Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A major characteristic of type 2 diabetes mellitus (T2DM) is insulin resistance in skeletal muscle. A growing body of evidence indicates that oxidative stress that results from increased production of reactive oxygen species and/or reactive nitrogen species leads to insulin resistance, tissue damage, and other complications observed in T2DM. It has been suggested that muscular free fatty acid accumulation might be responsible for the mitochondrial dysfunction and insulin resistance seen in T2DM, although the mechanisms by which increased levels of free fatty acid lead to insulin resistance are not well understood. To help resolve this situation, we report that saturated fatty acid palmitate stimulated the expression of inducible nitric oxide (NO) synthase and the production of reactive oxygen species and NO in L6 myotubes. Additionally, palmitate caused a significant dose-dependent increase in mitochondrial DNA (mtDNA) damage and a subsequent decrease in L6 myotube viability and ATP levels at concentrations as low as 0.5 mM. Furthermore, palmitate induced apoptosis, which was detected by DNA fragmentation, caspase-3 cleavage, and cytochrome c release. N-acetyl cysteine, a precursor compound for glutathione formation, aminoguanidine, an inducible NO synthase inhibitor, and 5,10,15,20-tetrakis(4-sulphonatophenyl) porphyrinato iron (III), a peroxynitrite inhibitor, all prevented palmitate-induced mtDNA damage and diminished palmitate-induced cytotoxicity. We conclude that exposure of L6 myotubes to palmitate induced mtDNA damage and triggered mitochondrial dysfunction, which caused apoptosis. Additionally, our findings indicate that palmitate-induced mtDNA damage and cytotoxicity in skeletal muscle cells were caused by overproduction of peroxynitrite.
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PMID:Palmitate induced mitochondrial deoxyribonucleic acid damage and apoptosis in l6 rat skeletal muscle cells. 1702 29

Dietary epidemiological studies indicate correlations between the consumption of red meat and/or processed meat and cancer of the colon, rectum, stomach, pancreas, bladder, endometrium and ovaries, prostate, breast and lung, heart disease, rheumatoid arthritis, type 2 diabetes and Alzheimer's disease. The correlation of all these major diseases with dietary red meat indicates the presence of factors in red meat that damage biological components. This hypothesis will focus on the biochemistry of heme compounds and their oxidative processes. Raw red meat contains high levels of oxymyoglobin and deoxymyoglobin and oxyhemoglobin and deoxyhemoglobin and cytochromes in muscle and other tissues. Cooked and processed meat contain hemichromes and hemochromes. After being eaten heme proteins are hydrolyzed to amino acids and peptides and the heme group which is coordinated with strong ligands. The iron of heme coordinates to the sulfur, nitrogen or oxygen of amino acids and peptides and other biological components. The coordinated heme groups are absorbed and transported by the blood to every organ and tissue. Free and coordinated heme preferentially catalyze oxidative reactions. Heme catalyzed oxidations can damage lipids, proteins, DNA and other nucleic acids and various components of biological systems. Heme catalysis with hydroperoxide intermediates can initiate further oxidations some of which would result in oxidative chain reactions. Biochemical and tissue free radical damage caused by heme catalyzed oxidations is similar to that resulting from ionizing radiation. Oxidative biochemical damage is widespread in diseases. It is apparent that decreasing the amount of dietary red meat will limit the level of oxidative catalysts in the tissues of the body. Increasing consumption of vegetables and fruits elevates the levels of antioxidative components, for example, selenium, vitamin E, vitamin C, lycopene, cysteine-glutathione and various phytochemicals. These detrimental processes of heme catalysis of oxidative damage hypothesized here are not well recognized. More investigative studies in this field need to be done.
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PMID:Heme of consumed red meat can act as a catalyst of oxidative damage and could initiate colon, breast and prostate cancers, heart disease and other diseases. 1704 17

The effect of olmesartan medoxomil (OLM), an angiotensin II receptor blocker (ARB), on advanced nephropathy and mortality was evaluated in Zucker Diabetic Fatty (ZDF) rats, a type 2 diabetes model. OLM was administered from 36 weeks of age, when the animals developed advanced proteinuria. OLM effectively suppressed the progression of proteinuria. The ZDF rats started to die at 50 weeks of age, which was accompanied by abrupt increase in blood urea nitrogen, suggesting that the cause of death was renal insufficiency. OLM suppressed increases in blood urea nitrogen and increased the survival rate of the ZDF rats. The histological examination revealed that the renal damage was ameliorated by OLM. The macrophage infiltration and monocyte chemoattractant protein-1 (MCP-1) expression was increased in the glomeruli and tubulointerstitium of the ZDF rat kidneys, and the increase was lessened by OLM. In a separate study, albumin increased MCP-1 release from cultured tubular epithelial cells. These results suggest that protein leakage from the glomeruli stimulates MCP-1 production in tubular cells and that MCP-1 released into the interstitial space induces macrophage infiltration and inflammation. It is conceivable that the beneficial actions of ARB on diabetic nephropathy are, at least in part, due to decrease of proteinuria and the subsequent reduction of inflammatory changes in tubular cells.
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PMID:The effect of angiotensin II receptor blockade on an end-stage renal failure model of type 2 diabetes. 1708 90

Metabolic syndrome consists of a cluster of metabolic conditions, such as hypertriglyceridemia, hyper-low-density lipoproteins, hypo-high-density lipoproteins, insulin resistance, abnormal glucose tolerance and hypertension, that-in combination with genetic susceptibility and abdominal obesity-are risk factors for type 2 diabetes, vascular inflammation, atherosclerosis, and renal, liver and heart disease. One of the defects in metabolic syndrome and its associated diseases is excess cellular oxidative stress (mediated by reactive oxygen and nitrogen species, ROS/RNS) and oxidative damage to mitochondrial components, resulting in reduced efficiency of the electron transport chain. Recent evidence indicates that reduced mitochondrial function caused by ROS/RNS membrane oxidation is related to fatigue, a common complaint of MS patients. Lipid replacement therapy (LRT) administered as a nutritional supplement with antioxidants can prevent excess oxidative membrane damage, restore mitochondrial and other cellular membrane functions and reduce fatigue. Recent clinical trials have shown the benefit of LRT plus antioxidants in restoring mitochondrial electron transport function and reducing moderate to severe chronic fatigue. Thus LRT plus antioxidant supplements should be considered for metabolic syndrome patients who suffer to various degrees from fatigue.
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PMID:Metabolic syndrome and mitochondrial function: molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function. 1724 17

The most common form of diabetes, type 2 diabetes (T2D) is a major Public Health issue which is receiving a great deal of attention both in industrial and public research, in order to develop new and more effective drugs. The hyperglycaemia of T2D is the result of two interdependent defects : decreased biological efficacy of insulin in target tissues (insulin resistance), and a decreased capacity for beta cells to secrete insulin in response to glucose. Furthermore, hyperglycaemia evolves with time and even with rigorous treatment there is a progressive deterioration of glucose homeostasis. Seventy five percent of DT2 patients are obese and show a perturbed lipid profile. beta-cell plasticity is a unique property of these cells to adapt their number and volume (beta-cell mass) and their function to the increased secretory demand linked to insulin resistance. This is well documented in physiological (pregnancy) as well in pathophysiological conditions (obesity, acromegaly). Although the lack of reliable techniques makes it very difficult to document it in humans, this property is likely altered in DT2, mainly as a consequence of the prolonged exposure of islet cells to high plasma levels of glucose and free fatty acids (gluco-lipotoxicity). The mechanisms by which hyperglycaemia and hyperlipidemia exert their deleterious effects on the beta-cell include the generation of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) and Advanced Glycosylation End Products (AGE). Altogether the prevailing clinical and experimental data urge us to consider that the pathophysiology of DT2 lies, at least in part, the inability of beta-cells to adapt their functional mass to the prevailing insulin demand. This re-evaluation of the pathophysiology of DT2 stimulates the research of new therapeutic approaches aimed at maintaining and/or restoring the functional beta-cell mass by targeting the mechanisms responsible for its decrease.
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PMID:[Anatomical and functional plasticity of pancreatic beta-cells and type 2 diabetes]. 1793 2

We reported the first case of simultaneous pancreas-kidney transplantation (SPK) in our hospital. The recipient is a 65 year old male, who suffered type 2 diabetes for 15 years and renal dysfunction for 5 years and other diabetic complications such as retinopathy, peripheral neuropathy. SPK was performed successfully for him in March, 2007, in which the donor kidney was put in left iliac fossa, while the donor pancreas grafted to set in right iliac fossa of recipient, with pancreas exocrine drainage controlled by anastomosis to the small bowel and endocrine release done to the circulatory system. Serum C-peptide, Creatinine and Blood urea nitrogen became normal levels at day 1, 4 and 11 of post-operation respectively. The concentration of blood glucose was stabilized gradually to normal level and therefore the injected insulin was stopped using to the patient at day 16 of post-operative days. OGTT test showed the function of grafted pancreas was normal 3 weeks after transplant, and no transplantation-related complications occurred. With the recipient followed up for 6 months, both his blood glucose level and renal function maintained normal without using injected insulin, and he was getting to recover from other diabetic complications also.
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PMID:[Simultaneous pancreas-kidney transplantation (SPK) for an old age male with type 2 diabetes complicated with end-stage renal disease (ESRD): a case report]. 1809 18

The objective of this paper is to evaluate adaptations in hepatic mitochondrial protein mass, function and efficiency in a rat model of high-fat diet-induced obesity and insulin resistance that displays several correlates to human obesity. Adult male rats were fed a high-fat diet for 7 weeks. Mitochondrial state 3 and state 4 respiratory capacities were measured in liver homogenate and isolated mitochondria by using nicotinamide adenine dinucleotide, flavin adenine dinucleotide and lipid substrates. Mitochondrial efficiency was evaluated by measuring proton leak kinetics. Mitochondrial mass was assessed by ultrastructural observations and citrate synthase (CS) activity measurements. Mitochondrial oxidative damage and antioxidant defence were also considered by measuring lipid peroxidation, aconitase and superoxide dismutase (SOD) specific activity. Whole body metabolic characteristics were obtained by measuring 24-h oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory quotient (RQ) and nonprotein respiratory quotient (NPRQ), using indirect calorimetry with urinary nitrogen analysis. Whole body glucose homeostasis was assessed by measuring plasma insulin and glucose levels after a glucose load. Adult rats fed a high-fat diet for 7 weeks, exhibit not only obesity, insulin resistance and hepatic steatosis, but also reduced respiratory capacity and increased oxidative stress in liver mitochondria. Our present results indicate that alterations in the mitochondrial compartment induced by a high-fat diet are associated with the development of insulin resistance and ectopic fat storage in the liver. Our results thus fit in with the emerging idea that mitochondrial dysfunction can led to the development of metabolic diseases, such as obesity, type 2 diabetes mellitus and nonalcoholic steatohepatitis.
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PMID:Alterations in hepatic mitochondrial compartment in a model of obesity and insulin resistance. 1827 91

A new series of alpha-aryl or alpha-heteroarylphenyl propanoic acid derivatives was synthesized that incorporate acetylene-, ethylene-, propyl-, or nitrogen-derived linkers as a replacement of the commonly used ether moiety that joins the central phenyl ring with the lipophilic tail. The effect of these modifications in the binding and activation of PPARalpha and PPARgamma was first evaluated in vitro. Compounds possessing suitable profiles were then evaluated in the ob/ob mouse model of type 2 diabetes. The propylene derivative 40 and the propyl derivative 53 demonstrated robust plasma glucose lowering activity in this model. Compound 53 was also evaluated in male Zucker diabetic fatty rats and was found to achieve normalization of glucose, triglycerides, and insulin levels. An X-ray crystal structure of the complex of 53 with the PPARgamma-ligand-binding domain was obtained and discussed in this report.
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PMID:Effects of modifications of the linker in a series of phenylpropanoic acid derivatives: Synthesis, evaluation as PPARalpha/gamma dual agonists, and X-ray crystallographic studies. 1839 7

The Spontaneously Diabetic Torii (SDT) fatty rat, established by introducing the fa allele of the Zucker fatty rat into the SDT rat genome, is a new model of obese type 2 diabetes. The SDT-fa/fa (SDT fatty) rat shows overt obesity, and hyperglycemia and hyperlipidemia are observed at a young age as compared with the SDT-+/+ (SDT normal) rat. However, the features of the diabetic complications in the SDT fatty rat have not been reported. In the present study, the incidence and the progression of diabetic complications in the SDT fatty rat were examined, and compared with those of the SDT normal rat. Renal function parameters, such as blood urea nitrogen, urine volume and urinary protein, increased from 4 weeks of age in the SDT fatty rat, and pathological findings in the renal tubule were observed from 8 weeks. Furthermore, cataract was observed in the SDT fatty rat from 8 weeks of age, and prolongation of peak latencies on electroretinograms was observed at 16 and 24 weeks of age. On the other hand, in the SDT normal rat, renal or ocular changes were observed from 24 weeks of age. With early incidence of diabetes mellitus, diabetes-associated complications in the SDT fatty rat were seen at younger ages than those in the SDT normal rat. In conclusion, the SDT fatty rat is expected to be a useful model for the analysis of diabetic complications and the evaluation of drugs related to metabolic diseases.
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PMID:Diabetes-associated complications in Spontaneously Diabetic Torii fatty rats. 1842 Nov 73

In patients with type 2 diabetes mellitus (DM), the factors associated with under- or overreporting of protein intake in nutrition assessment tools, as well as the variability of diet records, have not been fully established. The aim of this cross-sectional study was to evaluate factors associated with under- or overreporting of protein intake and its variability in patients with type 2 DM. Protein intake was estimated in 205 patients (aged 59.8+/-9.6 years) using 3-day weighed diet records and 24-hour nitrogen output (criterion standard). Twenty-three patients repeated the 3-day weighed diet records three times. Clinical, nutrition, and lifestyle evaluations were performed. Coefficients of variation were calculated for protein intake. Factors associated with under- and overreporting were assessed using multivariate logistic regression models. Coefficients of variation for protein intake estimated by weighed diet records or nitrogen output were similar (11.9% vs 11.3%; P>0.05). Using Beaton's formula, a difference of 16.5% in protein intake between two 3-day weighed diet records was acceptable. The lowest A1c test tertile (< or =6.9%) was associated with protein intake underreporting (odds ratio [OR]=0.40; 95% confidence interval [CI]=0.16 to 0.99; P=0.046] after adjustment for sex, age, employment status, and living alone. Male sex (OR=6.66; 95% CI: 2.08 to 22.07; P=0.002), A1c test (OR=1.29; 95% CI: 1.02 to 1.64; P=0.036), and body mass index (OR=0.89; 95% CI: 0.80 to 0.994; P=0.039), adjusted for physical and employment status, education, and preparing one's own meals, were associated with overreporting. In conclusion, in patients with type 2 DM, a difference >16.5% in protein intake between two 3-day weighed diet records should be interpreted as a true discrepancy. Poor glucose control and male sex increase the chance of inaccurate 3-day weighed diet records.
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PMID:Protein intake estimated by weighed diet records in patients with type 2 diabetes: misreporting and intra-individual variability using 24-hour nitrogen output as criterion standard. 1844 13


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