Standardized Dietary Conditions Research Articles

Modulation of mitochondrial dynamism in Kupffer cells impacts systemic metabolism

Background: Kupffer cells (KCs) are hepatoresident macrophages that are essential for liver physiology and contribute to the development of nonalcoholic hepatic steatosis (NAFLD). The liver of patients with MAFLD shows different expressions of some key regulators of inner mitochondrial membrane fusion compared with healthy subjects, including OPA1 protein, which is a mitochondrial protein whose activity promotes mitochondrial fusion and modulation of oxidative phosphorylation. Aims: Given the close interaction that KCs have with cells in the hepatic niches, they play both a crucial immune and metabolic role, which is why their mitochondria are critical for their function. This project aims to investigate how modulation of OPA1-driven mitochondrial fusion in KCs can affect lipid metabolism and immune response at the systemic and hepatic levels. Methods: Mice selectively lacking OPA1 in the KCs were fed a Standard Diet or a High Fat Diet for 20 weeks. The immune phenotype was assessed by cytofluorimetry while the metabolic profile by in vivo indirect calorimetry and with plasma and tissue lipid profile analysis. Single cell RNA sequencing was also performed to profile the impact of OPA1 deficiency on KC function and possible paracrine effects on hepatocytes. Results: Under standard dietary conditions, mice selectively lacking OPA1 in KCs show a different metabolic substrate preference compared to wild type, with an immunophenotype characterized by a higher proportion of pro-resolution KC2 than pro-inflammatory KC1. Functionally, KCs also exhibit dissimilar phagocytic and proliferative capacity. During the high-fat diet, we observed a significant reduction in liver fibrosis. Conclusions: Taken together, these data suggest that OPA1 plays a key role in the function of Kupffer cells and that the lack of OPA1, causing metabolic reprogramming, affects their interaction with resident liver cells, influencing the development of fibrosis and the progression of MAFLD.

Absence of the Peptide Transporter 1 Induces a Prediabetic and Depressive-Like Phenotype in Mice.

Protein-enriched diets improve glycemic control in diabetes or emotional behavior in depressive patients. In mice, these benefits depend on intestinal gluconeogenesis activation by di-/tripeptides. Intestinal di-/tripeptides absorption is carried out by the peptide transporter 1, PEPT1. The lack of PEPT1 might thus alter glucose and emotional balance. To determine the effects of PEPT1 deficiency under standard dietary conditions or during a dietary challenge known to promote both metabolic and cognitive dysfunction, insulin sensitivity, anxiety, and depressive-like traits, hippocampal serotonin (5-HT) and insulin signaling pathway were measured in wild-type (WT) and Pept1-/- mice fed either a chow or a high-fat high-sucrose (HF-HS) diet. Pept1-/- mice exhibited slight defects in insulin sensitivity and emotional behavior, which were aggravated by an HF-HS diet. Pept1-/- mice fed a chow diet had lower hippocampal 5-HT levels and exhibited cerebral insulin resistance under HF-HS diet. These defects were independent of intestinal gluconeogenesis but might be linked to increased plasma amino acids levels. Pept1-/- mice develop prediabetic and depressive-like traits and could thus be used to develop strategies to prevent or cure both diseases.

SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression

Adipose tissue modulates energy homeostasis by secreting leptin, but little is known about the factors governing leptin production. We show that succinate, long perceived as a mediator of immune response and lipolysis, controls leptin expression via its receptor SUCNR1. Adipocyte-specific deletion of Sucnr1 influences metabolic health according to nutritional status. Adipocyte Sucnr1 deficiency impairs leptin response to feeding, whereas oral succinate mimics nutrient-related leptin dynamics via SUCNR1. SUCNR1 activation controls leptin expression via the circadian clock in an AMPK/JNK-C/EBPα-dependent manner. Although the anti-lipolytic role of SUCNR1 prevails in obesity, its function as a regulator of leptin signaling contributes to the metabolically favorable phenotype in adipocyte-specific Sucnr1 knockout mice under standard dietary conditions. Obesity-associated hyperleptinemia in humans is linked to SUCNR1 overexpression in adipocytes, which emerges as the major predictor of adipose tissue leptin expression. Our study establishes the succinate/SUCNR1 axis as a metabolite-sensing pathway mediating nutrient-related leptin dynamics to control whole-body homeostasis.

Dysregulated insulin secretion is associated with pancreatic β-cell hyperplasia and direct acinar-β-cell trans-differentiation in partially eNOS-deficient mice.

eNOS‐deficient mice were previously shown to develop hypertension and metabolic alterations associated with insulin resistance either in standard dietary conditions (eNOS−/− homozygotes) or upon high‐fat diet (HFD) (eNOS+/− heterozygotes). In the latter heterozygote model, the present study investigated the pancreatic morphological changes underlying the abnormal glycometabolic phenotype. C57BL6 wild type (WT) and eNOS+/− mice were fed with either chow or HFD for 16 weeks. After being longitudinally monitored for their metabolic state after 8 and 16 weeks of diet, mice were euthanized and fragments of pancreas were processed for histological, immuno‐histochemical and ultrastructural analyses. HFD‐fed WT and eNOS+/− mice developed progressive glucose intolerance and insulin resistance. Differently from WT animals, eNOS+/− mice showed a blunted insulin response to a glucose load, regardless of the diet regimen. Such dysregulation of insulin secretion was associated with pancreatic β‐cell hyperplasia, as shown by larger islet fractional area and β‐cell mass, and higher number of extra‐islet β‐cell clusters than in chow‐fed WT animals. In addition, only in the pancreas of HFD‐fed eNOS+/− mice, there was ultrastructural evidence of a number of hybrid acinar‐β‐cells, simultaneously containing zymogen and insulin granules, suggesting the occurrence of a direct exocrine‐endocrine transdifferentiation process, plausibly triggered by metabolic stress associated to deficient endothelial NO production. As suggested by confocal immunofluorescence analysis of pancreatic histological sections, inhibition of Notch‐1 signaling, likely due to a reduced NO availability, is proposed as a novel mechanism that could favor both β‐cell hyperplasia and acinar‐β‐cell transdifferentiation in eNOS‐deficient mice with impaired insulin response to a glucose load.

Drosophila melanogaster as a Model Organism to Study Lithium and Boron Bioactivity.

The fruit fly Drosophila melanogaster has become a valuable model organism in nutritional science, which can be applied to elucidate the physiology and the biological function of nutrients, including trace elements. Importantly, the application of chemically defined diets enables the supply of trace elements for nutritional studies under highly standardized dietary conditions. Thus, the bioavailability and bioactivity of trace elements can be systematically monitored in D. melanogaster. Numerous studies have already revealed that central aspects of trace element homeostasis are evolutionary conserved among the fruit fly and mammalian species. While there is sufficient evidence of vital functions of boron (B) in plants, there is also evidence regarding its bioactivity in animals and humans. Lithium (Li) is well known for its role in the therapy of bipolar disorder. Furthermore, recent findings suggest beneficial effects of Li regarding neuroprotection as well as healthy ageing and longevity in D. melanogaster. However, no specific essential function in the animal kingdom has been found for either of the two elements so far. Here, we summarize the current knowledge of Li and B bioactivity in D. melanogaster in the context of health and disease prevention.

Constitutive depletion of Slc34a2/NaPi-IIb in rats causes perinatal mortality

Absorption of dietary phosphate (Pi) across intestinal epithelia is a regulated process mediated by transcellular and paracellular pathways. Although hyperphosphatemia is a risk factor for the development of cardiovascular disease, the amount of ingested Pi in a typical Western diet is above physiological needs. While blocking intestinal absorption has been suggested as a therapeutic approach to prevent hyperphosphatemia, a complete picture regarding the identity and regulation of the mechanism(s) responsible for intestinal absorption of Pi is missing. The Na+/Pi cotransporter NaPi-IIb is a secondary active transporter encoded by the Slc34a2 gene. This transporter has a wide tissue distribution and within the intestinal tract is located at the apical membrane of epithelial cells. Based on mouse models deficient in NaPi-IIb, this cotransporter is assumed to mediate the bulk of active intestinal absorption of Pi. However, whether or not this is also applicable to humans is unknown, since human patients with inactivating mutations in SLC34A2 have not been reported to suffer from Pi depletion. Thus, mice may not be the most appropriate experimental model for the translation of intestinal Pi handling to humans. Here, we describe the generation of a rat model with Crispr/Cas-driven constitutive depletion of Slc34a2. Slc34a2 heterozygous rats were indistinguishable from wild type animals under standard dietary conditions as well as upon 3 days feeding on low Pi. However, unlike in humans, homozygosity resulted in perinatal lethality.

Three Minutes of All-Out Intermittent Exercise per Week Increases Skeletal Muscle Oxidative Capacity and Improves Cardiometabolic Health

We investigated whether a training protocol that involved 3 min of intense intermittent exercise per week — within a total training time commitment of 30 min including warm up and cool down — could increase skeletal muscle oxidative capacity and markers of health status. Overweight/obese but otherwise healthy men and women (n = 7 each; age = 29±9 y; BMI = 29.8±2.7 kg/m2) performed 18 training sessions over 6 wk on a cycle ergometer. Each session began with a 2 min warm-up at 50 W, followed by 3×20 s “all-out” sprints against 5.0% body mass (mean power output: ∼450–500 W) interspersed with 2 min of recovery at 50 W, followed by a 3 min cool-down at 50 W. Peak oxygen uptake increased by 12% after training (32.6±4.5 vs. 29.1±4.2 ml/kg/min) and resting mean arterial pressure decreased by 7% (78±10 vs. 83±10 mmHg), with no difference between groups (both p<0.01, main effects for time). Skeletal muscle biopsy samples obtained before and 72 h after training revealed increased maximal activity of citrate synthase and protein content of cytochrome oxidase 4 (p<0.01, main effect), while the maximal activity of β-hydroxy acyl CoA dehydrogenase increased in men only (p<0.05). Continuous glucose monitoring measured under standard dietary conditions before and 48–72 h following training revealed lower 24 h average blood glucose concentration in men following training (5.4±0.6 vs. 5.9±0.5 mmol/L, p<0.05), but not women (5.5±0.4 vs. 5.5±0.6 mmol/L). This was associated with a greater increase in GLUT4 protein content in men compared to women (138% vs. 23%, p<0.05). Short-term interval training using a 10 min protocol that involved only 1 min of hard exercise, 3x/wk, stimulated physiological changes linked to improved health in overweight adults. Despite the small sample size, potential sex-specific adaptations were apparent that warrant further investigation.

Tragopogon Porrifolius improves serum lipid profile and increases short‐term satiety in rats

Tragopogon Porrifolius is an edible plant commonly used in folk medicine in Mediterranean countries. This study investigates the potential role of aqueous extract of the aerial part of T. porrifolius in lipemia, and appetite regulation using the rat model. Food intake, abdominal fat percent, blood lipid profile, liver weights and liver enzymes were assessed after 4 weeks of extract intake via drinking water (50, 100, or 250 mg/kg bodyweight) in standard and high‐fat dietary conditions. In a separate study, the short term effect of T. porrifolius water extract on food intake was assessed. Results showed that treatment for four weeks with the plant extract caused a marked improvement in the lipid profile (triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol). Body weight, food intake and intra‐abdominal fat were also lower in animals given the plant extract at doses of 100 and 250 mg/kg body weight. In addition, T. porrifolius extract preload produced a dose dependent decrease in food intake observed over 24 hours. In conclusion, the aqueous extract of T. porrifolius exhibited potential benefits in lipemia and increased satiety with no visible adverse effect.

Enteric hyperoxaluria, recurrent urolithiasis, and systemic oxalosis in patients with Crohn’s disease

Prevalence of recurrent calcium-oxalate (CaOx) urolithiasis (UL) is up to fivefold higher in Crohn's disease than in the general population. Treatment options are scarce and the risk of recurrent UL or progressive renal CaOx deposition, (oxalosis) based early end-stage renal failure (ESRF), subsequent systemic oxalosis, and recurrence in the kidney graft is pronounced. We aimed to find proof that secondary hyperoxaluria is the main risk factor for the devastating course and correlates with intestinal oxalate absorption. 24-h urines were collected and analyzed for urinary oxalate (Uox) in 27 pediatric (6-18 years) and 19 adult patients (20-62 years). In the 21 patients (8 adults and 13 children) with hyperoxaluria a [(13)C(2)]oxalate absorption test was performed under standardized dietary conditions. Mean Uox was significantly higher in patients with UL or oxalosis (0.92 ± 0.57) compared with those without (0.53 ± 0.13 mmol/1.73 m(2)/24 h, p<0.05, normal < 0.5). Hyperoxaluria then significantly correlated with intestinal oxalate absorption (p< 0.05). As UL/oxalosis has major implications for the general health in patients with Crohn's disease (ESRF and systemic oxalosis), new medication, e.g. to reduce intestinal oxalate absorption, is definitely needed.

Acute high‐intensity interval exercise reduces the postprandial glucose response and prevalence of hyperglycaemia in patients with type 2 diabetes

High-volume endurance exercise (END) improves glycaemic control in type 2 diabetes (T2D) but many individuals cite 'lack of time' as a barrier to regular participation. High-intensity interval training (HIT) is a time-efficient method to induce physiological adaptations similar to END, but little is known regarding the effect of HIT in T2D. Using continuous glucose monitoring (CGM), we examined the 24-h blood glucose response to one session of HIT consisting of 10 × 60 s cycling efforts at ~90% maximal heart rate, interspersed with 60 s rest. Seven adults with T2D underwent CGM for 24-h on two occasions under standard dietary conditions: following acute HIT and on a non-exercise control day (CTL). HIT reduced hyperglycaemia measured as proportion of time spent above 10 mmol/l (HIT: 4.5 ± 4.4 vs. CTL: 15.2 ± 12.3%, p = 0.04). Postprandial hyperglycaemia, measured as the sum of post-meal areas under the glucose curve, was also lower after HIT vs. CTL (728 ± 331 vs. 1142 ± 556 mmol/l·9 h, p = 0.01). These findings highlight the potential for HIT to improve glycaemic control in T2D.

Low-volume high-intensity interval training reduces hyperglycemia and increases muscle mitochondrial capacity in patients with type 2 diabetes

Low-volume high-intensity interval training (HIT) is emerging as a time-efficient exercise strategy for improving health and fitness. This form of exercise has not been tested in type 2 diabetes and thus we examined the effects of low-volume HIT on glucose regulation and skeletal muscle metabolic capacity in patients with type 2 diabetes. Eight patients with type 2 diabetes (63 ± 8 yr, body mass index 32 ± 6 kg/m(2), Hb(A1C) 6.9 ± 0.7%) volunteered to participate in this study. Participants performed six sessions of HIT (10 × 60-s cycling bouts eliciting ∼90% maximal heart rate, interspersed with 60 s rest) over 2 wk. Before training and from ∼48 to 72 h after the last training bout, glucose regulation was assessed using 24-h continuous glucose monitoring under standardized dietary conditions. Markers of skeletal muscle metabolic capacity were measured in biopsy samples (vastus lateralis) before and after (72 h) training. Average 24-h blood glucose concentration was reduced after training (7.6 ± 1.0 vs. 6.6 ± 0.7 mmol/l) as was the sum of the 3-h postprandial areas under the glucose curve for breakfast, lunch, and dinner (both P < 0.05). Training increased muscle mitochondrial capacity as evidenced by higher citrate synthase maximal activity (∼20%) and protein content of Complex II 70 kDa subunit (∼37%), Complex III Core 2 protein (∼51%), and Complex IV subunit IV (∼68%, all P < 0.05). Mitofusin 2 (∼71%) and GLUT4 (∼369%) protein content were also higher after training (both P < 0.05). Our findings indicate that low-volume HIT can rapidly improve glucose control and induce adaptations in skeletal muscle that are linked to improved metabolic health in patients with type 2 diabetes.

Short-Term High-Intensity Interval Training Reduces Hyperglycemia in Type 2 Diabetics

Glycemic regulation is impaired in individuals with type 2 diabetes (T2D). Current guidelines recommend that people with T2D should participate in a cumulative total of 150 minutes of continuous, moderate-intensity aerobic exercise each week, or at least 90 minutes of vigorous intensity exercise. While effective for improving glycemic control, most individuals with T2D do not perform sufficient activity to achieve health benefits, often citing "lack of time" as a key barrier to regular exercise participation. Low-volume high-intensity interval training (HIT) is a potent stimulus for inducing metabolic adaptations typically associated with traditional high-volume endurance training. However, the effects of low-volume HIT on glycemic control in people with T2D is currently unknown. PURPOSE: To determine the utility of HIT to reduce hyperglycemia in patients with T2D in a practical, time-efficient manner. METHODS: 7 subjects with T2D (age: 62 ± 3 yr, BMI: 33 ± 3.8 kg/m2, Wmax: 125 ± 18 W) performed 6 training sessions over 2 wk. Each session consisted of 10 × 1 min cycling efforts at ∼90% Wmax elicited during a ramp VO2peak test, interspersed with 1 min of rest (113 ± 11 W). Continuous Glucose Monitoring (CGM) technology (Medtronic CGMS® iPro Recorder) was employed under standard dietary conditions for a 24 hr period on a pre-training control day and ∼48-72 hr following the final training session. RESULTS: CGM data revealed lower mean 24 hr blood glucose concentration following HIT (7.6 ± 0.5 mmol/L vs. 6.6 ± 0.3 mmol/L, p < 0.05). The sum of the 3 hr postprandial area under the glucose curve for breakfast, lunch and dinner was also reduced following training (689 ± 196 mmol/L × 9hr vs. 991 ± 214 mmol/L × 9hr, p < 0.05). CONCLUSIONS: These preliminary data shed light on the potential for low-volume HIT to represent a unique, time-efficient exercise strategy to improve glycemic regulation in people with T2D. Supported by the Canadian Diabetes Association

Excess diuresis and natriuresis during acute sleep deprivation in healthy adults

The transition from wakefulness to sleep is associated with a pronounced decline in diuresis, a necessary physiological process that allows uninterrupted sleep. The aim of this study was to assess the effect of acute sleep deprivation (SD) on urine output and renal water, sodium, and solute handling in healthy young volunteers. Twenty young adults (10 male) were recruited for two 24-h studies under standardized dietary conditions. During one of the two admissions, subjects were deprived of sleep. Urine output, electrolyte excretions, and osmolar excretions were calculated. Activated renin, angiotensin II, aldosterone, arginine vasopressin, and atrial natriuretic peptide were measured in plasma, whereas prostaglandin E(2) and melatonin were measured in urine. SD markedly increased the diuresis and led to excess renal sodium excretion. The effect was more pronounced in men who shared significantly higher diuresis levels during SD compared with women. Renal water handling and arginine vasopressin levels remained unaltered during SD, but the circadian rhythm of the hormones of the renin-angiotensin-aldosterone system was significantly affected. Urinary melatonin and prostaglandin E(2) excretion levels were comparable between SD and baseline night. Hemodynamic changes were characterized by the attenuation of nocturnal blood pressure dipping and an increase in creatinine clearance. Acute deprivation of sleep induces natriuresis and osmotic diuresis, leading to excess nocturnal urine production, especially in men. Hemodynamic changes during SD may, through renal and hormonal processes, be responsible for these observations. Sleep architecture disturbances should be considered in clinical settings with nocturnal polyuria such as enuresis in children and nocturia in adults.

13C2]oxalate absorption in children with idiopathic calcium oxalate urolithiasis or primary hyperoxaluria

Intestinal oxalate absorption is an important part of oxalate metabolism influencing its urinary excretion and its measurement can be a valuable diagnostic tool in hyperoxaluric disorders. In this study, we use [(13)C(2)]oxalate absorption under standardized dietary conditions to assess intestinal oxalate absorption and its impact on urinary oxalate excretion. Tests were conducted in age-matched pediatric patients that included 60 with idiopathic calcium oxalate urolithiasis, 13 with primary hyperoxaluria, and 35 healthy children. In the idiopathic stone formers, median oxalate absorption was significantly higher than that in the controls or in patients with primary disease. From standardized values obtained in control patients, oxalate hyperabsorption was detected in 23 patients with idiopathic disease but not in any patients with primary hyperoxaluria; therefore, a significant correlation between intestinal absorption and urinary excretion was found only in those with the idiopathic disease. We have shown that increased intestinal oxalate absorption is an important risk factor of idiopathic calcium oxalate urolithiasis. In contrast, low intestinal oxalate absorption in patients with primary hyperoxaluria indicates that only foods with excessive oxalate content be restricted from their diet.

Glycaemic instability is an underestimated problem in Type II diabetes

The aim of the present study was to assess the level of glycaemic control by the measurement of 24 h blood glucose profiles and standard blood analyses under identical nutritional and physical activity conditions in patients with Type II diabetes and healthy normoglycaemic controls. A total of 11 male patients with Type II diabetes and 11 healthy matched controls participated in a 24 h CGMS (continuous subcutaneous glucose-monitoring system) assessment trial under strictly standardized dietary and physical activity conditions. In addition, fasting plasma glucose, insulin and HbA(1c) (glycated haemoglobin) concentrations were measured, and an OGTT (oral glucose tolerance test) was performed to calculate indices of whole-body insulin sensitivity, oral glucose tolerance and/or glycaemic control. In the healthy control group, hyperglycaemia (blood glucose concentration >10 mmol/l) was hardly present (2+/-1% or 0.4+/-0.2/24 h). However, in the patients with Type II diabetes, hyperglycaemia was experienced for as much as 55+/-7% of the time (13+/-2 h over 24 h) while using the same standardized diet. Breakfast-related hyperglycaemia contributed most (46+/-7%; P<0.01 as determined by ANOVA) to the total amount of hyperglycaemia and postprandial glycaemic instability. In the diabetes patients, blood HbA(1c) content correlated well with the duration of hyperglycaemia and the postprandial glucose responses (P<0.05). In conclusion, CGMS determinations show that standard measurements of glycaemic control underestimate the amount of hyperglycaemia prevalent during real-life conditions in Type II diabetes. Given the macro- and micro-vascular damage caused by postprandial hyperglycaemia, CGMS provides an excellent tool to evaluate alternative therapeutic strategies to reduce hyperglycaemic blood glucose excursions.

Effect of oxalate test dose size on absolute and percent oxalate absorption

The purpose of this pilot study was to establish the dependence or independence of oxalate absorption on the quantity of the test dose of sodium oxalate over a range of test doses corresponding to physiological dietary oxalate intake values. Gastrointestinal oxalate absorption was measured with the [13C2]oxalate absorption test. Six healthy volunteers were always tested under standardized dietary conditions with 63 mg dietary oxalate and 800 mg dietary calcium per day. The volunteers were tested thrice each with sodium oxalate test doses of 25, 50, 200, and 600 mg. Additionally, 1000 mg sodium oxalate was applied once to three of these volunteers. The oxalate absorption of the six volunteers tested under the standardized conditions with 50 mg sodium [13C2]oxalate was 7.2 ± 2.62 % (mean ± SD), similar to the 120 volunteers tested previously: 8.0 ± 4.4 % (mean ± SD). The tests with sodium [13C2]oxalate doses in the range 25–1000 mg revealed similar percent oxalate absorption values. In conclusion, in healthy volunteers, the amount of oxalate absorbed in the gastrointestinal tract increased proportionally with the higher test doses of oxalate. However, percent oxalate absorption remained unchanged with test doses in the dose range of physiological dietary oxalate intakes.

Bile Acid Synthesis in Humans Has a Rapid Diurnal Variation That Is Asynchronous With Cholesterol Synthesis

The conversion of cholesterol to bile acids by the liver is an important regulator of body cholesterol homeostasis. In rodents, both cholesterol and bile acid synthesis have marked diurnal rhythms that peak synchronously at midnight. The aim of this study was to establish whether such diurnal rhythms are also present in healthy humans. Serum levels of the markers 7alpha-hydroxy-4-cholesten-3-one (C4) monitoring bile acid biosynthesis and lathosterol reflecting cholesterol synthesis were determined at 90-minute intervals in 8 human volunteers during standardized dietary conditions. Serum C4 showed 2 distinct peaks (2- to 4-fold above baseline) during a 24-hour period, the first at 1:00 pm and the second at 9:00 pm. During the night, C4 levels declined, and they returned to baseline levels the next morning. In contrast, serum lathosterol levels peaked at night, between midnight and 4:00 am. The diurnal changes of C4 were not synchronous with serum lipid changes or with the postprandial increase in serum bile acids and were maintained in cholecystectomized subjects. Bile acid synthesis in humans has a diurnal rhythm, with 2 peaks during the daytime, that is opposite from the circadian rhythm of cholesterol synthesis. This is completely different from the pattern in rodents and indicates the presence of an important species variation in the regulation of cholesterol homeostasis.

Methohexital Impairs Osmoregulation

Anesthetic agents influence central regulations. This study investigated the effects of methohexital anesthesia on renal and hormonal responses to acute sodium and water loading in dogs in the absence of surgical stress. Fourteen experiments (two in each dog) were performed in seven well-trained, chronically tracheotomized beagle dogs kept in highly standardized environmental and dietary conditions (2.5 mmol sodium and 91 ml water/kg body weight daily). Experiments lasted 3 h, while the dogs were conscious (7 experiments) or, after 1 h control, while they were anesthetized (7 experiments) with methohexital (initial dose 6.6 mg/kg body weight and maintenance infusion 0.34 mg.min-1.kg-1 body weight) over a period of 2 h. In both experiments, extracellular volume expansion was performed by intravenous infusion of a balanced isoosmolar electrolyte solution (0.5 ml.min-1.kg-1 body weight). Normal arterial blood gases were maintained by controlled mechanical ventilation. In another five dogs the same protocol was used, and vasopressin (0.05 mU.min-1.kg-1 body weight) was infused intravenously during methohexital anesthesia. Values are given as means. During methohexital anesthesia, mean arterial pressure decreased from 108 to 101 mmHg, and heart rate increased from 95 to 146 beats/min. Renal sodium excretion decreased; urine volume increased; and urine osmolarity decreased from 233 to 155 mosm/l, whereas plasma osmolarity increased from 301 to 312 mosm/l because of an increase in plasma sodium concentration from 148 to 154 mmol/l. Plasma renin activity, plasma aldosterone concentration, plasma atrial natriuretic peptide, and plasma antidiuretic hormone concentrations (range 1.8-2.8 pg/ml) did not change in either protocol. In the presence of exogenous vasopressin (antidiuretic hormone 3.3 pg/ml), water diuresis did not occur, and neither plasma osmolarity nor the plasma concentration of sodium changed. Methohexital may impair osmoregulation by inhibiting adequate pituitary antidiuretic hormone release in response to an osmotic challenge.

New enteric-coated high-lipase pancreatic extract in the treatment of pancreatic steatorrhea.

We studied a new enteric-coated pancreatic extract with very high lipase content in 12 patients with steatorrhea due to chronic pancreatitis. Fecal fat was measured under standard dietary conditions (100 g lipid/day) with no enzyme supplementation and during treatment with 75,000, 150,000, or 225,000 IU of lipase per day. The median fecal fat output (g/day) was significantly (p < 0.005) lower after each increase in dosage: basal, 20.5 (range, 10.3-92.2); 3 cps/day at meals, 13.3 (6.4-38.2); 6 cps/day, 9.9 (4.8-31.4); 9 cps/day, 7.3 (2.6-17.3). For the five patients with a basal fecal fat output of < 15 g/day, steatorrhea was totally corrected by 3 cps a day. Of the seven patients with more severe steatorrhea, the fecal fat output of only two was not normalized with the highest dose of 9 cps/day: for one it was reduced to 13.3 g/day from a basal of 92.2 g/day and for the other to 17.3 g/day from 25.4 g/day. This pilot study demonstrates that the tested pancreatic extract very effectively corrects pancreatic steatorrhea in a simple low-dose regimen. Good compliance can be expected.

Effect of an essential fatty acid deficiency on the phospholipid composition in anterior pituitary membranes

The effects of an essential fatty acid deficient diet were investigated on the phospholipid fatty acids of several membrane fractions of the rat anterior pituitary, the secretion of which is known to be partly dependent on the membrane phospholipidic constituents. In standard dietary conditions, arachidonic acid (20:4n-6) and its elongation product, adrenic acid (22:4n-6), were the two main polyunsaturated fatty acids in all fractions studied. In rats deprived of EFA for 6 weeks after weaning, the levels of both 20:4n-6 and 22:4n-6 were not changed in microsomal + plasma membrane and nuclear fractions, whereas they were decreased in heavy mitochondrial and light mitochondrial fractions. The present data suggest a mechanism of compensation between membrane fractions which may preferentially preserve 20:4n-6 and 22:4n-6 in discrete membrane fractions.