Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolic syndrome (MS) is a common risk factor for cardiovascular disease and type-2 diabetes. Recently, telmisartan, an angiotensin II receptor antagonist that has an antihypertensive effect, has been reported to be a partial peroxisome proliferator-activated receptor gamma (PPARgamma) agonist. The anti-diabetic hormone adiponectin has been recognized as a marker of in vivo PPARgamma activation. Therefore, we studied telmisartan's effect on the metabolic profile and adiponectin levels in a fructose-induced hypertensive, hyperinsulinemic, hyperlipidemic rat model. Twenty-four male Sprague-Dawley rats were divided into three groups (eight in each). One group of control rats was fed standard chow for 5 weeks while a second was fed a fructose-enriched diet. A third group was fed a fructose-enriched diet for 5 weeks and treated with telmisartan 5 mg/kg/day during the last 2 weeks. Fructose feeding increased systolic blood pressure (mean+/-SEM), from 130+/-1 to 148+/-2 mmHg, insulin from 0.26+/-0.03 to 0.68+/-0.08 ng/mL, and triglycerides from 102+/-6 to 285+/-23 mg/dL (p<0.05 for all variables). Telmisartan treatment reversed these effects and reduced blood pressure to 125+/-2 mmHg, insulin levels to 0.41+/-0.07 ng/mL, and triglycerides to 146+/-18 mg/dL (p<0.05 for all variables), while attenuating the increase in body weight during weeks 3 to 5. In contrast, telmisartan did not affect plasma adiponectin levels. In conclusion, although telmisartan is considered a partial PPARgamma agonist, its beneficial effect in the fructose-induced hypertension, hypertriglyceridemia, and hyperinsulinemia rat model is apparently not mediated by adiponectin elevation but rather by direct inhibition of AT1 receptor.
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PMID:Effect of telmisartan, angiotensin II receptor antagonist, on metabolic profile in fructose-induced hypertensive, hyperinsulinemic, hyperlipidemic rats. 1836 28

Fructose is now such an important component of human diets that increasing attention is being focused on the fructose transporter GLUT5. In this review, we describe the regulation of GLUT5 not only in the intestine and testis, where it was first discovered, but also in the kidney, skeletal muscle, fat tissue, and brain where increasing numbers of cell types have been found to have GLUT5. GLUT5 expression levels and fructose uptake rates are also significantly affected by diabetes, hypertension, obesity, and inflammation and seem to be induced during carcinogenesis, particularly in the mammary glands. We end by highlighting research areas that should yield information needed to better understand the role of GLUT5 during normal development, metabolic disturbances, and cancer.
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PMID:Regulation of the fructose transporter GLUT5 in health and disease. 1839 11

Increased consumption of fructose may play an important role in the epidemic of metabolic syndrome and may presage the development of diabetes, cardiovascular disease, and chronic kidney disease. Once in the cell, fructose is phosphorylated by ketohexokinase (KHK), leading to consumption of ATP, formation of AMP, and generation of uric acid through xanthine oxidoreductase (XOR). This study aimed to examine the direct effects of fructose in human kidney proximal tubular cells (HK-2) and whether they are mediated by the fructose metabolism via KHK. At a similar concentration to that observed in peripheral blood after a meal, fructose induced production of monocyte chemotactic protein 1 (MCP-1) and reactive oxygen species in HK-2 cells. Knockdown of KHK by stable transfection with small hairpin RNA demonstrated that these processes were KHK dependent. Several antioxidants, including specific inhibitors of NADPH oxidase and XOR, prevented MCP-1 secretion. We detected XOR mRNA in HK-2 cells and confirmed its activity by identifying uric acid by mass spectrometry. Fructose increased intracellular uric acid, and uric acid induced production of MCP-1 as well. In summary, postprandial concentrations of fructose stimulate redox- and urate-dependent inflammatory mediators in proximal tubular cells.
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PMID:Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. 1924 71

A molecular understanding of the unique aspects of dietary fructose metabolism may be the key to understanding and controlling the current epidemic of fructose-related obesity, diabetes and related adverse metabolic states in Western populations. Fructose catabolism is initiated by its phosphorylation to fructose 1-phosphate, which is performed by ketohexokinase (KHK). Here, the crystal structures of the two alternatively spliced isoforms of human ketohexokinase, hepatic KHK-C and the peripheral isoform KHK-A, and of the ternary complex of KHK-A with the substrate fructose and AMP-PNP are reported. The structure of the KHK-A ternary complex revealed an active site with both the substrate fructose and the ATP analogue in positions ready for phosphorylation following a reaction mechanism similar to that of the pfkB family of carbohydrate kinases. Hepatic KHK deficiency causes the benign disorder essential fructosuria. The effects of the disease-causing mutations (Gly40Arg and Ala43Thr) have been modelled in the context of the KHK structure.
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PMID:Structures of alternatively spliced isoforms of human ketohexokinase. 1923 42

Many hypotheses of disease risk and prevention depend on inferences about the metabolic effects of fructose; however, there is inadequate attention to dose dependency. Fructose is proving to have bidirectional effects. At moderate or high doses, an effect on any one marker may be absent or even the opposite of that observed at very high or excessive doses; examples include fasting plasma triglyceride, insulin sensitivity, and the putative marker uric acid. Among markers, changes can be beneficial for some (e.g., glycated hemoglobin at moderate to high fructose intake) but adverse for others (e.g., plasma triglycerides at very high or excessive fructose intake). Evidence on body weight indicates no effect of moderate to high fructose intakes, but information is scarce for high or excessive intakes. The overall balance of such beneficial and adverse effects of fructose is difficult to assess but has important implications for the strength and direction of hypotheses about public health, the relevance of some animal studies, and the interpretation of both interventional and epidemiological studies. By focusing on the adverse effects of very high and excessive doses, we risk not noticing the potential benefits of moderate to higher doses, which might moderate the advent and progress of type-2 diabetes, cardiovascular disease, and might even contribute to longevity. A salutary rather than hyperbolic examination of the evidence base needs to be undertaken.
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PMID:Fructose ingestion: dose-dependent responses in health research. 1938 21

Fructose feeding has been shown to induce insulin resistance and hypertension. Renal protein expression for the cytochrome P (CYP) 450 arachidonic acid metabolizing enzymes has been shown to be altered in other models of diet-induced hypertension. Of special interest is CYP4A, which produces the potent vasoconstrictor, 20-hydroxyeicosatetraenoic acid and CYP2C, which catalyzes the formation of the potent dilators epoxyeicosatrienoic acids as well as soluble epoxide hydrolase (sEH) which metabolizes the latter to dihydroxyeicosatrienoic acids. The RhoA/Rho kinase (ROCK) signaling pathway is downstream of arachidonic acid and is reported to mediate metabolic-cardio-renal dysfunctions in some experimental models of insulin resistance and diabetes. The aim of the present study was to determine the expression of CYP4A, CYP2C23, CYP2C11, sEH, RhoA, ROCK-1, ROCK-2, and phospho-Lin-11/Isl-1/Mec-3 kinase (LIMK) in kidneys of fructose-fed (F) rats. Male Wistar rats were fed a high fructose diet for 8 weeks. Body weight, systolic blood pressure, insulin sensitivity, and renal expression of the aforementioned proteins were assessed. No change was observed in the body weight of F rats; however, euglycemia and hyperinsulinemia implicating impaired glucose tolerance and significant elevation in systolic blood pressure were observed. Renal expression of CYP4A and CYP2C23 was significantly increased while that of CYP2C11 and sEH was not changed in F rats. Equal expression for RhoA in both control and F rats and an enhanced level of ROCK-1 and ROCK-2 constitutively activate 130 kDa cleavage fragments as well as phospho-LIMK. These data suggest that the kidneys could be actively participating in the pathogenesis of insulin resistance-induced hypertension through the arachidonic acid CYP 450-RhoA/Rho kinase pathway(s).
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PMID:Renal expression of arachidonic acid metabolizing enzymes and RhoA/Rho kinases in fructose insulin resistant hypertensive rats. 1963 17

Genome-wide association studies have identified a number of signals for both Type 2 Diabetes and related quantitative traits. For the majority of loci, the transition from association signal to mutational mechanism has been difficult to establish. Glucokinase (GCK) regulates glucose storage and disposal in the liver where its activity is regulated by glucokinase regulatory protein (GKRP; gene name GCKR). Fructose-6 and fructose-1 phosphate (F6P and F1P) enhance or reduce GKRP-mediated inhibition, respectively. A common GCKR variant (P446L) is reproducibly associated with triglyceride and fasting plasma glucose levels in the general population. The aim of this study was to determine the mutational mechanism responsible for this genetic association. Recombinant human GCK and both human wild-type (WT) and P446L-GKRP proteins were generated. GCK kinetic activity was observed spectrophotometrically using an NADP(+)-coupled assay. WT and P446L-GKRP-mediated inhibition of GCK activity and subsequent regulation by phosphate esters were determined. Assays matched for GKRP activity demonstrated no difference in dose-dependent inhibition of GCK activity or F1P-mediated regulation. However, the response to physiologically relevant F6P levels was significantly attenuated with P446L-GKRP (n = 18; P <or= 0.03). Experiments using equimolar concentrations of both regulatory proteins confirmed these findings (n = 9; P < 0.001). In conclusion, P446L-GKRP has reduced regulation by physiological concentrations of F6P, resulting indirectly in increased GCK activity. Altered GCK regulation in liver is predicted to enhance glycolytic flux, promoting hepatic glucose metabolism and elevating concentrations of malonyl-CoA, a substrate for de novo lipogenesis, providing a mutational mechanism for the reported association of this variant with raised triglycerides and lower glucose levels.
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PMID:The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. 1964 13

The main role of carbohydrates in the human body is to provide energy. Carbohydrates should always be infused with PN (parenteral nutrition) in combination with amino acids and lipid emulsions to improve nitrogen balance. Glucose should be provided as a standard carbohydrate for PN, whereas the use of xylite is not generally recommended. Fructose solutions should not be used for PN. Approximately 60% of non-protein energy should be supplied as glucose with an intake of 3.0-3.5 g/kg body weight/day (2.1-2.4 mg/kg body weight/min). In patients with a high risk of hyperglycaemia (critically ill, diabetes, sepsis, or steroid therapy) an lower initial carbohydrate infusion rate of 1-2 g/kg body weight/day is recommended to achieve normoglycaemia. One should aim at reaching a blood glucose level of 80-110 mg/dL, and at least a glucose level <145 mg/dL should be achieved to reduce morbidity and mortality. Hyperglycaemia may require addition of an insulin infusion or a reduction (2.0-3.0 g/kg body weight/day) or even a temporary interruption of glucose infusion. Close monitoring of blood glucose levels is highly important.
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PMID:Carbohydrates - Guidelines on Parenteral Nutrition, Chapter 5. 2004 80

While virtually absent in our diet a few hundred years ago, fructose has now become a major constituent of our modern diet. Our main sources of fructose are sucrose from beet or cane, high fructose corn syrup, fruits, and honey. Fructose has the same chemical formula as glucose (C(6)H(12)O(6)), but its metabolism differs markedly from that of glucose due to its almost complete hepatic extraction and rapid hepatic conversion into glucose, glycogen, lactate, and fat. Fructose was initially thought to be advisable for patients with diabetes due to its low glycemic index. However, chronically high consumption of fructose in rodents leads to hepatic and extrahepatic insulin resistance, obesity, type 2 diabetes mellitus, and high blood pressure. The evidence is less compelling in humans, but high fructose intake has indeed been shown to cause dyslipidemia and to impair hepatic insulin sensitivity. Hepatic de novo lipogenesis and lipotoxicity, oxidative stress, and hyperuricemia have all been proposed as mechanisms responsible for these adverse metabolic effects of fructose. Although there is compelling evidence that very high fructose intake can have deleterious metabolic effects in humans as in rodents, the role of fructose in the development of the current epidemic of metabolic disorders remains controversial. Epidemiological studies show growing evidence that consumption of sweetened beverages (containing either sucrose or a mixture of glucose and fructose) is associated with a high energy intake, increased body weight, and the occurrence of metabolic and cardiovascular disorders. There is, however, no unequivocal evidence that fructose intake at moderate doses is directly related with adverse metabolic effects. There has also been much concern that consumption of free fructose, as provided in high fructose corn syrup, may cause more adverse effects than consumption of fructose consumed with sucrose. There is, however, no direct evidence for more serious metabolic consequences of high fructose corn syrup versus sucrose consumption.
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PMID:Metabolic effects of fructose and the worldwide increase in obesity. 2008 73

Sustained fructose consumption has been shown to induce insulin resistance and glucose intolerance, in part, by promoting oxidative stress. Alpha-lipoic acid (LA) is an antioxidant with insulin-sensitizing activity. The effect of sustained fructose consumption (20% of energy) on the development of T2DM and the effects of daily LA supplementation in fructose-fed University of California, Davis-Type 2 diabetes mellitus (UCD-T2DM) rats, a model of polygenic obese T2DM, was investigated. At 2 mo of age, animals were divided into three groups: control, fructose, and fructose + LA (80 mg LA.kg body wt(-1).day(-1)). One subset was followed until diabetes onset, while another subset was euthanized at 4 mo of age for tissue collection. Monthly fasted blood samples were collected, and an intravenous glucose tolerance test (IVGTT) was performed. Fructose feeding accelerated diabetes onset by 2.6 +/- 0.5 mo compared with control (P < 0.01), without affecting body weight. LA supplementation delayed diabetes onset in fructose-fed animals by 1.0 +/- 0.7 mo (P < 0.05). Fructose consumption lowered the GSH/GSSG ratio, while LA attenuated the fructose-induced decrease of oxidative capacity. Insulin sensitivity, as assessed by IVGTT, decreased in both fructose-fed and fructose + LA-supplemented rats. However, glucose excursions in fructose-fed LA-supplemented animals were normalized to those of control via increased glucose-stimulated insulin secretion. Fasting plasma triglycerides were twofold higher in fructose-fed compared with control animals at 4 mo, and triglyceride exposure during IVGTT was increased in both the fructose and fructose + LA groups compared with control. In conclusion, dietary fructose accelerates the onset of T2DM in UCD-T2DM rats, and LA ameliorates the effects of fructose by improving glucose homeostasis, possibly by preserving beta-cell function.
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PMID:Dietary fructose accelerates the development of diabetes in UCD-T2DM rats: amelioration by the antioxidant, alpha-lipoic acid. 2014 7


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