(1/526) Effects of fatty acids and ketone bodies on basal insulin secretion in type 2 diabetes.

The objective of this study was to assess the role of free fatty acids (FFAs) as insulin secretagogues in patients with type 2 diabetes. To this end, basal insulin secretion rates (ISR) in response to acute increases in plasma FFAs were evaluated in patients with type 2 diabetes and in age- and weight-matched nondiabetic control subjects during 1) intravenous infusion of lipid plus heparin (L/H), which stimulated intravascular lipolysis, and 2) the FFA rebound, which followed lowering of plasma FFAs with nicotinic acid (NA) and was a consequence of increased lipolysis from the subject's own adipose tissue. At comparable euglycemia, diabetic patients had similar ISR but higher plasma beta-hydroxybutyrate (beta-OHB) levels during L/H infusion and higher plasma FFA and beta-OHB levels during the FFA rebound than nondiabetic control subjects. Correlating ISR with plasma FFA plus beta-OHB levels showed that in response to the same changes in FFA plus beta-OHB levels, diabetic patients secreted approximately 30% less insulin than nondiabetic control subjects. In addition, twice as much insulin was secreted during L/H infusion as during the FFA rebound in response to the same FFA/beta-OHB stimulation by both diabetic patients and control subjects. Glycerol, which was present in the infused lipid (272 mmol/l) did not affect ISR. We concluded that 1) assessment of FFA effects on ISR requires consideration of effects on ISR by ketone bodies; 2) ISR responses to FFA/beta-OHB were defective in patients with type 2 diabetes (partial beta-cell lipid blindness), but this defect was compensated by elevated plasma levels of FFAs and ketone bodies; and 3) approximately two times more insulin was released per unit change in plasma FFA plus beta-OHB during L/H infusion than during the FFA rebound after NA. The reason for this remains to be explored.  (+info)

(2/526) Within- and between-subject variation in commonly measured anthropometric and biochemical variables.

BACKGROUND: The biological variation of some commonly assessed metabolic variables in healthy subjects has not been studied extensively. The aim of the study was to assess, in 12 healthy subjects (6 male and 6 female; mean (SD) age; 22.7 (1.5) years) following an overnight fast, the day-to-day variation of body fat (impedance method), triglycerides, nonesterified fatty acid (NEFAs), glycerol, 3-hydroxybutyrate (3-OHB), lactate, glucose, insulin (RIA), C-peptide, and glucagon on 12 consecutive days. METHODS: Between- and within-subject coefficients of variation (CVG and CVW) were estimated using a random effects analysis of variance, and assay variation was subtracted to give the coefficient of within-subject biological variation (CVI). Individuality indices were calculated as CVW/CVG. RESULTS: The overall means, CVI, and individuality indices were as follows: for body fat, 24.2%, 10%, and 0.3; for triglycerides, 0.61 mmol/L, 21%, and 1.1; for NEFAs, 376 micromol/L, 45%, and 1.4; for glycerol, 48 micromol/L, 36%, and 0.8; for 3-OHB, 43 micromol/L, 61%, and 1.5; for lactate, 0.88 mmol/L, 31%, and 1.1; for glucose, 4.9 mmol/L, 4.8%, and 0.7; for insulin, 52 pmol/L, 26%, and 1.0; for C-peptide, 0.39 nmol/L, 24%, and 0.9; and for glucagon, 53 ng/L, 19%, and 0.8. CONCLUSIONS: The data presented here are necessary for the evaluation of several important metabolic variables in individual and group studies. The biological variation of some metabolites makes it difficult to characterize the status of healthy subjects with a single measurement.  (+info)

(3/526) Production of poly(3-hydroxybutyric acid-co-4-hydroxybutyric acid) and poly(4-hydroxybutyric acid) without subsequent degradation by Hydrogenophaga pseudoflava.

A Hydrogenophaga pseudoflava strain was able to synthesize poly(3-hydroxybutyric acid-co-4-hydroxybutyric acid) [P(3HB-co-4HB)] having a high level of 4-hydroxybutyric acid monomer unit (4HB) from gamma-butyrolactone. In a two-step process in which the first step involved production of cells containing a minimum amount of poly(3-hydroxybutyric acid) [P(3HB)] and the second step involved polyester accumulation from the lactone, approximately 5 to 10 mol% of the 3-hydroxybutyric acid (3HB) derived from the first-step culture was unavoidably reincorporated into the polymer in the second cultivation step. Reincorporation of the 3HB units produced from degradation of the first-step residual P(3HB) was confirmed by high-resolution 13C nuclear magnetic resonance spectroscopy. In order to synthesize 3HB-free poly(4-hydroxybutyric acid) [P(4HB)] homopolymer, a three-stage cultivation technique was developed by adding a nitrogen addition step, which completely removed the residual P(3HB). The resulting polymer was free of 3HB. However, when the strain was grown on gamma-butyrolactone as the sole carbon source in a synthesis medium, a copolyester of P(3HB-co-4HB) containing 45 mol% 3HB was produced. One-step cultivation on gamma-butyrolactone required a rather long induction time (3 to 4 days). On the basis of the results of an enzymatic study performed with crude extracts, we suggest that the inability of cells to produce 3HB in the multistep culture was due to a low level of 4-hydroxybutyric acid (4HBA) dehydrogenase activity, which resulted in a low level of acetyl coenzyme A. Thus, 3HB formation from gamma-butyrolactone is driven by a high level of 4HBA dehydrogenase activity induced by long exposure to gamma-butyrolactone, as is the case for a one-step culture. In addition, intracellular degradation kinetics studies showed that P(3HB) in cells was completely degraded within 30 h of cultivation after being transferred to a carbon-free mineral medium containing additional ammonium sulfate, while P(3HB-co-4HB) containing 5 mol% 3HB and 95 mol% 4HB was totally inert in interactions with the intracellular depolymerases. Intracellular inertness could be a useful factor for efficient synthesis of the P(4HB) homopolymer and of 4HB-rich P(3HB-co-4HB) by the strain used in this study.  (+info)

(4/526) Requirement for the heart-type fatty acid binding protein in cardiac fatty acid utilization.

Nonenzymatic cytosolic fatty acid binding proteins (FABPs) are abundantly expressed in many animal tissues with high rates of fatty acid metabolism. No physiological role has been demonstrated for any FABP, although these proteins have been implicated in transport of free long-chain fatty acids (LCFAs) and protection against LCFA toxicity. We report here that mice lacking heart-type FABP (H-FABP) exhibit a severe defect of peripheral (nonhepatic, non-fat) LCFA utilization. In these mice, the heart is unable to efficiently take up plasma LCFAs, which are normally its main fuel, and switches to glucose usage. Altered plasma levels of LCFAs, glucose, lactate and beta-hydroxybutyrate are consistent with depressed peripheral LCFA utilization, intensified carbohydrate usage, and increased hepatic LCFA oxidation; these changes are most pronounced under conditions favoring LCFA oxidation. H-FABP deficiency is only incompletely compensated, however, causing acute exercise intolerance and, at old age, a localized cardiac hypertrophy. These data establish a requirement for H-FABP in cardiac intracellular lipid transport and fuel selection and a major role in metabolic homeostasis. This new animal model should be particularly useful for investigating the significance of peripheral LCFA utilization for heart function, insulin sensitivity, and blood pressure.  (+info)

(5/526) Relations between plasma acetate, 3-hydroxybutyrate, FFA, glucose levels and energy nutrition in lactating dairy cows.

To clarify the implication of an energy nutrition on a metabolic alteration with advancing lactation, total 270 blood samples were taken from 16 lactating dairy cows. Amounts of dietary allowance and the refusals were measured daily, and the energy (TDN) intakes and a satisfaction (energy balance) of each cow were estimated. Plasma acetate, 3-hydroxybutyrate (3-HB), free fatty acid (FFA) and glucose levels were estimated. The data were divided into 3 groups depending on the days in milk; early (up to 70 days postpartum), mid (71 to 140 days), and late (after 141 days) lactation. There were many cases of higher FFA level in early lactation, especially with declining acetate and glucose levels. There were proportional elevations of 3-HB in connection with FFA levels in many samples of early lactation, though the 3-HB increased independently of FFA levels in the most cases of the mid and late lactations. Plasma 3-HB levels increased in many cases of decreased glucose level, especially in the early lactation. Plasma acetate level correlated positively with 3-HB level, but not correlated with glucose level. Higher FFA level and elevation of FFA/3-HB ratio were observed in the conditions of negative energy balance. This implies the metabolic importance of FFA in a ketogenesis of the early lactation.  (+info)

(6/526) Effect of hyperketonemia on plasma lipid peroxidation levels in diabetic patients.

OBJECTIVE: This study was undertaken to examine the effect of ketosis on plasma lipid peroxidation levels in diabetic patients. RESEARCH DESIGN AND METHODS: Plasma levels of lipid peroxidation products (malondialdehyde) and ketone bodies (acetoacetate and beta-hydroxybutyrate) were determined in diabetic patients (n = 70) and age-matched normal volunteers (n = 25). Diabetic patients with total ketone body levels > 1.0 mmol/l were considered hyperketonemic, and those with levels < or = 1.0 mmol/l were considered normoketonemic. RESULTS: After normalization versus total lipids, levels of lipid peroxidation were significantly higher in the plasma of hyperketonemic diabetic patients (P < 0.05), but not in normoketonemic diabetic patients, compared with age-matched normal volunteers. In addition, low ketonemia was associated with lower lipid peroxidation levels when lipid peroxidation and ketonemia were determined in the same patient (n = 7) at two different clinic visits. CONCLUSIONS: This study demonstrated an association between hyperketonemia and increased lipid peroxidation levels in diabetic patients, which suggests that ketosis is a risk factor in the elevated lipid peroxidation levels associated with diabetes. Further investigation is needed to determine whether antioxidant supplementation can be particularly beneficial in reducing lipid peroxidation and complications in type 1 diabetic patients who frequently encounter ketosis.  (+info)

(7/526) The metabolic effects of estriol in female rat liver.

The effects of estriol on oxygen uptake, glucose release, lactate and pyruvate production, beta-hydroxybutyrate and acetoacetate production in perfused rat liver as well as, carbon uptake in rat liver and intracellular calcium in isolated Kupffer cells were investigated. Basal oxygen consumption of perfused liver increased significantly in estriol or ethanol-treated rats. But these increased effects were blocked by gadolinium chloride pretreatment. In a metabolic study, pretreatment with estriol resulted in a decrease in glucose production and in glycolysis while an increase in ketogenesis. A more oxidized redox state of the mitochondria was indicated by increased ratios of perfusate [lactate]/[pyruvate] and decreased ratios of perfusate [beta-hydroxybutyrate]/[acetoacetate]. Carbon uptake of Kupffer-cell increased significantly in estriol-treated rats. But these increased uptake were not shown in rats pre-treated by gadolinium chloride blocking phagocytosis. In isolated Kupffer cells from estriol-treated rats, intracellular calcium was more significantly increased after addition of lipopolysaccharide (LPS) than in controls. These findings suggest that the metabolic effects of estriol (two mg per 100 mg body wt) can be summarized to be highly toxic in rat liver, and these findings suggest that oral administration of estrogens may induce hepatic dysfunctions and play a role in the development of liver disease.  (+info)

(8/526) Hormonal and metabolic responses to maintained hyperglycemia during prolonged exercise.

We studied the effects of maintained hyperglycemia (12 mmol/l) on endurance exercise to determine the hormonal and metabolic responses, the maximal rate of glucose infusion (i.e., utilization), and the effects on muscle glycogen stores. Eight men undertook two trials during which they exercised on a cycle ergometer at an intensity of approximately 70% peak O(2) uptake for 120 min. In the first trial (trial A), subjects had their blood glucose concentration clamped at 12 mmol/l 30 min before exercise and throughout exercise. The same rate and volume of infusion of saline as had occurred for trial A were used in a placebo trial (trial B). Maintained hyperglycemia resulted in significantly lowered plasma concentrations of nonesterified fatty acid, glycerol, 3-hydroxybutyrate, epinephrine, norepinephrine, and growth hormone (P < 0.001) during exercise, whereas concentrations of plasma insulin were significantly elevated (P < 0.001). Calculations of the rates of total carbohydrate oxidation showed that trial A resulted in significantly higher values when compared with trial B (P < 0.01) and that the maximal rates of glucose infusion varied between 1.33 and 2.78 g/min at 100-120 min. Muscle glycogen concentrations were significantly depleted (P < 0.01) after both trials (trial A, 170.3 micromol/g dry wt decrease; trial B, 206 micromol/g dry wt decrease), although this apparent difference may be accounted for by storage of 22.6 g glucose during the 30-min prime infusion. The results from this study confirm that maintained hyperglycemia attenuates the hormonal response and promotes carbohydrate oxidation and utilization and that muscle glycogen may not be spared.  (+info)

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