| 1. |
- Agardh, Daniel, et al.
(författare)
-
HLA-DQB1*0201/0302 is associated with severe retinopathy in patients with IDDM
- 1996
-
Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 39:11, s. 1313-1317
-
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.
|
|
| 2. |
- Agardh, Daniel, et al.
(författare)
-
Inverse relationship between GAD65 antibody levels and severe retinopathy in younger type 1 diabetic patients
- 1998
-
Ingår i: Diabetes Research and Clinical Practice. - 1872-8227. ; 40:1, s. 9-14
-
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.
|
|
| 3. |
- Agardh, Carl-David, et al.
(författare)
-
Altered endothelial/pericyte ratio in Goto-Kakizaki rat retina
- 1997
-
Ingår i: Journal of Diabetes and its Complications. - 1873-460X .- 1056-8727. ; 11:3, s. 158-162
-
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.
|
|
| 4. |
- Agardh, Carl-David, et al.
(författare)
-
Glutathione levels are reduced in diabetic rat retina but are not influenced by ischemia followed by recirculation
- 1998
-
Ingår i: Metabolism, Clinical and Experimental. - 1532-8600. ; 47:3, s. 269-272
-
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.
|
|
| 5. |
- Agardh, Carl-David, et al.
(författare)
-
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
-
Ingår i: Diabetes Research and Clinical Practice. - 1872-8227. ; 35:2-3, s. 113-121
-
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.
|
|
| 6. |
- Agardh, Carl-David, et al.
(författare)
-
The glutathione levels are reduced in Goto-Kakizaki rat retina, but are not influenced by aminoguanidine treatment
- 1998
-
Ingår i: Current Eye Research. - : Informa UK Limited. - 0271-3683 .- 1460-2202. ; 17:3, s. 251-256
-
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.
|
|
| 7. |
- Agardh, Carl-David, et al.
(författare)
-
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
-
Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 1872-8227 .- 0168-8227. ; 32:1-2, s. 35-44
-
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.
|
|
| 8. |
- 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.
|
|
| 9. |
- Hansson-Lundblad, C, et al.
(författare)
-
Retinal examination intervals in diabetic patients on diet treatment only
- 1997
-
Ingår i: Acta Ophthalmologica Scandinavica. - 1395-3907. ; 75:3, s. 244-248
-
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.
|
|
| 10. |
- Hultberg, Björn, et al.
(författare)
-
Plasma beta-hexosaminidase isoenzymes A and B exhibit different relations to blood glucose levels in a population of Type 1 diabetic patients
- 1995
-
Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 55:8, s. 723-728
-
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.
|
|
