Spontaneous Ketosis Research Articles

Maturity-onset diabetes of the young type 3 complicated with type 5: A case report and literature review.

This report describes a case of maturity-onset diabetes of the young (MODY) type 3 (MODY3) complicated with type 5 (MODY5), including the patient's clinical features, diagnosis, and treatment, and reviews relevant literature. Using next-generation sequencing of MODY (types 1-14) gene exons and Sanger sequencing for verification, the patient and her mother were assessed. Based on the clinical phenotype and genetic test results, the patient was diagnosed as MODY3 combined with MODY5. Treatment included insulin and linagliptin, with monitoring of blood glucose changes. Clinicians should enhance their understanding of MODY clinical phenotypes. In adolescents with diabetes who have congenital pancreatic and renal developmental defects, elevated high-density lipoprotein cholesterol, no spontaneous ketosis, insulin secretion defects, negative pancreatic autoantibodies, no significant insulin resistance, and who are not obese, gene testing should be conducted to screen for MODY. Accurate diagnosis and personalized treatment can aid in achieving glycemic control, improving quality of life, and optimizing reproductive planning.

Negative energy balance up‐regulate the levels of hepatokines in dairy cows during the peripartum period

IntroductionThe periparturient period is vitally important to the health status and the reproductive performance of dairy cows. Negative energy balance (NEB) is considered as the pathological basis of energy metabolic disorders. Serum non‐esterified fatty acids (NEFA) and β‐hydroxybutyrate (BHBA) concentrations are the indicators of energy balance status. Angiopoietin‐like protein 4 (ANGPTL4) and fibroblast growth factor 21 (FGF21), known as hepatokines, play essential roles in lipid metabolism. However, in vivo the kinetics of ANGPTL4 and FGF21 are not entirely clear of dairy cows, particularly in dairy cows with ketosis and fatty liver. The purposes of this project were to evaluate the variations in serum concentrations of ANGPTL4 and FGF21 in periparturient dairy cows, and to examine the correlations between serum NEFA, BHBA concentrations and ANGPTL4, FGF21 concentrations, respectively, in the serum of experimental cows. Moreover, the serum concentrations of hepatokines from cows with spontaneous ketosis and fatty liver, and healthy cows were compared.MethodsExperiment IBlood parameters were measured in healthy periparturient Holstein cows from 4 wk antepartum to 4 wk postpartum (n=219). In this experiment, weekly blood samples were obtained from 4 wk before the expected calving date to 4 wk after calving.Experiment IIBlood parameters were measured in healthy cows (n=30), cows with ketosis (n=29) and fatty liver (n=25) within the first 4 wk of lactation. In this present study, all blood samples were collected from the coccygeal vein in the early morning before feeding.ResultsSerum concentrations of ANGPTL4 and FGF21 peaked at parturition, and declined rapidly over the following 2 wk. Serum ANGPTL4 and FGF21 concentrations were positively correlated with serum NEFA concentration (ANGPTL4 and NEFA: r=0.856, P=003; FGF21 and NEFA: r=0.848, P=0.004). However, the correlations between serum BHBA concentration and the serum concentrations of ANGPTL4 and FGF21 were not observed in experimental cows. Cows with ketosis and fatty liver had significantly higher serum concentrations of ANGPTL4 and FGF21 when compared with healthy cows (P<0.01).ConclusionSerum concentrations of ANGPTL4 and FGF21 were elevated during peripartum period in dairy cows, demonstrating that the energy balance changes that were associated with parturition contributed significantly to these effects. We propose that blood ANGPTL4 and FGF21 concentrations could be used as supplementary biomarkers of “energy balance” status in postpartum dairy cows. Although FGF21 and ANGPTL4 could play important roles in the adaptation of energy metabolism, they may be involved in the pathological processes of energy metabolism disorders of dairy cows in the peripartum period.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Etiology of Lipid-Related Metabolic Disorders in Periparturient Dairy Cows

Plasma NEFA concentrations increase prior to and at parturition, resulting in increased fatty acid uptake by the liver, fatty acid esterification, and triglyceride storage. Liver triglyceride concentration increases four- to fivefold between d 17 prior to calving and d 1 following calving. Increases in liver triglyceride following calving do not appear to be dramatic. Severity of fatty liver 1 d postpartum is correlated negatively with feed intake 1 d prepartum. Export of newly synthesized triglyceride as very low density lipoprotein occurs slowly in ruminants and is a major factor in the development of fatty liver. Nutritional strategies to minimize the elevation in plasma NEFA prior to calving results in lower liver triglyceride at calving. Fatty liver probably precedes clinical spontaneous ketosis. Liver triglyceride to glycogen ratio may be used to predict susceptibility of cows to ketosis. Consequently, strategies to reduce liver triglyceride at calving may decrease incidence of ketosis. Research to determine methods to reduce fatty acid delivery to the liver or to enhance hepatic export of very low density lipoprotein near calving is warranted. Identification of the cause for the slow rate of assembly and secretion of hepatic very low density lipoprotein in ruminants will be required to assess the feasibility of increasing export of very low density lipoprotein.

Major Metabolic Determinants of Milk Volume, Mammary Efficiency, and Spontaneous Ketosis in Dairy Cows

Mammary uptakes of glucose and long-chain fatty acids are proposed to be the major metabolic determinants of milk volume production and mammary efficiency, respectively. Moreover, the ratio of glucogenic to lipogenic nutrients in the diet is proposed to be the major determinant of spontaneous ketosis. Experimental evidence and clinical observations are adduced in support of these three interrelated propositions. Their heuristic value would be demonstrable in tests of formulations of high-fat rations and administrations of articles, such as growth hormone preparations, intended to promote maximal production and efficiency with least risk of ketosis.

Effects of starvation on intermediary metabolism in the lactating cow. A comparison with metabolic changes occurring during bovine ketosis.

1. The purpose of this study was to determine the nature of the metabolic changes associated with carbohydrate and fat metabolism that occurred in the blood and liver of lactating dairy cows during starvation for 6 days. 2. During starvation, the blood concentrations of the free fatty acids and ketone bodies increased, whereas that of citrate decreased. After an initial increase, the blood concentration of glucose subsequently declined as starvation progressed. Starvation caused a significant decrease in the plasma concentration of serine and a significant increase in that of leucine. 3. After 6 days of starvation the hepatic concentrations of oxaloacetate, citrate, phosphoenolpyruvate, 2-phosphoglycerate, 3-phosphoglycerate, glucose, glycogen, ATP and NAD(+) had all decreased, as had the hepatic activities of phosphopyruvate carboxylase (EC 4.1.1.32) and pyruvate kinase (EC 2.7.1.40). 4. The above metabolic changes are similar to those previously found to occur in cows suffering from spontaneous ketosis (Baird et al., 1968; Baird & Heitzman, 1971). 5. Milk yield decreased progressively during starvation. 6. There were marked differences in the ability of individual animals to resist the onset of severe starvation ketosis.

Hypoglycemia in Ketotic Cows

Two types of hypoglycemia have been differentiated in ketotic cows by tracer parkinetics. One is associated with fasting kebetosis and is characterized by decreases in the mass of glucose in rapid exchange with plasma glucose and in the rate of glucose transport through this pool. The other occurs in cows with spontaneous ketosis and is characterized by undiminished glucose transport or mass and by changes in glucose distribution. Similar changes follow insulin administration and opposite changes follow glucocorticoid administration. These differences in glucose kinetics between fasting ketosis and spontaneous ketosis are complemented by a dozen other demonstrated differences between the two conditions, mainly concerning ruminal, hepatic and mammary metabolism. These metabolic differences suggest the desirability of distinguishing between different types of ketosis for designing and testing control measures.

Propionate Utilization by Pregnant, Lactating, and Spontaneously Ketotic Dairy Cows

Twelve Holstein cows were employed in propionate tolerance studies during the dry period and in the normal and spontaneously ketotic state during lactation. Propionate utilization, measured by the rate of disappearance of an injected dose from the peripheral circulation, was less rapid in the dry period than during lactation, and was reduced during spontaneous ketosis. Blood glucose levels rose as propionate levels dropped, reaching peak values as propionate returned to basal level. During lactation there was a negative relationship between rate of propionate utilization and rate of increase in blood glucose, suggesting that cows with higher rates of utilization may have metabolized a larger part of the propionate in extrahepatic tissues. However, rate of utilization was not significantly correlated with milk production.Serum vitamin B12 levels were not significantly correlated with rate of propionate disappearance; with one aberrant value omitted, however, there was a significant correlation during lactation between serum B12 level and rate of increase in blood glucose. The three cows that developed spontaneous ketosis in early lactation had low serum vitamin B12 levels when sampled during late gestation.

Metabolic Changes in Liver Associated with Spontaneous Ketosis and Starvation in Cows

Although some information is available concerning the physiological alterations in vivo associated with spontaneous bovine ketosis, a broad study of pathways and possible changes of enzyme activities has not been carried out. To this aim, liver samples were taken from spontaneously ketotic cows, from the same cows when normal, and when starved for 96 hours. Measurements were made to ascertain the degree of ketosis and to compare changes in lipid synthesis, substrate oxidation, enzyme activities and the level of several metabolic intermediates. This research was particularly directed to a comparison of differences and similarities between the normal and spontaneously ketotic animal and between spontaneous ketosis and starvation ketosis. The liver of the spontaneously ketotic cow had a lower activity of mitochondrial NAD-malate dehydrogenase than the normal, higher levels of lactate, pyruvate, acetoacetate and β-hydroxybutyrate, and a substantially lower concentration of citrate. Livers from the spontaneously ketotic cows, when compared to with those of the starved animal, had a lower activity of mitochondrial pyruvate carboxylase, lower levels of NADH and higher levels of citrate, β-hydroxybutyrate and acetoacetate. Many other parameters of carbohydrate and lipid metabolism were measured and found to be unchanged from the normal in the two ketotic conditions. Notable among these was the lack of any alterations in the activity of phosphoenolpyruvate carboxykinase or levels of oxaloacetate. These findings conflict with the oxaloacetate shortage theory of bovine ketosis as generally stated.

Acetate Kinetics in Normal and Ketotic Cows

A solution containing acetate-1-14C was infused into two cows during spontaneous ketosis, then later when each was normal. A series of blood samples was taken, and radiochemical analyses were performed for plasma acetate and glucose, and blood CO2. The acetate entry rates were 1,900 and 3,500 g/day during ketosis, 3,100 and 4,300 g/day normal, respectively. The fraction of plasma glucose-carbon derived from plasma acetate-carbon was 6% in all four experiments. The fraction of blood CO2-carbon derived from plasma acetate-carbon was 33% in three experiments and 64% in one normal. The entry rates in normal cows were about 25–30% higher than previous estimates of ruminal production rates of acetate; this agrees with a previous estimate of endogenous acetate production in fed sheep. The lower entry rates during ketosis probably reflect lower ruminal production rates, as these two cows had exhibited inappetence for several days.

Evaluation by gas chromatography of the urinary steroids of normal and ketotic dairy cows.

SUMMARY The ketonic and non-ketonic neutral steroids in the urine of normal lactating cows and cows suffering from either primary spontaneous ketosis or an experimentally induced ketosis were studied by gas-chromatographic methods. The chromatographic patterns on QF-1 and SE-30 were similar in all cases. Neither were any significant quantitative differences observed. The 14 steroid metabolites identified in the urine of the normal lactating and ketotic cows had all been found previously in the urine of pregnant cows. However, the combined concentrations in the urine of androsterone, aetiocholanolone and epiandrosterone in both normal (20–130 μg./l.; mean 43±21·8 μg./l.) and ketotic cows (52–84 μg./l.; mean 66 ± 6·1 μg./l.) were lower than the previously reported levels for cows in late pregnancy (600 μg./l.). The results are discussed in relation to the hypothesis that bovine ketosis is associated with an impaired pituitary function.

Growth Hormone-Induced Ketosis in the Cow

Crystalline bovine growth hormone (GH) in daily doses of 1 mg/kg was injected intramuscularly into two lactating cows for ten days starting 2 wk after parturition. In both cows, plasma concentrations of nonesterified fatty acids and acetone-plus-acetoacetate rose during the period of GH administration, and fell after GH administration ceased. Decreased incorporation of acetate-C14 (injected intracisternally) into milk fat during GH-induced ketosis resembled that seen previously during spontaneous ketosis. Since exogenous GH can induce ketosis in the cow, excessive secretion of endogenous GH could conceivably play a role in the pathogenesis of naturally occurring bovine ketosis.

Formation of ketone bodies from long-chain fatty acids in rumen epithelium and liver from ketotic sheep

The metabolism of palmitate, stearate, oleate, and linoleate, major constituents of ruminant depot fats, was compared in rumen epithelium and liver tissue from both normal and ketotic sheep to study the role of these fatty acids in ruminant ketosis. Endogenous acetoacetate was readily produced by liver and rumen tissues from normal non-pregnant ewes, while significantly greater quantities were produced by tissues from ketotic pregnant ewes. The unsaturated long-chain fatty acids, oleate and linoleate, were associated with higher levels of ketone body formation than were the saturated acids while both groups of fatty acids caused higher levels of ketone body formation with rumen epithelium than with liver. Heretofore the rumen wall has not been recognized as a site of ketone body formation from long-chain fatty acids. It appears that the capacity of rumen epithelium to produce ketone bodies from the fatty acids found in depot fats is a factor in the high susceptibility of ruminants to spontaneous ketosis.

Insulin-Resistant Diabetes after Total Pancreatectomy

CONTRARY to speculation diabetes mellitus that follows total pancreatectomy in man is relatively mild. In the absence of infection or other complications the requirement for insulin is usually stable and ranges from 20 to 40 units daily. There is relatively little tendency to spontaneous ketosis and coma, but insulin sensitivity has been a frequent problem in management. The marked contrast of these findings with those in many cases of naturally occurring diabetes mellitus has stimulated consideration of factors besides lack of insulin that produce hyperglycemia and ketosis and require large doses of insulin for correction.In the following case, which . . .

Studies on Ketosis in Dairy Cattle. XI. Lipids, Minerals and Ascorbic Acid in the Blood of Cows with Spontaneous Ketosis

Summary In a study with 18 cows diagnosed as having ketosis, an analysis was made of various blood and blood plasma substances. Plasma phospholipids and cholesterol ester fractions were somewhat low, particularly in the later stages of ketosis. Free cholesterol in the plasma was relatively normal. The amount of free ether-petroleum ether soluble non-volatile acids in plasma determined by acidometric titration was relatively high in the later stages of ketosis. The neutral fat fraction was relatively low in the early stages of ketosis and normal or high in the later stages. Marked variations were observed in the plasma ascorbic acid values. The serum phosphatase activity was relatively low. The plasma acid-soluble phosphorus values, both inorganic and organic, were sometimes low but were normal in most cases. Plasma sodium and potassium were normal and the blood chloride values also were in the normal range. Additional data on the effect of fasting and other factors secondary to ketosis are needed before the data can be properly evaluated.

Studies on Ketosis in Dairy Cattle. X. The Effect of a Vitamin A Deficiency

Summary Detailed observations were made on 13 cows which were maintained on a low carotene diet for approximately 4 mo. prepartum and 3 wk. postpartum. The vitamin A depletion of these cows was accentuated by the feeding of a concentrate ration containing 40 per cent soybeans which was later shown to exert a marked depressing action on blood plasma and liver vitamin A. Five of the cows received a vitamin A supplement prepartum which resulted in the birth of four normal-appearing calves. The other eight cows dropped calves which showed marked signs and/or symptoms of a vitamin A deficiency. The blood plasma vitamin A values of these eight cows were extremely low during the postpartal period and one cow exhibited marked symptoms of a vitamin A deficiency. Of the eight cows, four were maintained on a low level of energy intake for 3 wk. postpartum (50 per cent of requirements). The five cows receiving the vitamin A supplement prepartum were on the same low level of energy intake postpartum. In spite of the severe vitamin A depletion and deficiency produced in these cows, none showed symptoms of ketosis and the degree of hypoglycemia produced by partial fasting was as large in the case of the vitamin A-supplemented cows as in the vitamin A-depleted cows. The cows exhibiting a marked vitamin A depletion but receiving higher levels of energy intake postpartum exhibited normal levels of glucose during the postpartal period. None of the cows showed symptoms of ketosis. It is concluded that not only is spontaneous ketosis, as it is observed under field conditions, not due to a vitamin A deficiency but that a vitamin A deficiency per se does not produce ketosis in dairy cows in the postpartal period.