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)

Normal serum can increase the rate of lipolysis in isolated adipocytes. Recently, we reported that the lipolytic effect of serum could be partly explained by effects of iron and transferrin. To further investigate these effects on fat cell metabolism, we have investigated effects of serum, iron, and transferrin on glucose transport in isolated rat adipocytes. Adipocytes were isolated by collagenase digestion of rat epididymal fat pads, and glucose transport was measured as uptake of [3H]2-deoxyglucose, measured in the presence of 0 to 25 ng/mL insulin. Insulin stimulated glucose transport approximately 8- to 10-fold, with a half-maximally effective concentration (EC50) of approximately 0.15 ng/mL. This was not affected by 45-minute treatment with normal human serum. However, when adipocytes were incubated with serum for 4 hours, cells became markedly insulin resistant. This was manifested as decrease in maximally stimulated glucose transport and a rightward shift in the dose-response curve. Both FeS04 (3 microg/mL) and transferrin (100 microg/mL) had similar, although less pronounced effects on insulin-stimulated glucose transport. Treatment of adipocytes with palmitic acid (120 micromol/L), representing the concentration of fatty acids released into the media after 4 hours of serum treatment, did not alter the effect of insulin on glucose transport. We conclude that transferrin and iron induce insulin resistance of glucose transport in adipocytes through a mechanism independent of fatty acids. These findings may further explain the association between body iron stores and risk of type 2 diabetes mellitus.
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PMID:Transferrin and iron induce insulin resistance of glucose transport in adipocytes. 1683 39

The oxidative modification of low-density lipoproteins (LDL) plays a central role in the initiation and acceleration of atherosclerosis. Iron plays a part in the formation of highly toxic free radicals such as hydroxide and superoxide anions, which can induce lipid peroxidation. We investigated whether serum iron status was associated with circulating oxidized LDL (oxLDL) levels in type 2 diabetic patients, in whom oxidative stress and susceptibility to lipid oxidation were supposedly increased. Serum ferritin levels were significantly correlated with plasma oxLDL concentrations in both male and female patients (p<0.02 and p<0.05, respectively). No correlation was detected between ferritin and LDL-cholesterol (LDL-C) concentrations despite the close correlation between LDL-C and oxLDL concentrations (p<0.0001). Stepwise regression analysis showed that ferritin concentration was an independent positive determinant of oxLDL level, in addition to triglyceride concentration, body mass index and sex. This is the first report to show that serum ferritin is associated with circulating oxLDL levels in patients with type 2 diabetes. Further work is required to establish a causative link between iron excess and the development of diabetic vascular complications.
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PMID:Association between serum ferritin and circulating oxidized low-density lipoprotein levels in patients with type 2 diabetes. 1690 60

There are a few reports suggesting that subtle disturbances of iron metabolism are frequently found in patients with type 2 diabetes (DM2), but it is not known if these disturbances precede or accompany the diabetic state. We investigated the serum iron indices in 41 offspring of DM2 parents (group I) with normal glucose tolerance, and in 49 offspring whose parents had no history of DM2 and were matched for sex, age, body mass index (BMI), waist to hip ratio (WHR) and blood pressure (group II). Serum iron, ferritin, total iron binding capacity (TIBC), transferrin saturation, serum triglycerides, cholesterol, Apo-B, high density lipoprotein (HDL) and glucose and insulin values during an oral glucose tolerance test were measured. Insulin resistance was assessed using the homeostasis model assessment (HOMA - Insuline resistence index-IRI). In comparison to controls (group II), the offspring of DM2 subjects (group I) had higher fasting serum triglycerides (mean +/- SD 2.25+/-2.08 vs. 1.6+/-0.8 mmol/L, p<0,05), lower HDL cholesterol (0.96 +/- 0.2 vs. 1.1 +/- 0.2 mmol/L, p<0.001), higher total cholesterol (5.5 +/- 1.1 vs. 5.1 +/- 0.8 mmol/L, p < 0.05), higher apo-B-lipoprotein (133.2+/-34.3 vs. 125.5+/-30.5 mg/dl, p<0.05), higher LDL-C (3.7 +/- 0.8 vs. 3.2 +/- 0.6 mmol/L), higher gamma-GT (28+/-10 vs. 17+/-5.6 iu/L, p<0.01) higher insulin in the Area Under the Curve (204.7+/-140.8 v. 153.1 +/- 63.0 microU/ml, p<0.05) and higher HOMA-IRI (2.84+/-1.39 vs. 1.67+/-0.77, p<0.001), higher serum ferritin concentrations (98.3+/-57.7 vs. 62.0+/-41.1 ng/ml, p<0.01), higher serum iron concentration (20.2+/-6.0 micromol/L vs. 14.5+/-4.3, p<0.001) and higher transferrin saturation index (31.3+/-8.4 vs. 22.6+/-7.3, p<0.0001). By single linear analysis in the offspring of DM2 parents, there was a positive correlation of IRI with transferrin saturation (r=0.400, p<0.01), fibrinogen (r=0.377, p=0.025) and ferritin concentration (r=0.344, p=0.041), and a negative correlation with TIBC (r=-0.477, p < 0.0001), while stepwise multiple regression analysis, IRI showed a positive correlation with fibrinogen (b=0.64, t=3.746, p<0.001), triglycerides (b=0.37, t=2.619, p<0.01) and ferritin (b=0.20, t=1.827, p=0.05). No correlation of IRI, with any of the above parameters was seen in the offspring of normal parents. By logistic regression analysis the parameters characterizing the offspring of parents with DM2 were IRI (OR 14.9 CI 2.4-91.0) serum iron (OR 44.2 CI 6.9-281), TIBC (OR 6.1 CI 1.01-37.0 and gamma-GT (OR 29.6 CI 5.0-174). In conclusion, the data indicate that the iron load, is significantly increased in offspring of DM2 subjects with unaffected glucose tolerance. Furthermore, ferritin concentration is related to insulin resistance. Hence, the relative iron "overload" in offspring of type 2 diabetics is present along with insulin resistance and might worsen the hepatic insulin insensitivity already present in these patients.
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PMID:Relative iron "overload" in offspring of patients with type 2 diabetes mellitus: a new component in the conundrum of insulin resistance syndrome? 1700 17

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

Decreased glucose tolerance is a first sign of diabetes mellitus and therefore rigorous control must be taken in carbohydrate and lipid metabolisms. Herbal remedies (lyophilized extracts of Myrtilli folium and Phaseoli fructus sine seminibus (L1), Myrtilli folium, Phaseoli fructus sine seminibus, and Salviae folium (L2) are traditionally used in mid-European folk medicine and in common adjuvant therapy for the prevention of complications in type 2 diabetes. Significant iron (355.7 +/- 13.8 mg/kg) and zinc (84.73 +/- 1.83 mg/kg) concentration was found in L1 and chromium (3.82 +/- 2.71 mg/kg) in L2. Ion concentrations in teas made from L1 and L2 are relatively low because the quantities of metal ions in teas do not cover the daily need, although the teas are good sources for some elements. According to the Recommended Daily Allowances, the tea of L1 is a good source for iron and manganese, whereas for chromium, the tea of L2 is better. For evaluating the element bioavailability, an in vitro dialysis system was applied to determine the element transfer from tea of the lyophilized sample to the plasma (buffer pH=7.4). Measurements showed that the elements transferred between 6.90% (iron from tea of L2) and 90.05% (chromium from tea of L2) through the membrane from teas to the plasma. Metal ions in teas of herbal remedies might contribute to the favorable therapeutic effect of preventing complications, because they might transfer through the membranes in relatively high percentages.
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PMID:In vitro study of elements in herbal remedies. 1720 97

Red meat intake has been associated with increased risk of coronary heart disease and type 2 diabetes, but it remains uncertain whether these associations are causally related to unprocessed lean red meat. It has been proposed that iron derived from red meat may increase iron stores and initiate oxidative damage and inflammation. We aimed to determine whether an increase in unprocessed lean red meat intake, partially replacing carbohydrate-rich foods, adversely influences markers of oxidative stress and inflammation. Sixty participants completed an 8-wk parallel-designed study. They were randomized to maintain their usual diet (control) or to partially replace energy from carbohydrate-rich foods with approximately 200 g/d of lean red meat (red meat) in isoenergetic diets. Markers of oxidative stress and inflammation were measured at baseline and at the end of intervention. Results are presented as the mean between-group difference in change and [95% CI]. Red meat, relative to control, resulted in: higher protein [5.3 (3.7, 6.9) % of energy], lower carbohydrate [-5.3 (-7.9, -2.7)% of energy], and higher iron [3.2 (1.1, 5.4) mg/d] intakes; lower urinary F2-isoprostane excretion [-137 (-264, -9) pmol/mmol creatinine], lower leukocyte [-0.51 (-0.99, -0.02)x10(9)/L] counts, and a trend for lower serum C-reactive protein concentrations [-1.6 (-3.3, 0.0) mg/L, P=0.06]; and no differences in concentrations of plasma F2-isoprostanes [-12 (-122, 100) pmol/L], serum gamma-glytamyltransferase [-0.8 (-3.2, 1.5) U/L], serum amyloid A protein [-1.4 (-3.4, 0.5) mg/L], and plasma fibrinogen concentrations [-0.08 (-0.40. 0.24) g/L]. Our results suggest that partial replacement of dietary carbohydrate with protein from lean red meat does not elevate oxidative stress or inflammation.
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PMID:Increased lean red meat intake does not elevate markers of oxidative stress and inflammation in humans. 1723 12

The authors performed a case-cohort study nested within the Atherosclerosis Risk in Communities (ARIC) Study to determine the association between plasma ferritin level and risk of type 2 diabetes mellitus. Persons with incident cases of type 2 diabetes diagnosed over an average follow-up period of 7.9 years (n = 599) were compared with a random sample of the cohort (n = 690). After adjustment for age, gender, menopausal status, ethnicity, center, smoking, and alcohol intake, the hazard ratio for diabetes, comparing the fifth quintile of ferritin with the first quintile, was 1.74 (95% confidence interval: 1.14, 2.65; p-trend < 0.001). After further adjustment for body mass index and components of the metabolic syndrome, the hazard ratio was 0.81 (95% confidence interval: 0.49, 1.34; p-trend = 0.87). From a causal perspective, there are two alternative interpretations of these findings. Elevated iron stores, reflected in elevated plasma ferritin levels, may induce baseline metabolic abnormalities that ultimately result in diabetes. Alternatively, elevated ferritin may be just one of several metabolic abnormalities related to the underlying process that ultimately results in diabetes, rather than a causal factor for diabetes. Longitudinal studies with repeated measurements of glucose and iron metabolism parameters are needed to establish the role of iron stores and plasma ferritin in diabetes development.
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PMID:A prospective study of plasma ferritin level and incident diabetes: the Atherosclerosis Risk in Communities (ARIC) Study. 1728 22

Members of the thiazolidinedione (TZD) class of insulin-sensitizing drugs are extensively used in the treatment of type 2 diabetes. Pioglitazone, a member of the TZD family, has been shown to bind specifically to a protein named mitoNEET [Colca JR, McDonald WG, Waldon DJ, Leone JW, Lull JM, Bannow CA, Lund ET, Mathews WR (2004) Am J Physiol 286:E252-E260]. Bioinformatic analysis reveals that mitoNEET is a member of a small family of proteins containing a domain annotated as a CDGSH-type zinc finger. Although annotated as a zinc finger protein, mitoNEET contains no zinc, but instead contains 1.6 mol of Fe per mole of protein. The conserved sequence C-X-C-X(2)-(S/T)-X(3)-P-X-C-D-G-(S/A/T)-H is a defining feature of this unique family of proteins and is likely involved in iron binding. Localization studies demonstrate that mitoNEET is an integral protein present in the outer mitochondrial membrane. An amino-terminal anchor sequence tethers the protein to the outer membrane with the CDGSH domain oriented toward the cytoplasm. Cardiac mitochondria isolated from mitoNEET-null mice demonstrate a reduced oxidative capacity, suggesting that mito- NEET is an important iron-containing protein involved in the control of maximal mitochondrial respiratory rates.
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PMID:MitoNEET is an iron-containing outer mitochondrial membrane protein that regulates oxidative capacity. 1737 63

The two most frequent endocrine complications of hemochromatosis are diabetes mellitus and hypogonadotrophic hypogonadism. Other endocrine disorders related to this disease are very rare and are described especially in the most severe and earliest posttransfusion iron overloads. Endocrine complications are evidence of advanced hemochromatosis, often already associated with cirrhosis. Given the low frequency of HFE mutations in type 2 diabetes, routine genetic testing in this population does not seem reasonable. Testing for iron overload is recommended in subjects with atypical type 2 diabetes (for example, patients who are not overweight) and in cases of hypogonadism, characteristic pigmentation, or cirrhosis. Phlebotomy plays an important role in the management of endocrine complications of hemochromatosis, especially when diagnosis is early. In all cases of hypogonadotrophic hypogonadism, primary hemochromatosis must be considered.
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PMID:[Endocrine consequences of hemochromatosis]. 1752 8


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