 g/kg/24 hr) or thiamine tetrahydrofurfuryl disulfide had no measurable effect on the clinical or biochemical status of the patient. Tissue taken postmortem showed normal levels of key gluconeogenic enzymes but a deficiency in the activity of pyruvate dehydrogenase in all tissues tested (liver, brain, kidney, skeletal muscle, and heart). Examination of the individual activities of pyruvate dehydrogenase complex showed pyruvate decarboxylase (E1) to be normal in liver and other tissues. Dihydrolipoyl dehydrogenase (E3), on the other hand, was deficient in all tissues tested. alpha-Ketoglutarate dehydrogenase complex, which depends of E3 for its total activity, was also deficient in all tissues tested. The absence of this enzyme id discussed in relation to the clinical and biochemical status of the patient.

Biochemical Aspects of Cobalt Deficiency in Sheep with Special Reference to Vitamin Status and a Possible Involvement in the Aetiology of Cerebrocortical Necrosis

SUMMARY The development of cobalt deficiency in sheep was best indicated by low plasma vitamin B12 levels, loss of appetite and elevated blood pyruvate. The susceptibility of cobalt-deficient animals to infection was attributed to an induced vitamin C deficiency and evidence was obtained of thiamine deficiency in the advanced cobalt-deficient state despite faecal thiaminase not usually being detected until near the terminal stages of cerebrocortical necrosis. Faecal thiaminase activity was inversely related to erythrocyte transketolase activity. Cobalt supplementation was effective in preventing the development of these vitamin deficiencies and of cerebrocortical necrosis.

Blood pyruvate and plasma glucose levels during oral and intravenous glucose tolerance tests in obese and non-obese women

Studies of venous blood pyruvate and plasma glucose levels before and after the administration of oral/intravenous glucose are described in a group of 98 women, 27 of whom were obese. The fasting plasma glucose level and intravenous glucose tolerance were similar in obese and non-obese groups. Oral glucose tolerance, however, was impaired in the obese group. The mean blood pyruvate level was elevated in the obese group, both before and after oral/intravenous glucose administration. While the total area under the oral/intravenous pyruvate curve was increased, the incremental area above the fasting base line was not significantly greater in the obese group. Elevated blood pyruvate levels were observed in certain obese subjects whose glucose tolerance was normal. The fasting blood pyruvate, and area under the oral/intravenous blood pyruvate curve, correlated better with the degree of obesity than with glucose tolerance. It was not possible to determine whether the elevated blood pyruvate levels in obese subjects were due to impaired pyruvate removal or increased formation.

Pyruvic Acid in Blood and Cerebrospinal Fluid.

Summary1. The stability of pyruvic acid in the spinal fluid is described. 2. The relationship of blood to spinal fluid pyruvate is reported. The amount found in the cerebrospinal fluid is usually 70-120% of that found in a blood sample taken simultaneously. 3. Of the 16 cases with elevated blood pyruvate, 13 occurred in cases of known vitamin B1 deficiency. These latter constituted the only cases in the entire study with definite clinical evidences of vitamin B1 deficiency. In the other 3. it is suggested that a relative deficiency of vitamin B1 may have existed. In 51 additional cases, without clinical evidence of vitamin B1 deficiency, the blood pyruvate was normal in every instance.