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PubMed1999

Fructose malabsorption is associated with decreased plasma tryptophan.

Fructose malabsorption is characterized by the inability to absorb fructose efficiently. Consequently fructose reaches the colon and is broken down by bacteria to short-fatty-acids, CO2 and H2. Recently we found that fructose malabsorption was associated with signs of depression. It was therefore of interest to find out whether fructose malabsorption is associated with abnormal tryptophan metabolism. Breath hydrogen concentrations were measured in 50 after an oral dose of 50 g fructose allowing to classify them as normals (n = 15) or fructose malabsorbers (n = 35). Blood samples were taken for tryptophan and kynurenine measurements. Fructose malabsorbers showed significantly lower plasma tryptophan concentrations and significantly higher depression scores compared to normals. Fructose malabsorption is associated with lower tryptophan levels which may play a role in the development of depressive disorders.

Adolescent↗

PubMed1996

Changes in angiotensin AT1 receptor density during hypertension in fructose-fed rats.

Feeding carbohydrate-enriched diets to normal rats has been shown to induce insulin resistance and hyperinsulinemia associated with an elevation of blood pressure. Previously we reported that the renin-angiotensin system (RAS) is likely to be involved in the elevation of blood pressure. The purpose of this study was to determine the changes in plasma angiotensin II (AII) and AII receptor density associated with the elevation of blood pressure in fructose-treated rats. Male Sprague-Dawley rats were divided into two groups and were fed either normal rat chow or a 60% fructose-enriched diet for four weeks. Plasma insulin of fructose-treated rats was significantly elevated (p < 0.05) by the end of first week of fructose treatment and remained elevated throughout the study. Plasma AII levels of fructose-fed rats was 3.5 fold greater than the controls at the end of second week and returned to basal levels at the end of the fourth week of dietary treatment. Blood pressure was significantly elevated in the fructose-fed rats within two weeks of fructose treatment. Elevation of blood pressure was associated with left ventricular hypertrophy. Angiotensin II type I receptor (AT1) density was determined in the left ventricle, aorta, adrenal gland and hypothalamus. There was a significant increase in AT1 receptor density in the ventricle at the end of third and fourth weeks of treatment, whereas there was a significant decrease in the receptor density in the aorta at the end of the fourth week of treatment. Receptor density in the adrenal gland and hypothalamus of fructose-fed rats was similar to their respective controls. The results of this study suggest that the RAS plays a role in the elevation of blood pressure of fructose-fed rats and also contributes to the ventricular hypertrophy observed in these rats.

Angiotensin II↗

PubMed1977

Fructose metabolism in four Pseudomonas species.

1. ATP-Dependent phosphorylation of fructose could not be detected in extracts of fructose-grown cells of Pseudomonas extorquens strain 16, Pseudomonas 3A2, Pseudomonas acidovorans and Pseudomonas fluorescens. Instead, phosphorylation of fructose to fructose-1-phosphate was found to occur when cell-free extracts were incubated with fructose and phosphoenolpyruvate. Such an activity could not be detected in cell-free extracts of succinate-grown cells. 2. High levels of 1-phosphofructokinase were found in extracts of the above organisms when growth on fructose. 3. Mutants of Pseudomonas extorquens strain 16 lacking 1-phosphofructokinase were unable to grow on fructose. Revertants to growth on fructose had regained the capacity to synthesize this enzyme, indicating its necessary involvement in fructose metabolism. 4. A survey has been carried out of enzymes involved in carbohydrate metabolism in the species listed above.

Cell-Free System↗

PubMed1994

Fructose-induced enhanced mitogenicity of diploid human cells: possible relationship with cell differentiation.

Fructose strongly stimulates the growth of normal diploid human skin fibroblasts (SFs) and induces marked changes in their morphology and lipid accumulation. This mitogenic effect occurs despite very low fructose consumption and depends on the presence of glutamine. The cell kinetics of cultured fructose-fed human skin fibroblasts were different from those fed on glucose: in the presence of fructose a high proliferative index persisted at Day 14 of culture and the duration of the total cell cycle and of the G1 + 1/2 M and S phases was slightly shorter. The mitogenic effect of fructose on SF was largest in the presence of human serum: it was small or undetectable when fibroblasts were cultured in media supplemented with dialyzed human serum, fetal bovine serum, or serum substitutes. This suggests that serum growth factor(s) mediate the mitogenic effect of fructose. Only normal diploid human cells seem to be sensitive to this mitogenic effect of fructose: the long-term growth of normal human liver cells on fructose was slightly better or similar to that on glucose. In contrast, fructose could only support limited growth of hamster fibroblastic Nil cells and of a transformed human fibroblastic line, which grew better with glucose.

Animals↗

PubMed2001

High-fructose diet decreases catalase mRNA levels in rat tissues.

Insulin resistance and hyperinsulinemia have recently been identified as independent determinants of several risk factors for cardiovascular disease. The generation of reactive oxygen species (ROS) may play an important role as a final common mediator by which glucose and insulin resistance might contribute to development of cardiovascular disease and hypertension. The aim of the present study was to evaluate changes on mRNA expression of antioxidant enzymes [catalase, Cu-Zn superoxide dismutase (Cu-ZnSOD), MnSOD], blood pressure and metabolic parameters in insulin resistance that follow feeding normotensive Wistar rats a high-fructose-enriched diet. In our investigation 26 normal male Wistar rats were fed a high-fructose diet for 2 weeks (no.=14) or normal chow to serve as a control group (no.=12). In vivo insulin resistance was verified in a subgroup of control and fructose-fed rats by the euglycemic hyperinsulinemic clamp technique at 2 different insulin infusion rates, 29 (submaximal stimulation) and 290 (maximal stimulation) pmol/kg/min respectively. The glucose infusion rate (GIR) was not significantly different in the two groups during the submaximal infusion of insulin (1.4 +/- 0.8 mmol/kg/min in fructose-fed rats vs 1.6 +/- 0.7 mmol/kg/min in control rats, NS) while in fructose-fed rats it was significantly lower (-29.8%) than in control rats during maximal infusion of insulin (2.6 +/- 0.3 mmol/kg/min vs 3.7 +/- 0.3 mmol/kg/min, p<0.05). Fructose feeding markedly reduced the expression of catalase mRNA and Cu-ZnSOD mRNA in the liver, catalase mRNA in the heart (p<0.05). A tendency of fructose feeding to reduce the expression of antioxidant enzymes in skeletal muscle and adipose tissue was also observed (NS). Fructose feeding also increased plasma uric acid (119.9 +/- 30.4 vs 42.1 +/- 10 pmol/l, p<0.05) and systemic blood pressure (128 +/- 4 vs 109 +/- 5 mmHg, p<0.05) respect to control animals. No significant changes were observed in plasma levels of glycemia and tryglycerides. Our study suggests that in non-hyperglycemic, fructose-fed insulin-resistant rats the expression of catalase is inhibited in liver and heart. This condition might lead to higher susceptibility to oxidative stress in insulin resistance. However, an adaptive cellular response to maintain the effectiveness of intracellular signaling pathways mediated by insulin-activated hydrogen peroxide generating systems may also be hypothesized.

Animals↗

PubMed1998

Fructose uptake in rat adipocytes: GLUT5 expression and the effects of streptozotocin-induced diabetes.

Previous studies have shown that rat adipocytes possess the capacity to take up fructose by a mechanism that is distinct from that involved in the transport of glucose. In this investigation we report that rat adipocytes express the GLUT5 fructose transporter and that it is responsible for mediating a substantial component (approximately 80%) of the total cellular fructose uptake. This proposition is based on the finding that only 21% of the total fructose uptake was cytochalasin B (CB) sensitive which most likely reflects transport via GLUT1 and/or GLUT4. Consistent with this suggestion we found (i) that insulin caused a small, but significant stimulation in fructose uptake (approximately 35%) which was abolished in the presence of CB and (ii) that 3-O-methyl glucose inhibited fructose uptake to a level comparable with that observed in the presence of CB. GLUT5 was found to be localised only in the adipocyte plasma membrane and, unlike GLUT4 or GLUT1, its cell surface abundance was not modulated by insulin. GLUT5 expression fell substantially (by approximately 75%) in adipocytes of streptozotocin-diabetic rats and was accompanied by a reduction in fructose uptake by approximately 50%. Treatment of streptozotocin-diabetic rats with sodium orthovanadate for a period of 3 days led to a significant reduction in blood glycaemia by approximately 40% and a partial restoration in both GLUT5 expression and adipocyte fructose uptake. We suggest that fructose uptake in rat adipocytes is principally mediated by GLUT5 in an insulin- and CB-insensitive manner and that expression of GLUT5 in rat adipocytes may be regulated by changes in blood glycaemia.

3-O-Methylglucose↗

PubMed1985

Evidence for multiple catalytic sites of human acrosin from kinetic evaluation of fructose-induced acrosin inhibition.

Acrosin (acrosomal proteinase; EC 3.4.21.10) is a sperm-specific serine proteinase implicated in sperm penetration of the mammalian oocyte. Previously, we had shown that human acrosin, unlike human trypsin (EC 3.4.21.4), was inhibited by beta-D-fructose and related carbohydrates. The present study was undertaken to more fully elucidate the mechanism of action of fructose as an acrosin inhibitor, and to further differentiate the kinetic properties of acrosin from those of trypsin. Fructose produced a complex pattern of inhibition. At relatively low concentrations (10-60 mM), fructose acted as a competitive inhibitor with an apparent inhibition constant of 13 mM. In contrast, at high concentrations (80-320 mM), fructose behaved as a noncompetitive inhibitor, with an apparent inhibition constant of 205 mM. A Hill plot of enzyme activity as a function of fructose concentration suggested only a single binding site for fructose (slope = -0.90). The pattern of inhibition is not consistent with an enzyme containing only a single catalytic site, based either upon steady-state or rapid equilibrium assumptions; however, good agreement between observed and simulated data were obtained based upon the assumption of two catalytic sites with equal or similar binding and catalytic constants. The data suggested that fructose interacts with a single binding site (Ki = 8 mM) which alters both catalytic sites to produce an enzyme species having a higher apparent Michaelis constant and lower kcat as compared to the uninhibited enzyme. Fructose had no effect upon the rate of acrosin inactivation by either diisopropylfluorophosphate or tosyl-lysine-chloromethylketone, suggesting that neither substrate binding nor acylation were altered by this agent. The above data indicate substantial differences between the catalytic properties of human acrosin and those of trypsin.

Acrosin↗

PubMed1981

The kinetics of unphosphorylated, phosphorylated and proteolytically modified fructose bisphosphatase from fat liver.

Phosphorylation of fructose-bisphosphatase (D-fructose-1,6-bisphosphate 1-phosphohydrolase, EC 3.1.3.11) by the catalytic subunit of cyclic AMP-dependent protein kinase from pig muscle decreased the K0.5 for fructose-bisphosphate from 21 to 11 microM. When the phosphorylated fructose-bisphosphatase was treated with trypsin the K0.5 increased to 22 microM. The K0.5 also increased when the phosphoenzyme was treated with a partially purified phosphatase from rat liver. There was no difference between the unphosphorylated and phosphorylated enzyme with respect to pH dependence, the pH optimum being about 7.0 for both. Limited treatment of fructose-bis-phosphatase with subtilisin, which cleaves the enzyme at its unphosphorylatable N-terminal part, increased the pH optimum more than limited treatment with trypsin, which releases the phosphorylated peptide at the C-terminal part of fructose-bisphosphatase. The phosphorylated site on the phosphorylated fructose-bisphosphatase was more easily split off by trypsin treatment than the corresponding unphosphorylated site. The results suggest in addition to the glucagon-induced phosphorylation of fructose-bisphosphatase described by Claus et al. [1] that the phosphorylation-dephosphorylation of fructose-bisphosphatase could be of importance for the hormonal regulation of the enzyme in vivo.

Animals↗

PubMed1991

Non-enzymic modification of lens proteins by glucose and fructose: effects of ibuprofen.

Cataract is the major cause of blindness worldwide. Non-enzymic modification of lens proteins leading to a disruption of their short range order is an important route to cataract formation. A reaction between lens proteins and a compound found in the lens indicates a potential role for that compound in cataract formation. The reactions of glucose and fructose with lens protein in vitro were investigated. Fructose bound to lens protein at pH 6.9 in a time-dependent fashion over a period of 20 days. The reactions of both glucose and fructose with lens proteins and bovine serum albumin led to the formation of coloured and fluorescent compounds. The formation of such compounds was greater with fructose than with glucose. The kinetics of the reactions of lens proteins and bovine serum albumin with fructose as measured by the formation of the above compounds were not identical. This point must be appreciated when attempting to extrapolate from results obtained with bovine serum albumin as to the reactions of lens proteins. The incubation of lens proteins with fructose led to an enhancement of protein aggregation. The implications of the reactions between lens proteins and fructose for the formation of cataract in diabetics are discussed. Ibuprofen intake is associated with protection against cataract. At relatively high concentrations (10-20 mM) ibuprofen decreased the binding of fructose to lens protein: this decrease was statistically significant at selected times (Student's t-test, P less than 0.05). The formation of fluorescent compounds in the presence of fructose was also decreased by ibuprofen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Partial characterization of the fructose-induced defect in very-low-density lipoprotein triglyceride metabolism.

Very-low-density lipoprotein triglyceride (VLDL-TG) catabolism was studied in rats receiving either fructose or glucose as a 10% drinking solution. Consumption of either of the hexoses for 16 hours significantly elevated postheparin plasma (PHP) lipoprotein lipase (LPL) activity compared with normal control animals. Prolonged feeding of the carbohydrates for 14 days abolished the higher LPL activities, which were similar to control levels. PHP hepatic lipase (HL) activity was significantly reduced in carbohydrate-fed rats compared with control animals despite the duration of feeding. The kinetic parameters Km and Vmax cannot be obtained with lipoproteins and so the first-order rate constant (k1) of triglyceride hydrolysis was used to assess the effectiveness of VLDL-TG as substrates for endothelial lipases. VLDL-TG from fructose and VLDL-TG from glucose donors was lipolyzed with PHP LPL and HL from normal rats. The k1 (fraction of VLDL-TG lipolyzed) of VLDL-TG was found to be lower when donors had been fed fructose compared with VLDL that had come from glucose-fed donors. Rates of VLDL-TG removal from fructose and glucose donors were determined simultaneously in perfused livers of normal control, fructose-fed, and glucose-fed animals. Livers of fructose-fed animals cleared VLDL-TG at a slower rate than livers from glucose-fed or control rats. VLDL-TG from fructose-fed rats was cleared less effectively than VLDL-TG from glucose-fed rats in livers of both control and glucose-fed animals. We conclude that an impairment in the ability of fructose-fed rats to hydrolyze VLDL-TG, and of their livers to remove VLDL-TG, may in part explain fructose-induced hypertriglyceridemia.

Animals↗

PubMed1994

Lipid metabolism and substrate oxidation during intravenous fructose administration in cirrhosis.

We used isotope dilution techniques (constant intravenous [IV] infusion of 2-3H-glycerol and 1-14C-palmitate) and indirect calorimetry to measure lipid kinetics and substrate oxidation rates during IV fructose administration at 200 and then 500 mg/kg/h in eight cirrhotic patients and seven normal control subjects. Fasting plasma glucose, glycerol, and glycerol appearance rate (Ra) were similar in both groups, but insulin levels were fourfold higher in cirrhotics (P < .01). Fasting serum nonesterified fatty acid (NEFA) levels (cirrhotics, 869 +/- 124, controls, 717 +/- 90 mumol/L) and NEFA Ra (7.1 +/- 0.8 v 5.5 +/- 0.9 mumol/min/kg) were higher in cirrhotics, but the differences were not significant. Plasma fructose was similar in both groups at both fructose infusion rates. Fructose appeared to stimulate insulin secretion. With i.v. fructose, serum NEFA levels decreased, reaching similar low levels when 500 mg/kg/h was infused, due to a reduction in NEFA Ra and an increase in the NEFA metabolic clearance rate (MCR). Glycerol levels showed little change. As glycerol Ra decreased by less than 20% in both groups, the decrease in serum NEFA was primarily due to enhanced reesterification of fatty acids both within adipose tissue (preventing their release) and in other tissues (enhancing their removal from plasma). Although total fructose utilization was normal in cirrhotics, they oxidized more of the infused fructose; nonoxidative disposal was reduced (first step, 242 +/- 12 v 318 +/- 16 mg/kg in 2 hours, P < .002; second step, 657 +/- 32 v 786 +/- 21 mg/kg in 2 hours, P < .005). Although tissue fructose uptake is insulin-independent, insulin resistance in cirrhosis may influence the intracellular metabolism of fructose.

Adult↗

PubMed1994

Sucrose and fructose have qualitatively different flavors to rats.

Previous studies suggest that rats might be able to discriminate between sucrose and fructose, but no previous study has examined this possibility in much detail. Rats were conditioned to avoid either sucrose or fructose by injecting them with lithium chloride when they drank these substances. Control rats were given the same injections but were not exposed to either sugar during training. After training, the rats were given a choice of fructose vs. sucrose. Data from control rats provided information about the relative taste intensity of the sugars. If the sugars possess only a single gustatory quality, control rats should prefer the sweeter sugar; under this assumption, sucrose appears to be two-four times sweeter than fructose. The two sugars share a common taste because rats trained to avoid sucrose avoided fructose when the fructose concentration was much greater than the sucrose concentration. Nevertheless, the two sugars are discriminable because, when the apparent sweetness of the sugars was matched, rats showed a greater aversion to the sugar they were trained to avoid. Aversions to sucrose and fructose also generalized to maltodextrins, but sucrose may have a somewhat greater maltodextrin flavor than does fructose. It is proposed that the biological function of maltodextrin taste is to allow animals to sense the ratio of glucose to fructose in foods.

Animals↗

PubMed1994

Hepatic metabolism during constant infusion of fructose; comparative studies with 31P-magnetic resonance spectroscopy in man and rats.

A protocol of constant infusion of fructose has been carried out both in human volunteers and in the perfused rat liver, aiming at a steady-state blood fructose concentration of 6-8 mM. Localized 31P-NMR spectroscopy and biochemical analyses were used to evaluate the metabolic changes. Comparison of the model experiment and the clinical study allowed an evaluation of this protocol as a clinically relevant assessment of the metabolic function of the liver. The time course of change, as well as the quasi steady-state levels reached during fructose infusion, for phosphomonoesters (PME), ATP and inorganic phosphate (Pi) provided the following results: During fructose infusion, ATP and Pi reached a steady-state level of 74.0 +/- 5.9 and 54.6 +/- 3.3% of control respectively, in the human volunteers. The corresponding data in the rat liver was 71.3 +/- 4.3 and 54.4 +/- 4.3%. Hepatic clearance of fructose was 0.53 and 0.52 ml.g liver-1.min-1 for volunteers and rats, respectively. The time course of intracellular metabolite recovery after fructose could be approximated by a first order kinetic. The rate constants for PME and ATP change were similar during fructose infusion and recovery, while after the discontinuation of fructose infusion, Pi increased with a rate constant significantly greater than during its fructose-induced depletion in human liver (P < 0.005). Thus, this relatively simple clinically applicable protocol seems to be verifiable in the well controlled perfused rat liver model, and it is argued that it may be useful in the clinical evaluation of the metabolic functional capacity of the human liver.

Adult↗

PubMed1996

Fructose feeding in rats is not associated with sodium retention.

Chronic fructose treatment in rats repeatedly has been shown to elevate blood pressure associated with insulin resistance and hyperinsulinemia. Activation of the sympathetic nervous system and the renin-angiotensin system, vascular hypertrophy, and sodium retention by the kidney tubules have been proposed to be some of the mechanisms by which insulin elevates blood pressure. The precise mechanism by which hypertension develops in fructose fed rats is still not known. The purpose of the current study was twofold. The first objective was to assess the effect of a fructose-enriched diet on urinary sodium excretion. The second objective was to investigate any changes in plasma volume and extracellular volume in fructose-fed rats. In both experiments, male Sprague-Dawley rats were divided into equal groups. Rats in the control group were fed Purina Laboratory Chow, whereas those in the experimental group were fed a 60% fructose diet. There was a significant elevation in the blood pressure of fructose-fed rats at the end of the second week of treatment, and it remained elevated for the remainder of the dietary intervention. In the first experiment, there was no significant difference in sodium, potassium or urine excretion throughout the 6 weeks of dietary treatment. At the end of this study, the serum insulin levels of fructose-fed rats were significantly greater than the levels in the control group. In the second experiment, which was a 4-week study, there was no significant difference in hematocrit, plasma volume, or extracellular fluid volume between control and fructose-fed animals at 2 or 4 weeks of dietary treatment. The results of these two in vivo studies are the first to document that elevation of blood pressure in fructose-fed rats does not occur directly via sodium retention or an increase in fluid volume.

Animals↗

PubMedDate not supplied

Effects of fructose on D-[6-3H]-glucose uptake and sorbitol metabolism of bovine retina in vitro.

In order to study the influence of fructose on sorbitol formation, bovine retinal tissue was incubated with different concentrations of glucose and fructose, and supplemented with tracer amounts of D-[6-3H]-glucose. Combining high-performance liquid chromatography (HPLC) with radioactivity determinations allowed detection of sorbitol and fructose derived from glucose in the incubation medium. In addition, the total amount of sorbitol was measured with a sensitive bioluminescence method. In this way, it was possible to distinguish between sorbitol formation from glucose and fructose. High concentrations of glucose in the medium increased the formation of sorbitol and fructose from glucose. Addition of fructose to the incubation medium diminished the sorbitol and fructose formation from glucose although the total amount of sorbitol increased significantly. Incubating retinal tissue with an aldose reductase inhibitor decreased sorbitol formation from glucose but did not influence the formation of sorbitol from fructose. Thus, the present findings clearly demonstrate the important influence exerted by fructose on sorbitol formation. The possible significance of the present finding is discussed with respect to diabetes retinopathy and retinal osmoregulation.

Animals↗

PubMed2026

Does high fructose consumption trigger microglia activation and neuroinflammation? A systematic review.

This systematic review evaluated the effects of fructose intake on neuroinflammatory markers in rodent models. The search terms Fructose AND neuroinflammation OR Neurodegeneration OR chemokines OR interleukins OR microglia OR behaviour OR memory OR cognition were used in Google Scholar, Scopus and Web of Science. Thirteen animal studies investigating fructose-induced neuroinflammation that matched the eligibility criteria were included in the study. Across the studies, 16 inflammatory markers were identified and significantly altered following exposure to fructose. The findings consistently demonstrated elevated expression of pro-inflammatory cytokines, TNF-α, IL-6, and IL-1β, following fructose administration. Fructose consumption also dysregulated MCP-1, fractalkine, and CX3CR1 levels, thereby promoting inflammatory signalling and microglial activation. Furthermore, fructose exposure significantly increased IBA-1 and CD11b, indicating sustained neuroimmune activation. Alterations in important inflammatory pathways involving TLR4, NLRP3, NF-κB, MyD88, iNOS, and cyclooxygenases (COX-1 and COX-2) were also observed. In contrast, expression of the anti-inflammatory regulator peroxisome proliferator-activated receptor gamma (PPARγ) was reduced after fructose treatment. Overall, the findings suggest that chronic fructose consumption induces neuroinflammation through multiple inflammatory and immune-related mechanisms in the brain. These effects appear to be dose- and duration-dependent and may contribute significantly to neurodegeneration and cognitive impairment.

Microglia↗

PubMed2005

Molecular and functional characterization of a fructose specific transporter from the gray mold fungus Botrytis cinerea.

In the gray mold fungus Botrytis cinerea, spore germination and plant infection are stimulated in the presence of nutrients, in particular sugars. Applied at micromolar concentrations, fructose is a more potent inducer of germination than glucose. To test whether preferred fructose uptake is responsible for this effect, and to study the mechanism of fructose transport in B. cinerea, a gene (frt1) encoding a fructose transporter was cloned. FRT1 is highly similar to recently identified fructose transporters of yeasts, but much less to other fungal hexose transporters characterized so far. By using a hexose uptake deficient yeast strain for expression, FRT1 was found to be a high affinity proton coupled symporter specific for fructose but not for glucose. B. cinerea frt1 disruption mutants were created and showed normal vegetative growth and plant infection, but a delay in fructose-induced germination when compared to wild-type. Sugar uptake experiments with both wild-type and mutant conidia showed a higher affinity for glucose than for fructose. Thus, we propose that the specific effect of fructose on germination is not due to transport but rather to an as yet unknown intracellular sensing.

Amino Acid Sequence↗

PubMed2004

The effect of nitric oxide synthase inhibitor on improved insulin action by pioglitazone in high-fructose-fed rats.

The present study was performed to investigate whether nitric oxide synthase (NOS) inhibition influences the increased whole-body insulin action by pioglitazone in high-fructose-fed rats. Male Wistar rats aged 6 weeks were randomly divided into 3 groups and each group was fed one of the following diets for 3 weeks: standard chow diet (control group), high-fructose diet (fructose-fed group), and high-fructose diet plus pioglitazone (pioglitazone-treated group). The control and pioglitazone-treated groups were further divided into 2 subgroups respectively, and some rats of each subgroup were infused the NOS inhibitor, N(G)-monomethyl-l-arginine (L-NMMA), during the euglycemic clamp studies. In vivo insulin action was determined by the 2-step (3 and 30 mU/kg body weight [BW]/min low- and high-dose, respectively) hyperinsulinemic euglycemic clamp procedure in the awake condition. Glucose infusion rate (GIR) was considered as the index of insulin action. Endothelium-type NOS (eNOS) and inducible NOS (iNOS) in skeletal muscle were also measured. At the low-dose clamp, high-fructose feeding produced a marked decrease in GIR compared with the control group. Pioglitazone-treated animals showed a significant increase in GIR, reaching a similar level as the control group. However, the improved GIR was decreased to the level of the fructose-fed group by L-NMMA infusion. The GIR of the control group was not affected by L-NMMA infusion. The same tendency as the low-dose clamp was found at the high-dose clamp. In skeletal muscle, eNOS and iNOS protein content were not affected by high-fructose feeding and/or pioglitazone treatment. These results suggest that NOS inhibition can decrease the improved insulin resistance by pioglitazone in high-fructose-fed rats. Therefore, although NOS protein content is not changed by high-fructose feeding and/or pioglitazone treatment, it could be concluded that nitric oxide (NO) plays an important role in the improvement of insulin action by pioglitazone.

Animals↗