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)

Mexiletine, an anti-arrhythmic agent, is used for the control of ventricular arrhythmias and for neuropathic pain from cancer or diabetes mellitus. It is sometimes used together with psychotropic drugs in patients with depression, schizophrenia or sleep disorder. It is metabolized mainly by cytochrome P450 (CYP) 2 D 6 and, to a minor extent, by CYP1A2. To predict possible drug interactions between mexiletine and psychotropic drugs, the inhibitory effects of 14 psychotropic drugs (phenytoin, carbamazepine, fluvoxamine, paroxetine, fluoxetine, citalopram, sertraline, imipramine, desipramine, haloperidol, thioridazine, olanzapine, etizolam, and quazepam) on mexiletine metabolism in human liver microsomes were determined. Fluoxetine (Ki=0.6+/- 0.1 microM), sertraline (Ki=7.6+/- 0.8 microM) and desipramine (Ki=3.2+/- 0.5 microM) competitively inhibited the mexiletine p-hydroxylation in human liver microsomes. Thioridazine (Kis=0.5+/- 0.2 microM; Kii =3.6+/-1.6 microM) and paroxetine (Kis=1.7+/- 0.7 microM; Kii=3.6+/- 0.9 microM) exhibited a mixed-type inhibition (competitive and non-competitive) toward mexiletine p-hydroxylation in human liver microsomes. The changes of the in vivo clearance of mexiletine by the psychotropic drugs were predicted by 1+(I/Ki) using the in vitro Ki and unbound inhibitor concentrations in liver. The values were calculated as 2.4 for paroxetine, 5.5 for fluoxetine, 1.1 for sertraline, 2.8 for desipramine and 2.2 for thioridazine. In addition, paroxetine exhibited a mechanism-based inactivation with Ki=0.7 microM and Kinact=0.15 min(-1). The present study predicted the possibility of drug interactions between mexiletine and paroxetine, fluoxetine, desipramine, and thioridazine in clinical use.
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PMID:Inhibitory effects of psychotropic drugs on mexiletine metabolism in human liver microsomes: prediction of in vivo drug interactions. 1619 7

Clinical and pathological features were reviewed in 76 Japanese patients with non-alcoholic steatohepatitis (NASH). Forty-one were male and 35 were female with the mean age of 49.7 years old (range 15-75 years old, males; 46.3, females; 53.7 years old). Fifty-four percent of patients were preobese with a body mass index (BMI) between 25 and 30, while 16% of the patients were non-obese, and only 30% of the cases were morbidly obese, indicating that Japanese have a greater tendency to develop insulin-resistance and fatty liver disease than Western people. Hyperlipidemia was found in 51%, diabetes mellitus in 38%, and hypertension in 33% of the patients. Abnormally elevated liver function tests were found in one-third to two-thirds of the patients and were characteristically mild with 2- to 3-fold elevation from the normal range in the majority of the cases. Histological features of the liver were similar or identical to those reported in English literature and were characterized by fatty change, perivenular and pericellular fibrosis in zone 3, hepatocyte ballooning and necrosis with occasional Mallory's body formation and polymorphonuclear leukocyte infiltration. Mallory's bodies were found in 39% of patients and were characteristically small and poorly formed compared with those in alcoholic hepatitis. Eosinophilic granular or dirty foggy aggregated, not sufficient to be identified as Mallory's bodies, were a rather characteristic cytoplasmic expression in NASH patients. Portal inflammation and fibrosis were not found in the early stage of NASH, but were found as the disease progresses with formation of C-C and/or P-C bridging fibrosis, and eventually resulting in liver cirrhosis.
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PMID:Clinical and pathological features of non-alcoholic steatohepatitis. 1627 57

The hormone ghrelin is secreted mainly from the gut, rises in peripheral plasma before meals, and is implicated in stimulating hunger, initiating meals, and developing obesity. We hypothesize that activation of the sympathetic nervous system contributes to preprandial ghrelin surges. The present studies in isoflurane-anesthetized Wistar rats were designed to determine whether sympathetic nerves and neurohormones are capable of stimulating ghrelin secretion. We activated gut sympathetic nerves by two methods: electrical sympathetic nerve stimulation (SNS) and chemical sympathetic nerve activation with iv tyramine (TYR) administration. Portal venous blood was sampled before and during a 10-min sympathetic stimulation. Successful activation of gut sympathetic nerves was verified by increments in portal venous norepinephrine. SNS increased portal ghrelin by 206 +/- 50%. In contrast, simply isolating gut sympathetic nerves without applying current had a minimal effect on ghrelin levels. TYR also increased portal ghrelin [change (Delta), +52 +/- 11%], whereas saline infusion had little effect. We next determined whether the neural stimulation of ghrelin secretion was mediated indirectly via the suppression of insulin secretion during SNS and TYR. Streptozotocin-induced diabetes prevented a fall in insulin during TYR, yet the portal ghrelin response (Delta = +47 +/- 18%) was similar to that in nondiabetic rats. Lastly, to test for humoral stimulation of ghrelin, we infused the sympathetic neurohormone, epinephrine, to achieve levels found during severe stress. Epinephrine failed to stimulate ghrelin secretion (Delta = +4 +/- 35%). We conclude that the neural, but not the neurohumoral, branch of the sympathetic nervous system can directly stimulate ghrelin secretion.
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PMID:Direct stimulation of ghrelin secretion by sympathetic nerves. 1652 47

Cerebral dysfunctions, including a high incidence of depression, are common findings in human type 1 diabetes mellitus. An association between depression and defective hippocampal neurogenesis has been proposed and, in rodents, antidepressant therapy restores neuronal proliferation in the dentate gyrus. Hippocampal neurogenesis is also deficient in diabetic mice, which led us to study whether the selective serotonin reuptake inhibitor fluoxetine influences cell proliferation in streptozotocin-diabetic animals. Diabetic and control C57BL/6 mice received fluoxetine (10 mg/kg/day, i.p., 10 days) and dentate gyrus cell proliferation was measured after a single injection of 5-bromo-2'-deoxyuridine (BrdU). Diabetic mice showed reduced cell proliferation. Fluoxetine treatment, although having no effect in controls, corrected this parameter in diabetic mice. The phenotype of newly generated cells was analysed by confocal microscopy after seven daily BrdU injections, using Tuj-1/beta-III tubulin as a marker for immature neurones and glial fibrillary acidic protein for astrocytes. In controls, the proportion of Tuj-1-BrdU-positive cells over total BrdU cells was approximately 70%. In vehicle-treated diabetic mice, immature neurones decreased to 56% and fluoxetine brought this proportion back to control values without affecting astrocytes. Therefore, fluoxetine preferentially increased the proliferation of cells with a neuronal phenotype. In addition, neurones were counted in the hilus of the dentate gyrus; a 30% decrease was found in diabetic mice compared with controls, whereas this neuronal loss was prevented by fluoxetine. In conclusion, fluoxetine treatment restored neuroplasticity-related hippocampal alterations of diabetic mice. These findings may be potentially important to counteract diabetes-associated depression in humans.
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PMID:Reduced hippocampal neurogenesis and number of hilar neurones in streptozotocin-induced diabetic mice: reversion by antidepressant treatment. 1655 17

The current study sought to ascertain whether portal vein glucose sensing is mediated by a metabolic fuel sensor analogous to other metabolic sensors presumed to mediate hypoglycemic detection (e.g., hypothalamic metabosensors). We examined the impact of selectively elevating portal vein concentrations of lactate, pyruvate, or beta-hydroxybutyrate (BHB) on the sympathoadrenal response to insulin-induced hypoglycemia. Male Wistar rats (n = 36), chronically cannulated in the carotid artery (sampling), jugular vein (infusion), and portal vein (infusion), underwent hyperinsulinemic-hypoglycemic ( approximately 2.5 mmol/l) clamps with either portal or jugular vein infusions of lactate, pyruvate, or BHB. By design, arterial concentrations of glucose and the selected metabolite were matched between portal and jugular (NS). Portal vein concentrations were significantly elevated in portal versus jugular (P < 0.0001) for lactate (5.03 +/- 0.2 vs. 0.84 +/- 0.08 mmol/l), pyruvate (1.81 +/- 0.21 vs. 0.42 +/- 0.03 mmol/l), or BHB (2.02 +/- 0.1 vs. 0.16 +/- 0.03 mmol/l). Elevating portal lactate or pyruvate suppressed both the epinephrine (64% decrease; P < 0.01) and norepinephrine (75% decrease; P < 0.05) responses to hypoglycemia. In contrast, elevating portal BHB levels failed to impact epinephrine (P = 0.51) or norepinephrine (P = 0.47) levels during hypoglycemia. These findings indicate that hypoglycemic detection at the portal vein is mediated by a sensor responding to some metabolic event(s) subsequent to the uptake and oxidation of glucose.
Diabetes 2006 May
PMID:Metabolic sensors mediate hypoglycemic detection at the portal vein. 1664 83

Clinical and experimental studies have been reported that antidepressant drugs can be used as co-analgesics in the management of neuropathic pain. However, the mechanism through which they alleviate pain still remains unclear. The aim of the present study was to investigate the possible mechanism of action of fluoxetine-induced antinociceptive effect in streptozotocin-induced diabetic mice, especially the involvement of non-serotonergic neurotransmitters and their receptors. Diabetes was induced in male Laka mice with a single intraperitoneal injection of streptozotocin (200 mg/kg). Four weeks after streptozotocin, diabetic mice were tested for pain responses in the tail-immersion and hot-plate assays. Diabetic mice exhibited significant hyperalgesia as compared with control mice. Fluoxetine (10 and 20 mg/kg, i.p) injected into diabetic mice produced an antinociceptive effect in both tail-immersion and hot-plate assays. The antinociceptive effect of fluoxetine in diabetic mice was significantly lower as compared with that in control mice. Pretreatment with a muscarinic receptor antagonist, atropine (2 and 5 mg/kg, i.p) and an opioid receptor antagonist, naloxone (2 and 5 mg/kg, i.p), but not the alpha(2)-adrenoreceptor antagonist, yohimbine (2 and 5 mg/kg, i.p) reversed the antinociceptive effect of fluoxetine (20 mg/kg). These results suggest that apart from serotonin pathway, muscarinic and opioid receptors also participate in fluoxetine-induced antinociception in diabetic neuropathic pain.
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PMID:Possible involvement of cholinergic and opioid receptor mechanisms in fluoxetine mediated antinociception response in streptozotocin-induced diabetic mice. 1665 Apr 2

Insulin suppresses glucose production (GP) via both extrahepatic (indirect) and hepatic (direct) effects. We have shown that the direct effect, undetectable in moderately hyperglycemic diabetic dogs, is restored by insulin-induced euglycemia. The first aim of the present study was to determine whether euglycemia per se, and not the excess insulin needed to obtain it, restores the direct effect of insulin on GP. Basal insulin was given portally in depancreatized dogs to attain only moderate hyperglycemia, then an additional insulin was given portally or peripherally to match the peripheral insulin levels and thus to obtain a greater hepatic insulinization with portal delivery. Plasma glucose was allowed to fall to euglycemia before a euglycemic clamp was performed. During euglycemia, there was a tendency (P=0.075) for greater suppression of GP by portal than peripheral insulin. Also, there was a significantly different effect of time (P=0.01) on GP in the two groups, with greater suppression over time in the portal group. The second aim was to test the hypothesis that because of inadequate hepatic insulinization and consequent lack of direct inhibition of GP, peripheral insulin replacement requires peripheral hyperinsulinemia to achieve euglycemia. Portal or peripheral insulin was given to achieve euglycemia and basal GP, and insulin levels were measured. More peripheral insulinemia was required with peripheral than portal insulin replacement to maintain similar euglycemia and GP. Our conclusions are as follows: (1) euglycemia per se is sufficient to acutely restore the direct effect of insulin on GP and (2) at euglycemia, peripheral replacement of insulin, as in insulin-treated diabetes, results in peripheral hyperinsulinemia but unchanged basal GP.
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PMID:Direct and indirect effects of insulin on hepatic glucose production in diabetic depancreatized dogs during euglycemia. 1700 70

Although excess visceral fat is associated with noninfectious inflammation, it is not clear whether visceral fat is simply associated with or actually causes metabolic disease in humans. To evaluate the hypothesis that visceral fat promotes systemic inflammation by secreting inflammatory adipokines into the portal circulation that drains visceral fat, we determined adipokine arteriovenous concentration differences across visceral fat, by obtaining portal vein and radial artery blood samples, in 25 extremely obese subjects (mean +/- SD BMI 54.7 +/- 12.6 kg/m(2)) during gastric bypass surgery at Barnes-Jewish Hospital in St. Louis, Missouri. Mean plasma interleukin (IL)-6 concentration was approximately 50% greater in the portal vein than in the radial artery in obese subjects (P = 0.007). Portal vein IL-6 concentration correlated directly with systemic C-reactive protein concentrations (r = 0.544, P = 0.005). Mean plasma leptin concentration was approximately 20% lower in the portal vein than in the radial artery in obese subjects (P = 0.0002). Plasma tumor necrosis factor-alpha, resistin, macrophage chemoattractant protein-1, and adiponectin concentrations were similar in the portal vein and radial artery in obese subjects. These data suggest that visceral fat is an important site for IL-6 secretion and provide a potential mechanistic link between visceral fat and systemic inflammation in people with abdominal obesity.
Diabetes 2007 Apr
PMID:Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. 1728 68

Nonalcoholic steatohepatitis (NASH) may cause progressive hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Treatment, thus far, has been restricted to diet and weight loss, but without compelling results. In this study we aimed to evaluate the efficacy of orlistat therapy in obese patients with NASH. Fourteen obese patients with NASH underwent liver biopsy prior to and subsequent to 6 months treatment with orlistat (120 mg tid). Hepatic fat extension was graded as normal, mild, moderate, or severe. Hepatic fibrosis was scored on a scale from 0 to 4, with 0 denoting no fibrosis and 4, cirrhosis. Portal inflammation was scored as 0-3, with 0 = normal, 1 = mild, 2 = moderate, and 3 = severe inflammation. Fourteen patients had NASH associated with diabetes, hyperlipidemia, or obesity. Orlistat reduced fatty infiltration in 10 patients (70%; P<0.01), 3 of whom had normal liver fat content after treatment. Orlistat improved inflammatory activity by 2 grades in 28% and by 1 grade in 50% of patients and effected no change in 22% of patients. Five patients (35%) returned to normal inflammatory activity. Orlistat improved hepatic fibrosis by 2 grades in three patients (21%) and by 1 grade in seven patients (50%). There was no change in four patients (28%). Orlistat lowered aminotransferases levels, total cholesterol, triglycerides and low-density lipoprotein, respectively. Insulin resistance index and malonyl dialdehyde levels improved significantly after orlistat therapy, whereas HbAic remained unchanged. In conclusion, in obese patients with NASH, liver fibrosis and inflammation improved after therapy with orlistat.
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PMID:Orlistat reverse fatty infiltration and improves hepatic fibrosis in obese patients with nonalcoholic steatohepatitis (NASH). 1740 56

Nutrient - gene interactions are responsible for maintaining health and preventing or delaying disease. Unbalanced diets for a given genotype lead to chronic diseases such as obesity, diabetes, cardiovascular, and are likely to contribute to increased severity and/or early-onset of many age-related diseases. Many nutrition and many genetic studies still fail to properly include both variables in the design, execution, and analyses of human, laboratory animal, or cell culture experiments. The complexity ofnutrient-gene interactions has led to the realization that strategic international alliances are needed to improve the completeness of nutrigenomic studies - a task beyond the capabilities of a single laboratory team. Eighty-eight researchers from 22 countries recently outlined the issues and challenges for harnessing the nutritional genomics for public and personal health. The next step in the process of forming productive international alliances is the development of a virtual center for organizing collaborations and communications that foster resources sharing, best practices improvements, and creation of databases. We describe here plans and initial efforts of creating the Nutrigenomics Information Portal, a web-based resource for the international nutrigenomics society. This portal aims at becoming the prime source ofinformation and interaction for nutrigenomics scientists through a collaborative effort.
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PMID:Harnessing Nutrigenomics: Development of web-based communication, databases, resources, and tools. 1885 Feb 16


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