Fetal over- and undernutrition differentially program thyroid axis adaptability in adult sheep.

OBJECTIVE: We aimed to test, whether fetal under- or overnutrition differentially program the thyroid axis with lasting effects on energy metabolism, and if early-life postnatal overnutrition modulates implications of prenatal programming. DESIGN: Twin-pregnant sheep (n = 36) were either adequately (NORM), under- (LOW; 50% of NORM) or overnourished (HIGH; 150% of energy and 110% of protein requirements) in the last-trimester of gestation. From 3 days-of-age to 6 months-of-age, twin lambs received a conventional (CONV) or an obesogenic, high-carbohydrate high-fat (HCHF) diet. Subgroups were slaughtered at 6-months-of-age. Remaining lambs were fed a low-fat diet until 2½ years-of-age (adulthood). METHODS: Serum hormone levels were determined at 6 months- and 2½ years-of-age. At 2½ years-of-age, feed intake capacity (intake over 4-h following 72-h fasting) was determined, and an intravenous thyroxine tolerance test (iTTT) was performed, including measurements of heart rate, rectal temperature and energy expenditure (EE). RESULTS: In the iTTT, the LOW and nutritionally mismatched NORM:HCHF and HIGH:CONV sheep increased serum T3, T3:T4 and T3:TSH less than NORM:CONV, whereas TSH was decreased less in HIGH, NORM:HCHF and LOW:HCHF. Early postnatal exposure to the HCHF diet decreased basal adult EE in NORM and HIGH, but not LOW, and increased adult feed intake capacity in NORM and LOW, but not HIGH.Conclusions: The iTTT revealed a differential programming of central and peripheral HPT axis function in response to late fetal malnutrition and an early postnatal obesogenic diet, with long-term implications for adult HPT axis adaptability and associated consequences for adiposity risk.

Late gestation undernutrition can predispose for visceral adiposity by altering fat distribution patterns and increasing the preference for a high-fat diet in early postnatal life.

We have developed a sheep model to facilitate studies of the fetal programming effects of mismatched perinatal and postnatal nutrition. During the last trimester of gestation, twenty-one twin-bearing ewes were fed a normal diet fulfilling norms for energy and protein (NORM) or 50% of a normal diet (LOW). From day 3 postpartum to 6 months (around puberty) of age, one twin lamb was fed a conventional (CONV) diet and the other a high-carbohydrate-high-fat (HCHF) diet, resulting in four groups of offspring: NORM-CONV; NORMHCHF; LOW-CONV; LOW-HCHF. At 6 months of age, half of the lambs (all males and three females) were slaughtered for further examination and the other half (females only) were transferred to a moderate sheep diet until slaughtered at 24 months of age (adulthood). Maternal undernutrition during late gestation reduced the birth weight of LOW offspring (P<0·05), and its long-term effects were increased adrenal size in male lambs and adult females (P<0·05), increased neonatal appetite for fat-(P=0·004) rather than carbohydrate-rich feeds (P<0·001) and reduced deposition of subcutaneous fat in both sexes (P<0·05). Furthermore, LOW-HCHF female lambs had markedly higher visceral:subcutaneous fat ratios compared with the other groups (P<0·001). Postnatal overfeeding (HCHF) resulted in obesity (.30% fat in soft tissue) and widespread ectopic lipid deposition. In conclusion, our sheep model revealed strong pre- and postnatal impacts on growth, food preferences and fat deposition patterns. The present findings support a role for subcutaneous adipose tissue in the development of visceral adiposity, which in humans is known to precede the development of the metabolic syndrome in human adults.

In cirrhotic patients reduced muscle strength is unrelated to muscle capacity for ATP turnover suggesting a central limitation.

BACKGROUND AND AIMS: We investigated whether in patients with liver cirrhosis reduced muscle strength is related to dysfunction of muscle mitochondria. METHODS: The mitochondrial respiratory capacity of the tibial anterior muscle was evaluated in seven patients and eight healthy control subjects by 31P nuclear magnetic resonance spectroscopy (31PMRS) to express ATP turnover in vivo and by respirometry of permeabilized fibres from the same muscle to express the in vitro capacity for oxygen consumption. RESULTS: Maximal voluntary contraction force for plantar extension was low in the patients (46% of the control value; P < 0.05), but neither the capacity for mitochondrial ATP synthesis, V(max-ATP) (0.38 ± 0.26 vs. 0.50 ± 0.07 mM s(-1) ; P = 0.13) nor the in vitro VO(2max) (0.52 ± 0.21 vs. 0.48 ± 0.21 µmol O2 (min g wet wt.)(-1) P = 0.25) were lowered correspondingly. Also, the activity of citrate synthesis and the respiratory chain complexes II and IV were similar in patients and controls. However during the contractions, the contribution to initial anaerobic ATP production from glycolysis relative to that from PCr was reduced in the patients (0.73 ± 0.22 vs. 0.99 ± 0.09; P < 0.01). CONCLUSIONS: These results demonstrate that the markedly lower capacity for force generation in patients with liver cirrhosis is unrelated to their capacity for muscle ATP turnover, but the attenuated initial acceleration of anaerobic glycolysis suggests that these patients could be affected by a central limitation to force generation.

The intracellular to extracellular proton gradient following maximal whole body exercise and its implication for anaerobic energy production.

Maximal exercise elicits systemic acidosis where venous pH can drop to 6.74 and here we assessed how much lower the intracellular value (pH(i)) might be. The wrist flexor muscles are intensively involved in rowing and (31)P-magnetic resonance spectroscopy allows for calculation of forearm pH(i) and energy metabolites at high time resolution. Arm venous blood was collected in seven competitive rowers (4 males; 72 +/- 5 kg; mean +/- SD) at rest and immediately after a "2,000 m" maximal rowing ergometer effort when hemoglobin O(2) saturation decreased from 51 +/- 4 to 29 +/- 9% and lactate rose from 1.0 +/- 0.1 to 16.8 +/- 3.6 mM. Venous pH and pH(i) decreased from 7.43 +/- 0.01 to 6.90 +/- 0.01 and from 7.05 +/- 0.02 to 6.32 +/- 0.19 (P < 0.05), respectively, while the ratio of inorganic phosphate to phosphocreatine increased from 0.12 +/- 0.03 to 1.50 +/- 0.49 (P < 0.05). The implication of the recorded intravascular and intracellular acidosis and the decrease in PCr is that the anaerobic contribution to energy metabolism during maximal rowing corresponds to 4.47 +/- 1.8 L O(2), a value similar to that defined as the "accumulated oxygen deficit". In conclusion, during maximal rowing the intracellular acidosis, expressed as proton concentration, surpasses approximately 4-fold the intravascular acidosis, while the resting gradient is approximately 2.

Short bowel patients treated for two years with glucagon-like Peptide 2: effects on intestinal morphology and absorption, renal function, bone and body composition, and muscle function.

BACKGROUND AND AIMS: In a short-term study, Glucagon-like peptide 2 (GLP-2) has been shown to improve intestinal absorption in short bowel syndrome (SBS) patients. This study describes longitudinal changes in relation to GLP-2 treatment for two years. METHODS: GLP-2, 400 micrograms, s.c.,TID, were offered, to eleven SBS patients keeping parenteral support constant. 72-hour nutritional balance studies were performed at baseline, weeks 13, 26, 52 during two years intermitted by an 8-week washout period. In addition, mucosal morphometrics, renal function (by creatinine clearance), body composition and bone mineral density (by DEXA), biochemical markers of bone turnover (by s-CTX and osteocalcin, PTH and vitamin D), and muscle function (NMR, lungfunction, exercise test) were measured. RESULTS: GLP-2 compliance was >93%. Three of eleven patients did not complete the study. In the remaining 8 patients, GLP-2 significantly reduced the fecal wet weight from approximately 3.0 to approximately 2.0 kg/day. This was accompanied by a decline in the oral wet weight intake, maintaining intestinal wet weight absorption and urinary weight constant. Renal function improved. No significant changes were demonstrated in energy intake or absorption, and GLP-2 did not significantly affect mucosal morphology, body composition, bone mineral density or muscle function. CONCLUSIONS: GLP-2 treatment reduces fecal weight by approximately 1000 g/d and enables SBS patients to maintain their intestinal fluid and electrolyte absorption at lower oral intakes. This was accompanied by a 28% improvement in creatinine clearance.

Short bowel patients treated for two years with glucagon-like peptide 2 (GLP-2): compliance, safety, and effects on quality of life.

BACKGROUND AND AIMS: Glucagon-like peptide 2 (GLP-2) has been shown to improve intestinal absorption in short bowel syndrome (SBS) patients in a short-term study. This study describes safety, compliance, and changes in quality of life in 11 SBS patients at baseline, week 13, 26, and 52 during two years of subcutaneous GLP-2 treatment, 400 microgram TID, intermitted by an 8-week washout period. METHODS: Safety and compliance was evaluated during the admissions. The Sickness Impact Profile (SIP), Short Form 36 (SF 36), and Inflammatory Bowel Disease Questionnaire (IBDQ) evaluated quality of life. RESULTS: The predominant adverse event was transient abdominal discomfort in 5 of 11 patients, but in 2, both suffering from Crohns disease, it progressed to abdominal pain and led to discontinuation of GLP-2 treatment. One had a fibrostenotic lesion electively resected at the jejuno-ascendo-anastomosis. The investigator excluded a patient due to unreliable feedback. Stoma nipple enlargement was seen in all 9 jejunostomy patients. Reported GLP-2 compliance was excellent (>93%). GLP-2 improved the overall quality of life VAS-score (4.1 +/- 2.8 cm versus 6.0 +/- 2.4 cm, P < .01), the overall SIP score (10.3 +/- 8.9% versus 6.2 +/- 9.5%, P < .001), the mental component of the SF-36 (45 +/- 13% versus 53 +/- 11%, P < .05), and the overall IBDQ score (5.1 +/- 0.9 versus 5.4 +/- 0.9, P < .007) in the 8 patients completing the study. CONCLUSIONS: Long-term treatment with GLP-2 is feasible in SBS patients, although caution must be exercised in patients with a history of abdominal pain. Although conclusions cannot be made in a noncontrolled trial, the high reported compliance might reflect a high treatment satisfaction, where the clinical benefits of GLP-2 may outweigh the discomforts of injections.

Muscle mitochondrial function in patients with type 2 diabetes mellitus and peripheral arterial disease: implications in vascular surgery.

OBJECTIVES: (1) To review the available information on mitochondrial function in type 2 diabetes mellitus (T2DM) and peripheral arterial disease (PAD) obtained by non-invasive phosphorus magnetic resonance spectroscopy ((31)PMRS), near-infrared spectroscopy (NIRS) in vivo and respirometry on mitochondria isolated from muscle biopsies in vitro (2) to evaluate the usefulness of such data in the diagnosis, treatment and prognosis of these patients. DESIGN: Review. SEARCH STRATEGY: PubMed (http://www.ncbi.nlm.nih.gov/PubMed) and manual literature search. MAIN RESULTS: Fifty-three articles were retrieved, which included (31)PMRS, 15, NIRS, 11, Combined, 1 and Respirometry, 2 and background literature, 24. CONCLUSION: Muscle mitochondrial function is impaired in both T2DM and PAD patients, but differently. Patients suffering from both pathological conditions will display more serious impairment of the mitochondrial function. Mitochondrial function and the degree of ischaemic disease as evaluated by (31)PMRS and NIRS are well correlated. The NIRS technique appears to determine the degree of PAD better than (31)PMRS. It is argued that systematic testing of mitochondrial function may be a useful prognostic tool with PAD and T2DM, but clinical studies are needed.

31P-MRS characterization of sprint and endurance trained athletes.

Muscle metabolism and force production were studied in sprint trained runners, endurance trained runners and in untrained subjects, using 31P-MRS. 31P-spectra were obtained at a time resolution of 5 s during four maximal isometric contractions of 30-sec duration, interspersed by 60-sec recovery intervals. Resting CrP/ATP ratio averaged 3.3 +/- 0.3, with no difference among the three groups. The sprint trained subjects showed about 20 % larger contraction forces in contraction bouts 1 and 2 (p < 0.05). The groups differed with respect to CrP breakdown (p < 0.05), with sprinters demonstrating about 75 % breakdown in each contraction compared to about 60 % and 40 % for untrained and endurance trained subjects, respectively (p < 0.05). The endurance trained runners showed almost twice as fast CrP recovery (t 1/2 = 12.5 +/- 1.5) compared to sprint trained (t 1/2 = 22.5 +/- 2.53) and untrained subjects (t 1/2 = 26.4 +/- 2.8). From the initial rate of CrP resynthesis the rate of maximal aerobic ATP synthesis was estimated to 0.74 +/- 0.07, 0.73 +/- 0.10 and 0.33 +/- 0.07 mmol ATP x kg -1 wet muscle x sec -1 for sprint trained, endurance trained and untrained subjects, respectively. Only the sprint trained and the untrained subjects displayed a significant drop in pH and only during the first of the four contractions, about 0.2 and 0.1 pH units, respectively, indicating that only under those contractions was the glycolytic proton production larger than the proton consumption by the CK reaction. Also, in the first contraction the energy cost of contraction was higher for the sprinters compared to the two other groups. The simple 31P-MRS protocol used in the present study demonstrates marked differences in force production, aerobic as well as anaerobic muscle metabolism, clearly allowing differentiation between endurance trained, sprint trained and untrained subjects.

Bicarbonate attenuates intracellular acidosis.

BACKGROUND: This study was prompted by concern that administration of bicarbonate for correction of lactate acidosis aggravates a low intracellular pH (pHi). In healthy subjects we evaluated skeletal muscle pHi using 31P-magnetic resonance spectroscopy during 5-minute rhythmic handgrip to provoke intracellular acidosis. METHODS: Subjects were randomized to treatment with bicarbonate or saline infused intravenously in a cross-over study design with 1 h between trials. RESULTS: In response to rhythmic handgrip, muscle venous O(2) hemoglobin saturation decreased from 51 +/- 4% to 36 +/- 2% and lactate increased from 1.0 +/- 0.1 to 4.9 +/- 0.5 mmol/l with a reduction in pH from 7.43 +/- 0.01-7.23 +/- 0.01 (P<0.05). pHi decreased from 7.06 +/- 0.02-6.36 +/- 0.08 (P<0.05). Infusion of bicarbonate increased the arterial blood concentration from 26 +/- 1 to 39 +/- 1 mmol/l (P<0.05). The arterial CO(2) partial pressure decreased from 5.6 +/- 0.2 to 5.2 +/- 0.3 kPa during rhythmic handgrip, whereas it increased to 5.9 +/- 0.2 kPa (P<0.05) during infusion of bicarbonate. Bicarbonate treatment also increased pH of arterial and venous blood (7.55 +/- 0.01 vs. 7.44 +/- 0.02 and 7.31 +/- 0.01 vs. 7.23 +/- 0.02, respectively; P<0.05). In the last min of rhythmic handgrip the decrease in pHi was attenuated by the administration of bicarbonate (6.60 +/- 0.11 vs. 6.40 +/- 0.12; P<0.05). CONCLUSION: During exercise-induced metabolic acidosis, intravenous administration of bicarbonate increased the buffering capacity of blood and attenuated the decrease in intracellular muscle pH, although there was a small increase in the arterial carbon dioxide pressure.

Muscle heat production and anaerobic energy turnover during repeated intense dynamic exercise in humans.

1. The aim of the present study was to examine muscle heat production, oxygen uptake and anaerobic energy turnover throughout repeated intense exercise to test the hypotheses that (i) energy turnover is reduced when intense exercise is repeated and (ii) anaerobic energy production is diminished throughout repeated intense exercise. 2. Five subjects performed three 3 min intense one-legged knee-extensor exercise bouts (EX1, EX2 and EX3) at a power output of 65 +/- 5 W (mean +/- S.E.M.), separated by 6 min rest periods. Muscle, femoral arterial and venous temperatures were measured continuously during exercise for the determination of muscle heat production. In addition, thigh blood flow was measured and femoral arterial and venous blood were sampled frequently during exercise for the determination of muscle oxygen uptake. Anaerobic energy turnover was estimated as the difference between total energy turnover and aerobic energy turnover. 3. Prior to exercise, the temperature of the quadriceps muscle was passively elevated to 37.02 +/- 0.12 degrees C and it increased 0.97 +/- 0.08 degrees C during EX1, which was higher (P < 0.05) than during EX2 (0.79 +/- 0.05 degrees C) and EX3 (0.77 +/- 0.06 degrees C). In EX1 the rate of muscle heat accumulation was higher (P < 0.05) during the first 120 s compared to EX2 and EX3, whereas the rate of heat release to the blood was greater (P < 0.05) throughout EX2 and EX3 compared to EX1. The rate of heat production, determined as the sum of heat accumulation and release, was the same in EX1, EX2 and EX3, and it increased (P < 0.05) from 86 +/- 8 during the first 15 s to 157 +/- 7 J s(-1) during the last 15 s of EX1. 4. Oxygen extraction was higher during the first 60 s of EX2 and EX3 than in EX 1 and thigh oxygen uptake was elevated (P < 0.05) during the first 120 s of EX2 and throughout EX3 compared to EX1. The anaerobic energy production during the first 105 s of EX2 and 150 s of EX3 was lower (P < 0.05) than in EX1. 5. The present study demonstrates that when intense exercise is repeated muscle heat production is not changed, but muscle aerobic energy turnover is elevated and anaerobic energy production is reduced during the first minutes of exercise.

Quantitative estimates of vascularity in solid tumors by non-invasive near-infrared spectroscopy.

We examined the relationship between non-invasive estimates of the tumor hemoglobin concentration by near-infrared spectroscopy (NIRS) and histological scores of tumor vascularity by Chalkley counts in seven tumor lines in nude mice [malignant gliomas: U87, U118, U373; small cell lung cancers (SCLC): 54A, 54B, DMS79; prostate cancer: MatLyLu (MLL)]. We also evaluated the effect of continuous anti-angiogenic treatment with TNP-470 on tumor hemoglobin concentration and tumor vascularity in U87 and MLL tumors. Non-invasive NIRS recordings were performed with a custom-built flash near-infrared spectrometer using light guide-coupled reflectance measurements at 800+/-10 nm. Chalkley counts were obtained from CD31-immunostained cryosections. The NIRS recordings in arbitrary absorbance units increased with tumor size in the individual tumors until a plateau was reached at approximately 150 mm(3). This plateau was relatively tumor line-specific. NIRS recordings at the plateau phase were strongly correlated (P<.001, n=71) to the histological vessel score (Chalkley count) of the same individual tumors excised immediately after the NIRS was performed. Non-invasive NIRS recordings of the highly vascularized gliomas (U87, U118, and U373) plus the MatLyLu tumor line were significantly higher than the three less vascularized SCLC tumor lines (P<.001). Continuous treatment with the anti-angiogenic compound TNP-470, an endothelial cell inhibitor, significantly retarded tumor growth in both U87 and MLL tumors, but all tumors eventually grew. When comparing treated and untreated tumors of similar size, both NIRS recordings and Chalkley counts were significantly lower in TNP-470-treated tumors (P<.05). In conclusion, the NIRS technique provides a non-invasive measure of the degree of vascularization in untreated tumors and the NIRS technique can measure modifications in tumor vascularization by anti-angiogenic therapy.

Reduced mitochondrial adenosine triphosphate synthesis in skeletal muscle in patients with Child-Pugh class B and C cirrhosis.

Patients with cirrhosis of the liver often complain of tiredness and a lack of strength at physical exercise. Other investigators have found that muscle strength, work capacity, and maximal oxygen consumption are reduced in cirrhosis. We hypothesized that mitochondrial maximal rate of ATP synthesis in skeletal muscle may be impaired in these patients. This was tested with (31)P nuclear magnetic resonance spectroscopy in anterior tibial muscle of cirrhotic patients and healthy controls at rest, during exercise, and subsequent recovery. In patients with Child-Pugh class B and C cirrhosis resting PCr/P(i) ratio (8.3 +/- 1.0; n = 7) was lower than in patients with Child-Pugh class A cirrhosis (12.1 +/- 2.1; n = 7) and controls (11. 7 +/- 1.1; n = 6; P =.03), while the resting P(i)/gammaATP ratio was higher in Child-Pugh class B and C patients (0.43, 0.30, and 0.27, respectively; P =.03). Maximal rate of mitochondrial adenosine triphosphate (ATP) synthesis (V(max)) as calculated from the initial rate of phosphocreatine (PCr) recovery after work was lower in Child-Pugh class B and C cirrhosis (0.189 mmol/L/s +/- 0.034) than in both Child-Pugh class A patients (0.402 mmol/L/s +/- 0.103) and controls (0.425 mmol/L/s +/- 0.064; P =.01). V(max) was significantly correlated to intracellular free [Mg(2+)] obtained from the (31)P nuclear magnetic resonance (NMR) spectra (P =.003). Insufficient oxygen delivery did not seem a likely cause of reduced ATP synthesis in the patients. These findings suggest either a decreased number of mitochondria in skeletal muscle of the cirrhotic patient in Child-Pugh class B and C or a defective mitochondrial function that could be related to low intracellular free [Mg(2+)].

Exercise intolerance in mitochondrial myopathy is not related to lactic acidosis.

In a double-blinded, placebo-controlled, crossover study in seven mitochondrial myopathy patients (MM), we investigated whether lowering of lactate with dichloroacetate (DCA) can improve exercise tolerance and oxidative capacity in MM. DCA lowered plasma lactate at rest and during exercise (from 10.5 +/- 2.0 to 5.0 +/- 1.6 mM; p = 0.005) but did not improve maximal work load or VO2 in cycle exercise or phosphorous magnetic resonance spectroscopy (31P-MRS)-assessed indices of muscle oxidative metabolism. This indicates that lactate acidosis is not the primary cause of exercise intolerance in MM.

Quantitative estimates of angiogenic and anti-angiogenic activity by laser Doppler flowmetry (LDF) and near infra-red spectroscopy (NIRS).

The use of laser Doppler flowmetry (LDF) and near-infra-red spectroscopy (NIRS) for non-invasive in vivo measurements of angiogenic and anti-angiogenic activity in nude mice was evaluated. Angiogenic foci were induced in the skin by implantation of slow release pellets containing 200 ng basic fibroblast growth factor (bFGF). LDF and NIRS recordings from induced foci were significantly higher than placebo implants (P<0.05) and controls (P<0.001), proving that LDF and NIRS provide measures of angiogenic activity. Correspondingly, by these methods, an anti-angiogenic activity was significantly demonstrated in bFGF-stimulated animals treated with either the specific anti-angiogenic compound TNP-470 (P<0.05) or the anti-inflammatory agent dexamethasone (P<0.001). We conclude that LDF and NIRS, alone or in combination, are useful non-invasive tools for early evaluation of angiogenic and anti-angiogenic activity in vivo.

Aerobic metabolism of human quadriceps muscle: in vivo data parallel measurements on isolated mitochondria.

The aim of the present study was to examine whether parameters of isolated mitochondria could account for the in vivo maximum oxygen uptake (VO2max) of human skeletal muscle. VO2max and work performance of the quadriceps muscle of six volunteers were measured in the knee extensor model (range 10-18 mmol O2 x min(-1) x kg(-1) at work rates of 22-32 W/kg). Mitochondria were isolated from the same muscle at rest. Strong correlations were obtained between VO2max and a number of mitochondrial parameters (mitochondrial protein, cytochrome aa3, citrate synthase, and respiratory activities). The activities of citrate synthase, succinate dehydrogenase, and pyruvate dehydrogenase, measured in isolated mitochondria, corresponded to, respectively, 15, 3, and 1.1 times the rates calculated from VO2max. The respiratory chain activity also appeared sufficient. Fully coupled in vitro respiration, which is limited by the rate of ATP synthesis, could account for, at most, 60% of the VO2max. This might be due to systematic errors or to loose coupling of the mitochondrial respiration under intense exercise.

Effects of oral D-tagatose, a stereoisomer of D-fructose, on liver metabolism in man as examined by 31P-magnetic resonance spectroscopy.

D-tagatose, which is a stereoisomer of D-fructose, is phosphorylated to D-tagatose-1-phosphate by fructokinase in the liver. Because of a slow degradation rate of D-tagatose-1-phosphate, this substance may accumulate, and ingested D-tagatose may therefore cause a longer lasting reduction in inorganic phosphate (Pi) and adenosine triphosphate (ATP) levels in the liver compared with D-fructose. Similar to what is seen in patients with hereditary fructose intolerance, this may increase purine nucleotide degradation and thereby increase uric acid production. The effect of 30 g D-tagatose or D-fructose administered orally on ketohexose-1-phosphates, ATP, and Pi levels in the liver was studied by 31P-magnetic resonance spectroscopy (PMRS) in 5 young male volunteers. Blood and urine were collected to detect a possible increased uric acid production. A peak at 5.2 ppm assigned as D-tagatose-1-phosphate equivalent to about 1 mmol/L was found in the spectrum within 30 minutes after D-tagatose was administered in all subjects. Concomitantly, ATP was reduced by about 12% (P < .05). Both effects had vanished after 150 minutes. Serum uric acid concentration was increased by 17% 50 minutes after D-tagatose (P < .05) and did not reach baseline level when the experiment was terminated 230 minutes after the load. Although renal fractional extraction of uric acid decreased by approximately 12%, this could not explain the acute hyperuricemic effect of D-tagatose. No changes in 31PMRS spectra or serum uric acid concentration were found after D-fructose. These results suggest that a moderate intake of D-tagatose may affect liver metabolism by phosphate trapping despite the fact that the sugar may only be incompletely absorbed in the gut.

Effects of isoenergetic overfeeding of either carbohydrate or fat in young men.

Ten pairs of normal men were overfed by 5 MJ/d for 21 d with either a carbohydrate-rich or a fat-rich diet (C- and F-group). The two subjects in each pair were requested to follow each other throughout the day to ensure similar physical activity and were otherwise allowed to maintain normal daily life. The increase in body weight, fat free mass and fat mass showed great variation, the mean increases being 1.5 kg, 0.6 kg and 0.9 kg respectively. No significant differences between the C- and F-group were observed. Heat production during sleep did not change during overfeeding. The RQ during sleep was 0.86 and 0.78 in the C- and F-group respectively. The accumulated faecal loss of energy, DM, carbohydrate and protein was significantly higher in the C- compared with the F-group (30, 44, 69 and 51% higher respectively), whereas the fat loss was the same in the two groups. N balance was not different between the C- and F-group and was positive. Fractional contribution from hepatic de novo lipogenesis, as measured by mass isotopomer distribution analysis after administration of [1-(13)C]acetate, was 0.20 and 0.03 in the C-group and the F-group respectively. Absolute hepatic de novo lipogenesis in the C-group was on average 211 g per 21 d. Whole-body de novo lipogenesis, as obtained by the difference between fat mass increase and dietary fat available for storage, was positive in six of the ten subjects in the C-group (mean 332 (SEM 191)g per 21 d). The change in plasma leptin concentration was positively correlated with the change in fat mass. Thus, fat storage during overfeeding of isoenergetic amounts of diets rich in carbohydrate or in fat was not significantly different, and carbohydrates seemed to be converted to fat by both hepatic and extrahepatic lipogenesis.

[Effects of excessive isocaloric intake of either carbohydrate or fat on body composition, fat mass, de novo lipogenesis and energy expenditure in normal young men]. / Virkninger af isokalorisk overindtagelse af kulhydrat eller fedt på legemsvaegt, fedtmasse, de novo lipogenese og energiomsaetning hos normale unge maend.

Ten pairs of normal young men were overfed by 5 MJ per day for 21 days with either a carbohydrate-rich or a fat-rich diet (C- and F-group). The two subjects of a pair were requested to follow each other throughout the day to ensure similar physical activity. The increase in body weight and fat mass were not significantly different between the C- and the F-group. Heat production during sleep did not change during overfeeding. The accumulated faecal loss of energy, dry matter, carbohydrate and protein was significantly higher in the C- than in the F-group. Hepatic de novo lipogenesis was 212 g per 21 days in the C-group and was too low to be determined in the F-group. Whole body de novo lipogenesis was positive in six of the ten subjects in the C-group (mean: 332 g per 21 days). It is concluded that the increase in body weight and fat mass during overfeeding of isocaloric amounts of diets rich in carbohydrate or in fat was not significantly different, and that surplus of carbohydrate seemed to be converted to fat both by hepatic and extrahepatic de novo lipogenesis.

Kinetic and functional characterization of 1,4-dideoxy-1, 4-imino-d-arabinitol: a potent inhibitor of glycogen phosphorylase with anti-hyperglyceamic effect in ob/ob mice.

The effects of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) were investigated on preparations of glycogen phosphorylase (GP) and in C57BL6J (ob/ob) mice by (13)C NMR in vivo. Independent of the phosphorylation state or the mammalian species or tissue from which GP was derived, DAB inhibited GP with K(i)-values of approximately 400 nM. The mode of inhibition was uncompetitive or noncompetitive, with respect to glycogen and P(i), respectively. The effects of glucose and caffeine on the inhibitory effect of DAB were investigated. Taken together, these data suggest that DAB defines a novel mechanism of action. Intraperitoneal treatment with DAB (a total of 105 mg/kg in seven doses) for 210 min inhibited glucagon-stimulated glycogenolysis in obese and lean mice. Thus, liver glycogen levels were 361 +/- 19 and 228 +/- 19 micromol glucosyl units/g with DAB plus glucagon in lean and obese mice, respectively, compared to 115 +/- 24 and 37 +/- 8 micromol glucosyl units/g liver with glucagon only. Moreover, with glucagon only end-point blood glucose levels were at 29 +/- 2 and 17.5 +/- 2 mM in obese and lean mice, respectively, compared to 17.5 +/- 1 and 12 +/- 1 mM with glucagon plus DAB. In conclusion, DAB is a novel and potent inhibitor of GP with an apparently distinct mechanism of action. Further, DAB inhibited the hepatic glycogen breakdown in vivo and displayed an accompanying anti-hyperglycemic effect, which was most pronounced in obese mice. The data suggest that inhibition of GP may offer a therapeutic principle in Type 2 diabetes.

Heat production in human skeletal muscle at the onset of intense dynamic exercise.

1. We hypothesised that heat production of human skeletal muscle at a given high power output would gradually increase as heat liberation per mole of ATP produced rises when energy is derived from oxidation compared to phosphocreatine (PCr) breakdown and glycogenolysis. 2. Five young volunteers performed 180 s of intense dynamic knee-extensor exercise ( approximately 80 W) while estimates of muscle heat production, power output, oxygen uptake, lactate release, lactate accumulation and ATP and PCr hydrolysis were made. Heat production was determined continuously by (i) measuring heat storage in the contracting muscles, (ii) measuring heat removal to the body core by the circulation, and (iii) estimating heat transfer to the skin by convection and conductance as well as to the body core by lymph drainage. 3. The rate of heat storage in knee-extensor muscles was highest during the first 45 s of exercise (70-80 J s-1) and declined gradually to 14 +/- 10 J s-1 at 180 s. 4. The rate of heat removal by blood was negligible during the first 10 s of exercise, rising gradually to 112 +/- 14 J s-1 at 180 s. The estimated rate of heat release to skin and heat removal via lymph flow was < 2 J s-1 during the first 5 s and increased progressively to 24 +/- 1 J s-1 at 180 s. The rate of heat production increased significantly throughout exercise, being 107 % higher at 180 s compared to the initial 5 s, with half of the increase occurring during the first 38 s, while power output remained essentially constant. 5. The contribution of muscle oxygen uptake and net lactate release to total energy turnover increased curvilinearly from 32 % and 2 %, respectively, during the first 30 s to 86 % and 8 %, respectively, during the last 30 s of exercise. The combined energy contribution from net ATP hydrolysis, net PCr hydrolysis and muscle lactate accumulation is estimated to decline from 37 % to 3 % comparing the same time intervals. 6. The magnitude and rate of elevation in heat production by human skeletal muscle during exercise in vivo could be the result of the enhanced heat liberation during ATP production when aerobic metabolism gradually becomes dominant after PCr and glycogenolysis have initially provided most of the energy.