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)

To elucidate the mechanisms by which troglitazone, which is a direct ligand for peroxisome proliferator-activated receptor (PPAR) gamma, ameliorates insulin resistance, we have demonstrated that PPAR gamma is expressed in a pancreatic beta cell line, INS-1, using reverse transcription-polymerase chain reaction (RT-PCR). We incubated the cells with 5 micromol/l troglitazone and 1 mmol/l of each major free fatty acid (FFA; palmitic acid, oleic acid, and linoleic acid), alone or in combination, for 48 h. After that, we evaluated glucose-stimulated insulin secretion (GSIS) and 25 mmol/l KCl-induced insulin secretion in the presence of diazoxide, which clamps membrane potential. Our results showed: (1) treatment with troglitazone for 48 h caused enhancement of GSIS, although troglitazone significantly suppressed cell viability assessed by MTT assay. (2) In cells co-treated with troglitazone and FFA, troglitazone ameliorated lipotoxicity due to FFA. (3) In the presence of 300 micromol/l diazoxide and 25 mmol/l KCl, troglitazone did not affect the recovery of GSIS in INS-1 cells. These results suggest that insulin secretion from the rat insulinoma cell line, INS-1, is modulated by troglitazone, acting somewhere in the ATP-sensitive K(+) channel pathway, possibly through PPAR gamma.
Diabetes Res Clin Pract 2002 May
PMID:Troglitazone ameliorates lipotoxicity in the beta cell line INS-1 expressing PPAR gamma. 1189 Oct 15

An enhanced susceptibility to infections is well known to occur in a poorly controlled diabetic state. Since glucose and glutamine are essential for lymphocyte function, we investigated whether their metabolism is changed in lymphocytes obtained from mesenteric lymph nodes of alloxan-induced diabetic rats (40 mg/kg body weight). The activities of hexokinase, phosphofructokinase, glucose-6-phosphate dehydrogenase (G6PDH), citrate synthase and phosphate-dependent glutaminase were determined. Decarboxylation of metabolites [U-14C]-, [1-14C]- and [6-14C]-glucose, [1-14C]- and [2-14C]-pyruvic acid, [U-14C]-palmitic acid and [U-14C]-glutamine was evaluated in incubated lymphocytes isolated from mesenteric lymph nodes. The measurements were carried out in cells following three experimental protocols: (1) lymphocytes freshly obtained from control and alloxan-induced diabetic rats, (2) lymphocytes from insulin-treated (2 U/rat per day) diabetic rats and (3) lymphocytes obtained from control and diabetic rats and cultured in the presence of insulin (1 mU/ml) for 6 h. The activities of hexokinase, G6PDH and citrate synthase were decreased by the diabetic state, whereas that of phosphofructokinase was raised. Decarboxylation of [U-14C]- and [6-14C]-glucose, [1-14C]- and [2-14C]-pyruvate and [U-14C]-glutamine were also decreased in lymphocytes from diabetic rats, whereas [U-14C]-palmitic acid decarboxylation was increased. Insulin administration in vivo or added to the culture medium reversed the changes observed in freshly obtained lymphocytes. Alloxan-induced diabetes did change lymphocyte metabolism and this may be an important mechanism leading to impairment of lymphocyte function.
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PMID:Diabetes causes marked changes in lymphocyte metabolism. 1209 63

Using stable isotopic labeling of dietary fatty acids in conjunction with arteriovenous difference measurements, we have assessed the regulation of lipoprotein lipase-derived fatty acid entrapment in subcutaneous adipose tissue and forearm muscle in healthy subjects in the postprandial state. Eight volunteers fasted overnight and were then given a mixed meal containing [ 1-(13)C]palmitic acid and [1-(13)C]oleic acid. At baseline and for 6 h after the meal, blood samples were obtained from an arterialized hand vein and veins draining subcutaneous abdominal adipose tissue and forearm muscle, and arteriovenous differences were calculated. Entrapment of labeled fatty acids released by circulating triacylglycerol hydrolysis was close to 100% at 60 min, decreasing to 10-30% by 360 min. Entrapment of labeled fatty acids in forearm muscle was >100% and did not change with time. This study shows that entrapment of dietary fatty acids in adipose tissue in the postprandial period is a highly regulated process (varying with time) and that this can be studied in humans using stable isotope- labeled fatty acids in combination with measurement of appropriate arteriovenous differences. Also, fatty acid trapping in skeletal muscle is fundamentally different from that in adipose tissue, in that all the fatty acids released by lipoprotein lipase in skeletal muscle are taken up by the tissue.
Diabetes 2002 Sep
PMID:Regulation of dietary fatty acid entrapment in subcutaneous adipose tissue and skeletal muscle. 1219 59

In this research, it has been aimed to evaluate the improvement effects of alpha lipoic acid (ALA), ascorbic acid-6-palmitate (AA6P), fish oil (FO), and their combination (COM) on some biochemical properties in erythrocytes of streptozotocin (STZ)-induced diabetic male rats. According to experimental results, glutathione (GSH) level in erythrocytes decreased in diabetes (P < 0.01), D + ALA, and D + AA6P groups (P < 0.001). Malonaldehyde (MA) level increased in diabetes (P < 0.05), D + FO, and D + COM groups (P < 0.001), but its level in D + AA6P and D + ALA groups was lower in diabetes group (P < 0.01). Total lipid level in diabetes and diabetes plus antioxidant administered groups were higher than control. Total cholesterol level was high in diabetes and D + ALA groups (P < 0.05), but its level reduced in D + FO compared to control and diabetes groups, P < 0.05, < 0.001, respectively. Total triglyceride (TTG) level was high in the D + ALA (P < 0.05) and D + COM (P < 0.001) groups. In contrast, TTG level in blood of diabetes group was higher than diabetes plus antioxidant and FO administered groups (P < 0.001). According to gas chromatography analysis results, while the palmitic acid raised in diabetes group (P < 0.05), stearic acid in D + FO, D + ALA, and diabetes groups was lower than control (P < 0.05), oleic acid reduced in D + COM and D + FO groups, but its level raised in D + AA6P and D + ALA groups (P < 0.01). As the linoleic acid (LA) elevated in ALA + D, D + AA6P, and diabetes groups, linolenic acid level in diabetes, D + AA6P, and D + FO groups was lower than control (P < 0.001). Arachidonic acid (AA) decreased in D + ALA, D+ AA6P, and diabetes groups (P < 0.01), but its level in D + COM and D + FO was higher than control (P < 0.05). Docosahexaenoic acid (DHA) increased in D + AA6P and D + COM (P < 0.05). While the total saturated fatty acid level raised in diabetes group, its level reduced in D + ALA and D + FO groups (P < 0.05). In contrast, total unsaturated fatty acid level in D + ALA and D + FO groups was higher than control (P < 0.05). In conclusion, present data have confirmed that the combination of the ALA, AA6P, and FO have improvement effects on the recycling of GSSG to reduced GSH in erythrocytes of diabetic rats, and in addition to this, oxidative stress was suppressed by ALA and AA6P, and unsaturated fatty acid degree was raised by the effects of ALA and FO.
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PMID:Effects of alpha lipoic acid, ascorbic acid-6-palmitate, and fish oil on the glutathione, malonaldehyde, and fatty acids levels in erythrocytes of streptozotocin induced diabetic male rats. 1221 Jul 59

There are only few data on skeletal muscle lipid metabolism in diabetes. The aim of the present study was to examine effect of streptozotocin diabetes on incorporation of the blood-borne 14C-palmitic acid into different fractions of skeletal muscle lipids at rest and during contractile activity. The experiments were carried out on male Wistar rats. Streptozotocin was administered intravenously. The control rats received saline. Seven days later, the rats were anaesthetized and the calf muscles of one hindleg were made to contract for 1 min by stimulation of the sciatic nerve with tetanic pulses (30 tetani/min). Thereafter, 14C-palmitic acid was administered intravenously and the stimulation was continued for 5 min. The contralateral resting leg served as a control. Samples of the soleus, red and white gastrocnemius were taken. Lipids were extracted with chloroform/methanol and separated into the following fractions by means of thin layer chromatography: phospholipids, mono-, di-, and triacylglycerols, free fatty acids, cholesterol and cholesterol esters. Radioactivity of each fraction was counted. It has been found, that the label was always incorporated mostly into the fraction of triacylglycerols and phospholipids. Diabetes increased radioactivity of each lipid fraction, both at rest and during contractile activity, comparing to the respective values in the control rats. It is concluded that transport of the blood-borne free fatty acids into the myocytes and their incorporation into different lipid fraction increases in acute diabetes.
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PMID:Effect of diabetes and contractile activity on incorporation of the plasma-borne fatty acids into skeletal muscle lipids. 1253 57

Glucotoxicity and lipotoxicity contribute to the impaired beta-cell function observed in type 2 diabetes. Here we examine the effect of saturated and monounsaturated fatty acids at different glucose concentrations on human beta-cell turnover and secretory function. Exposure of cultured human islets to saturated fatty acid and/or to an elevated glucose concentration for 4 days increased beta-cell DNA fragmentation and decreased beta-cell proliferation. In contrast, the monounsaturated palmitoleic acid or oleic acid did not affect DNA fragmentation and induced beta-cell proliferation. Moreover, each monounsaturated fatty acid prevented the deleterious effects of both palmitic acid and high glucose concentration. The cell-permeable ceramide analogue C(2)-ceramide mimicked both the palmitic acid-induced beta-cell apoptosis and decrease in proliferation. Furthermore, the ceramide synthetase inhibitor fumonisin B1 blocked the deleterious effects of palmitic acid on beta-cell turnover. In addition, palmitic acid decreased Bcl-2 expression and induced release of cytochrome c from the mitochondria into the cytosol, which was prevented by fumonisin B1 and by oleic acid. Finally, each monounsaturated fatty acid improved beta-cell secretory function that was reduced by palmitic acid and by high glucose. Thus, in human islets, the saturated palmitic acid and elevated glucose concentration induce beta-cell apoptosis, decrease beta-cell proliferation, and impair beta-cell function, which can be prevented by monounsaturated fatty acids. The deleterious effect of palmitic acid is mediated via formation of ceramide and activation of the apoptotic mitochondrial pathway, whereas Bcl-2 may contribute to the protective effect of monounsaturated fatty acids.
Diabetes 2003 Mar
PMID:Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. 1260 14

Insulin-resistant states such as obesity can result in an increase in the function and mass of pancreatic beta-cells, so that insulin secretion is up-regulated and Type II diabetes does not develop. However, expansion of beta-cell mass is not indefinite and may well decrease with time. Changes in circulating concentrations of nutritional factors, such as fatty acids and/or glucose, may lead to a reduction in beta-cell mass in vivo. Few previous studies have attempted to explore the interplay between glucose, amino acids and fatty acids with respect to beta-cell mass and functional integrity. In the present study, we demonstrate that culture of clonal BRIN-BD11 cells for 24 h with the polyunsaturated fatty acid arachidonic acid (AA) increased beta-cell proliferation and enhanced alanine-stimulated insulin secretion. These effects of AA were associated with significant decreases in the cellular consumption of D-glucose and L-alanine as well as decreased rates of production of nitric oxide and ammonia. Conversely 24 h exposure to the saturated fatty acid palmitic acid (PA) was found to decrease beta-cell viability (by increasing apoptosis), increase the intracellular concentration of triacylglycerol (triglyceride), while inhibiting alanine-stimulated insulin secretion. These effects of PA were associated with significant increases in D-glucose and L-glutamine consumption as well as nitric oxide and ammonia production. However, L-alanine consumption was decreased in the presence of PA. The effects of AA, but not PA, were additionally dependent on glucose concentration. These studies indicate that AA may have a critical role in maintaining the appropriate mass and function of islet beta-cells by influencing rates of cell proliferation and insulin secretion. This regulatory effect may be compromised by high circulating levels of glucose and/or PA, both of which are elevated in Type II diabetes and may impact upon dysfunctional and apoptotic intracellular events in the beta-cell.
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PMID:Arachidonic acid, palmitic acid and glucose are important for the modulation of clonal pancreatic beta-cell insulin secretion, growth and functional integrity. 1456 Dec 12

Insulin resistance in skeletal muscle in vivo is associated with reduced lipid oxidation and lipid accumulation. It is still uncertain whether changes in lipid metabolism represent an adaptive compensation at the cellular level or a direct expression of a genetic trait. Studies of palmitate metabolism in human myotubes established from control and type 2 diabetic subjects may solve this problem, as genetic defects are preserved and expressed in vitro. In this study, total uptake of palmitic acid was similar in myotubes established from both control and type 2 diabetic subjects under basal conditions and acute insulin stimulation. Myotubes established from diabetic subjects expressed a primary reduced palmitic acid oxidation to carbon dioxide with a concomitantly increased esterification of palmitic acid into phospholipids compared with control myotubes under basal conditions. Triacylglycerol (TAG) content and the incorporation of palmitic acid into diacylglycerol (DAG) and TAG at basal conditions did not vary between the groups. Acute insulin treatment significantly increased palmitate uptake and incorporation of palmitic acid into DAG and TAG in myotubes established from both study groups, but no difference was found in myotubes established from control and diabetic subjects. These results indicate that the reduced lipid oxidation in diabetic skeletal muscle in vivo may be of genetic origin; it also appears that TAG metabolism is not primarily affected in diabetic muscles under basal physiological conditions.
Diabetes 2004 Mar
PMID:Reduced lipid oxidation in skeletal muscle from type 2 diabetic subjects may be of genetic origin: evidence from cultured myotubes. 1498 36

The present investigation was carried out to evaluate the effect of Phaseolus vulgaris, an indigenous plant used in Unani and Ayurvedic medicine in India, on blood glucose, plasma insulin, cholesterol, triglycerides, free fatty acids, phospholipids, and fatty acid composition of total lipids in liver, kidney, and brain of normal and streptozotocin (STZ) diabetic rats. The results show that there was a significant increase in tissue cholesterol, triglycerides, free fatty acids, and phospholipids in STZ diabetic rats. The analysis of fatty acids showed that there was a significant increase in the concentrations of palmitic acid (16:1), stearic acid (18:0), and oleic acid (18:1) in liver, kidney, and brain, whereas the concentrations of linolenic acid (18:3) and arachidonic acid (20:4) were significantly decreased. Oral administration of the aqueous extract of P. vulgaris pods (200 mg/kg of body weight) for 45 days to diabetic rats decreased the concentrations of lipids and fatty acids, viz., palmitic, stearic, and oleic acids, whereas linolenic and arachidonic acids were elevated. Similarly, the administration of P. vulgaris pod extract (PPEt) to normal animals resulted in a significant hypolipidemic effect. These results suggest that PPEt exhibits hypoglycemic and hypolipidemic effects in STZ diabetic rats. It also prevents the fatty acid changes produced during diabetes. The effect of PPEt at 200 mg/kg of body weight was better than that of glibenclamide.
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PMID:Protective role of Phaseolus vulgaris on changes in the fatty acid composition in experimental diabetes. 1529 69

Data obtained with the neutral red cytotoxicity assay reveal that human lens epithelial cells in culture are highly sensitive to low micromolar concentrations of unsaturated, cis-configured fatty acids in the following order: arachidonic acid>linolenic acid=linoleic acid=oleic acid, whereas the saturated fatty acids are much less effective. Though the cytotoxic effects of the unsaturated fatty acids could not be discerned from effects of their oxidation products, the fact that oleic acid is equally cytotoxic as linoleic acid or linolenic acid as well as previously reported findings with bovine lens epithelial cells support the idea that the unsaturated fatty acid molecules directly account for the cytotoxicity and not their products of lipid peroxidation. Bleb formation and cell retraction are early morphological signs of fatty acid-induced lens cell damage. These cellular alterations are accompanied by an aggregation of intermediate filaments in a first step, whereas the disorganization of microfilaments occurs at a later time and only at higher fatty acid concentrations. Measurements of protein-, RNA- and DNA-synthesis turned out to be much less sensitive parameters for the fatty acid-induced damage of lens cells. The uptake rate of linoleic acid by human lens cells is relatively high (4.35 fmol sec(-1) per 1000 cells), 30 and 50% higher as compared with diploid human embryonal lung fibroblasts and chemically transformed mouse fibroblasts, respectively. Saturation kinetics in combination with competition between linoleic acid, oleic acid and palmitic acid on one hand and ineffectiveness of trypsin and DIDS treatment on the other hand hint at cytoplasmic fatty acid binding proteins as receptors with high binding affinity (5.55 micromol l(-1), calculated for the linoleic acid-albumin complex) to be involved in the fatty acid uptake in human lens cells. Cellular fatty acid uptake is mainly influenced by the albumin concentrations present in physiological solutions. Albumin determinations in aqueous humor from 177 cataract patients reveal an age-dependent, statistically significant albumin rise with average values below 2 micromol l(-1) up to the age of 40 years to about 4 micromol l(-1) at the age between 80 and 90 years with single values up to 10 micromol l(-1). Using physiological fatty acid mixtures it is demonstrated that fatty acid-induced lens cell damage is strongly increased by elevated albumin concentrations found in aqueous humor of the elderly, who already have cataracts. Free fatty acid induced lens cell damage as a possible cause for age-dependent cataracts as well as a molecular link between systemic diseases such as diabetes and cataract formation is discussed.
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PMID:Fatty acid cytotoxicity to human lens epithelial cells. 1550 Aug 27


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