Urinary Excretion Of Ketone Bodies Research Articles

On the occasion of the centennial of the Nobel Prize in Physiology or Medicine, 1923: Nicolae C. Paulescu-between scientific creativity and political fanatism.

On the occasion of the centennial of the Nobel Prize in Physiology or Medicine, 1923: Nicolae C. Paulescu-between scientific creativity and political fanatism.

SGLT2 Inhibitors May Predispose to Ketoacidosis.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis. Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism. SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels. Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.

A Case of Diabetic Ketoacidosis Associated with Guillain-Barre Syndrome

A 64-year-old woman was referred to our center presenting with thirst, malaise, and pain in both legs which occurred one week before admission. She was revealed to have hyperglycemia and diabetic ketoacidosis (DKA). After therapy for diabetic ketoacidosis was started, her blood glucose levels were improved, but urinary ketone body excretion persisted. Laboratory examination indicated a significant impairment of insulin secretion, although anti-GAD and anti-IA-2 antibody were not detected. After admission, she complained about weakness of lower extremities, which spread to her upper extremities. The diagnosis of Guillain-Barré syndrome (GBS) was made based on the nerve conduction study and cerebrospinal fluid analysis. The intravenous immunoglobulin therapy was started, and her muscle weakness showed gradual improvement. Although the possibility that GBS was casually accompanied with DKA could not be completely excluded, we considered that DKA triggered the development of GBS in this case. Although GBS is a rare condition, the present case suggests that GBS should be included in the differential diagnosis of DKA with its atypical course.

Necessity of carnitine supplementation in semistarved rats fed a high-fat diet

We investigated the effects of carnitine supplementation on lipid metabolism in semistarved rats. The semistarved rats were fed a high-fat diet and half the normal energy intake for 2 wk. Carnitine was supplied daily at a dose of 250 mg/kg of body weight. The results showed that the concentration of plasma free carnitine increased significantly in semistarved and carnitine-supplemented rats compared with normal and semistarved rats. The activities of muscle carnitine palmitoyltransferase I and preheparin plasma lipoprotein lipase also were significantly increased in semistarved and carnitine-supplemented rats. The plasma triacylglycerol secretion rate was restored to normal by carnitine supplementation in semistarved rats. Urinary excretion of ketone bodies was reduced significantly after carnitine supplementation. We concluded that supplementation of carnitine can significantly increase the concentration of plasma free carnitine and improve lipid metabolism in semistarved rats fed a high-fat diet.

Effects of Starvation and of Selenium Deficiency on the Urinary Excretion of Electrolytes, Ketone Bodies, Creatinine, Urea and Uric acid

The aim of this study was to investigate whether urinary excretion of other compounds than ketone bodies are also increased in starved, selenium (Se)-deficient rats. Two groups of male rats were fed an Se-deficient diet with 0.009 mg Se/kg, ("Se-deficient" and "Se-repleted") and one group was fed the same diet with 0.23 mg Se/kg as control for eleven weeks. The urinary excretion of ketone bodies was highly enhanced in Se deficiency, with a 7-fold increase in 3-hydroxybutyrate and an 18-fold increase in acetoacetate. Despite this, the plasma concentration of ketone bodies and the glomerular filtration rate were unaffected in the Se-deficient rats. Starvation resulted in a significant decrease in the urinary content of potassium, magnesium and calcium, in both dietary groups of rats and of urea in the Se-adequate group. No Se-dependent difference was noted for the urinary excretion of these compounds or of sodium, phosphate, creatinine and uric acid in any of the groups. This was unexpected in view of certain previous results and indicates that disturbances in the renal handling of compounds are progressive in Se deficiency, with increased excretion of ketone bodies being an early event while more severe deficiency is required to impair the renal handling of electrolytes and other compounds studied.

Effect of ingestion of 6-propyl-2-thiouracil on biochemical indices of selenium status in rats.

Biochemical indices of selenium (Se) deficiency (liver Se content and glutathione peroxidase (GSHPx) activity, and urinary ketone bodies during fasting) were measured in Se-deficient or Se-sufficient control rats with or without ingestion of 6-propyl-2-thiouracil (PTU). Male weanling Wistar rats (50 to 60 g) were fed on a Torula yeast-based Se-deficient diet (Se content, < 0.01 microgram/g), or on the same diet supplemented with sodium selenite (0.1 microgram Se/g). The rats were given 0.05% PTU solution or deionized water as drinking water. After feeding for 6 weeks, the rats given PTU showed severe inhibition of growth and marked decreases in serum thyroxine (T4) and 3,5,3'-triiodothyronine (T3) levels. Animals fed the Se-deficient diet showed remarkably low hepatic Se content and GSHPx activity compared to the Se-sufficient control rats, irrespective of PTU-ingestion. In the rats without PTU, the Se deficiency was accompanied by significantly elevated serum T4 and lower T3 levels. Urinary ketone body excretion during fasting was significantly higher in the Se-deficient rats than in controls, irrespective of serum thyroid hormone levels. These results suggest that the increase in urinary ketone body excretion in Se deficiency may be independent of serum thyroid hormone.

Excretion from rats of ketone bodies and methylmalonic acid in urine resulting from dietary vitamin B12 deficiency.

Ketone bodies were assayed in the urine of ten-week-old vitamin B12-deficient rats by a high-performance liquid chromatography. The urinary excretion of ketone bodies (352.5 +/- 68.3 mumol/day) as well as of methylmalonic acid was increased significantly by dietary vitamin B12 deficiency.

Impaired ketogenesis in patients with adult-type citrullinemia

Background/Aims: To clarify the mechanism causing fatty liver in adult-type citrullinemia, the effect of fasting on blood levels of free fatty acids, triglycerides, and ketone bodies was investigated in two cases. Methods: Blood and urine samples were collected from two patients and healthy volunteers 12, 15, 17, 21.5, and 24 hours after their last meal. Results: During 24-hour fasting free fatty acid concentrations increased in both cases to the concentrations found in the healthy volunteers. The levels of blood ketone bodies (β-hydoxybutyrate and acetoacetate) were markedly suppressed throughout the fasting test without any increase in urinary excretion of ketone bodies or organic acids in both cases when plasma citrulline concentrations were more than 10-fold higher than in controls. Serum triglyceride concentrations in case 1 paradoxically increased from 185 mg/dL to 294 mg/dL during 24-hour fasting when the citrulline concentration was extremely high. When hemodialysis was performed and plasma citrulline consequently decreased to near the normal level in case 1, levels of both serum triglycerides and blood ketone bodies responded normally to 24-hour fasting. Conclusions: These data suggest that ketogenesis was impaired in adult-type citrullinemia.

Transport of beta-hydroxybutyrate and acetoacetate along rat nephrons: a micropuncture study

The transport of ketone bodies across the luminal membrane of the nephron was studied by means of micropuncture techniques in rats in normal acid-base state. The concentration of beta-hydroxybutyrate (beta-HB) and acetoacetate (AcAc) in plasma, tubular fluid and urine was measured by an ultramicromethod using enzymatic cycling. At endogenous plasma ketone body concentration, approximately 80% of the filtered load of beta-HB and AcAc was reabsorbed in the proximal convoluted tubule, the remaining fraction being almost completely reabsorbed between the late proximal convoluted and the distal tubule; under these conditions, the urinary excretion of ketone bodies was less than 1% of the filtered load. A progressive elevation to steady-state levels of plasma beta-HB resulted in a progressive reduction of the fractional reabsorption of beta-HB and AcAc in the proximal convoluted tubule, which means that reabsorption of ketone bodies in this nephron segment is saturable. No net secretion of ketone bodies could be demonstrated along the nephron even at the highest plasma ketone body concentrations reached. In clearance experiments, the capacity of the rat kidney for reabsorbing both beta-HB and AcAc was found to be limited by a maximal tubular capacity (Tm). The data suggest that, in the young Wistar rat nephron, most of the reabsorption of ketone bodies is carrier mediated.

Effect of Selenium Deficiency on Urinary Ketone Body Excretion in Starved Rats

Abstract Rats were fed a Se-deficient (Se content: 0.011 μ g/g) or a Se-adequate diet (the basal diet supplemented with 0.1 μg Se/g as sodium selenite). On the 22nd week of the feeding period, the rats were starved for 72 h and the urinary excretion of ketone bodies (acetoacetate and 3-hydroxybutyrate), urea, and creatinine were examined. The urinary excretion of ketone bodies were markedly higher in the Se-deficient rats than in the Se-adequate rats 24 h after the start of starvation, while the excretion of urea and creatinine were similar in the Se-deficient and Se-adequate rats. Se status did not effect on the plasma urea and creatinine contents as well as urinary N-acetyl-β-D-glucosaminidase activity; renal function was not impaired by Se deficiency. These results indicate that Se deficiency causes an increase of urinary ketone body excretion in starved rats and that the increase is ketone-specific with no changes in major urinary profiles.

Increase of Urinary Ketone Body Excretion in Selenium-Deficient Rats Is a Ketone-Specific Change.

The effects of selenium (Se) deficiency on urinary ketone body excretion in starved rats were examined. Rats were fed a basal diet which was Se-deficient (Se content: 0.011 micrograms/g) or a Se-adequate diet (the basal diet supplemented with 0.1 micrograms Se/g as sodium selenite). On the 11th and 22nd week of the feeding period, Se-deficient status in rats fed the basal diet was verified by the observation that the Se content and glutathione peroxidase activity in their plasma, erythrocytes, and livers were markedly lowered. On the 4th, 6th, 11th, 15th, and 22nd week, the rats were starved for 48 h and the urinary excretion of ketone bodies (acetoacetate (AcAc) and 3-hydroxybutyrate (3-OHBA)), urea, and creatinine were examined. The urinary excretion of AcAc and 3-OHBA during the second 24 h of the 48-h starvation period were markedly higher in the Se-deficient rats than in the Se-adequate rats for all weeks examined, while the urine volume and the excretion of urea and creatinine were similar in the Se-deficient and Se-adequate rats, irrespective of the feeding period and the number of hours of starvation. On the 22nd week, the plasma ketone body levels were also determined and significantly higher plasma 3-OHBA levels were observed in the Se-deficient rats than in the Se-adequate rats 72 h after starvation began. These results indicate that Se deficiency causes an increase of urinary ketone body excretion in starved rats and that the increase is ketone-specific with no changes in major urinary profiles.

Impaired ketone body metabolism in the selenium deficient rat. Possible implications

Male rats were fed a selenium-deficient Torula yeast diet with or without 0.2 ppm selenium (as sodium selenite) in the drinking water. Selenium deficiency caused a significant increase of urinary acetoacetate excretion in fed rats, and 24 or 48 hours of starvation enhanced this effect. Two days of selenium supplementation decreased the amount of urinary acetoacetate and 3-hydroxybutyrate to 50% of the deficiency value, indicating an enzymatic impairment in the selenium-deficient rat. No selenium-dependent effect was found for the following: (1) urinary pH, amount of nitrite, glucose (negative), hemoglobin or protein, and the urine was negative for phenylketones; (2) blood content of glucose, acetoacetate, or 3-hydroxybutyrate; or (3) liver content of glycogen, glucose, acetoacetate, or 3-hydroxybutyrate. On the other hand, the liver content of triglycerides was significantly lower in selenium deficiency. Indications for a higher content of ketone bodies (acetoacetate plus 3-hydroxybutyrate) in the kidneys from selenium-deficient rats were found. The increased urinary excretion of ketone bodies on selenium deficiency may indicate an impairment of lipid and ketone body turnover (in the kidney), or a decreased kidney reabsorption rate. Possible implications of these results in connection with protective roles of selenium in atherosclerosis and carcinogenesis are suggested.

The djungarian hamster, a laboratory animal with inappropriate hyperglycaemia

1. 1. The physiology of the Djungarian hamster is described with special regard to breeding and development. 2. 2. The metabolic abnormalities are studied with special regard to carbohydrate and lipid metabolism. 3. 3. The data reveal this animal to exhibit a genetically determined inappropriate hyperglycaemia and to differ from all other species so far known by an early onset of urinary ketone body excretion.

Physiological Responses and Changes of Blood and Urine Constituents during Cold Exposure in Sheep

The present investigation was performed in a coldenvironment to determine the main substances used for heat production and for gluconeogenesis in sheep which have peculiar nutritional requirement as compared with a monogastric animal.Four clipped sheep were exposed to ambient temperature of 0°Cfor 7 days in the climatic chamber, and their physiological responses, blood and urine constituents were measured during the exposure period.Immediately after the start of the exposure, severe shivering arose from the limbs, extending over the body, and heart rate and heat production were both increased remarkably. These high levels were maintained for 7 days. Water intake and urine volume decreased distinctly but respiration rate only tended to decreased. Body temperature did not exhibit clear change but the diurnal fluctuations were smaller than those at 20°C.The plasma free fatty acid concentration increased rapidly. Blood glucose and blood Pco2 increased a little but not significantly on and after the 4th day of exposure. Blood free amino acids, lactic acid and volatile fatty acids concentrations did not show any clear changes. The daily urinary excretion of ketone bodies decreased slightly but that of nitrogen hardly changed.The present experiment confirmed that the changes observed in the sheep under the cold environment were almost the same as those of reported in human, dog and other monogastric animals.

The influence of diabetic regulation on the diurnal variation in blood and the urinary excretion of ketone bodies. Studies in newly diagnosed diabetics.

A typical diurnal variation of blood ketone bodies (acetacetate+3-hydroxybutyrate) has been found in 23 newly diagnosed, untreated diabetics regardless of diabetic type. It was characterized by high morning concentrations, followed by a fall, and later on a rise in concentration during the evening and night. Satisfactory diabetic regulation, judged from glucose measurements, did not change this diabetic pattern, which differed fundamentally from the normal diurnal variation. In the regulated state the morning concentration of ketone bodies in blood was still abnormally high in the juvenile and the non-obese maturity onset diabetics, while the concentration in the phenformin-treated diabetics had increased on each sampling time. The 24-hour urinary excretion of ketone bodies also remained abnormally high in the phenformin-treated patients.

Effect of cold adaptation and high-fat diet on cold resistance and metabolic responses to acute cold exposure in rats.

Effects of cold adaptation and high-fat diet on the metabolic responses as well as cold resistance to acute cold exposure were investigated in rats with emphasis on elucidating the mechanism underlying the favorable effect of high-fat diet in a cold environment previously reported.An increment in body weight was greater in rats on a high-fat diet and smaller in cold-adapted rats than in control rats. However, food intake was significantly greater in cold-adapted rats. Daily urine volume and urinary nitrogen excretion increased in cold-adapted rats, but did not change in rats on a high-fat diet. The high-fat diet caused higher bloodfree fatty acid (FFA) and ketone body concentrations, and lower urinary excretion of ketone bodies. Urinary vanilmandelic acid excretion was significantly elevated in cold-adapted rats, while it was lower in rats fed a high-fat diet as compared with that in control rats. This result suggests an increased sympathetic activity in cold-adapted rats and a rather suppressed activity in rats on a high-fat diet.The fall in the colonic temperature due to cold exposure for the period of time up to four hours was significantly less in cold-adapted rats, but did not differ in animals fed a high-fat diet from that in control rats. This result signifies that there is no significant difference in cold resistance between control rats and rats on a high-fat diet. Blood FFA level as well as blood ketone body level was significantly raised in all experimental groups in response to cold exposure. It was observed, however, that an increment in blood FFA concentration was less in cold-adapted rats. The degree of increase in blood FFA became greater with length of exposure to the cold. Blood glucose concentration was significantly elevated in cold-adapted rats after an eighty minutes exposure to the cold, but did not vary in control rats and rats on a high-fat diet. Four hours after the cold exposure the blood glucose level was significantly decreased in all groups as compared with that at 25°C.There was a significant correlation between the blood FFA and ketone body concentrations on the whole data before and after cold exposure in all groups. Regression coefficient between blood compositions was significantly greater in rats fed a high-fat diet than in control and coldadapted rats. It was also shown that there was an inverse correlation between the blood glucose and FFA levels after cold exposure. Furthermore, lessened falling of colonic temperature due to cold exposure was significantly associated with less variations in the blood FFA and glucose levels concomitantly determined in control and cold-adapted rats and this tendency was strongly documented in cold-adapted rats.The present results indicate that the prolonged cold exposure increases the cold resistance to acute cold exposure, while the high-fat diet feeding may not be necessarily favorable to the cold resistance, although a high-fat diet causes certain metabolic changes, suggesting a favorable effect to some extent.

Metabolism of acetate in scorbutic guinea pigs.

The effects of feeding acetate on the glucose tolerance, deposition of liver glycogen; urinary excretion of citric acid, malic acid and ketone bodies; total body lipid, phospholipid and cholesterol; and cholesterol content of different tissues were studied in normal and scorbutic guinea pigs. The effects of prolonged insulin treatment on the urinary excretion of citrate, malate and ketone bodies were also studied in normal and scorbutic guinea pigs fed acetate. It was observed that when normal guinea pigs were fed acetate, total body lipid and liver glycogen increased and there was no change in body cholesterol, tissue cholesterol and glucose tolerance. In scorbutic guinea pigs total body cholesterol and cholesterol contents of blood, small intestine and testes were increased and were further enhanced when the animals were fed acetate. Lowered glucose tolerance, diminished liver glycogen, total body lipid and phospholipid observed in scorbutic guinea pigs did not change after acetate feeding. The increased urinary excretions of ketone bodies, citric acid and malic acid by scorbutic guinea pigs came down to normal levels when they were injected with insulin. The increased cholesterogenesis in scurvy seems to be due to hypoinsulinism.

Relation of hepatic ketogenesis to radiation-induced decrease in fasting ketonemia.

Male, weanling rats were exposed to 500 r of whole-body x-irradiation and then fasted. Control rats were concurrently fasted. Ketonemia, ketonuria, hepatic glycogen, ketogenesis by liver slices and fatty acid oxidase activity of liver mitochondria were measured. A radiation-induced decrease in fasting ketonemia was observed. This decrease was mainly in the ß-hydroxybutyric acid fraction. Ketonuria was similar in both control and irradiated lots the 1st postirradiation day and lower in the irradiated lot during the 2nd day. Decreased ketonemia in the irradiated rats, which exhibited diuresis, was thus apparently not due to increased urinary excretion of ketone bodies. Ketogenesis by liver slices from irradiated rats was depressed. This indicated that an antiketogenic process contributed to the radiation-induced decrease in fasting ketonemia. Fatty acid oxidase activity of liver mitochondria isolated from control and irradiated rats was similar. Thus, rate-limiting fatty acid oxidizing enzymes were not altered by radiation under these conditions. This illustrates an apparent modifying effect of other cellular fractions on fatty acid oxidation in mitochondria.

Significance of Ketone Bodies in the Management of Diabetes Mellitus

As previously reported, the urinary content of ketone bodies reflects the condition of diabetics, even in those with negative qualitative test for ketone bodies. In order to elucidate the diabetic ketosis more precisely, urinary content of ketone bodies were measured quantitatively and hepatic formation of ketone bodies were measured in liver slices of alloxan diabetic rats, and the effect of treatment using insulin, sulfonylurea, mesoxalate and various types of vitamines were studied, and following results were obtained. 1. In alloxan diabetic rats, after treatment using insulin, mesoxalate, pantothenic acid or cocarboxylase, urinary excretion of ketone bodies decreased, although sulfonylurease did not show remarkable changes. 2. In addition insulin and mesoxalate added to the medium of incubation caused decrease in ketone bodies formation of liver slices of alloxan diabetic rats. 3. After treatment using insulin, mesoxalate, pantothenic acid or cocarboxylase, ketone body formation of liver slices was decreased, although sulfonylureas did not show such effect. 4. In high fat diet, urinary content of ketone bodies and ketone body formation of liver slices were found to be increased in comparison with that in high carbohydrate or high protein diet.

Comparison of urinary excretion of ketone bodies, non-protein nitrogen, citric acid and glucose in alloxan diabetic and depancreatized rats.

Comparison of urinary excretion of ketone bodies, non-protein nitrogen, citric acid and glucose in alloxan diabetic and depancreatized rats.