Incorporation of Oxidized Phenylalanine Derivatives into Insulin Signaling Relevant Proteins May Link Oxidative Stress to Signaling Conditions Underlying Chronic Insulin Resistance.

A link between oxidative stress and insulin resistance has been suggested. Hydroxyl free radicals are known to be able to convert phenylalanine (Phe) into the non-physiological tyrosine isoforms ortho- and meta-tyrosine (o-Tyr, m-Tyr). The aim of our study was to examine the role of o-Tyr and m-Tyr in the development of insulin resistance. We found that insulin-induced uptake of glucose was blunted in cultures of 3T3-L1 grown on media containing o- or m-Tyr. We show that these modified amino acids are incorporated into cellular proteins. We focused on insulin receptor substrate 1 (IRS-1), which plays a role in insulin signaling. The activating phosphorylation of IRS-1 was increased by insulin, the effect of which was abolished in cells grown in m-Tyr or o-Tyr media. We found that phosphorylation of m- or o-Tyr containing IRS-1 segments by insulin receptor (IR) kinase was greatly reduced, PTP-1B phosphatase was incapable of dephosphorylating phosphorylated m- or o-Tyr IRS-1 peptides, and the SH2 domains of phosphoinositide 3-kinase (PI3K) bound the o-Tyr IRS-1 peptides with greatly reduced affinity. According to our data, m- or o-Tyr incorporation into IRS-1 modifies its protein-protein interactions with regulating enzymes and effectors, thus IRS-1 eventually loses its capacity to play its role in insulin signaling, leading to insulin resistance.

Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients.

Although resveratrol has widely been studied for its potential health benefits, little is known about its metabolic effects in humans. Our aims were to determine whether the polyphenol resveratrol improves insulin sensitivity in type 2 diabetic patients and to gain some insight into the mechanism of its action. After an initial general examination (including blood chemistry), nineteen patients enrolled in the 4-week-long double-blind study were randomly assigned into two groups: a resveratrol group receiving oral 2 × 5 mg resveratrol and a control group receiving placebo. Before and after the second and fourth weeks of the trial, insulin resistance/sensitivity, creatinine-normalised ortho-tyrosine level in urine samples (as a measure of oxidative stress), incretin levels and phosphorylated protein kinase B (pAkt):protein kinase B (Akt) ratio in platelets were assessed and statistically analysed. After the fourth week, resveratrol significantly decreased insulin resistance (homeostasis model of assessment for insulin resistance) and urinary ortho-tyrosine excretion, while it increased the pAkt:Akt ratio in platelets. On the other hand, it had no effect on parameters that relate to ß-cell function (i.e. homeostasis model of assessment of ß-cell function). The present study shows for the first time that resveratrol improves insulin sensitivity in humans, which might be due to a resveratrol-induced decrease in oxidative stress that leads to a more efficient insulin signalling via the Akt pathway.

GCKR gene functional variants in type 2 diabetes and metabolic syndrome: do the rare variants associate with increased carotid intima-media thickness?

BACKGROUND: Recent studies revealed that glucokinase regulatory protein (GCKR) variants (rs780094 and rs1260326) are associated with serum triglycerides and plasma glucose levels. Here we analyzed primarily the association of these two variants with the lipid profile and plasma glucose levels in Hungarian subjects with type 2 diabetes mellitus and metabolic syndrome; and also correlated the genotypes with the carotid intima-media thickness records. METHODS: A total of 321 type 2 diabetic patients, 455 metabolic syndrome patients, and 172 healthy controls were genotyped by PCR-RFLP. RESULTS: Both GCKR variants were found to associate with serum triglycerides and with fasting plasma glucose. However, significant association with the development of type 2 diabetes mellitus and metabolic syndrome could not be observed. Analyzing the records of the patients, a positive association of prevalence the GCKR homozygous functional variants and carotid intima-media thickness was found in the metabolic syndrome patients. CONCLUSIONS: Our results support that rs780094 and rs1260326 functional variants of the GCKR gene are inversely associated with serum triglycerides and fasting plasma glucose levels, as it was already reported for diabetic and metabolic syndrome patients in some other populations. Besides this positive replication, as a novel feature, our preliminary findings also suggest a cardiovascular risk role of the GCKR minor allele carriage based on the carotid intima-media thickness association.

Fatty acid composition of plasma lipid classes in chronic alcoholic pancreatitis.

BACKGROUND/AIMS: Supplementation of n-3 long-chain polyunsaturated fatty acids (LCPUFA) is considered as adjuvant therapy in acute pancreatitis. We investigated plasma fatty acid status in chronic pancreatitis (CP). METHODS: Patients with alcoholic CP (n = 56, gender: 33/23 male/female, age: 60.0 [14.0] years (median [IQR]), who reported giving up alcohol consumption several years ago and 51 control subjects were included into the study. The fatty acid composition of plasma phospholipids (PL), triacylglycerols (TG) and sterol esters (STE) was analyzed. RESULTS: The sum of monounsaturated fatty acids was significantly higher in patients with CP than in controls (PL: 12.83 [3.35] vs. 12.20 [1.95], TG: 40.51 [6.02] vs. 37.52 [5.80], STE: 20.58 [7.22] vs. 17.54 [3.48], CP vs. control, % weight/weight, median [IQR], p < 0.05). Values of arachidonic acid were significantly lower in patients with CP than in controls (PL: 10.57 [3.56] vs. 11.66 [3.25], STE: 8.14 [2.63] vs. 9.24 [2.86], p < 0.05). Values of eicosapentaenoic acid and docosahexaenoic acid did not differ and there was no difference in the ratio of n-3 to n-6 LCPUFA. CONCLUSION: Our present data do not furnish evidence for the supplementation of n-3 LCPUFA to the diet of CP patients in relatively good clinical condition.

Serum total LDH activity and LDH-2 isozyme in nephrotic syndrome.

BACKGROUND/AIMS: Proteinuria, hypoproteinaemia, hypoalbuminaemia and oedema are major characteristics of nephrotic syndrome. Aims of this study were to detect serum total LDH activity and its isozymes in nephrotic syndrome. METHODS: In a cross-sectional study, clinical parameters were compared in three cohorts, namely kidney patients with or without nephrotic syndrome and hypoalbuminaemic controls (NEPHR, NON-NEPHR, CONTR, respectively). RESULTS: Serum total LDH activity in the NEPHR group was increased compared with the NON-NEPHR and CONTR groups (p < 0.001) and correlated with serum total protein (r = -0.549, p < 0.001), serum albumin (r = -0.596, p < 0.001), proteinuria (r = 0.456, p < 0.001) and serum total cholesterol (r = 0.523, p < 0.001). LDH isozyme pattern was analysed in three subgroups of the patients. Serum LDH-2 activity was higher in the NEPHR subgroup compared with the NON-NEPHR and CONTR subgroups (p < 0.001). Serum LDH-2 activity correlated with serum total protein (r = -0.665, p < 0.001), serum albumin (r = -0.615, p < 0.001), proteinuria (r = 0.694, p < 0.001), and serum total cholesterol (r = 0.723, p < 0.001). Linear regression analysis revealed that serum total protein proved to be an independent predictor of serum total LDH activity, while serum total protein and proteinuria were predictors of LDH-2. CONCLUSIONS: These findings suggest that serum total LDH activity might be a marker of the activity of the nephrotic syndrome.

[The pleiotropic effects of losartan--the importance of decreasing uric acid level]. / A losartan pleiotrop hatásai-- a húgysavszintcsökkentés jelentosége.

Nowdays the goal of the antihypertensive treatment is to decrease the cardiovascular risk of the patients by treating the associated diseases and possible hypertensive end-organ damages. Losartan is an antihypertensive drug with all these capabilities and placebo-like side-effect profile. Besides the most important effects of losartan, which are mediated by blocking the angiotensin II. type 1. receptors, it also has other, molecule specific beneficial effects. The most important, well documented pleiotropic effect of losartan is its uricosuric effect. The pleiotropic effects together with the blockade of the angiotensin II. receptors are considered more and more important in the hypertensive end-organ protection and in the treatment of associated diseases in hypertensive patients.

[Acute renal failure caused by plant extract]. / Növényi kivonat okozta akut veseelégtelenség.

The authors review the case of a 30 years old female patient presenting with a 48 hours-standing anuria, who permanently used products of grist of a virtuous plant, Guarana and occasionally used a parenteral non-steroid painkiller. The clinical history and laboratory results showed acute renal and hepatic failure. The histological picture of the renal biopsy specimen verified an acute tubular necrosis. After temporary dialysis treatment, her renal function recovered progressively with compensatory polyuria. The authors would like to draw the attention to the risks of the use of over-the-counter marketed paramedicinal products, per se or in combination with pharmaceutically registered products, sold in pharmacies and nutrition supplement stores.

[Importance of hereditary haemochromatosis in the care of diabetes mellitus]. / A hereditaer haemochromatosis jelentosége a diabeteses betegek gondozásában.

Interactions of iron and carbohydrate metabolism were examined using results of the literature. Special attention was paid to the description of processes involving free radical production because both hereditary haemochromatosis and diabetes mellitus lead to complications by inducing oxidative stress. High levels of blood and tissue glucose produce an excess of electrons. This overload of tissues by electrons may reduce redox-active, non-haeme ferric iron to ferrous one evolving oxidative stress. Hereditary haemochromatosis may cause an elevation in the concentration of the intracellular redox-active iron in both the general and in the diabetic populations. The ratio of carriers (hetero- + homozygotes) of mutations for hereditary haemochromatosis may be as high as 30.4% in the general and 35.8% in the diabetic Hungarian populations. Some data support the possibility that these common forms of hereditary haemochromatosis mutation (HFE-C282Y and HFE-H63D)--even in the heterozygote form--elevate the tissue level of iron without manifesting the phenotype of classical hereditary haemochromatosis. Elevated tissue iron--in patients with already damaged organs due to other diseases e.g. diabetes mellitus--may cause a progression of the complications. On the other hand, hereditary haemochromatosis may lead to endothelial damage and this way hypertension may precede the manifestation of diabetes mellitus. On the basis of these, it may be supposed that elevation of blood pressure should be taken into consideration as one of the earliest clinical symptoms of hereditary haemochromatosis. A therapy-resistant state caused by the hereditary haemochromatosis may be found in diabetes mellitus and hypertension.

Evidence of O-linked N-acetylglucosamine in diabetic nephropathy.

AIMS: There is increasing evidence that O-linked N-acetylglucosamine (O-GlcNAc) plays an important role in cell signaling pathways. It has also been reported that increases in O-GlcNAc contribute to the development of diabetes and diabetic complications; however, little is known about O-GlcNAc levels in diabetic nephropathy (DNP). Therefore the goal of this study was to determine whether O-GlcNAc could be detected in human kidney biopsy specimens, and if so to examine whether O-GlcNAc levels were increased in the kidneys of patients with DNP compared to the non-diabetic individuals. MAIN METHODS: Kidney biopsy specimens were obtained from type-2 diabetic patients (n=6) and patients diagnosed with thin basement membrane nephropathy (n=7) were used as non-diabetic controls. O-GlcNAc levels were assessed by immunohistochemistry using the anti-O-GlcNAc antibody CTD110.6. KEY FINDINGS: We show that O-GlcNAc modification of proteins can be detected in the human kidney biopsy specimens. Furthermore, in diabetic patients, we found significantly increased numbers of O-GlcNAc positive cells in the glomeruli and significantly elevated staining in the tubuli (both in the nucleus and in the cytosol). In addition we also observed an intense, granular O-GlcNAc staining specifically in diabetic tubuli. SIGNIFICANCE: In light of the increase in O-GlcNAc staining in the diabetic patients, we propose that increased O-GlcNAc levels might contribute to the development of diabetic nephropathy.

Effects of pentoxifylline and pentosan polysulphate combination therapy on diabetic neuropathy in type 2 diabetes mellitus.

Vascular dysfunction, including impaired perfusion has a pivotal role in the pathogenesis of microvascular complications in diabetes mellitus. Both pentoxifylline (PF) and pentosan polysulphate (PPS) are known to improve microcirculation. Antioxidant and antiproteinuric effects of PF are also known. In a placebo-controlled study, we determined the possible efficacy of PF-PPS combination therapy on diabetic neuropathy and nephropathy in type 2 diabetic patients. Patients in Verum group (n = 77) received PF-PPS infusions (100-100 mg/day) for 5 days. Control diabetics (Placebo group; n = 12) were given only saline infusions. Specialized cardiovascular autonomic reflex tests, vibration threshold values and urinary albumin excretion were assessed before and after therapy. In Verum group, autonomic score, indicating the severity of cardiac autonomic dysfunction, decreased after therapy (p < or = 0.001). Of the reflexes, deep breath and handgrip tests also improved after therapy (p < or = 0.001). Vibration threshold values, an indicator of the loss of sensory nerve function, were increased after therapy (p < or = 0.001). Results of cardiac autonomic tests and vibration threshold values remained unaltered in Placebo group. Majority of patients had normalbuminuria, which was not affected by PF-PPS. In conclusion, short-term PF-PPS therapy was effective on cardiovascular autonomic function and vibration perception, whereas it failed to reduce albuminuria within normal range in type 2 diabetic patients.

Association of n-3 and n-6 long-chain polyunsaturated fatty acids in plasma lipid classes with inflammatory bowel diseases.

In order to establish the biochemical basis for dietary interventions, we investigated the fatty acid composition of plasma lipid classes in patients with inactive inflammatory bowel disease. In this cross-sectional study thirty patients with ulcerative colitis (UC), twenty-one with Crohn disease (CD) and twenty-four controls were investigated (mean age: UC, 40.8 (sd 12.1); CD, 37.6 (sd 11.0); control, 31.5 (sd 8.4) years). Fatty acid composition of plasma lipids was determined by high-resolution capillary GLC. In plasma phospholipids, significantly higher values of eicosapentaenoic (20 : 5n-3), docosapentaenoic (22 : 5n-3) and gamma-linolenic (18 : 3n-6) acids were found in control patients and patients with UC as compared to patients with CD [median % (weight by weight), control v. UC v. CD : 20 : 5n-3, 0.09 (interquartile range (IQR) 0.05) v. 0.14 (IQR 0.10) v. 0.16 (IQR 0.10), P < 0.05; 22 : 5n-3, 0.14 (IQR 0.10) v. 0.27 (IQR 0.16) v. 0.31 (IQR 0.10), P < 0.001; 18 : 3n-6, 0.02 (IQR 0.02) v. 0.03 (IQR 0.02) v. 0.05 (IQR 0.03), P < 0.05]. When compared to the control, values of the principal n-3 and n-6 long-chain PUFA, arachidonic acid (20 : 4n-6) and DHA (22 : 6n-3) were significantly higher in patients with UC but not in patients with CD [median % (w/w), UC v. control: 20 : 4n-6, 8.43 (IQR 3.23) v. 6.92 (IQR 2.96), P < 0.05; 22 : 6n-3, 1.22 (IQR 0.56) v. 0.73 (IQR 0.39), P < 0.05]. As seen there are considerable differences between the long-chain PUFA status of patients suffering from UC or CD. The data obtained in the present study do not support the concept of eicosapentaenoic acid or DHA deficiency in patients with either UC or CD.