Ketone body kinetics in humans: a mathematical model

A model has been developed to account for ketone body kinetics in man based on data following bolus injections of [14C]acetoacetate (A) and [14C]beta-OH butyrate (B) into normal humans in the postabsorptive state. The model consists of separate compartments for blood A and B that are linked by a tissue compartment in which rapid interconversion of the ketone bodies occurs. The probability of movement from blood into this compartment was assumed to be the same for both ketone bodies. Two slowly equilibrating tissue compartments are required to account for the slow components in the tracer data, and thus a five-compartment model is proposed. By modeling the transient tracer data with the tracee in a steady state, ketone body kinetics were defined in terms of the rapid interconversions of A and B, and the slow exchanges of carbon within the tissues. The rates of release of new A and B into blood, (UA and UB) were calculated. These rates were less than the apparent production rates, PRA and PRB, as the PR's included carbon atoms first released as the other ketone body. The exchange constants between the compartments were determined in addition to the fractional catabolic rates (FCR) and metabolic clearance rates (MCR) of A and B. The initial space of distribution was 10 L and the mean values +/- SD (n = 11), normalized to this volume, were UA = 6.4 +/- 5.0, UB = 8.8 +/- 8.0 (mumol L-1 min-1), FCRA = 0.226 +/- 0.142, FCRB = 0.188 +/- 0.124 (min-1), MCRA = 2.26 +/- 1.42, MCRB = 1.87 +/- 1.23 (L min-1) and PRA = 11.1 +/- 7.6, PRB = 12.7 +/- 10.0 (mumol L-1 min-1).     

Ketone body kinetics in normal,diabetic, and obese humans

We have developed a model for the kinetics of acetoacetate (A) and β-OH-butyrate (B) in normal subjects. The model contains separate compartments for blood A, B, and acetone, as well as three exchange compartments. By using the model, the synthesis, utilization, and clearance rates of A and B were determined separately. We have compared the model with others that have been proposed for ketone body metabolism and have used the model to analyse studies undertaken in newly diagnosed diabetic patients and obese subjects (before and after a 2 week period of starvation). We found that in diabetic and obese individuals the synthesis of ketone bodies was higher than normal and that the fractional losses of A and B were reduced. The results suggest that ketosis develops as a result of high synthesis rates coupled with decreased fractional loss of ketone bodies. In each group the metabolism of B was altered more than A.     

Zinc kinetics in insulin-dependent diabetes mellitus patients

Zinc has an important role in the control of carbohydrate metabolism, and diabetic patients are at risk for zinc deficiency. However, there are conflicting data concerning nutritional zinc status. In order to investigate this topic, 10 normal and 10 insulin-dependent diabetic patients were studied following venous zinc tolerance test. Our results found no evidence of zinc deficiency or of changes on the kinetic parameters of zinc in patients with insulin-dependent diabetes mellitus following a venous zinc tolerance test.     

Ketone body synthesis in the brain: possible neuroprotective effects

Ketone bodies make an important contribution to brain energy production and biosynthetic processes when glucose becomes scarce. Although it is generally assumed that the liver supplies the brain with ketone bodies, recent evidence shows that cultured astrocytes are also ketogenic cells. Moreover, astrocyte ketogenesis might participate in the control of the survival/death decision of neural cells in at least two manners: first, by scavenging non-esterified fatty acids the ketogenic pathway would prevent the detrimental actions of these compounds and their derivatives (e.g. ceramide) on brain structure and function. Second, ketone bodies may exert pro-survival actions per se by acting as cellular substrates, thereby preserving neuronal synaptic function and structural stability. These findings support the notion that ketone bodies produced by astrocytes may be used in situ as substrates for neuronal metabolism, and raise the possibility that astrocyte ketogenesis is a neuroprotective pathway.     

Cellularity of rat adipose tissue: effects of growth, starvation, and obesity

The size, number, and rate of formation of mature adipocytes were studied in the epididymal pads and retroperitoneal adipose depots of the Sprague-Dawley rat. Early growth of these depots was accompanied by progressive enlargement of adipose cells as well as by increases in number. Beyond the 15th wk of life, the depot grew exclusively by the process of cellular enlargement, with no further change in cell number. Severe starvation during the 6th wk of life followed by normal feeding had no lasting effect on cell size or cell number; prolonged semistarvation beginning in the 15th wk greatly reduced cell size while cell number was unaffected. Likewise, extreme increases in depot size produced by hypothalamic lesions did not change cell number, but only cell size. The concept of a fixed number of mature adipocytes in the adult organism may be of central importance in caloric and metabolic equilibrium.     

VLDL-triglyceride kinetics during hyperglycemia-hyperinsulinemia: effects of sex and obesity

We have previously shown that sex and obesity independently affect basal very low density lipoprotein (VLDL)-triglyceride (TG) kinetics. In the present study, we investigated the effect of hyperglycemia-hyperinsulinemia on VLDL-TG kinetics in lean and obese men and women (n = 6 in each group). VLDL-TG kinetics were measured during basal, postabsorptive conditions and during glucose infusion (5.5 mg x kg FFM(-1) x min(-1)) by using [(2)H(5)]glycerol bolus injection in conjunction with compartmental modeling analysis. Basal VLDL-TG secretion in plasma was greater in obese than in lean men (7.8 +/- 0.6 and 2.9 +/- 0.4 micromol x l plasma(-1) x min(-1); P < 0.001) but was not different in lean and obese women (5.0 +/- 1.1 and 5.9 +/- 1.1 micromol x l plasma(-1) x min(-1)). Glucose infusion decreased the VLDL-TG secretion rate by approximately 50% in lean and obese men and in lean women (to 1.5 +/- 0.4, 4.0 +/- 0.6, and 2.2 +/- 0.4 micromol x l plasma(-1) x min(-1), respectively; all P < 0.05) but had no effect on the VLDL-TG secretion rate in obese women (4.9 +/- 1.0 micromol x l plasma(-1) x min(-1)). These results demonstrate that both sex and adiposity affect the regulation of VLDL-TG metabolism. Glucose and insulin decrease VLDL-TG production in both lean men and lean women; obesity is associated with resistance to the glucose- and insulin-mediated suppression of VLDL-TG secretion in women, but not in men.     

Dynamics of starvation in humans

A differential equation model describing the dynamics of stored energy in the form of fat mass, lean body mass and ketone body mass during prolonged starvation is developed. The parameters of the model are estimated using available data for 7 days into starvation. A simulation of energy stores for a normal individual with body mass index between 19 and 24 and an obese individual with body mass index over 30 are calculated. The length of time the obese subject can survive during prolonged starvation is estimated using the model. Authors are listed in alphabetical order.     

Ketone body metabolism in the mother and fetus

Pregnancy is characterized by a rapid accumulation of lipid stores during the first half of gestation and a utilization of these stores during the latter half of gestation. Lipogenesis results from dietary intake, an exaggerated insulin response, and an intensified inhibition of glucagon release. Increasing levels of placental lactogen and a heightened response of adipose tissue to additional lipolytic hormones balance lipogenesis in the fed state. Maternal starvation in late gestation lowers insulin, and lipolysis supervenes. The continued glucose drain by the conceptus aids in converting the maternal liver to a ketogenic organ, and ketone bodies produced from incoming fatty acids are not only utilized by the mother but cross the placenta where they are utilized in several ways by the fetus: as a fuel in lieu of glucose; as an inhibitor of glucose and lactate oxidation with sparing of glucose for biosynthetic disposition; and for inhibition of branched-chain ketoacid oxidation, thereby maximizing formation of their parent amino acids. Ketone bodies are widely incorporated into several classes of lipids including structural lipids as well as lipids for energy stores in fetal tissues, and may inhibit protein catabolism. Finally, it has recently been shown that ketone bodies inhibit the de novo biosynthesis of pyrimidines in fetal rat brain slices. Thus during maternal starvation ketone bodies may maximize chances for survival both in utero and during neonatal life by restraining cell replication and sustaining protein and lipid stores in fetal tissues.     

Ketone body metabolism in the neonate: development and the effect of diet

In the course of mammalian development milk has evolved with unique characteristics as has the capacity of the neonatal rat to process this nutrient source. The primary carbon source in milk is fat, which provides two readily utilized metabolites, acetoacetate and D(-)-3-hydroxybutyrate (ketone bodies), as well as free fatty acids and glycerol. Carbohydrate provides less than 12% of the caloric content of rat milk and glucose has to be produced by the suckling rat to maintain glucose homeostasis. One would predict that glucose would be used sparingly and in pathways that cannot be satisfied by other readily available metabolites. Studies of the uptake of metabolites and the development of key enzymes for the utilization of glucose and ketone bodies by developing brain support the concept that ketone bodies are preferred substrates for the supply of carbon to respiration and lipogenesis. Astrocytes, oligodendrocytes, and neurons from developing brain all have an excellent capacity to use ketone bodies for respiration. By contrast, glucose is utilized preferentially in the hexose monophosphate shunt by all three cell populations. We are examining the requirement for ketone bodies by developing brain with the application of a system to rear rat pups artificially on a milk substitute that promotes a hypoketonemia.     

HLA-dependent GM effects in insulin-dependent diabetes: evidence from pairs of affected siblings.

In a recent study of GM allotype frequencies in HLA-defined subsets of patients with insulin-dependent diabetes mellitus (IDDM) and similarly defined healthy sibling controls, we found evidence for an HLA-dependent GM effect on IDDM susceptibility. To circumvent problems inherent in such patient-control studies of complex diseases, we have now examined sharing of genes in the HLA and GM regions in 26 informative pairs of siblings who were both affected with IDDM. We found that: (1) in the total sample of affected sib-pairs, sharing of two HLA haplotypes was increased compared to Mendelian expectations, in agreement with many previous studies; (2) in the total sample, sharing of GM region genes (as measured by GM phenotype concordance) was not different from Mendelian expectations, given the distribution of parental mating types; and (3) affected sib-pairs who shared two HLA haplotypes showed significantly increased sharing of GM region genes compared to affected sib-pairs who shared one or zero HLA haplotypes (P = .018). These results provide new evidence for HLA-dependent effects of a locus at or near GM on susceptibility to IDDM.     

Assessing body composition with DXA and bioimpedance: effects of obesity, physical activity, and age

Objective: This study evaluated to what extent dual‐energy X‐ray absorptiometry (DXA) and two types of bioimpedance analysis (BIA) yield similar results for body fat mass (FM) in men and women with different levels of obesity and physical activity (PA). Methods and Procedures: The study population consisted of 37–81‐year‐old Finnish people (82 men and 86 women). FM% was estimated using DXA (GE Lunar Prodigy) and two BIA devices (InBody (720) and Tanita BC 418 MA). Subjects were divided into normal, overweight, and obese groups on the basis of clinical cutoff points of BMI, and into low PA (LPA) and high PA (HPA) groups. Agreement between the devices was calculated by using the Bland–Altman analysis. Results: Compared to DXA, both BIA devices provided on average 2–6% lower values for FM% in normal BMI men, in women in all BMI categories, and in both genders in both HPA and LPA groups. In obese men, the differences were smaller. The two BIA devices provided similar means for groups. Differences between the two BIA devices with increasing FM% were a result of the InBody (720) not including age in their algorithm for estimating body composition. Discussion: BIA methods provided systematically lower values for FM than DXA. However, the differences depend on gender and body weight status pointing out the importance of considering these when identifying people with excess FM.     

Obestatin, obesity and diabetes

The high prevalence of obesity and diabetes will lead to higher rates of morbidity and mortality. It is well known that ghrelin plays a potential role in obesity and diabetes. Obestatin, a novel 23 amino acid amidated peptide encoded by the same gene that encodes ghrelin, was initially reported to have opposite actions to ghrelin in the regulation of food intake, emptying of the stomach and body weight. Recent work suggests that obestatin also regulate beta-cell survival and insulin secretion. The ghrelin-obestatin system is, therefore, a promising target for the developing of new drugs for the treatment of obesity and diabetes. This review summarizes the interrelationship between obestatin, obesity and diabetes.     

Fibrinolytic and hypoglycemic effects of the Pro-Gly-Pro-Leu peptide during development of insulin-dependent diabetes in rats

Repeated (over 7 days) intranasal introduction of the Pro-Gly-Pro-Leu peptide into animals at a dose of 1 mg/kg before injection of the diabetogenic metabolite alloxan provided effective protection of an organism against development of insulin-dependent diabetes mellitus and prevented development of hyper-coagulating alterations in the system of hemostasis. An increasing in the anticoagulating and fibrinolytic activities in rat blood plasma was detected. The peptide under study also showed antidiabetogenic action: repeated intranasal introduction of the Pro-Gly-Pro-Leu peptide into animals for 7 days inhibited development of diabetes symptoms in rats pretreated with alloxan.     

The effects of starvation and experimental diabetes on phosphoenol-pyruvate carboxykinase in the guinea pig.

1. Approx. 85% of liver phosphoenolpyruvate carboxykinase is associated with the mitochondrial fraction in the fed guinea pig. Enzyme activity is unchanged in diabetes, but doubles during starvation. In contrast with earlier reports, both cytoplasmic and mitochondrial activities were found to be increased. 2. In kidney cortex, total enzyme activity is increased in both starved and diabetic animals. These changes are associated with increases in the cytoplasmic activity alone. 3. In diabetic animals the mean blood-glucose concentration was 23.1 mM. Other blood metabolites were lower than those in the rat, and the animals did not show significant ketosis. 4. Changes in the rates of gluconeogenesis from lactate and propionate paralleled those in phosphoenolpyruvate carboxykinase activity.     

Peer effects of obesity on child body composition

This study investigates whether peer obesity is a driver of individual weight changes in public school children and whether the impact of peer effects changes as children age. Quantifying peer effects is important for understanding the social determinants of obesity and for planning effective school wellness policies. However, the extant empirical research on peer effects is limited due to difficulties in separating causal influences from confounding factors. This study overcomes some of these difficulties by using a within-school, across-cohort empirical design to separate confounding factors at the individual, school and school-grade level for over one million public school children. The results show that increases a one standard deviation increase in average classmate body mass index (BMI) leads to a modest but meaningful increase of 0.395 standard deviation increase in a child's own BMI. Peer-effects are highest (0.813) for children in Kindergarten and decline with age. These findings suggest that the critical time for school-grade level intervention may be in the earliest ages of childhood development.     

Pharyngeal resistance in normal humans: influence of gender, age, and obesity

Investigation into the etiology of obstructive sleep apnea is beginning to focus increasing attention on upper airway anatomy and physiology (patency and resistance). Before conclusions concerning upper airway resistance in these patients can be made, the normal range of supraglottic and, more specifically, pharyngeal resistance needs to be better defined. We measured supraglottic and pharyngeal resistances during nasal breathing in a normal population of 35 men and women. Our technique measured epiglottic pressure with a balloon-tipped catheter, choanal pressure using anterior rhinometry, and flow with a sealed face mask and pneumotachograph. Resistance was measured at a flow rate of 300 ml/s during inspiration. Men had a mean pharyngeal resistance (choanae to epiglottis) of 4.6 +/- 0.8 (SE) cmH2O X l-1 X s, whereas women demonstrated a significantly (P less than 0.01) lower value, 2.3 +/- 0.3 cmH2O X l-1 X s. Supraglottic resistance was also higher in men (P = 0.01). Age (r = 0.73, P less than 0.01) correlated closely with pharyngeal resistance in men, but no such correlations could be found in women. These results may have implications in the epidemiology of obstructive sleep apnea.     

Ketone bodies in fish skin mucus as an indicator of starvation: a preliminary report

The detection of starvation is a major problem in fish husbandry. Too often the discovery of starving animals is not made until pathogenic organisms are about to overcome the weakened animals. A simple test, using a commercial plastic strip with a reagent area that changes colour in the presence of starvation-induced ketones, was applied to this problem in the mullet, Mugil cephalus. The strip identified ketones in the fish skin mucus, and demonstrated its value in detecting starvation in fishes.