| 1. |
- Agardh, Daniel, et al.
(författare)
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HLA-DQB1*0201/0302 is associated with severe retinopathy in patients with IDDM
- 1996
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 39:11, s. 1313-1317
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Tidskriftsartikel (refereegranskat)abstract
- Some insulin-dependent diabetic (IDDM) patients develop severe forms of retinopathy. Putative risk factors such as hypertension, poor metabolic control, nephropathy and growth hormone levels do not fully explain the progress of retinopathy in these patients. It has been discussed whether there is a genetic marker, since some diabetic patients without any known predisposing risk factors develop severe retinopathy and others do not. In the present study, HLA-DR and DQ were compared in two patient groups with IDDM. One group consisted of patients with early-onset diabetes, with severe non-proliferative or proliferative retinopathy; the other group had no or only mild signs of retinopathy. High resolution HLA typing was carried out by polymerase chain reaction (PCR) and hybridization with allele specific probes. Alleles on the DR3-DQ2 haplotype, DRB1*0301, DQA1*0501 and DQB1*0201, were more frequent in patients with severe retinopathy. A difference was seen when combining certain alleles in the genotypes of DQA1*03/0501 (p > 0.05) and DQB1*0201/0302 (p < 0.01). The findings of the present study suggest that DQB1*0201/0302 is the strongest genetic marker for severe retinopathy and DRB1*0301/0401 only has a secondary influence when combined with this genotype. It seems as if IDDM patients who are positive for the genotype DR3-DQ2/DR4-DQ8 (DRB1*0301-DQA1*0501-DQB1*0201/DRB1*0401 -DQA1*03-DQB1*0302) are at greater risk of developing severe retinopathy.
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| 2. |
- Agardh, Daniel, et al.
(författare)
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Inverse relationship between GAD65 antibody levels and severe retinopathy in younger type 1 diabetic patients
- 1998
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Ingår i: Diabetes Research and Clinical Practice. - 1872-8227. ; 40:1, s. 9-14
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Tidskriftsartikel (refereegranskat)abstract
- Several risk factors for severe non-proliferative and proliferative retinopathy in type 1 diabetes mellitus have been proposed without explaining the rapid progression of retinopathy in some patients. Since GAD65 autoantibodies (GAD65Abs) are detected against glutamic acid decarboxylase (GAD), which is mainly expressed in islets and nervous tissue in type 1 diabetic patients, the aim of the present investigation was to test the hypothesis whether GAD65Abs are associated with rapidly progressing severe retinopathy. Patients with severe non-proliferative or proliferative retinopathy (n = 27) were compared with another group, which in spite of long diabetes duration had no or only mild signs of retinopathy (n = 28). GAD65Abs were analysed in a radioimmunoassay using in vitro translated human GAD65, and the levels were expressed as an index in relation to positive and negative reference samples. Using a cut-off level representing the 99th percentile of normals, 6/27 (22%) with and 9/28 (32%) without severe retinopathy were considered GAD65Ab positive. Although there was no difference in the number of GAD65Ab positive patients, the GAD65Ab levels were lower in patients with (0.30; 0.11-0.64) than without (0.68; 0.34-1.12) severe retinopathy (P = 0.03). The patients were also subjected to HLA-DR and DQ typing by PCR and hybridization with oligospecific probes. DQ2/8 was more common in patients with (56%) than without (29%) severe retinopathy (P = 0.05), but DQ2/8 could not account for the lower GAD65Ab levels in patients with severe retinopathy. It is concluded that GAD65Ab levels are inversely correlated with severe retinopathy in young type 1 diabetic patients.
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| 3. |
- Agardh, Carl-David, et al.
(författare)
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Altered endothelial/pericyte ratio in Goto-Kakizaki rat retina
- 1997
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Ingår i: Journal of Diabetes and its Complications. - 1873-460X .- 1056-8727. ; 11:3, s. 158-162
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Tidskriftsartikel (refereegranskat)abstract
- The Goto-Kakizaki (GK) rat represents a model of hereditary non-insulin-dependent diabetes mellitus (NIDDM), characterized by nonobesity, mild hyperglycemia from early life, impaired glucose tolerance test results, and a markedly defective insulin response to glucose. The rats develop signs of both nephropathy and neuropathy, but, to our knowledge, retinal changes have not been reported so far in this model of NIDDM. Hence, the aim of the present study was to assess whether morphological vascular changes could be demonstrated in retinal vessel preparations of GK rats. The endothelial/pericyte ratio was found to be higher in GK rats aged 8 months as well as after 24-30 months compared to their matched controls (2.3 +/- 0.2 versus 2.0 +/- 0.1; p < 0.01, and 2.6 +/- 0.2 versus 1.9 +/- 0.1; p < 0.001, respectively). Furthermore, in 24 to 30-months-old GK rats, the endothelial/pericyte ratio was higher than in 8 month old GK rats (p < 0.05). Thus, the GK rat appears to be a suitable model for experimental studies of chronic complications, including diabetic retinopathy, in NIDDM.
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| 4. |
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| 5. |
- Agardh, Carl-David, et al.
(författare)
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Association between urinary N-acetyl-beta-glucosaminidase and its isoenzyme patterns and microangiopathy in type 1 diabetes mellitus
- 1991
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Ingår i: Clinical Chemistry. - 0009-9147. ; 37:10 Pt 1, s. 1696-1699
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Tidskriftsartikel (refereegranskat)abstract
- Urinary N-acetyl-beta-glucosaminidase (NAG) and its isoenzymes (NAG A and NAG B) in samples from 87 type 1 diabetic patients and 40 apparently healthy reference subjects were studied with enzyme immunoassays. The diabetic patients had higher concentrations of urinary NAG than did the control subjects (P less than 0.01), but the isoenzyme pattern did not differ. There was a positive correlation between metabolic control (Hb A1c concentrations) and total NAG (P less than 0.01), NAG A (P less than 0.01), and NAG B (P less than 0.001). The diabetic patients were divided into three groups, depending on the degree of retinopathy. Subjects with severe forms of retinopathy did not have increased concentrations of urinary NAG unless they had concomitant nephropathy. The isoenzyme pattern was similar irrespective of degree of retinopathy or nephropathy. The results indicate that concentrations of urinary NAG are positively correlated to the degree of nephropathy, whereas there is no such correlation to the degree of retinopathy.
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| 6. |
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| 7. |
- Agardh, Carl David, et al.
(författare)
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Effects of inhibition of glycation and oxidative stress on the development of diabetic nephropathy in rats.
- 2002
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Ingår i: Journal of Diabetes and its Complications. - 1873-460X. ; 16:6, s. 395-400
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Tidskriftsartikel (refereegranskat)abstract
- We investigated whether aminoguanidine (AG), an inhibitor of advanced glycated end product formation, or probucol (PB), a free radical scavenger, could influence signs of glomerular and distal tubular function and morphological changes in kidneys of male Wistar rats after 6 months of streptozocin (STZ)-induced diabetes. Diabetic rats had a higher kidney weight/body weight ratio (P<.001), but neither AG nor PB influenced the increased ratio. Diabetes caused an increased urinary albumin excretion (P<.05), which was normalized by AG, but further exaggerated by PB (P<.001). Diabetes also caused an increase in the urinary excretion of Tamm–Horsfall protein (P<.001). Both AG and PB attenuated this increase (P<.05 for both). A few glomeruli displayed focal thickening of varying degrees. Silver staining disclosed the glomerulopathy to be intercapillary glomerulosclerosis. Rats on PB-enriched diet displayed less pronounced changes than untreated rats (P<.01), while AG had no effect. The results suggest that oxidative stress could be involved in the development of diabetic nephropathy.
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| 8. |
- Agardh, Carl-David, et al.
(författare)
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Expression of antioxidant enzymes in rat retinal ischemia followed by reperfusion.
- 2006
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Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600. ; 55:7, s. 892-898
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate the expression and protein levels of antioxidant enzymes in the rat retina exposed to oxidative stress induced by ischemia-reperfusion injury. Retinal ischemia was induced in female Wistar rats by ligation of the optic nerve and vessels behind the left eye bulb, and was followed by reperfusion for 0, 3, 6, or 24 hours. The right eye served as control. RNA and protein were extracted simultaneously from each retina. Expressions of the endogenous antioxidant enzymes glutathione peroxidase (GPx1), catalase (CAT), copper/zinc superoxide dismutase, manganese superoxide dismutase, and the catalytic subunit of glutamylcysteine ligase (GCLc) were analyzed with real-time reverse transcription polymerase chain reaction and related to the endogenous control cyclophilin B. Protein levels were measured with Western blot analysis. During the early phase (0 or 3 hours) of reperfusion, no changes were seen in enzyme expression. After 6 hours, GCLc expression increased by a factor of 1.14 (P =.034), followed by a decline of 0.80 after 24 hours (P =.00004), according to the comparative Ct method. After 24 hours of reperfusion, GPx1 expression increased by a factor of 1.14 (P =.028), and CAT had decreased by 0.82 (P =.022). Expressions of copper/zinc superoxide dismutase and manganese superoxide dismutase showed a tendency toward a decrease by factors of 0.86 (P =.055) and 0.88 (P =.053), respectively, after 24 hours. Protein levels did not differ for any of the antioxidants, regardless of reperfusion time. The slightly increased messenger RNA expression of GPx1 after 24 hours of reperfusion with a concomitant very modest decrease in CAT and GCLc expression and no change in protein levels indicate a very modest, if any, response to oxidative stress generated by ischemia followed by reperfusion in rat retina.
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| 9. |
- Agardh, Carl-David, et al.
(författare)
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Glutathione levels are reduced in diabetic rat retina but are not influenced by ischemia followed by recirculation
- 1998
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Ingår i: Metabolism, Clinical and Experimental. - 1532-8600. ; 47:3, s. 269-272
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Tidskriftsartikel (refereegranskat)abstract
- Free radicals have recently been proposed to play a role in the development of diabetic retinopathy. The aim of the present study was to examine whether the abnormal metabolism caused by diabetes and by ischemia followed by recirculation interferes with a free radical enzyme defense system in the retina, ie, glutathione. Diabetes mellitus was induced by injecting streptozotocin ([STZ] 60 mg/kg body weight [BW] intraperitoneally). After 2 and 6 months, respectively, glutathione levels were measured in the retina and compared against those of age-matched normal control rats. Retinal ischemia was induced by careful ligation of the vessels and the accompanying optic nerve behind the left eye bulb. The right eye served as a control. After 90 minutes of ischemia, retinal circulation was reestablished by removing the ligature. Two-month-old diabetic rats were kept for an additional 3 days and normal rats for 5 minutes, 15 minutes, or 3 days before they were killed for measurement of glutathione. Retinal levels of glutathione were significantly lower in 6-month diabetic compared with 2-month diabetic rats (16.6 +/- 2.9 v 19.0 +/- 2.2 nmol/mg protein, P < .05) and 6-month normal control rats (16.6 +/- 2.9 v 21.0 +/- 2.1 nmol/mg protein, P < .001). Ischemia followed by recirculation did not influence the total tissue level of glutathione either in 2-month-old diabetic rats or in normal rats. The present study indicates that the abnormal metabolism caused by diabetes, rather than by changes in retinal circulation, results in an impaired defense mechanism against free radicals, a factor that may be of importance for the development of diabetic retinopathy. However, since glutathione levels in the present study were measured in the whole retina, it cannot be excluded that particular cell types, such as vascular cells, show an alteration in glutathione that is masked by the glutathione levels in the other nonvascular cells of the retina. Studies using other techniques are needed to further explore this subject.
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| 10. |
- Agardh, Carl-David, et al.
(författare)
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Growth hormone levels in the basal state and after thyrotropin-releasing hormone stimulation in young type 1 (insulin-dependent) diabetic patients with severe retinopathy
- 1992
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Ingår i: Diabetes Research (Edinburgh, Scotland). - 0265-5985. ; 19:2, s. 81-85
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Tidskriftsartikel (refereegranskat)abstract
- Sixteen young patients with type 1 diabetes mellitus and rapidly progressive severe retinopathy were examined regarding serum levels of growth hormone before and after the i.v. administration of 200 micrograms thyrotropin-releasing hormone (TRH). Serum IGF I, HbA1c, blood pressure, urinary albumin, and serum creatinine levels were also measured. The control group consisted of type 1 diabetic patients matched for age, duration of diabetes and metabolic control with no or minimal background retinopathy. The results show that basal growth hormone levels were above normal in both groups, and that there was a paradoxical increment in growth hormone levels after TRH stimulation (p < 0.05) in patients with severe retinopathy, but the values did not differ from patients with background retinopathy. IGD I levels were normal in all patients but one, and no differences were seen between the two groups. HbA1c, serum creatine, blood pressure, and urinary albumin levels were similar in the groups but patients with severe retinopathy were treated with more insulin (p < 0.001). Thus, neither abnormal growth hormone levels, nor IGF I, seems to be associated with the development of severe retinopathy in young type 1 diabetic patients.
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