| 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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| 11. |
- Agardh, Carl-David, et al.
(författare)
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Irreversible progression of severe retinopathy in young type I insulin-dependent diabetes mellitus patients after improved metabolic control
- 1992
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Ingår i: Journal of Diabetes and its Complications. - 1873-460X. ; 6:2, s. 96-100
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Tidskriftsartikel (refereegranskat)abstract
- The impact of metabolic control on the development of rapidly progressive severe retinopathy was studied in 14 young type I insulin-dependent diabetes mellitus (IDDM) patients. Glycosylated hemoglobin (HbAlc) levels 45 months prior to and 12 months after the diagnosis of retinopathy were compared with HbAlc levels in 17 type I IDDM patients with no or minimal background retinopathy, matched for age and duration of diabetes. HbAlc levels were generally higher in patients with severe retinopathy (p less than 0.05) from 39 months until 6 months before the diagnosis of retinopathy. Thereafter, there was a gradual decrease in HbAlc levels reaching the same level as in control patients 6 months after diagnosis of retinopathy. Patients with severe retinopathy required higher doses of insulin prior to the diagnosis of retinopathy (p less than 0.05), but the insulin requirement decreased, and 12 months afterward, the insulin dosage was similar to patients with background retinopathy. Systolic blood pressure levels were slightly increased and higher in patients with severe retinopathy compared with control patients from 18 months before to diagnosis of retinopathy (p less than 0.05). Diastolic blood pressure levels likewise differed at 18 and 12 months before and at the time of diagnosis of retinopathy as well as 12 months afterward (p less than 0.05); however, no differences were seen in urinary albumin or serum creatinine levels between the groups. Thus, years of poor metabolic control, drastically improved, preceded the development of irreversible severe retinopathy in these young type I IDDM patients.
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| 12. |
- Agardh, Carl-David, et al.
(författare)
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Lack of association between plasma homocysteine levels and microangiopathy in type 1 diabetes mellitus
- 1994
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 54:8, s. 637-641
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Tidskriftsartikel (refereegranskat)abstract
- The reactive vascular-injuring amino acid homocysteine was previously shown to be increased in plasma in diabetic patients with clinical signs of nephropathy. In this study, plasma homocysteine was measured in type 1 diabetic patients with normoalbuminuria (n = 22), microalbuminuria (n = 40) and proteinuria (n = 14) in order to investigate whether plasma homocysteine levels are increased already at the stage of incipient nephropathy, i.e. microalbuminuria. Furthermore, patients were characterized according to the degree of retinopathy. Plasma homocysteine in the whole population (n = 76) was related to B-Folate (r = 0.38, p < 0.01), S-Creatinine (r = 0.55, p < 0.001), S-Urea (r = 0.37, p < 0.01), U-Albumin (r = 0.46, p < 0.001), urinary N-acetyl-beta- glucosaminidase (r = 0.40, p < 0.001), systolic blood pressure (r = 0.36, p < 0.01) and diabetes duration (r = 0.44, p < 0.001). There were no differences in plasma homocysteine levels between patients with normoalbuminuria (8.0 +/- 1.7 mumol l-1; mean +/- SD) and those with microalbuminuria (9.1 +/- 3.4 mumol l-1). However, patients with clinical signs of nephropathy had higher plasma homocysteine levels (12.9 +/- 5.7 mumol l-1, p < 0.01) compared to the other two groups. There was no association between plasma homocysteine levels and different degrees of retinopathy. Thus, the present study does not show any relation between plasma homocysteine levels and early stages of diabetic nephropathy or retinopathy indicating that elevated concentrations of plasma homocysteine does not explain the increased risk for atherosclerosis observed in patients with microalbuminuria.
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| 13. |
- Agardh, Carl-David, et al.
(författare)
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Lack of relationship between beta-hexosaminidase activity and retinopathy in insulin dependent diabetics
- 1987
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Ingår i: Clinica Chimica Acta. - : Elsevier BV. - 0009-8981. ; 167:1, s. 37-42
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Tidskriftsartikel (refereegranskat)abstract
- Beta-hexosaminidase activity in plasma and urine was measured and compared in insulin dependent diabetics (IDDM) with and without proliferative retinopathy. No difference in the activity of beta-hexosaminidase was found between the two groups indicating that this enzyme is not involved in the development of diabetic microangiopathy.
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| 14. |
- Agardh, Carl-David, et al.
(författare)
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Long-standing hyperglycemia in C57BL/6J mice does not affect retinal glutathione levels or endothelial/pericyte ratio in retinal capillaries
- 2000
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Ingår i: Journal of Diabetes and its Complications. - 1873-460X. ; 14:3, s. 146-153
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Tidskriftsartikel (refereegranskat)abstract
- Free radicals have been suggested to play a role in the development of diabetic retinopathy. The aim of the present study was to examine whether the metabolic perturbations caused by high-fat feeding of two strains of mice, the C57BL6/J mice and the NMRI mice, interfere with one of the free radical enzyme defense systems in the retina, i. e., glutathione (GSH), and whether morphological changes occur in the retinal vessels. C57BL/6J mice and NMRI mice were fed a high-fat diet (55%) for 18 months. High-fat fed mice of both strains developed overweight, hyperinsulinemia, and hyperlipidemia. In addition, the high-fat fed C57BL/6J mice also developed sustained hyperglycemia for at least 15 months. The C57BL/6J mice had lower retinal GSH levels than the NMRI mice, both when given a normal diet (29.6+/-1.2 vs. 37.1+/-1.4 nmol/mg protein; p<0.01) and when given a high-fat diet (27.0+/-1.6 vs. 34.7+/-2.6 nmol/mg protein; p<0.05). Despite the long-standing hyperglycemia, hyperinsulinemia and hyperlipidemia in the C57BL/6J mice, high-fat feeding did not cause any changes in the retinal tissue levels of GSH (27.0+/-1.6 vs. 29. 6+/-1.2 nmol/mg protein) or cysteine (7.61+/-0.63 vs. 6.80+/-0.59 nmol/mg protein). Similarly, high-fat feeding did not affect retinal GSH or cysteine levels in NMRI mice. No light microscopical retinal vessel changes were seen, either in C57BL/6J or in NMRI mice. The study therefore shows that long-standing metabolic perturbations induced by dietary obesity do not induce signs of retinopathy in two different strains of mice. Further studies are needed to explore whether this is explained by increased expression of protecting systems making these strains of mice resistant to effects of oxidative stress.
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| 15. |
- Agardh, Carl-David, et al.
(författare)
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Optic disc swelling in an insulin-dependent diabetic. A result of drastic improvement of glucose control?
- 1988
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Ingår i: Acta Ophthalmologica. - 0001-639X. ; 66:2, s. 206-209
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Tidskriftsartikel (refereegranskat)abstract
- Rapid improvement of glucose control in diabetics may cause a transient progression of ischemic retinopathy. We report a transient bilateral acute asymptomatic optic disc swelling associated with rapid improvement of metabolic control in a male Type I diabetic. It is d, suggested that the optic disc swelling could be caused n of by a rapid near-normal normalization of the blood glucose.
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| 16. |
- Agardh, Carl-David, et al.
(författare)
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Plasma lipids and plasma lipoproteins in diabetics with and without proliferative retinopathy
- 1988
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Ingår i: Acta Medica Scandinavica. - 0001-6101. ; 223:2, s. 165-169
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Tidskriftsartikel (refereegranskat)abstract
- The single most important factor related to the development of diabetic retinopathy is the duration of diabetes. Little is known about the underlying mechanisms, but many factors have been suggested to be involved, among them derangements in plasma lipids and plasma lipoproteins. In the present study we examined the relation between plasma lipids, plasma lipoproteins, and the duration of diabetes in Type I diabetics with and without proliferative retinopathy. The duration of diabetes in the two groups was 12.2 +/- 2.8 and 21.5 +/- 9.0 years, respectively (mean +/- SD; p less than 0.01). Except for moderately low HDL levels, plasma lipid and lipoprotein concentrations were normal in both groups of patients. The levels of lipids and lipoproteins did not correlate with the duration of diabetes. Furthermore, no differences were seen between patients with and without proliferative retinopathy. Thus, the present study does not indicate that plasma lipids and plasma lipoproteins play any major role in the development of diabetic proliferative retinopathy.
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| 17. |
- Agardh, Carl-David, et al.
(författare)
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Platelet aggregation in type I diabetics with and without proliferative retinopathy
- 1987
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Ingår i: Acta Ophthalmologica. - 0001-639X. ; 65:3, s. 358-362
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Tidskriftsartikel (refereegranskat)abstract
- The cause of retinopathy in diabetes mellitus is unknown. Among factors suggested to be involved in the development of retinopathy is altered platelet function. In the present study, platelet aggregation was measured in vitro after stimulation with adenosine diphosphate (ADP) and collagen in patients with and without proliferative retinopathy. The results show that patients with proliferative retinopathy have an increased platelet aggregation in vitro after stimulation with collagen and ADP. However, the increased platelet aggregation was also found to be correlated to the duration of diabetes. Thus, the present study does not support the opinion that abnormal platelet function can be regarded as a primary cause of diabetic retinopathy. Increased platelet aggregation seems to be coupled to the duration of diabetes and to still unknown factors developing with prolonged duration of the disease.
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| 18. |
- Agardh, Carl-David, et al.
(författare)
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The Aldose Reductase Inhibitor Fidarestat Suppresses Ischemia-Reperfusion-Induced Inflammatory Response in Rat Retina.
- 2009
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Ingår i: Pharmacology. - : S. Karger AG. - 1423-0313 .- 0031-7012. ; 84:5, s. 257-263
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies suggest that increased aldose reductase (AR) activity plays an important role in ischemia-reperfusion injury in the retina. The mechanisms are not completely understood, but may be linked to inflammation. In the present study, we investigated whether the AR inhibitor fidarestat suppressed the retinal inflammatory response induced by ischemia-reperfusion in a rat model. The inflammatory response was manifested by increased gene expression of tumor necrosis factor-alpha and intercellular adhesion molecule-1 (ICAM-1) as well as elevated protein levels of soluble ICAM-1. This response was partially suppressed by the AR inhibitor fidarestat. The findings may reveal beneficial effects of AR inhibition on retinal inflammation associated with ischemia-reperfusion and are in agreement with recent developments in pharmacological research suggesting that pathological conditions other than diabetes may benefit from AR inhibitors.
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| 19. |
- Agardh, Carl-David, et al.
(författare)
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The association between retinopathy, nephropathy, cardiovascular disease and long-term metabolic control in type 1 diabetes mellitus: a 5 year follow-up study of 442 adult patients in routine care
- 1997
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Ingår i: Diabetes Research and Clinical Practice. - 1872-8227. ; 35:2-3, s. 113-121
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to examine mean HbA1c and blood pressure levels during a 5 year period in 442 type 1 adult diabetic patients in relation to the incidence and progression of retinopathy, nephropathy and to cardiovascular morbidity and mortality. The study showed, that in patients under routine care at a diabetic unit with four visits to the out-patient clinic per year, the intraindividual coefficient of variation for HbA1c values was 11 +/- 4% (mean +/- S.D.), and 7 +/- 3 and 8 +/- 2% for systolic and diastolic blood pressure, respectively. In 121 patients without retinopathy at entry, the 5 year incidence of any retinopathy was 47% (n = 57). Patients who developed retinopathy had higher mean HbA1c levels (P < 0.01), as well as mean systolic (P < 0.01) and diastolic (P < 0.05) blood pressure levels. In 123 patients with background retinopathy at entry, progression to severe retinopathy, i.e. clinically significant macular oedema, severe non-proliferative or proliferative retinopathy, occurred in 41% (n = 51). In those patients, the degree of metabolic control was worse (P < 0.001), the systolic (P < 0.05) and diastolic (P < 0.01) blood pressure levels were higher. The patients were stratified into four groups according to their urinary albumin concentration at entry: (1) normal albuminuria (< 12.5 mg/l), (2) borderline albuminuria (12.5-30 mg/l), (3) microalbuminuria (31-299 mg/l), i.c. incipient nephropathy and (4) clinical nephropathy (> or = 300 mg/l). An increase of urinary albumin concentration in patients who had normoalbuminuria or borderline albuminuria at entry was associated with mean HbA1c levels (r = 0.24, P < 0.01 and r = 0.27, P < 0.01, respectively). No such association was seen in patients with microalbuminuria or clinical nephropathy at entry. There was no association between the increase of urinary albumin level and mean systolic blood pressure levels in patients who had normoalbuminuria and microalbuminuria at entry. In contrast, there was an association between the increase of urinary albumin level in patients with borderline albuminuria (r = 0.36, P < 0.001), clinical nephropathy (r = 0.26, P < 0.05) and mean systolic blood pressure (P < 0.05). There was no association between the increase of urinary albumin levels and mean diastolic blood pressure in any of the albuminuria groups. As for the incidence of cardiovascular disease, renal insufficiency or death, the duration of diabetes (P < 0.01), urinary albumin concentration at entry (P < 0.001), mean systolic blood pressure (P < 0.05) and treatment with loop diuretics (P < 0.001) were but age, age at onset of diabetes, mean levels of HbA1c and diastolic blood pressure as well as treatment with beta- or Ca-blockers or ACE inhibitors were not related to these end-points. In conclusion, the present study showed that there was an association between the degree of metabolic control and both development and progression of retinopathy and progression of nephropathy of early stages in type 1 diabetic patients treated under routine conditions. Moreover, both the incidence and progression of retinopathy and progression of nephropathy at later stages were also associated with the long-term blood pressure levels. However, HbA1c levels were not associated with morbidity and mortality in cardiovascular disease or development of renal insufficiency.
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| 20. |
- Agardh, Carl-David, et al.
(författare)
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The glutathione levels are reduced in Goto-Kakizaki rat retina, but are not influenced by aminoguanidine treatment
- 1998
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Ingår i: Current Eye Research. - : Informa UK Limited. - 0271-3683 .- 1460-2202. ; 17:3, s. 251-256
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To examine the levels of the free radical protecting enzyme glutathione and the endothelial/pericyte ratio in retinal capillaries in the Goto-Kakizaki (GK) Wistar rat, with and without aminoguanidine treatment. METHODS: Eight-month-old GK rats, with non-obese, spontaneous non-insulin-dependent diabetes mellitus (NIDDM), were examined after a six month period of aminoguanidine treatment. Glutathione levels were measured with high performance liquid chromatography and the endothelial/pericyte ratio was calculated in trypsin digested vessel preparations. RESULTS: The levels of glutathione in GK rat retina were significantly lower compared to controls (p = 0.0108). There was no difference in the endothelial/pericyte ratio compared to matched control rats (1.8 +/- 0.2 vs. 1.8 +/- 0.1, respectively). Aminoguanidine treatment did not influence either the degree of hyperglycemia, the levels of glutathione or the endothelial/pericyte ratio in GK or control rat retina. CONCLUSIONS: The results indicate that impaired glucose metabolism may influence one of the defense mechanisms for oxidative stress, but also suggest that decreased glutathione levels occur prior to morphological signs of pericyte loss and/or endothelial cell proliferation in this animal model of hereditary NIDDM.
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| 21. |
- Agardh, Carl-David, et al.
(författare)
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The prognostic value of albuminuria for the development of cardiovascular disease and retinopathy: a 5-year follow-up of 451 patients with type 2 diabetes mellitus
- 1996
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Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 1872-8227 .- 0168-8227. ; 32:1-2, s. 35-44
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to evaluate the risk for vascular morbidity or death and retinopathy in relation to urinary albumin concentration. To that end, we performed a 5-year follow-up study of all type 2 diabetic patients attending the outpatient-clinic. A total of 444 (98.4%) out of 451 adult patients initially studied were evaluated for the degree of retinopathy and levels of HbA1c blood pressure, serum creatinine and urinary albumin. Vascular morbidity and causes of death were registered by one and the most severe event only. Forty-seven patients developed atherosclerotic vascular disease, i.e. myocardial infarction (n = 19), cerebrovascular disease (n = 20), or amputation (n = 8), and 42 died. The observed annual mortality rate was 22.1/1000 compared to an expected rate of 13.6/1000 for the general population with corresponding age and sex. Urinary albumin concentration was found to be a prognostic marker for the development of vascular disease and death in patients treated with insulin at baseline (P < 0.01), whereas this was not the case in patients treated with diet and/or oral agents at baseline. However, insulin treatment per se was not associated with an increased mortality or mortality or morbidity. Urinary albumin concentration was not correlated with incidence or progression of retinopathy regardless of type of diabetes treatment. In conclusion, this study showed that albuminuria was a prognostic factor for vascular morbidity and death in type 2 diabetic patients treated with insulin but not in patients treated with diet or oral agents. Furthermore, albuminuria was not a predictor for incidence or progression of retinopathy.
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| 22. |
- Agardh, Elisabet, et al.
(författare)
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A 5-year follow-up study on the incidence of retinopathy in type 1 diabetes mellitus in relation to medical risk indicators
- 1994
-
Ingår i: Journal of Internal Medicine. - 1365-2796. ; 235:4, s. 353-358
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES. The aim of the present study was to describe the 5-year incidence of retinopathy in type 1 diabetes mellitus and to characterize risk indicators for the development and progression of retinopathy. DESIGN. A cross-sectional study of type 1 diabetic patients taken care of at a medical department. SETTING. All type 1 diabetic patients attending the Department of Internal Medicine, University Hospital, Lund, during a 2-year period were offered ophthalmological examination. SUBJECTS. A total of 396 out of 461 (85.9%) initially examined type 1 diabetic patients formed the basis for this 5-year follow-up study. MAIN OUTCOME MEASURES. The degree of retinopathy was based on fundus photography or biomicroscopy. Degree of metabolic control was assessed by HbA1c levels, signs of nephropathy by albumin creatinine clearance ratio and urinary albumin levels. Blood pressure was measured in the supine position. Duration of diabetes, age, and insulin dosage were registered. RESULTS. The incidence of retinopathy was 47.2% and progression from background to severe retinopathy occurred in 41%. Risk indicators for the development of retinopathy were duration of diabetes (P < 0.001), degree of metabolic control (P < 0.001), insulin dosage (P < 0.05) and signs of nephropathy based on measurements of albumin creatinine clearance ratio (P < 0.01) and urinary albumin concentration (P < 0.05). Two risk indicators could be identified for progression of retinopathy, i.e. the degree of metabolic control (P < 0.01) and diastolic blood pressure (P < 0.05). CONCLUSIONS. The results suggest that apart from poor metabolic control, development of retinopathy in type 1 diabetes is associated with long diabetes duration and clinical signs of diabetic nephropathy. Progression of retinopathy is associated with poor metabolic control and elevated diastolic blood pressure levels.
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| 23. |
- Agardh, Elisabet, et al.
(författare)
-
A four-year follow-up study on the incidence of diabetic retinopathy in older onset diabetes mellitus
- 1994
-
Ingår i: Diabetic Medicine. - 1464-5491. ; 11:3, s. 273-278
-
Tidskriftsartikel (refereegranskat)abstract
- Out of 369 diabetic patients with an age at onset of diabetes > or = 30 years previously studied, 325 (88%) were included in an ophthalmological follow-up examination 4 years later. In patients treated with oral drugs at baseline, the incidence of any type of retinopathy was 30.8% and of severe retinopathy 5.7%. All patients who developed severe retinopathy received insulin during the follow-up period. At baseline, duration of diabetes, diastolic blood pressure, and signs of nephropathy (p < 0.05 in all cases) as well as degree of metabolic control (p < 0.01) differed between patients who developed retinopathy and those who did not. At follow-up, there were no longer any differences regarding degree of metabolic control and diastolic blood pressure. In patients treated with insulin at baseline, the incidence of any type of retinopathy was 41.0% and of severe retinopathy 16.1%. At baseline, duration of diabetes (p < 0.01), degree of metabolic control, and insulin dosage (p < 0.05 in both cases) differed between patients who developed retinopathy and those who did not. At follow-up, there was no longer any difference in insulin dosage.
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| 24. |
- Agardh, Elisabet, et al.
(författare)
-
Diabetic retinopathy
- 2004
-
Ingår i: International textbook of diabetes mellitus. - Chichester, UK : John Wiley & Sons, Ltd. - 0471486558 ; , s. 1187-1187
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Diabetic retinopathy is the most common cause of blindness in the Western world in people aged 65 years or less. Intensive blood glucose control reduces the risk for development and progression of retinopathy. There is also a strong association between hypertension and retinopathy, and antihypertensive treatment seems to reduce the risk for both development and progression of retinopathy. The retinal vascular changes may vary from occasional hemorrhages and microaneurysms, to multiple hemorrhages and microaneurysms, prominent retinal thickening and exudates along blood vessels and in the macular region, new vessels, fibrosis, and retinal detachment. Sight-threatening lesions may well be present without disturbed visual function and visual outcome is dependent on timely treatments like laser photocoagulation and vitrectomy. Therefore, regular screening for diabetic retinopathy is of utmost importance. The molecular pathophysiology of diabetic retinopathy includes factors that initiate and promote the vascular disease like hyperglycemia, the polyol pathway, nonenzymatic glycation, oxidative stress, activation of protein kinase C, different growth factors, and vasoactive hormones. Several changes also take place in the retinal vasculature, which cause changed retinal blood flow and heterogeneity of its distribution, areas of nonperfusion and ischemia and hypoxia, which in turn leads to an increased production of vasoactive factors like vascular endothelial growth factor.
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| 25. |
- Agardh, Elisabet, et al.
(författare)
-
Effects of inhibition of glycation and oxidative stress on the development of cataract and retinal vessel abnormalities in diabetic rats
- 2000
-
Ingår i: Current Eye Research. - 0271-3683. ; 21:1, s. 543-549
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To study effects of inhibition of glycation, and oxidative stress on the development of cataract and retinal vessel abnormalities in diabetic rats. METHODS: Diabetes was induced in male Wistar rats with streptozocin (STZ; 60 mg/kg BW, i.p.). Diabetic as well as strain matched control rats were fed 1) a normal diet, 2) addition of aminoguanidine in the drinking water (0.5 g/l for diabetic rats and 1.0 g/l for control rats) or 3) probucol in the pellets (1% w/w). After 6 months, the number of acellular vessels, endothelial cells and pericytes were counted in trypsin digested retinal vessel preparations, and the total retinal tissue amount of glutathione (GSH) and cysteine was measured with HPLC. RESULTS: Cataract formation occurred after 13 weeks in diabetic animals compared with 17 weeks for those treated with aminoguanidine, and 16 weeks for those treated with probucol (p < 0.001 in both cases). Aminoguanidine inhibited the formation of acellular collapsed capillary strands, 9 (3-14) vs. 18 (12-262) (median, range) per quadrant in untreated diabetic rats (p = 0.004), while probucol did not have any effect. Neither aminoguanidine, nor probucol influenced the endothelial/pericyte ratio. Diabetes caused a reduction in the GSH/cysteine ratio (10.7 +/- 0.6 vs. 15.3 +/- 1. 5) (mean +/- SD; p < 0.001). Probucol partly restored this imbalance (p < 0.05) whereas aminoguanidine did not. CONCLUSIONS: The results indicate that cataract formation in diabetes involves both glycation and oxidative stress processes. The reduced formation of acellular collapsed capillary strands by aminoguanidine suggests a potential role for glycation in vascular damage. The positive effect of probucol on cysteine/GSH metabolism imbalance indicates that derangements of one of the retinal defense systems against oxidative stress can be normalized by antioxidants.
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| 26. |
- Agardh, Elisabet, et al.
(författare)
-
Fetal growth is not associated with early onset of severe retinopathy in type 1 diabetes mellitus
- 2000
-
Ingår i: Diabetes Research and Clinical Practice. - 1872-8227. ; 48:1, s. 61-65
-
Tidskriftsartikel (refereegranskat)abstract
- Reduced fetal growth has been suggested as a possible risk factor for diabetic nephropathy. The aim of the present study was to examine whether there could be an association also with rapidly progressing severe retinopathy in younger type 1 diabetic patients. Maternal pregnancy, as well as birth parameters of 27 type 1 diabetic patients with severe retinopathy diagnosis at a median age of 25 years, were studied retrospectively. The control group consisted of 22 type 1 diabetic patients with mild background retinopathy and with similar age, age at onset, and duration of diabetes. Mothers of the subjects with severe retinopathy had a higher body mass index (P = 0.03) but similar age, blood pressure levels, and weight gain during pregnancy as those of the control group. All but four babies, two in each group, were born after 37 completed gestational weeks. There were no differences regarding birth weight or of relative birth weight corrected for gestational length. Head circumference, birth length, and placenta weight were similar. The results indicate that fetal growth is not a factor of major importance for the development of severe retinopathy in younger type 1 diabetic patients.
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| 27. |
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| 28. |
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| 29. |
- Agardh, Elisabet, et al.
(författare)
-
Modifying a standard method allows simultaneous extraction of RNA and protein, enabling detection of enzymes in the rat retina with low expressions and protein levels
- 2006
-
Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600. ; 55:2, s. 168-174
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to evaluate messenger RNA and protein expression in limited amounts of tissue with low protein content. The Chomczynski method was used for simultaneous extraction of RNA, and protein was modified in the protein isolation step. Template mass and cycling time for the complementary DNA synthesis step of real-time reverse transcription-polymerase chain reaction (RT-PCR) for analysis of catalase, copper/zinc superoxide dismutase, manganese superoxide dismutase, the catalytic subunit of glutamylcysteine ligase, glutathione peroxidase 1, and the endogenous control cyclophilin B (CypB) were optimized before PCR. Polymerase chain reaction accuracy and efficacy were demonstrated by calculating the regression (R2) values of the separate amplification curves. Appropriate antibodies, blocking buffers, and running conditions were established for Western blot, and protein detection and multiplex assays with CypB were performed for each target. During the extraction procedure, the protein phase was dissolved in a modified washing buffer containing 0.1% sodium dodecyl sulfate, followed by ultrafiltration. Enzyme expression on real-time RT-PCR was accomplished with high reliability and reproducibility (R2, 0.990-0.999), and all enzymes except for glutathione peroxidase 1 were detectable in individual retinas on Western blot. Western blot multiplexing with CypB was possible for all targets. In conclusion, connecting gene expression directly to protein levels in the individual rat retina was possible by simultaneous extraction of RNA and protein. Real-time RT-PCR and Western blot allowed accurate detection of retinal protein expressions and levels.
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| 30. |
- Agardh, Elisabet, et al.
(författare)
-
Normal eyes in type 1 diabetics stay normal after one year of treatment with continuous subcutaneous insulin pump
- 1986
-
Ingår i: Acta Ophthalmologica. - 0001-639X. ; 64:5, s. 530-532
-
Tidskriftsartikel (refereegranskat)abstract
- Seven patients with type 1 diabetes mellitus were restored to near normoglycaemia by treatment with continuous subcutaneous insulin infusion pumps (CSII). The patients were examined with ophthalmoscopy, fundus photography and fluorescein angiography before and one year after the start of CSII treatment. In addition, ophthalmoscopy was performed after 6 months of treatment. All 14 eyes were normal prior to the CSII treatment and none had developed any signs of retinopathy after 6 months or 1 year. It is concluded that metabolic control can be near normalized with CSII treatment without any risk for development of diabetic microangiopathy in type 1 diabetics with normal eyes.
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| 31. |
- Agardh, Elisabet, et al.
(författare)
-
Putative risk factors associated with retinopathy in patients with diabetes diagnosed at or after 30 years of age
- 1989
-
Ingår i: Diabetic Medicine. - 1464-5491. ; 6:8, s. 724-727
-
Tidskriftsartikel (refereegranskat)abstract
- In a cross-sectional study of diabetic patients diagnosed at or after 30 years, and with different stages of retinopathy, factors such as duration of diabetes, treatment mode, metabolic control, blood pressure, and clinical signs of nephropathy were examined. The different stages of retinopathy used were absence of retinopathy, simplex, and severe retinopathy. Patients with simplex and severe retinopathy were older than those without retinopathy (p less than 0.001, and p less than 0.01, respectively). They also had a longer duration of diabetes (p less than 0.001), and were more often treated with insulin (p less than 0.001) and in larger doses (p less than 0.001). Their glycosylated haemoglobin levels were higher (p less than 0.01). Their systolic blood pressure was higher (p less than 0.01), but the diastolic blood pressure did not differ, and the number of patients treated for hypertension was similar in all groups. Albumin clearance was higher (p less than 0.01 and p less than 0.001), as were urinary albumin levels (p less than 0.001). The only variables that distinguished patients with simplex from those with severe retinopathy were albumin clearance (p less than 0.01) and urinary albumin levels (p less than 0.05).
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| 32. |
- Agardh, Elisabet, et al.
(författare)
-
Retinal glial cell immunoreactivity and neuronal cell changes in rats with STZ-induced diabetes
- 2001
-
Ingår i: Current Eye Research. - : Informa UK Limited. - 0271-3683 .- 1460-2202. ; 23:4, s. 276-284
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To study whether diabetes could influence glial cells, retinal neurons, and pigment epithelial cells and if so, to evaluate whether any changes could be influenced by aminoguanidine (AG) or probucol (PB). METHODS: Streptozocin (STZ)-induced diabetic male Wistar rats and age-matched control rats were fed a normal diet, addition of AG in the drinking water (0.5 g/l for diabetic and 1.0 g/l for control rats) or PB in the pellets (1 % w/w) for one or six months. Paraffin embedded retinal sections were incubated in the primary antibodies GFAP, calbindin, RPE65, and Hu, for glial, horizontal, pigment epithelial, and ganglion cells, respectively, and in fluorescent secondary antibodies. RESULTS: One month after STZ injection, GFAP immunoreactivity was sparse, but after six months it was prominent in glial cells in 5/5 diabetic and 1/7 control retinas (p = 0.015). Neither AG, nor PB influenced this immunoreactivity. Numbers of retinal pigment epithelial cells and cells in the ganglion cell layer, were similar at one and six months of diabetes. By time, the number of horizontal cells decreased (p < 0.001) and branching and numbers of their terminals were reduced (p < 0.001). CONCLUSION: Diabetes for six months resulted in increased glial cell immunoreactivity, and by age, horizontal cell numbers and branching of their terminals decreased, morphological patterns that were unaffected by AG or PB. The numbers of retinal pigment epithelial cells and cells in the ganglion cell layer were unaffected both by age and diabetes.
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| 33. |
- Agardh, Elisabet, et al.
(författare)
-
Retinopathy and nephropathy in insulin-dependent diabetics: an inconsistent relationship?
- 1987
-
Ingår i: Diabetic Medicine. - 1464-5491. ; 4:3, s. 248-250
-
Tidskriftsartikel (refereegranskat)abstract
- The association between retinopathy and nephropathy was investigated in a retrospective study of 52 insulin-dependent diabetics with preproliferative or proliferative retinopathy and in 48 patients without or with background retinopathy. The duration of diabetes was 23.2 +/- 1.0 years (mean +/- SEM) and 22.0 +/- 1.2 years in the two groups. Patients in the retinopathy group showed a higher frequency of detectable nephropathy and were more often treated with antihypertensive drugs. However, a high proportion (35%) of patients with proliferative retinopathy did not show any detectable signs of nephropathy. Furthermore, nephropathy did not seem to develop in patients with retinopathy during an observation period of up to 9 years. The data suggest that the factors underlying the development of retinal and renal microangiopathy might be of different origin.
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| 34. |
- Agardh, Elisabet, et al.
(författare)
-
Severe retinopathy in type 1 diabetic patients is not related to the level of plasma homocysteine
- 2000
-
Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 60:3, s. 169-174
-
Tidskriftsartikel (refereegranskat)abstract
- The vascular-injuring amino acid homocysteine was previously shown to be increased in plasma in type 1 diabetic patients with clinical signs of nephropathy. Previous studies have also shown an inconsistent relationship between the development of diabetic nephropathy and retinopathy, indicating different pathogenetic mechanisms. In this study, plasma homocysteine was measured in 25 type 1 diabetic patients with a well-characterized form of severe retinopathy. Furthermore, a group of 24 type 1 diabetic patients with similar age at onset of diabetes and diabetes duration with no or minimal background retinopathy were investigated, in order to determine whether plasma homocysteine levels are different from those in patients with severe retinopathy. Patients with severe retinopathy did not have higher plasma levels of homocysteine (13.9 micromol/L; 5.9-30.7, median and range) than those without retinopathy (10.4 micromol/L; 5.7-18.9). Within the group of patients with severe retinopathy, increased homocysteine levels were confined to the patients (19.9 micromol/L; 10.0-30.7, n=9) with serum creatinine levels > 100 micromol/L, compared to those patients (9.6; 5.9-14.3 micromol/L, n=15) with a serum creatinine below 100 micromol/L. None of the patients without or with minimal background retinopathy had serum creatinine levels > 100 micromol/L. We conclude that diabetic retinopathy is not associated with increased plasma homocysteine levels, but plasma homocysteine accumulates, probably owing to reduced glomerular filtration, in diabetic patients with signs of nephropathy. In these patients, the promoting effect of nephropathy on the development of retinopathy does not seem to be mediated through homocysteine.
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| 35. |
- Agardh, Elisabet, et al.
(författare)
-
The five-year incidence of blindness after introducing a screening programme for early detection of treatable diabetic retinopathy
- 1993
-
Ingår i: Diabetic Medicine. - 1464-5491. ; 10:6, s. 555-559
-
Tidskriftsartikel (refereegranskat)abstract
- The incidence of moderate visual impairment and blindness due to diabetic retinopathy was studied 5 years after introducing a screening system for early detection of treatable retinopathy. Photocoagulation was performed in patients with clinically significant macular oedema, severe preproliferative, and proliferative retinopathy. Eighty-eight percent of 470 Type 1 and 88% of 388 Type 2 diabetic patients were still available for follow-up. In the Type 1 group, the five-year incidence of blindness and moderate visual impairment were 0.5% and 1.2%, respectively. Corresponding figures for the Type 2 diabetic patients were 0.6% and 1.7%, respectively. The majority of patients with loss of vision had severe retinopathy at baseline. Among those who entered the screening programme with no or mild retinopathy, loss of vision occurred in only one of the Type 1 and four of the Type 2 diabetic patients. It is concluded that the risk for visual impairment and blindness due to diabetes can be substantially reduced by using programmes for early detection of and effective treatment of diabetic retinopathy.
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| 36. |
- Agardh, Elisabet, et al.
(författare)
-
The importance of early diagnosis of treatable diabetic retinopathy for the four-year visual outcome in older-onset diabetes mellitus
- 1996
-
Ingår i: Acta Ophthalmologica Scandinavica. - 1395-3907. ; 74:2, s. 166-170
-
Tidskriftsartikel (refereegranskat)abstract
- The four-year visual outcome was retrospectively studied in patients with older-onset diabetes mellitus and diabetic retinopathy in need of laser treatment. Visual acuity in 53 patients examined by ophthalmologists who referred the patients for an evaluation of retinopathy before laser treatment, was compared to that of 47 patients examined by ophthalmologists who also performed the photocoagulation. The number of eyes that became blind (visual acuity < or = 6/60) during the four-year period was higher (23/90 vs 9/91; p < 0.01) among referred patients, whereas the number of retinal examinations per patient during the three-year period prior to laser treatment did not differ between the two groups. Among referred patients, 13% had not been ophthalmologically examined before the treatment-requiring retinopathy was found. Corresponding figure for those examined at the laser centre was 23%. Severe macular oedema in regularly examined patients was more common among referred patients (9/30 vs 1/32; p < 0.01). The results indicate that screening for diabetic retinopathy in older-onset diabetes was not performed satisfactorily. In addition, laser treatment was delayed in older-onset diabetic patients controlled by ophthalmologists who referred patients for photocoagulation, resulting in an increased incidence of legally blind eyes. The study also stresses the importance of carrying out knowledge of when and how to diagnose early sight-threatening diabetic retinopathy to ophthalmologists referring patients for laser treatment.
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| 37. |
- Agardh, Elisabet, et al.
(författare)
-
The prevalence of retinopathy and associated medical risk factors in type I (insulin-dependent) diabetes mellitus
- 1989
-
Ingår i: Journal of Internal Medicine. - 1365-2796. ; 226:1, s. 47-52
-
Tidskriftsartikel (refereegranskat)abstract
- The prevalence of diabetic retinopathy and the associated medical risk factors, such as age at onset and duration of diabetes, metabolic control, blood pressure, albumin clearance and serum creatinine, were studied in 501 patients with type I diabetes mellitus. The prevalence of retinopathy, characterized as simplex, maculopathy, preproliferative, and proliferative, was 60.5%. Patients with retinopathy were younger at the onset of diabetes, and had a longer duration of disease. In patients with more than 10 years of diabetes, proliferative retinopathy was more frequent if onset was before they were 15 years old, despite the fact that the duration of diabetes did not differ. Patients with severe retinopathy had worse metabolic control, and were more frequently treated for hypertension. In addition, the systolic blood pressure was elevated in all groups of patients with any type of retinopathy, whereas the diastolic blood pressure was elevated only in patients with more severe forms. Patients with severe retinopathy also had higher levels of albumin clearance.
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| 38. |
- Agardh, Elisabet, et al.
(författare)
-
Ögon
- 2002
-
Ingår i: Diabetes. - 9147048999 ; , s. 236-236
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 39. |
- Berglund, Lisa, et al.
(författare)
-
Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia
- 2010
-
Ingår i: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY. - Baltimore : Lippincott Williams & Wilkins. - 1079-5642. ; 30, s. 154-218
-
Tidskriftsartikel (refereegranskat)abstract
- Objective-Hyperglycemia is a recognized risk factor for cardiovascular disease in diabetes. Recently, we reported that high glucose activates the Ca2+/calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in arteries ex vivo. Here, we sought to determine whether hyperglycemia activates NFAT in vivo and whether this leads to vascular complications. Methods and Results-An intraperitoneal glucose-tolerance test in mice increased NFATc3 nuclear accumulation in vascular smooth muscle. Streptozotocin-induced diabetes resulted in increased NFATc3 transcriptional activity in arteries of NFAT-luciferase transgenic mice. Two NFAT-responsive sequences in the osteopontin (OPN) promoter were identified. This proinflammatory cytokine has been shown to exacerbate atherosclerosis and restenosis. Activation of NFAT resulted in increased OPN mRNA and protein in native arteries. Glucose-induced OPN expression was prevented by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. The calcineurin inhibitor cyclosporin A or the novel NFAT blocker A-285222 prevented glucose-induced OPN expression. Furthermore, diabetes resulted in higher OPN expression, which was significantly decreased by in vivo treatment with A-285222 for 4 weeks or prevented in arteries from NFATc3(-/-) mice. Conclusions-These results identify a glucose-sensitive transcription pathway in vivo, revealing a novel molecular mechanism that may underlie vascular complications of diabetes.
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| 40. |
- Fosmark, DS, et al.
(författare)
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Increased serum levels of the specific advanced glycation end product methylglyoxal-derived hydroimidazolone are associated with retinopathy in patients with type 2 diabetes mellitus
- 2006
-
Ingår i: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600. ; 55:2, s. 232-236
-
Tidskriftsartikel (refereegranskat)abstract
- Advanced glyeation end products (AGEs) are thought to play a major pathogenic role in diabetic retinopathy. The most important AGE is unknown, but as increased serum methylglyoxal-derived hydroimidazolone has been demonstrated in patients with type 2 diabetes mellitus, the aim of the present study was to elucidate possible associations between serum levels of hydroimidazolone and retinopathy in patients with type 2 diabetes mellitus. We recruited 227 patients with type 2 diabetes mellitus and retinopathy ranging from none to proliferative. Level of retinopathy was determined from 7 standard field stereo photographs per eye according to the Early Treatment Diabetic Retinopathy Study. The patients were 66 +/- 11 years old, with a known diabetes duration of 14 9 years. Serum levels of hydroimidazolone were determined with a competitive immunoassay. Serum levels of hydroimidazolone were increased in nonproliferative (median, 4.50 U/mL; interquartile range, 3.69-5.77 U/mL) and proliferative retinopathy (median, 4.88 U/mL; interquartile range, 3.70-6.52 U/mL) compared with patients without retinopathy (median, 4.02 U/mL; interquartile range, 3.47-4.88 U/mL) (P =.008 and .002, respectively). There was no association between hydroimidazolone and hemoglobin A(1c) (r = 0.04, P =.57). In addition, patients with proliferative retinopathy and a relatively short known duration of diabetes, that is, less than the median of 14 years, had increased serum levels of hydroimidazolone (median, 6.91 U/mL; interquartile range, 4.70-8.91 U/mL) compared with those with nonproliferative retinopathy (median, 4.34; interquartile range, 3.86-5.53U/mL, P =.015). Serum levels of hydroimidazolone are increased in type 2 diabetic patients with retinopathy. This association is independent of hitherto known associated factors, such as hemoglobin A(1c).
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| 41. |
- Fosmark, Dag S., et al.
(författare)
-
Increased retinopathy occurrence in type 1 diabetes patients with increased serum levels of the advanced glycation endproduct hydroimidazolone
- 2009
-
Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-3768 .- 1755-375X. ; 87:5, s. 498-500
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: We aimed to investigate associations between serum levels of the advanced glycation endproduct methylglyoxal-derived hydroimidazolone (MG-H1) and retinopathy in a sample of patients with type 1 diabetes. Methods: We conducted a cross-sectional study in a Scandinavian ophthalmology outpatient clinic on 61 randomly selected patients with type 1 diabetes. Blood samples and retinal photographs were taken at the same visit. Serum levels of hydroimidazolone immunoreactivity were determined using an immunoassay, and levels of retinopathy were determined from seven standard field stereo photographs of each eye according to the ETDRS method. Results were compared between patients with and without retinopathy. Results: Hydroimidazolone quartiles were significantly associated with retinopathy (p = 0.013). The most profound increase in occurrence of retinopathy was observed from the lowest to the second-lowest hydroimidazolone quartile. Adjusted for duration of diabetes using logistic regression, a significant difference in the presence of retinopathy was found when comparing the lowest quartile with the rest (p = 0.022). Conclusions: In our patients with type 1 diabetes, serum levels of hydroimidazolone were found to be associated with retinopathy. This is in keeping with findings in a larger sample of patients with type 2 diabetes.
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| 42. |
- Gustavsson, Carin, et al.
(författare)
-
Inflammatory markers in nondiabetic and diabetic rat retinas exposed to ischemia followed by reperfusion.
- 2008
-
Ingår i: Retina. - 0275-004X. ; 28:4, s. 645-652
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE:: To examine the retinal inflammatory response to ischemia-reperfusion in nondiabetic and diabetic rats injected with either an omega-3-polyunsaturated fatty acid (docosahexaenoic acid [DHA]) or a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (pravastatin). METHODS:: Diabetes was induced by an intraperitoneal injection of streptozocin, and retinal ischemia was induced by ligation of the optic nerve and vessels, followed by reperfusion for 1 hour or 24 hours. Five minutes before surgery, an intravenous injection of DHA, pravastatin, or vehicle (ethanol) was administered. The mRNA expressions of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, caspase-1, IL-1beta, P-selectin, vascular cellular adhesion molecule (VCAM)-1, and intercellular adhesion molecule (ICAM)-1 were compared between ischemic and nonischemic retinas as well as diabetic and nondiabetic nonischemic retinas. RESULTS:: Ischemia induced increased expressions of TNF-alpha (P
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| 43. |
- Gustavsson, Carin, et al.
(författare)
-
Profile of intraocular tumour necrosis factor-α and interleukin-6 in diabetic subjects with different degrees of diabetic retinopathy.
- 2013
-
Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-3768 .- 1755-375X. ; 91:5, s. 445-452
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: To assess and correlate the levels of inflammatory mediators in the eyes from non-diabetic and diabetic subjects without retinopathy (NDR), with non-proliferative diabetic retinopathy (NPDR) or with proliferative diabetic retinopathy (PDR) to corresponding erum levels. Methods: The levels of interleukin 1β, interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were analysed by an ELISA-mimicking technique in the vitreous from 26 diabetic subjects with active PDR and 27 non-diabetic subjects, or by a multiplex bead assay in the aqueous humour from 35 diabetic subjects with NDR/NPDR and 40 non-diabetic subjects. Intraocular protein production was estimated in vitreous specimens by calculating a vitreous/serum ratio. Results: In the vitreous, IL-6 was higher in diabetic [157.5 (25.0-1401.0) pg/ml; median (min-max)] than in non-diabetic subjects [44.0 (5.0-4425) pg/ml; p = 0.021]. The vitreous/serum ratio was high (55.5:1 and 16:1, respectively), suggesting intraocular production. TNF-α was lower in diabetic [18.0 (8.0-46.0) pg/ml] than in non-diabetic subjects [22.0 (13.0-47.0) pg/ml; p = 0.034], but the vitreous/serum ratio was elevated in both groups (2:1 and 3.4:1, respectively). TNF-α levels were higher in serum from diabetic subjects [9.0 (5.0-53.0) pg/ml versus 6.7 (3.0-11.0) pg/ml; p < 0.001]. Aqueous levels of inflammatory mediators did not differ between diabetic subjects with NDR/NPDR and non-diabetic subjects despite elevated TNF-α in serum [27.8 (6.8-153.7) pg/ml versus 16.4 (4.1-42.4) pg/ml; p = 0.021]. Conclusion: Intraocular inflammation seems to be involved in PDR but does not seem to be prominent in early retinopathy stages, i.e. NDR or NPDR. Diabetic subjects have an overall increased inflammatory activity compared to non-diabetic subjects, as demonstrated by increased serum levels of TNF-α.
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| 44. |
- Gustavsson, Carin, et al.
(författare)
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Tnf-Alpha In Diabetic Retinopathy
- 2010
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Ingår i: European Journal of Ophthalmology. - 1120-6721. ; 20:3, s. 636-636
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Konferensbidrag (refereegranskat)
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| 45. |
- Gustavsson, Carin, et al.
(författare)
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TNF-alpha is an independent serum marker for proliferative retinopathy in type 1 diabetic patients.
- 2008
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Ingår i: Journal of Diabetes and its Complications. - : Elsevier BV. - 1873-460X .- 1056-8727. ; 22, s. 309-316
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: This study aimed to determine if there are any associations between serum levels of inflammatory markers and proliferative retinopathy (PDR) in type 1 diabetic patients. DESIGN: A cross-sectional design was utilized for this study. METHODS: One hundred twenty-eight type 1 diabetic patients underwent stereo fundus photography according to the Early Treatment Diabetic Retinopathy Study and were divided into two retinopathy groups: no or nonproliferative retinopathy (NDR/NPDR; n=62) and PDR (n=66). Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, soluble vascular cellular adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), P-selectin, and high-sensitivity C-reactive protein (hsCRP) were analyzed. Statistical analysis was performed using nonparametric Mann-Whitney U test and multivariate logistic regression analysis. RESULTS: Patients with PDR had higher levels of TNF-alpha [7.0 pg/ml (<4-17) vs. 6.0 pg/ml (<4-25); P=.009], sVCAM-1 [860 ng/ml (360-2120) vs. 700 ng/ml (310-1820); P<.001], and P-selectin [180 ng/ml (39-400) vs. 150 ng/ml (42-440); P=.017; figures are expressed as median (range)]. There were no differences in serum levels of sICAM-1 or hsCRP. IL-1beta was not detectable in any patient, and IL-6 was detectable in only 22.7% of the patients. In multivariate logistic regression analysis, TNF-alpha was the single, persistent, independent determinant inflammatory marker for PDR. CONCLUSION: The association between TNF-alpha and PDR in type 1 diabetic patients suggests that inflammation might play a role in the pathogenesis of proliferative diabetic retinopathy.
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| 46. |
- Gustavsson, Carin, et al.
(författare)
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Vascular cellular adhesion molecule-1 (VCAM-1) expression in mice retinal vessels is affected by both hyperglycemia and hyperlipidemia.
- 2010
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Inflammation has been proposed to be important in the pathogenesis of diabetic retinopathy. An early feature of inflammation is the release of cytokines leading to increased expression of endothelial activation markers such as vascular cellular adhesion molecule-1 (VCAM-1). Here we investigated the impact of diabetes and dyslipidemia on VCAM-1 expression in mouse retinal vessels, as well as the potential role of tumor necrosis factor-α (TNFα). METHODOLOGY/PRINCIPAL FINDINGS: Expression of VCAM-1 was examined by confocal immunofluorescence microscopy in vessels of wild type (wt), hyperlipidemic (ApoE(-/-)) and TNFα deficient (TNFα(-/-), ApoE(-/-)/TNFα(-/-)) mice. Eight weeks of streptozotocin-induced diabetes resulted in increased VCAM-1 in wt mice, predominantly in small vessels (<10 µm). Diabetic wt mice had higher total retinal TNFα, IL-6 and IL-1β mRNA than controls; as well as higher soluble VCAM-1 (sVCAM-1) in plasma. Lack of TNFα increased higher basal VCAM-1 protein and sVCAM-1, but failed to up-regulate IL-6 and IL-1β mRNA and VCAM-1 protein in response to diabetes. Basal VCAM-1 expression was higher in ApoE(-/-) than in wt mice and both VCAM-1 mRNA and protein levels were further increased by high fat diet. These changes correlated to plasma cholesterol, LDL- and HDL-cholesterol, but not to triglycerides levels. Diabetes, despite further increasing plasma cholesterol in ApoE(-/-) mice, had no effects on VCAM-1 protein expression or on sVCAM-1. However, it increased ICAM-1 mRNA expression in retinal vessels, which correlated to plasma triglycerides. CONCLUSIONS/SIGNIFICANCE: Hyperglycemia triggers an inflammatory response in the retina of normolipidemic mice and up-regulation of VCAM-1 in retinal vessels. Hypercholesterolemia effectively promotes VCAM-1 expression without evident stimulation of inflammation. Diabetes-induced endothelial activation in ApoE(-/-) mice seems driven by elevated plasma triglycerides but not by cholesterol. Results also suggest a complex role for TNFα in the regulation of VCAM-1 expression, being protective under basal conditions but pro-inflammatory in response to diabetes.
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| 47. |
- Hansson-Lundblad, Catharina, et al.
(författare)
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A small number of older type 2 diabetic patients end up visually impaired despite regular photographic screening and laser treatment for diabetic retinopathy.
- 2002
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Ingår i: Acta Ophthalmologica Scandinavica. - : Wiley. - 1395-3907. ; 80:3, s. 310-315
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The present study describes the prevalence of visual impairment and blindness in a geographically defined population 8 years after the introduction of a screening programme in 1987 for early detection of sight-threatening diabetic retinopathy. Methods: Of 374 patients with diabetes, comprising 2.6% of the population in the study community, 72% were examined with fundus photography or biomicroscopy during 1994-95. These patients form the basis of this study. The screening programme was fulfilled by 93% of subjects, all of whom underwent ophthalmic examinations at least every other year. A total of 79 eyes in 52 patients received photocoagulation for macular oedema alone or in combination with severe non-proliferative or proliferative retinopathy. Results: Eight years after the implementation of the programme, only three patients, all with type 2 diabetes (diabetes diagnosed at or after 30 years of age), had visual acuity <= 0.1. The total number of eyes with visual acuity <= 0.5 was higher in insulin-treated type 2 diabetic patients (n = 20) than in those on oral treatment (n = 5) or diet treatment only (n = 1) (p = 0.006 in both cases). The only independent risk factor for visual impairment in eyes with sight-threatening retinopathy was age. Conclusion: A small number of older type 2 diabetic patients end up with visual impairment due to unsuccessful photocoagulation of macular oedema.
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| 48. |
- Hansson-Lundblad, C, et al.
(författare)
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Retinal examination intervals in diabetic patients on diet treatment only
- 1997
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Ingår i: Acta Ophthalmologica Scandinavica. - 1395-3907. ; 75:3, s. 244-248
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of the present study was to examine whether type 2 diabetic patients with good metabolic control achieved on diet treatment only, developed sight-threatening retinopathy during a four-year follow-up period. METHODS: A retrospective four-year follow-up study was carried out including all diabetic patients on diet treatment only, registered at the out-patient clinic at the Department of Medicine and referred for fundus photography to the Department of Ophthalmology in 1989 as well as all patients referred from primary care units for fundus photography during 1988 and 1989. One hundred and seventeen diabetic patients treated with diet only were examined with fundus photography after remittance, and after two and four years. RESULTS: Age at diabetes diagnosis was 58.8 +/- 13.8 years (mean +/- SD), age at baseline was 61.5 +/- 13.6 years, and diabetes duration was 2.7 +/- 3.1 years. During the four-year follow-up period, 48 of the patients (41%) remained on diet treatment only whereas diabetes treatment was changed in 66 (56%), from diet to oral agents only in 57 (49%), and from diet to insulin alone or in combination with oral agents in 9 (8%) of the patients. One hundred and six patients (91%) did not have any retinopathy at baseline and 11 patients (9%) had minimal background retinopathy. At follow-up, there were no signs of retinopathy in 93 patients (79%), 22 (19%) had minimal background retinopathy, and two had developed moderate background retinopathy. Out of those patients who were still on diet at follow-up, five (10%) had developed minimal background retinopathy. Mean blood glucose and HbA1c levels, registered every year during the observation period, were higher at most time points in patients who received oral agents or insulin treatment compared to those who were treated with diet only during the entire observation period. No differences were observed between patients who received oral agents and those who received insulin alone or in combination with oral agents. CONCLUSION: It is suggested, that if the initial retinal examination reveals no or minimal diabetic retinopathy at the time of diagnosis of type 2 diabetes mellitus, the second examination can be postponed at least 4 years in patients with good metabolic control on diet treatment only.
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| 49. |
- Hultberg, Björn, et al.
(författare)
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Increased levels of plasma homocysteine are associated with nephropathy, but not severe retinopathy in type 1 diabetes mellitus
- 1991
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 51:3, s. 277-282
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Tidskriftsartikel (refereegranskat)abstract
- The reactive vascular-injuring amino acid homocysteine was measured in plasma samples from 79 well-characterized type 1 diabetic patients and 46 control subjects. Patients with proliferative retinopathy had higher homocysteine levels (15.0 +/- 6.3 mumols l-1; mean +/- SD, p less than 0.001; n = 42) than those with progressive retinopathy during a two-year period (10.4 +/- 1.6 mumols l-1; n = 12), no or minimal retinopathy (10.7 +/- 4.3 mumols l-1; n = 25), and the control subjects (11.0 +/- 3.4 mumols l-1). Within the group of patients with proliferative retinopathy increased homocysteine levels were confined to those patients that had serum creatinine levels greater than 115 mumols l-1 and/or an albumin:creatinine clearance ratio greater than or equal to 0.02 x 10(-3) (17.0 +/- 5.9 mumols l-1; n = 23), whereas those with no or only minimal nephropathy had levels (12.1 +/- 5.5 mumols l-1; n = 18) that were not different from the control group. We conclude that neither type 1 diabetes mellitus nor diabetic retinopathy per se is associated with increased plasma homocysteine levels. In contrast, homocysteine accumulates, probably owing to reduced glomerular filtration, in diabetic patients with advanced nephropathy. This suggests that homocysteine might contribute to the accelerated development of macroangiopathy seen especially in this subgroup of diabetic patients.
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| 50. |
- Hultberg, Björn, et al.
(författare)
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Plasma beta-hexosaminidase isoenzymes A and B exhibit different relations to blood glucose levels in a population of Type 1 diabetic patients
- 1995
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 55:8, s. 723-728
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Tidskriftsartikel (refereegranskat)abstract
- The activity of lysosomal enzymes, such as beta-hexosaminidase (Hex), is increased in the plasma and serum of diabetic patients. A positive association has been shown between enzyme activity and glycated proteins, indicating an association with the degree of metabolic control. Several isoenzymes of Hex exist. Studies have reported different proportions of the isoenzymes in plasma from diabetic patients, compared with healthy subjects. In the present study, Hex isoenzymes were examined in 76 Type 1 diabetic patients, of mean age 37.4 years (SD 12.9) compared with 38 age- and sex-matched healthy control subjects in an attempt to evaluate the influence of long- and short-term changes in blood glucose levels on these isoenzymes. The results show that Hex A activity (p<0.01), but not Hex B activity, was higher in the diabetic patients. Hex A activity was positively associated with both the actual blood glucose levels (r = 0.48, p<0.001) and haemoglobin A1c (HbA1c) (r = 0.43, p<0.001), while Hex B activity was associated with the level of HbA1c only (r = 0.42, p<0.001). Both Hex A and B activities were also positively associated with early signs of diabetic nephropathy (e.g. urinary excretion of Hex, fractional albumin excretion ratio and urinary albumin). There was no association between Hex A and B activities and different degrees of retinopathy. In conclusion, the present study demonstrates an association between Hex A and B and metabolic parameters in diabetes as well as with clinical signs of early diabetic nephropathy, but no association with the degree of retinopathy. Furthermore, Hex A seems to be more influenced than Hex B by short-term changes in blood glucose levels.
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