Effects of cigarette smoking and its cessation on lipid metabolism and energy expenditure in heavy smokers.

The relationship between thermogenic and potentially atherogenic effects of cigarette smoking (CS) and its cessation was investigated. Heavy smokers (n = 7, serum cotinine > 200 ng/ml, > 20 cigarettes/d) were maintained on isoenergetic, constant diets for 2 wk, 1 wk with and 1 wk without CS. Stable isotope infusions with indirect calorimetry were performed on day 7 of each phase, after an overnight fast. CS after overnight abstention increased resting energy expenditure by 5% (not significant vs. non-CS phase; P = 0.18). CS increased the flux of FFA by 77%, flux of glycerol by 82%, and serum FFA concentrations by 73% (P < 0.02 for each), but did not significantly affect fat oxidation. Hepatic reesterification of FFA increased more than threefold (P < 0.03) and adipocyte recycling increased nonsignificantly (P = 0.10). CS-induced lipid substrate cycles represented only 15% (estimated 11 kcal/d) of observed changes in energy expenditure. De novo hepatic lipogenesis was low (< 1-2 g/d) and unaffected by either acute CS or its chronic cessation. Hepatic glucose production was not affected by CS, despite increased serum glycerol and FFA fluxes. Cessation of CS caused no rebound effects on basal metabolic fluxes. In conclusion, a metabolic mechanism for the atherogenic effects of CS on serum lipids (increased hepatic reesterification of FFA) has been documented. Increased entry of FFA accounts for CS-induced increases in serum FFA concentrations. The thermogenic effect of CS is small or absent in heavy smokers while the potentially atherogenic effect is maintained, and cessation of CS does not induce a rebound lipogenic milieu that specifically favors accrual of body fat in the absence of increased food intake.     

Relationship between skeletal muscle lipoprotein lipase activity and 24-hour macronutrient oxidation.

A low ratio of whole-body 24-h fat/carbohydrate (CHO) oxidation has been shown to be a predictor of subsequent body weight gain. We tested the hypothesis that the variability of this ratio may be related to differences in skeletal muscle metabolism. Since lipoprotein lipase (LPL) plays a pivotal role in partitioning lipoprotein-borne triglycerides to adipose (storage) and skeletal muscle (mostly oxidation), we postulated that a low ratio of fat/CHO oxidation was associated with a low skeletal muscle LPL (SMLPL) activity. As an index of substrate oxidation, 24-h RQ was measured under sedentary and eucaloric conditions in 16 healthy nondiabetic Pima males. During a 6-h euglycemic, hyperinsulinemic clamp, muscle biopsies were obtained at baseline, 3, and 6 h. Heparin-elutable SMLPL activity was 2.92 +/- 0.56 nmol free fatty acids/g.min (mean +/- SD) at baseline, was unchanged (2.91 +/- 0.51) at the third hour, and increased significantly (P < 0.05) to 3.13 +/- 0.57 at the sixth hour of the clamp. The mean (of baseline and 3-h) SMLPL activity correlated inversely with 24-h RQ (r = 0.57, P < 0.03) but not with body size, body composition, or insulin-mediated glucose uptake. Since SMLPL activity is related to the ratio of whole body fat/CHO oxidation rate, a decreased muscle LPL activity may, therefore, predispose to obesity.     

Dietary sugar restriction reduces hepatic de novo lipogenesis in adolescent boys with fatty liver disease

BACKGROUNDHepatic de novo lipogenesis (DNL) is elevated in nonalcoholic fatty liver disease (NAFLD). Improvements in hepatic fat by dietary sugar reduction may be mediated by reduced DNL, but data are limited, especially in children. We examined the effects of 8 weeks of dietary sugar restriction on hepatic DNL in adolescents with NAFLD and correlations between DNL and other metabolic outcomes.METHODSAdolescent boys with NAFLD (n = 29) participated in an 8-week, randomized controlled trial comparing a diet low in free sugars versus their usual diet. Hepatic DNL was measured as percentage contribution to plasma triglyceride palmitate using a 7-day metabolic labeling protocol with heavy water. Hepatic fat was measured by magnetic resonance imaging–proton density fat fraction.RESULTSHepatic DNL was significantly decreased in the treatment group (from 34.6% to 24.1%) versus the control group (33.9% to 34.6%) (adjusted week 8 mean difference: –10.6% [95% CI: –19.1%, –2.0%]), which was paralleled by greater decreases in hepatic fat (25.5% to 17.9% vs. 19.5% to 18.8%) and fasting insulin (44.3 to 34.7 vs. 35.5 to 37.0 μIU/mL). Percentage change in DNL during the intervention correlated significantly with changes in free-sugar intake (r = 0.48, P = 0.011), insulin (r = 0.40, P = 0.047), and alanine aminotransferase (ALT) (r = 0.39, P = 0.049), but not hepatic fat (r = 0.13, P = 0.532).CONCLUSIONOur results suggest that dietary sugar restriction reduces hepatic DNL and fasting insulin, in addition to reductions in hepatic fat and ALT, among adolescents with NAFLD. These results are consistent with the hypothesis that hepatic DNL is a critical metabolic abnormality linking dietary sugar and NAFLD.TRIAL REGISTRYClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02513121","term_id":"NCT02513121"}}NCT02513121.FUNDINGThe Nutrition Science Initiative (made possible by gifts from the Laura and John Arnold Foundation, Ambrose Monell Foundation, and individual donors), the UCSD Altman Clinical and Translational Research Institute, the NIH, Children’s Healthcare of Atlanta and Emory University’s Children’s Clinical and Translational Discovery Core, Children’s Healthcare of Atlanta and Emory University Pediatric Biostatistical Core, the Georgia Clinical and Translational Science Alliance, and the NIH National Institute of Diabetes, Digestive, and Kidney Disease.     

Effects of dietary cholesterol and fat saturation on plasma lipoproteins in an ethnically diverse population of healthy young men.

The individual effects of dietary cholesterol and fat saturation on plasma lipoprotein concentrations were determined in an ethnically diverse population of normolipidemic young men (52 Caucasian, 32 non-Caucasian). The experimental diets contained approximately 200 or 600 mg/d of cholesterol, 36-38% of calories as fat, and high or low proportions of saturated and polyunsaturated fat (polyunsaturated/saturated fat ratio approximately 0.8 vs 0.3). At the lower cholesterol intake, the high saturated fat diet had only a modest effect on LDL cholesterol in Caucasians (+ 6 mg/dl-1) and none in non-Caucasians. 600 mg cholesterol with high saturated fat led to a substantial mean increase in LDL cholesterol, which was significantly greater in Caucasian than in non-Caucasian subjects (+ 31 mg/dl vs 16 mg/dl, P < 0.005). 600 mg cholesterol with increased polyunsaturated fat gave a mean LDL increase of 16 mg/dl, lower than found when the same high cholesterol intake was coupled with increased saturated fat. Variation in cholesterol rather than the proportions of saturated and polyunsaturated fat had the most influence on LDL-cholesterol levels. Among non-Caucasians it was the only significant factor.     

Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus.

We examined the in vivo metabolic effects of vanadyl sulfate (VS) in non-insulin-dependent diabetes mellitus (NIDDM). Six NIDDM subjects treated with diet and/or sulfonylureas were examined at the end of three consecutive periods: placebo for 2 wk, VS (100 mg/d) for 3 wk, and placebo for 2 wk. Euglycemic hyperinsulinemic (30 mU/m2.min) clamps and oral glucose tolerance tests were performed at the end of each study period. Glycemic control at baseline was poor (fasting plasma glucose 210 +/- 19 mg/dl; HbA1c 9.6 +/- 0.6%) and improved after treatment (181 +/- 14 mg/dl [P < 0.05], 8.8 +/- 0.6%, [P < 0.002]); fasting and post-glucose tolerance test plasma insulin concentrations were unchanged. After VS, the glucose infusion rate during the clamp was increased (by approximately 88%, from 1.80 to 3.38 mg/kg.min, P < 0.0001). This improvement was due to both enhanced insulin-mediated stimulation of glucose uptake (rate of glucose disposal [Rd], +0.89 mg/kg.min) and increased inhibition of HGP (-0.74 mg/kg.min) (P < 0.0001 for both). Increased insulin-stimulated glycogen synthesis (+0.74 mg/kg.min, P < 0.0003) accounted for > 80% of the increased Rd after VS, and the improvement in insulin sensitivity was maintained after the second placebo period. The Km of skeletal muscle glycogen synthase was lowered by approximately 30% after VS treatment (P < 0.05). These results indicate that 3 wk of treatment with VS improves hepatic and peripheral insulin sensitivity in insulin-resistant NIDDM humans. These effects were sustained for up to 2 wk after discontinuation of VS.     

Hyperglucagonemia and insulin-mediated glucose metabolism.

The effect of chronic physiologic hyperglucagonemia on basal and insulin-mediated glucose metabolism was evaluated in normal subjects, using the euglycemic insulin clamp technique (+50, +100, and +500 microU/ml). After glucagon infusion fasting glucose increased from 76 +/- 4 to 93 +/- 2 mg/dl and hepatic glucose production (HGP) rose from 1.96 +/- 0.08 to 2.25 +/- 0.08 mg/kg X min (P less than 0.001). Basal glucose oxidation after glucagon increased (P less than 0.05) and correlated inversely with decreased free fatty acid concentrations (r = -0.94; P less than 0.01) and decreased lipid oxidation (r = -0.75; P less than 0.01). Suppression of HGP and stimulation of total glucose disposal were impaired at each insulin step after glucagon (P less than 0.05-0.01). The reduction in insulin-mediated glucose uptake was entirely due to diminished non-oxidative glucose utilization. Glucagon infusion also caused a decrease in basal lipid oxidation and an enhanced ability of insulin to inhibit lipid oxidation and augment lipid synthesis. These results suggest that hyperglucagonemia may contribute to the disturbances in glucose and lipid metabolism in some diabetic patients.     

Metabolic effects of successful intraportal islet transplantation in insulin-dependent diabetes mellitus.

The intraportal injection of human pancreatic islets has been indicated as a possible alternative to the pancreas transplant in insulin-dependent diabetic patients. Aim of the present work was to study the effect of intraportal injection of purified human islets on: (a) the basal hepatic glucose production; (b) the whole body glucose homeostasis and insulin action; and (c) the regulation of insulin secretion in insulin-dependent diabetes mellitus patients bearing a kidney transplant. 15 recipients of purified islets from cadaver donors (intraportal injection) were studied by means of the infusion of labeled glucose to quantify the hepatic glucose production. Islet transplanted patients were subdivided in two groups based on graft function and underwent: (a) a 120-min euglycemic insulin infusion (1 mU/kg/min) to assess insulin action; (b) a 120-min glucose infusion (+75 mg/di) to study the pattern of insulin secretion. Seven patients with chronic uveitis on the same immunosuppressive therapy as grafted patients, twelve healthy volunteers, and seven insulin-dependent diabetic patients with combined pancreas and kidney transplantation were also studied as control groups. Islet transplanted patients have: (a) a higher basal hepatic glucose production (HGP: 5.1 +/- 1.4 mg/kg/ min; P < 0.05 with respect to all other groups) if without graft function, and a normal HGP (2.4 +/- 0.2 mg/kg/min) with a functioning graft; (b) a defective tissue glucose disposal (3.9 +/- 0.5 mg/kg/min in patients without islet function and 5.3 +/- 0.4 mg/kg/min in patients with islet function) with respect to normals (P < 0.01 for both comparisons); (c) a blunted first phase insulin peak and a similar second phase secretion with respect to controls. In conclusion, in spite of the persistence of an abnormal pattern of insulin secretion, successful intraportal islet graft normalizes the basal HGP and improves total tissue glucose disposal in insulin-dependent diabetes mellitus.     

Genetic loci controlling body fat, lipoprotein metabolism, and insulin levels in a multifactorial mouse model.

We analyzed the inheritance of body fat, leptin levels, plasma lipoprotein levels, insulin levels, and related traits in an intercross between inbred mouse strains CAST/Ei and C57BL/6J. CAST/Ei mice are unusually lean, with only approximately 8% of body weight as fat, whereas C57BL/6J mice have approximately 18% body fat. Quantitative trait locus analysis using > 200 F2 mice revealed highly significant loci (lod scores > 4.3) on chromosomes 2 (three separate loci) and 9 that contribute to mouse fat-pad mass for mice on a high-fat diet. Some loci also influenced plasma lipoprotein levels and insulin levels either on chow or high-fat diets. Two loci for body fat and lipoprotein levels (on central and distal chromosome 2) coincided with a locus having strong effects on hepatic lipase activity, an activity associated with visceral obesity and lipoprotein levels in humans. A locus contributing to plasma leptin levels (lod score 5.3) but not obesity was identified on chromosome 4, near the leptin receptor gene. These data identify candidate regions and candidate genes for studies of human obesity and diabetes, and suggest obesity is highly complex in terms of the number of genetic factors involved. Finally, they support the existence of specific genetic interactions between body fat, insulin metabolism, and lipoprotein metabolism.     

Diet-induced obese mice develop peripheral, but not central, resistance to leptin.

Leptin administration reduces obesity in leptin-deficient ob/ob mice; its effects in obese humans, who have high circulating leptin levels, remain to be determined. This longitudinal study was designed to determine whether diet-induced obesity in mice produces resistance to peripheral and/or central leptin treatment. Obesity was induced in two strains of mice by exposure to a 45% fat diet. Serum leptin increased in proportion to body weight (P < 0.00001). Whereas C57BL/6 mice initially responded to peripherally administered leptin with a marked decrease in food intake, leptin resistance developed after 16 d on high fat diet; mice on 10% fat diet retained leptin sensitivity. In AKR mice, peripheral leptin significantly decreased food intake in both 10 and 45% fat-fed mice after 16 d of dietary treatment. However, after 56 d, both groups became resistant to peripherally administered leptin. Central administration of leptin to peripherally leptin-resistant AKR mice on 45% fat diet resulted in a robust response to leptin, with a dose-dependent decrease in food intake (P < 0.00001) and body weight (P < 0.0001) after a single intracerebroventricular infusion. These data demonstrate that, in a diet-induced obesity model, mice exhibit resistance to peripherally administered leptin, while retaining sensitivity to centrally administered leptin.     

Protein dynamics in whole body and in splanchnic and leg tissues in type I diabetic patients.

To elucidate the mechanism of insulin's anticatabolic effect in humans, protein dynamics were evaluated in the whole-body, splanchnic, and leg tissues in six C-peptide-negative type I diabetic male patients in the insulin-deprived and insulin-treated states using two separate amino acid models (leucine and phenylalanine). L-(1-13C,15N)leucine, L-(ring-2H5)phenylalanine, and L-(ring-2H2) tyrosine were infused intravenously, and isotopic enrichments of [1-13C,15N]-leucine, (13C)leucine, (13C)ketoisocaproate, (2H5)phenylalanine, [2H4]tyrosine, (2H2)tyrosine, and 13CO2 were measured in arterial, hepatic vein, and femoral vein samples. Whole-body leucine flux, phenylalanine flux, and tyrosine flux were decreased (< 0.01) by insulin treatment, indicating an inhibition of protein breakdown. Moreover, insulin decreased (< 0.05) the rates of leucine oxidation and leucine transamination (P < 0.01), but the percent rate of ketoisocaproate oxidation was increased by insulin (P < 0.01). Insulin also reduced (< 0.01) whole-body protein synthesis estimated from both the leucine model (nonoxidative leucine disposal) and the phenylalanine model (disposal of phenylalanine not accounted by its conversion to tyrosine). Regional studies demonstrated that changes in whole body protein breakdown are accounted for by changes in both splanchnic and leg tissues. The changes in whole-body protein synthesis were not associated with changes in skeletal muscle (leg) protein synthesis but could be accounted for by the splanchnic region. We conclude that though insulin decreases whole-body protein breakdown in patients with type I diabetes by inhibition of protein breakdown in splanchnic and leg tissues, it selectively decreases protein synthesis in splanchnic tissues, which accounted for the observed decrease in whole-body protein synthesis. Insulin also augmented anabolism by decreasing leucine transamination.     

Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance.

The effect of graded, physiologic hyperinsulinemia (+5, +15, +30, +70, +200 microU/ml) on oxidative and nonoxidative pathways of glucose and FFA metabolism was examined in nine lean non-insulin dependent diabetic patients (NIDDM) and in eight age- and weight-matched control subjects. Glucose and FFA metabolism were assessed using stepwise insulin clamp in combination with indirect calorimetry and infusion of [3H]3-glucose/[14C]palmitate. The basal rate of hepatic glucose production (HGP) was higher in NIDDM than in control subjects, and suppression of HGP by insulin was impaired at all but the highest insulin concentration. Glucose disposal was reduced in the NIDD patients at the three highest plasma insulin concentrations, and this was accounted for by defects in both glucose oxidation and nonoxidative glucose metabolism. In NIDDs, suppression of plasma FFA by insulin was impaired at all five insulin steps. This was associated with impaired suppression by insulin of plasma FFA turnover, FFA oxidation (measured by [14C]palmitate) and nonoxidative FFA disposal (an estimate of reesterification of FFA). FFA oxidation and net lipid oxidation (measured by indirect calorimetry) correlated positively with the rate of HGP in the basal state and during the insulin clamp. In conclusion, our findings demonstrate that insulin resistance is a general characteristic of glucose and FFA metabolism in NIDDM, and involves both oxidative and nonoxidative pathways. The data also demonstrate that FFA/lipid and glucose metabolism are interrelated in NIDDM, and suggest that an increased rate of FFA/lipid oxidation may contribute to the impaired suppression of HGP and diminished stimulation of glucose oxidation by insulin in these patients.     

Carbohydrate Requirements for Prolonged,Fasted Exercise With and Without Basal Rate Reductions in Adults With Type 1 Diabetes on Continuous Subcutaneous Insulin Infusion

OBJECTIVEExercising while fasted with type 1 diabetes facilitates weight loss; however, the best strategy to maintain glucose stability remains unclear.RESEARCH DESIGN AND METHODSFifteen adults on continuous subcutaneous insulin infusion completed three sessions of fasted walking (120 min at 45% VO_2max) in a randomized crossover design: 50% basal rate reduction, set 90 min pre-exercise (−90_min50%_BRR); usual basal rate with carbohydrate intake of 0.3 g/kg/h (CHO-only); and combined 50% basal rate reduction set at exercise onset with carbohydrate intake of 0.3 g/kg/h (Combo).RESULTSCombo had a smaller change in glucose (5 ± 47 mg/dL) versus CHO-only (−49 ± 61 mg/dL, P = 0.03) or −90_min50%_BRR (−34 ± 45 mg/dL). The −90_min50%_BRR strategy produced higher β-hydroxybutyrate levels (0.4 ± 0.3 vs. 0.1 ± 0.1 mmol/L) and greater fat oxidation (0.51 ± 0.2 vs. 0.39 ± 0.1 g/min) than CHO-only (both P < 0.05).CONCLUSIONSAll strategies examined produced stable glycemia for fasted exercise, but a 50% basal rate reduction, set 90 min pre-exercise, eliminates carbohydrate needs and enhances fat oxidation better than carbohydrate feeding with or without a basal rate reduction set at exercise onset.     

Mechanism by which hyperglycemia inhibits hepatic glucose production in conscious rats. Implications for the pathophysiology of fasting hyperglycemia in diabetes.

To examine the relationship between the plasma glucose concentration (PG) and the pathways of hepatic glucose production (HGP), five groups of conscious rats were studied after a 6-h fast: (a) control rats (PG = 8.0 +/- 0.2 mM); (b) control rats (PG = 7.9 +/- 0.2 mM) with somatostatin and insulin replaced at the basal level; (c) control rats (PG = 18.1 +/- 0.2 mM) with somatostatin, insulin replaced at the basal level, and glucose infused to acutely raise plasma glucose by 10 mM; (d) control rats (PG = 18.0 +/- 0.2 mM) with somatostatin and glucose infusions to acutely reproduce the metabolic conditions of diabetic rats, i.e., hyperglycemia and moderate hypoinsulinemia; (e) diabetic rats (PG = 18.4 +/- 2.3 mM). All rats received an infusion of [3-3H]glucose and [U-14C]lactate. The ratio between hepatic [14C]UDP-glucose sp act (SA) and 2X [14C]-phosphoenolpyruvate (PEP) SA (the former reflecting glucose-6-phosphate SA) measured the portion of total glucose output derived from PEP-gluconeogenesis. In control rats, HGP was decreased by 58% in hyperglycemic compared to euglycemic conditions (4.5 +/- 0.3 vs. 10.6 +/- 0.2 mg/kg.min; P < 0.01). When evaluated under identical glycemic conditions, HGP was significantly increased in diabetic rats (18.9 +/- 1.4 vs. 6.2 +/- 0.4 mg/kg.min; P < 0.01). In control rats, hyperglycemia increased glucose cycling (by 2.5-fold) and the contribution of gluconeogenesis to HGP (91% vs. 45%), while decreasing that of glycogenolysis (9% vs. 55%). Under identical plasma glucose and insulin concentrations, glucose cycling in diabetic rats was decreased (by 21%) and the percent contribution of gluconeogenesis to HGP (73%) was similar to that of controls (84%). These data indicate that: (a) hyperglycemia causes a marked inhibition of HGP mainly through the suppression of glycogenolysis and the increase in glucokinase flux, with no apparent changes in the fluxes through gluconeogenesis and glucose-6-phosphatase; under similar hyperglycemic hypoinsulinemic conditions: (b) HGP is markedly increased in diabetic rats; however, (c) the contribution of glycogenolysis and gluconeogenesis to HGP is similar to control animals.     

DIET AND TISSUE GROWTH : I. THE REGENERATION OF LIVER TISSUE ON VARIOUS ADEQUATE DIETS.

1. The toxicity of chloroform varies according to the diets used in these experiments in the following order of decreasing susceptibility of the animals: high fat > standard > high carbohydrate > high protein diets. 2. On the high fat and high carbohydrate diets there may be a more or less marked proliferation of the endothelium and the connective tissue stroma in the necrotic area producing in some instances scars resembling the picture of an early cirrhosis. 3. On the diets studied, standard, high carbohydrate, high protein, and high fat, the most active and rapid repair is observed on the standard balanced diet. On the high fat diet the reparative process is definitely delayed in comparison with the others. There are only slight differences between the high carbohydrate and high protein diets which suggest but do not conclusively show a more rapid repair with the latter diet.     

13C-nuclear magnetic resonance spectroscopy studies of hepatic glucose metabolism in normal subjects and subjects with insulin-dependent diabetes mellitus.

To determine the effect of insulin-dependent diabetes mellitus (IDDM) on rates and pathways of hepatic glycogen synthesis, as well as flux through hepatic pyruvate dehydrogenase, we used 13C-nuclear magnetic resonance spectroscopy to monitor the peak intensity of the C1 resonance of the glucosyl units of hepatic glycogen, in combination with acetaminophen to sample the hepatic UDP-glucose pool and phenylacetate to sample the hepatic glutamine pool, during a hyperglycemic-hyperinsulinemic clamp using [1-13C]-glucose. Five subjects with poorly controlled IDDM and six age-weight-matched control subjects were clamped at a mean plasma glucose concentration of approximately 9 mM and mean plasma insulin concentrations approximately 400 pM for 5 h. Rates of hepatic glycogen synthesis were similar in both groups (approximately 0.43 +/- 0.09 mumol/ml liver min). However, flux through the indirect pathway of glycogen synthesis (3 carbon units-->-->glycogen) was increased by approximately 50% (P < 0.05), whereas the relative contribution of pyruvate oxidation to TCA cycle flux was decreased by approximately 30% (P < 0.05) in the IDDM subjects compared to the control subjects. These studies demonstrate that patients with poorly controlled insulin-dependent diabetes mellitus have augmented hepatic gluconeogenesis and relative decreased rates of hepatic pyruvate oxidation. These abnormalities are not immediately reversed by normalizing intraportal concentrations of glucose, insulin, and glucagon and may contribute to postprandial hyperglycemia.     

The Modifying Effects of Galactomannan from Canadian-Grown Fenugreek (Trigonella foenum-graecum L.) on the Glycemic and Lipidemic Status in Rats

Using high sucrose-fed male Sprague-Dawley rats, a study was conducted to determine the effects of feeding Galactomannan (GAL), a soluble dietary fiber extracted from Canadian-grown fenugreek seeds, on blood lipid and glucose responses. Rats (n = 8, 175–200 g) were randomly assigned to one of three high sucrose diets containing 10% cellulose (control), 7.5% cellulose + 2.5% GAL, and 5% cellulose + 5% GAL, respectively for 4 weeks. After 3 weeks, an oral glucose tolerance test (OGTT) was performed on each rat. A week later blood samples were collected to determine the effect on blood lipids. A significant reduction in glycemic response was observed only in 5% GAL group at 120 min following OGTT, when compared with that of control and 2.5% GAL groups. The plasma level of insulin was also significantly reduced (p<0.001) in 5% GAL-fed rats but at all times during OGTT. These animals also showed a reduction in body weight gain (p<0.05) in parallel with less food intake (p<0.05). All GAL-fed (2.5% and 5.0%) rats had significantly reduced plasma levels of triglycerides and total cholesterol in association with a reduction in epididymal adipose weight. Overall, this study demonstrated that feeding GAL from Canadian-grown fenugreek seeds has the potential to alter glycemic and lipidemic status and reduce abdominal fat in normal rats.     

Short-term effects of tumor necrosis factor on energy and substrate metabolism in dogs.

In vivo short-term effects of recombinant human TNF-alpha on lipolysis, FFA flux, fat oxidation, triglyceride-fatty acid cycling, and glucose kinetics were evaluated with stable isotopic tracers and indirect calorimetry along with monitoring of hemodynamic parameters in fasted dogs. High-dose TNF infusion (10 micrograms/kg) caused a fall in mean arterial pressure (P < 0.01), pulmonary arterial pressure (P < 0.001), and cardiac index (CI) (P < 0.05). The rate of appearance of glycerol (Ra glycerol) and the rate of appearance of FFA (Ra FFA) were decreased by 20% (P < 0.05) and by 42% (P < 0.01), respectively. Total fat oxidation fell by 23% (P < 0.05). In contrast, TNF infusion significantly increased glucose production by 13% (P < 0.05) and metabolic clearance rate of glucose by 25% (P < 0.01). However, TNF infusion did not change energy expenditure. Low-dose TNF infusion (3.5 micrograms/kg) caused changes similar in all respects, except magnitude, to the high-dose effects. There was a significant correlation between percent change of CI (delta CI) and percent change of rate of appearance of palmitate (Ra palmitate; delta Ra palmitate) (P < 0.0001, r = 0.69), Ra FFA (delta Ra FFA) (P < 0.0001, r = 0.60), and Ra glycerol (delta Ra glycerol) (P < 0.0329, r = 0.36). The correlation between delta CI and delta Ra palmitate was greater than the correlation between delta CI and delta Ra glycerol (P = 0.028). We conclude that the acute response to TNF causes a shift towards carbohydrate as an energy substrate in a dose-dependent manner by both decreasing the availability of FFAs and increasing glucose production.     

Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation.

The cytokines IL-1 beta and TNF-alpha cause cachexia and hypermetabolism in animal models, but their role in human inflammation remains controversial. The relationship between in vitro cytokine production and metabolism was examined in 23 adults with RA and 23 healthy control subjects matched on age, sex, race, and weight. Body composition was measured by multicompartmental analysis of body cell mass, water, fat, and bone mass. Resting energy expenditure (REE) was measured by indirect calorimetry. Cytokine production by PBMC was measured by radioimmunoassay. Usual energy intake, physical activity, disability scores, medication use, and other confounders were also measured. Body cell mass was 13% lower (P < 0.00001), REE was 12% higher (P < 0.008), and physical activity was much lower (P < 0.001) in subjects with RA. Production of TNF-alpha was higher in RA than controls, both before and after stimulation with endotoxin (P < 0.05), while production of IL-1 beta was higher with endotoxin stimulation (P < 0.01). In multivariate analysis, cytokine production was directly associated with REE (P < 0.001) in patients but not in controls. While energy and protein intake were similar in the two groups and exceeded the Recommended Dietary Allowances, energy intake in subjects with RA was inversely associated with IL-1 beta production (P < 0.005). In this study we conclude that: loss of body cell mass is common in RA; cytokine production in RA is associated with altered energy metabolism and intake, despite a theoretically adequate diet; and TNF-alpha and IL-1 beta modulate energy metabolism and body composition in RA.     

Mechanism of free fatty acid-induced insulin resistance in humans.

To examine the mechanism by which lipids cause insulin resistance in humans, skeletal muscle glycogen and glucose-6-phosphate concentrations were measured every 15 min by simultaneous 13C and 31P nuclear magnetic resonance spectroscopy in nine healthy subjects in the presence of low (0.18 +/- 0.02 mM [mean +/- SEM]; control) or high (1.93 +/- 0.04 mM; lipid infusion) plasma free fatty acid levels under euglycemic (approximately 5.2 mM) hyperinsulinemic (approximately 400 pM) clamp conditions for 6 h. During the initial 3.5 h of the clamp the rate of whole-body glucose uptake was not affected by lipid infusion, but it then decreased continuously to be approximately 46% of control values after 6 h (P < 0.00001). Augmented lipid oxidation was accompanied by a approximately 40% reduction of oxidative glucose metabolism starting during the third hour of lipid infusion (P < 0.05). Rates of muscle glycogen synthesis were similar during the first 3 h of lipid and control infusion, but thereafter decreased to approximately 50% of control values (4.0 +/- 1.0 vs. 9.3 +/- 1.6 mumol/[kg.min], P < 0.05). Reduction of muscle glycogen synthesis by elevated plasma free fatty acids was preceded by a fall of muscle glucose-6-phosphate concentrations starting at approximately 1.5 h (195 +/- 25 vs. control: 237 +/- 26 mM; P < 0.01). Therefore in contrast to the originally postulated mechanism in which free fatty acids were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase these results demonstrate that free fatty acids induce insulin resistance in humans by initial inhibition of glucose transport/phosphorylation which is then followed by an approximately 50% reduction in both the rate of muscle glycogen synthesis and glucose oxidation.     

Prospective randomized comparison of cefodizime versus cefuroxime for perioperative prophylaxis in patients undergoing coronary artery bypass grafting.

The effects of cefodizime and cefuroxime on neutrophil phagocytosis and reactive oxygen production in 54 patients undergoing elective coronary artery bypass grafting were studied. Both drugs were administered twice at a dosage of 40 mg/kg of body weight (pre- and intraoperative). Phagocytic capacity was assessed by measuring the uptake of fluorescein isothiocyanate-labeled Escherichia coli and Staphylococcus aureus by flow cytometry. Reactive oxygen generation after phagocytosis was estimated by determining the amount of dihydrorhodamine 123 converted to rhodamine 123 intracellularly. In both groups the mean phagocytic ability for E. coli and S. aureus decreased during surgery (-21 and -8%, respectively, for the cefodizime group and -39 and -38%, respectively, for the cefuroxime group; P < 0.05 for all). In the cefodizime group a normalization of mean E. coli and S. aureus neutrophil phagocytosis was seen on day 5 (+9 and -4% compared to preoperative values; P > 0.35 for both), whereas in cefuroxime-treated patients phagocytic ability remained depressed (-37 and -31%; P < 0.04 for both). In both groups mean neutrophil reactive oxygen intermediate (ROI) production after E. coli and S. aureus phagocytosis increased during cardiopulmonary bypass (+44 and +83%, respectively, in the cefodizime group and +58 and +73%, respectively, in the cefuroxime group; P < 0.05 for all). One day after surgery E. coli- and S. aureus-driven neutrophil ROI production was not different from the preoperative values (-2 and +12%, respectively, for the cefodizime group and +7 and +15%, respectively, for the cefuroxime group; P > 0.15 for all). Postoperative serum levels of the C-reactive protein on days 2 and 7 were lower in cefodizime-treated patients (19 +/- 6 and 4 +/- 2 mg/liter versus 23 +/- 6 and 11 +/- 5 mg/liter; P < 0.05 for both). In addition to cefodizime's antimicrobial activity during perioperative prophylaxis, its use in coronary artery bypass grafting can prevent procedure-related prolonged postoperative neutrophil phagocytosis impairment.