scholarly journals Accumulation of diabetic rat peripheral nerve myelin by macrophages increases with the presence of advanced glycosylation endproducts.

1984 ◽  
Vol 160 (1) ◽  
pp. 197-207 ◽  
Author(s):  
H Vlassara ◽  
M Brownlee ◽  
A Cerami
Keyword(s):  
Steady State ◽  
Peripheral Nerve ◽  
Diabetic Rats ◽  
Myelin Proteins ◽  
Diabetic Rat ◽  
Striking Difference ◽  
Nonenzymatic Glycosylation ◽  
Advanced Glycosylation

We have previously shown that increased nonenzymatic glycosylation occurs in peripheral nervous tissue of diabetic humans and animals, primarily on the PO-protein of peripheral nerve myelin. The pathophysiologic mechanism by which this biochemical alteration leads to myelin breakdown and removal is not as yet understood. In the present study we show that advanced glycosylation end-product (AGE) adducts that form during long-term exposure of peripheral nerve myelin proteins to glucose in vitro and in vivo markedly alter the way in which myelin interacts with elicited macrophages. In this interaction, macrophages appear to specifically recognize AGEs on myelin, since AGE-BSA competes nearly as effectively as AGE-myelin, while neither unmodified BSA nor unmodified myelin compete. The failure of yeast mannan to interfere with macrophage recognition of AGE-myelin suggests that the mannose/fucose receptor does not mediate this process. Recognition of AGE-protein by macrophages is associated with endocytosis, as demonstrated by resistance of cell-associated radioactivity to removal by trypsin action, and by low temperature inhibition of ligand accumulation in the cellular fraction. 125I-labeled myelin that had been incubated in vitro with 50 mM glucose for 8 wk reached a steady state accumulation within thioglycolate-elicited macrophages that was five times greater than that of myelin incubated without glucose. Similarly, myelin isolated from rats having diabetes for 1.5-2.0 years duration had a steady state level that was 9 times greater than that of myelin from young rats, and 3.5 times greater than that of myelin from age-matched controls. In contrast, myelin isolated from rats having diabetes for 4-5 wk had the same degree of accumulation observed with myelin of age-matched normal rats. These data suggest that the amount of increased nonenzymatic glycosylation observed in the myelin of short-term diabetic rats had not yet resulted in the significant accumulation of AGE-myelin present both in vitro and in the long-term diabetic rats. The disappearance of acid-insoluble radioactivity from within the cells and the appearance of acid-soluble radioactivity released into the medium were very similar for the two groups, suggesting that the striking difference in accumulation seen between normal myelin and AGE-myelin is due primarily to increased uptake. Formation of irreversible AGE-adducts on myelin appears to promote the recognition and uptake of the modified myelin by macrophages. This interaction between AGE-myelin and macrophages may initiate or contribute to the segmental demyelination associated with diabetes and the normal aging of peripheral nerve.

Regulation of hepatic triiodothyronine production in the streptozotocin-induced diabetic rat

1984 ◽  
Vol 247 (4) ◽  
pp. E526-E533
Author(s):  
A. S. Jennings
Keyword(s):  
Diabetic Rats ◽  
Diabetic Rat ◽  
Isolated Perfused Rat Liver ◽  
Perfused Rat Liver ◽  
Insulin Administration ◽  
Progressive Decline ◽  
Serum T4 ◽  
Fasted Rats

The effect of diabetes on 3,5,3'-triiodothyronine (T3) production was determined in the isolated perfused rat liver. Induction of diabetes with streptozotocin resulted in decreased serum thyroxine (T4) and T3 levels and a progressive decline in hepatic T3 production over 5 days. The decline in T3 production resulted from decreased conversion of T4 to T3, whereas T4 uptake was unchanged. Insulin administration restored serum T4 and T3, hepatic conversion of T4 to T3, and T3 production to normal levels. When serum T4 levels in diabetic rats were maintained by T4 administration, the conversion of T4 to T3 and T3 production returned to control levels. However, restoration of serum T4 levels in fasted rats failed to correct the decrease in hepatic T4 uptake or T3 production. Glucagon, at supraphysiological concentrations in vitro and in vivo, slightly decreased T4 uptake and T3 production without altering the conversion of T4 to T3. These data suggest that the fall in serum T4 levels observed in diabetic rats is important in mediating the decreased hepatic conversion of T4 to T3 and T3 production.

Peritoneal Accumulation of Advanced Glycosylation End-Products in Diabetic Rats on Dialysis with Icodextrin

2000 ◽  
Vol 20 (5_suppl) ◽  
pp. 39-47 ◽  
Author(s):  
Jeong Ho Lee ◽  
Dheerendra K. Reddy ◽  
Rajiv Saran ◽  
Harold L. Moore ◽  
Zbylut J. Twardowski ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Glucose Solution ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Peritoneal Membrane ◽  
Sprague Dawley ◽  
Advanced Glycosylation End Products ◽  
Group I ◽  
End Products ◽  
Advanced Glycosylation

Objective To evaluate and compare the effects of glucose-based solutions to those of icodextrin with respect to peritoneal transport characteristics and formation of advanced glycosylation end-products (AGEs) in the peritoneal membrane in the diabetic rat model of peritoneal dialysis (PD). Study Design Thirty-three male Sprague–Dawley rats weighing between 275 – 300 g were divided into 5 groups: group C ( n = 6), control rats with catheter but not dialyzed; group D ( n = 5), diabetic rats with catheter but not dialyzed; group G ( n = 7), diabetic rats dialyzed with standard 2.5% glucose solution for daytime exchanges and 4.25% glucose solution for the overnight exchange; group H ( n = 8), diabetic rats dialyzed with standard 2.5% glucose solution for daytime exchanges and 7.5% icodextrin solution for overnight exchanges; group I ( n = 7), diabetic rats dialyzed with 7.5% icodextrin solution for all exchanges. Dialysis exchanges were performed three times daily with an instillation volume of 25 mL per exchange for a period of 12 weeks. Tissue sections were stained using a monoclonal anti-AGE antibody. One-hour peritoneal equilibration tests (PET) were performed every 4 weeks for comparison of transport characteristics. Results The level of immunostaining was lowest in group C and highest in group G. Significant differences were seen between group C and groups G, H, and I ( p < 0.001, p = 0.001, and p < 0.05 respectively). Significant differences were also found between group G and groups D and I ( p < 0.05 and p < 0.05 respectively). Over time, glucose concentration at the end of an exchange versus concentration at instillation (D/D0 glucose) decreased and dialysate-to-plasma ratio (D/P) of urea increased. Significant differences were found between groups C and H for D/D0 glucose (0.40 ± 0.01 vs 0.35 ± 0.01, p < 0.05); and between groups C and H for D/P urea (0.87 ± 0.03 vs 0.97 ± 0.02, p < 0.05). Conclusions These results suggest that AGE formation is lower with the use of peritoneal dialysis solution containing icodextrin than with glucose-based solutions. We conclude that the use of icodextrin may be helpful in slowing the deterioration of the peritoneal membrane, prolonging its use for dialysis.

Metabolism of VLDL is increased in streptozotocin-induced diabetic rat hearts

2000 ◽  
Vol 278 (6) ◽  
pp. H1874-H1882 ◽  
Author(s):  
Nandakumar Sambandam ◽  
Mohammed A. Abrahani ◽  
Scott Craig ◽  
Osama Al-Atar ◽  
Esther Jeon ◽  
...  
Keyword(s):  
Lipolytic Activity ◽  
Isolated Heart ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Diabetic Rats ◽  
Diabetic Heart ◽  
Diabetic Rat ◽  
Rat Hearts ◽  
Heparin Plasma

In streptozotocin (STZ)-induced diabetic rats, we previously showed an increased heparin-releasable (luminal) lipoprotein lipase (LPL) activity from perfused hearts. To study the effect of this enlarged LPL pool on triglyceride (TG)-rich lipoproteins, we examined the metabolism of very-low-density lipoprotein (VLDL) perfused through control and diabetic hearts. Diabetic rats had elevated TG levels compared with control. However, fasting for 16 h abolished this difference. When the plasma lipoprotein fraction of density <1.006 g/ml from fasted control and diabetic rats was incubated in vitro with purified bovine or rat LPL, VLDL from diabetic animals was hydrolyzed as proficiently as VLDL from control animals. Post-heparin plasma lipolytic activity was comparable in control and diabetic animals. However, perfusion of control and diabetic rats with heparinase indicated that diabetic hearts had larger amounts of LPL bound to heparan sulfate proteoglycan-binding sites. [3H]VLDL obtained from control rats, when recirculated through the isolated heart, disappeared at a significantly faster rate from diabetic than from control rat hearts. This increased VLDL-TG hydrolysis was essentially abolished by prior perfusion of the diabetic heart with heparin, implicating LPL in this process. These findings suggest that the enlarged LPL pool in the diabetic heart is present at a functionally relevant location (at the capillary lumen) and is capable of hydrolyzing VLDL. This could increase the delivery of free fatty acid to the heart, and the resultant metabolic changes could induce the subsequent cardiomyopathy that is observed in the chronic diabetic rat.

Reversal of nerve damage in streptozotocin-diabetic rats by acute application of insulin in vitro

1988 ◽  
Vol 75 (6) ◽  
pp. 629-635 ◽  
Author(s):  
Geoffrey Burnstock ◽  
Rhona Mirsky ◽  
Abebech Belai
Keyword(s):  
Vasoactive Intestinal Polypeptide ◽  
Calcitonin Gene Related Peptide ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Rat Ileum ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Enteric Nerves ◽  
Intestinal Polypeptide

1. Immunohistochemical, immunoblotting and release experiments were performed on ileum from control rats, from 8-week streptozotocin-diabetic rats and from diabetic rats after acute application of insulin in vitro. 2. There was an increase in vasoactive-intestinal-polypeptide-like and a decrease in calcitonin-gene-related-peptide-like immunoreactivity in the myenteric plexus of the diabetic rat ileum, although electrically evoked release of both peptides from enteric nerves was defective. Acute application of insulin in vitro reversed the defective release and changes in immunoreactivity of vasoactive intestinal polypeptide and calcitonin-gene-related peptide seen in the enteric nerves of streptozotocin-diabetic rat ileum. 3. In addition, using a monoclonal neurofilament antibody RT 97 that recognizes a phosphorylated neurofilament epitope present in normal enteric nerves, it was shown that this phosphorylated neurofilament epitope was absent in diabetic nerves, even though a polyclonal neurofilament antibody revealed that neurofilaments were present in both axons and cell bodies of the myenteric plexus of diabetic rat ileum. After only 2 h of insulin incubation in vitro, the phosphorylated neurofilament epitope was again present in the nerves. 4. It is suggested that the abnormal distribution of phosphorylated neurofilaments and defective storage and release of vasoactive intestinal polypeptide and calcitonin-gene-related peptide in the present study may be a more general feature of diabetes. The restoration of these abnormalities by continuous acute insulin application in vitro shown here suggests that the availability of a steady level of insulin might prevent some of the changes which occur in early stages of diabetes. If so, this could influence the use of insulin in the treatment of diabetes, particularly in view of the recent report that short-term continuous subcutaneous insulin infusion restores the function of the autonomic and peripheral nerves in type I diabetic patients [Krönert, K., Hülsen, J., Luft, D., Stetter, T. & Eggstein, M. (1987) Journal of Clinical Endocrinology and Metabolism, 64, 1219–1223].

AMD3100-Mobilized CD34+ Cells Are Phenotypically Different and Better Targets for Retroviral Transduction Than G-CSF-Mobilized CD34+ Cells in Rhesus Macaques.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2686-2686
Author(s):  
Andre Larochelle ◽  
Allen Krouse ◽  
Donald Orlic ◽  
Robert E. Donahue ◽  
Cynthia E. Dunbar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Steady State ◽  
Genetic Manipulation ◽  
Rhesus Macaques ◽  
Post Transplantation ◽  
Alternative Source ◽  
Cd34 Cells

Abstract AMD3100 (AMD) has recently been shown to rapidly mobilize primitive hematopoietic cells in mice and humans, but little is known about the properties of cells mobilized with this agent. We initiated a study to determine retroviral (RV) in vivo gene marking efficiency in AMD-mobilized CD34+ cells in rhesus macaques. CD34+ cells collected 3 hours after administration of AMD to 2 animals were transduced using RV vectors containing the NeoR gene. Animals were irradiated and cells reinfused immediately after transduction. By molecular analysis, the levels of PB MNC and granulocyte NeoR gene marking at steady-state (up to 12 months post-transplantation) was 1–2% in animal RC909 and 30–40% in RQ2851. In two additional rhesus macaques, CD34+ cells were collected from steady-state BM and from the PB after mobilization with AMD or G-CSF (G). The two PB populations from each animal were transduced with one of two distinguishable NeoR vectors and simultaneously reinfused into irradiated animals. In animal RQ3590, 2% in vivo gene marking at steady-state (up to 4 months post-transplantation) was derived from AMD-mobilized cells compared to 0.05% from the G-mobilized fraction. Animal RQ3636 showed 10% in vivo marking from the AMD-mobilized fraction and no detectable marking from the G-mobilized cells. We also compared phenotypic and functional characteristics of CD34+ cells from BM, AMD-PB and G-PB. An average of 31% of the AMD-mobilized cells were in the Go phase of the cell cycle, compared to 79% of G-mobilized cells (p=0.02), and 45% for the BM fraction (p=0.24). In contrast, 64% AMD-mobilized cells were in G1 compared to 17% of G-mobilized cells (p=0.03) and 44% for the BM fraction (p=0.15). Flow cytometry showed CXCR4 expression on 59% AMD-mobilized cells, in comparison to 11% G-mobilized cells (p=0.02) and 22% BM cells (p=0.07). Similar results were obtained when comparing VLA-4 expression. The increased expression of CXCR4 on AMD-mobilized CD34+ cells correlated with their increased ability to migrate towards SDF-1α in vitro (45%) compared to G-mobilized cells (8%, p=0.01) and BM cells (17%, p=0.08). Our data indicate efficient long-term in vivo gene marking in the rhesus macaque model, validating the ability of AMD to induce mobilization of true long-term repopulating HSCs. AMD-mobilized PB HSCs represent an alternative source of HSCs amenable to genetic manipulation with integrating RV vectors, with potential applications in gene therapy approaches for patients with sickle cell anemia; documented complications have precluded mobilization using G or G/SCF in these patients. Also, cell cycle status and surface phenotype of AMD-mobilized CD34+ cells are more comparable to steady-state BM cells than G-mobilized PB HSCs. AMD-mobilized CD34+ cells are more actively cycling than G-mobilized CD34+ cells, correlating with the increased efficiency of replication-dependent retrovirus-mediated gene transduction. The increased expression of the adhesion receptors CXCR4 and VLA-4 on primitive AMD-mobilized cells compared to G-mobilized cells suggests fundamental differences in the mechanisms of AMD-mediated and cytokine-mediated stem cell mobilization.

scholarly journals Impaired Relaxation in Aorta from Streptozotocin-diabetic Rats: Effect of Aminoguanidine (AMNG) Treatment

2000 ◽  
Vol 1 (2) ◽  
pp. 145-153 ◽  
Author(s):  
Sibel Özyazgan ◽  
Yesim Unlucerci ◽  
Selda Bekpinar ◽  
Ahmet Gökhan Akkan
Keyword(s):  
Drinking Water ◽  
Product Formation ◽  
Diabetic Rats ◽  
Glucose Levels ◽  
Vasoactive Substances ◽  
Blood Glucose Levels ◽  
Body Weights ◽  
Endothelium Dependent Relaxation ◽  
Advanced Glycosylation

AimThe effect of 8 weeks′ streptozotocin (STZ)- induced diabetes and aminoguanidine (AMNG), the inhibitor of advanced glycosylation reaction, treatment on arteriolar reactivity to vasoactive substances was investigatedin vitro.Materials and MethodsStudies were performed in untreated control rats (n= 10), STZ-induced (60 mg/kg i.v.) diabetic rats (n= 10), AMNG-treated (600 mg/l given in drinking water throughout 8 weeks) control rats (n= 10) and AMNG-treated (600 mg/l given in drinking water, beginning at 72h after STZ and throughout 8 weeks of diabetes) diabetic rats (n= 10). Results are expressed as the mean ±s.e. Relaxant responses are expressed as a percentage (%) relaxation of noradrenaline-induced tone. Statistical comparisons were made by one-way analysis of variance (ANOVA) followed by Tukey–Kramer multiple comparisons test.Results1. The decreased body weights (205 ± 6 g) and increased blood glucose levels (583 ± 8 mg/dl) of diabetic rats were partially restored by treatment of aminoguanidine (253 ± 6 g,p< 0.05 and 480 ± 14 mg/dl,p< 0.001, respectively). 2. Diabetes caused a 71% deficit in maximal endothelium-dependent relaxation to acetylcholine for noradrenaline precontracted aortas (p< 0.001). AMNG treatment prevented the diabetes-induced impairment in endothelium dependent relaxation (58 ± 8%) to acetylcholine, maximum relaxation remaining in the non-diabetic range (78 ± 4%). 3. Neither diabetes nor treatment affected endothelium-independent relaxation (pD2and max. Relax.) to sodium nitroprusside. 4. Vasoconstrictor responses (pD2and Max. Contraction) to noradrenaline and KCl were not influenced by the diabetic state and treatment.ConclusionOur data suggest that 8 weeks of experimental diabetes is associated with a decreased endothelium-dependent vasodilatation. AMNG treatment may prevent diabetes-induced endothelial dysfunction. This may be mediatedviathe prevention of advanced glycosylation end product formation, the enhanced release of vasodilator substances such as prostacyclin, the increased elasticity of blood vessels, the antioxidant activity and inhibitor activity of enzyme aldose-reductase by AMNG.

scholarly journals Chitosan-sodium alginate-fatty acid nanocarrier composite: lutein bioavailability, absorption pharmacokinetics in diabetic rat and protection of retinal cells against H2O2 induced oxidative stress in vitro

2020 ◽  
Author(s):  
Veeresh B Toragall ◽  
Baskarn V
Keyword(s):  
Oxidative Stress ◽  
Sodium Alginate ◽  
Mitochondrial Membrane ◽  
Life Time ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Retinal Cells ◽  
Intracellular Ros ◽  
Pre Treatment

Abstract Aiming to enhance therapeutic efficiency of lutein, lutein loaded chitosan-sodium alginate (CS-SA) based nanocarrier composite (LNCs) were prepared and evaluated for lutein bioavailability and pharmacokinetics in diabetic rats in comparison to micellar lutein (control). Further, cytotoxicity, cellular uptake and protective activity against H2O2 induced oxidative stress in ARPE-19 cells were studied. Results revealed that LNCs displayed maximal lutein AUC in plasma, liver and eye respectively in normal (3.1, 2.7 and 5.2 folds) and diabetic (7.3, 3.4 and 2.8 folds) rats. Lutein from LNCs exhibited a higher half-life time, mean residence time and slow clearance from the plasma, indicating prolonged circulation compared to control. In ARPE-19 cells, pre-treatment with LNCs (10 µM) have significantly attenuated H2O2 induced cell death, intracellular ROS and mitochondrial membrane potential compared to control. In conclusion, LNCs improve the lutein bioavailability in conditions like diabetes, diabetic retinopathy and cataract to curtail oxidative stress in retinal cells.

scholarly journals Effects of Type II diabetes on exercising skeletal muscle blood flow in the rat

2010 ◽  
Vol 109 (5) ◽  
pp. 1347-1353 ◽  
Author(s):  
Steven W. Copp ◽  
K. Sue Hageman ◽  
Brad J. Behnke ◽  
David C. Poole ◽  
Timothy I. Musch
Keyword(s):  
Blood Flow ◽  
Steady State ◽  
Type Ii Diabetes ◽  
Blood Glucose Concentration ◽  
Muscle Blood Flow ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Type Ii ◽  
The Individual ◽  
And Control

The purpose of the present investigation was to examine the muscle hyperemic response to steady-state submaximal running exercise in the Goto-Kakizaki (GK) Type II diabetic rat. Specifically, the hypothesis was tested that Type II diabetes would redistribute exercising blood flow toward less oxidative muscles and muscle portions of the hindlimb. GK diabetic ( n = 10) and Wistar control ( n = 8, blood glucose concentration, 13.7 ± 1.6 and 5.7 ± 0.2 mM, respectively, P < 0.05) rats were run at 20 m/min on a 10% grade. Blood flows to 28 hindlimb muscles and muscle portions as well as the abdominal organs and kidneys were measured in the steady state of exercise using radiolabeled 15-μm microspheres. Blood flow to the total hindlimb musculature did not differ between GK diabetic and control rats (161 ± 16 and 129 ± 15 ml·min−1·100g−1, respectively, P = 0.18). Moreover, there was no difference in blood flow between GK diabetic and control rats in 20 of the individual muscles or muscle parts examined. However, in the other eight muscles examined that typically are comprised of a majority of fast-twitch glycolytic (IIb/IIdx) fibers, blood flow was significantly greater (i.e., ↑31–119%, P < 0.05) in the GK diabetic rats. Despite previously documented impairments of several vasodilatory pathways in Type II diabetes these data provide the first demonstration that a reduction of exercising muscle blood flow during submaximal exercise is not an obligatory consequence of this condition in the GK diabetic rat.

In vivo and in vitro resistance to maximal insulin-stimulated glucose disposal in insulin deficiency

1985 ◽  
Vol 249 (3) ◽  
pp. E312-E316 ◽  
Author(s):  
E. Dall'Aglio ◽  
H. Chang ◽  
C. B. Hollenbeck ◽  
C. E. Mondon ◽  
C. Sims ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glucose Transport ◽  
Diabetic Rats ◽  
Glucose Disposal ◽  
Diabetic Rat ◽  
Insulin Deficiency ◽  
Fat Cell ◽  
Total Body

The effect of streptozotocin-induced diabetes mellitus on maximal insulin-stimulated glucose uptake in the rat was studied in isolated adipocyte, perfused hindlimb, and the intact organism. Basal glucose transport per fat cell was reduced by approximately two-thirds (P less than 0.001), being associated with a similar decrease in glucose oxidation per fat cell (P less than 0.001). There was also a significant decrease (P less than 0.001) in basal glucose uptake by perfused hindlimb of diabetic rats of approximately 40%. Furthermore, maximal insulin-stimulated glucose transport and oxidation were approximately 50% lower (P less than 0.001) in fat cells of diabetic as compared with control rats. In contrast, maximal insulin-stimulated glucose disposal by perfused hindlimbs from diabetic and control rats was similar, and this was also true of the ability of insulin to maximally stimulate glucose uptake in the intact normal and diabetic rat. These findings indicate that variation exists in the manner in which insulin-sensitive tissues respond to experimentally induced insulin deficiency and support the view that total body glucose disposal is primarily related to insulin action on muscle.

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