| 1. |
- Hultberg, Björn, et al.
(author)
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Poor metabolic control, early age at onset, and marginal folate deficiency are associated with increasing levels of plasma homocysteine in insulin-dependent diabetes mellitus. A five-year follow-up study
- 1997
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In: Scandinavian Journal of Clinical & Laboratory Investigation. - 1502-7686. ; 57:7, s. 595-600
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Journal article (peer-reviewed)abstract
- In a previous study, we showed that diabetic patients exhibited significantly increased concentrations of total plasma homocysteine (tHcy), but not until the onset of nephropathy. It was suggested that the hyperhomocysteinaemia might contribute to the accelerated atherosclerotic process in diabetic patients. In the present study, we have analysed the main determinants of plasma homocysteine (i.e. serum cobalamin, blood folate and serum creatinine), and also some other parameters related to diabetes mellitus, such as medical history, metabolic and renal quantities, on two occasions with a 5-year interval in 50 patients with insulin-dependent diabetes mellitus, in order to further elucidate the relation between plasma tHcy and diabetes mellitus. The result of the present study shows that diabetic patients with the lowest age at onset and with the poorest metabolic control are those most prone to a rapid increase in plasma tHcy concentration. The increment in plasma tHcy concentration in this group of patients may at least partly be explained by a marginal deficiency of blood folate concentrations.
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| 2. |
- Gustavsson, Carin, et al.
(author)
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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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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:9
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Journal article (peer-reviewed)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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| 3. |
- Agardh, Carl-David, et al.
(author)
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Lack of association between plasma homocysteine levels and microangiopathy in type 1 diabetes mellitus
- 1994
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In: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 54:8, s. 637-641
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Journal article (peer-reviewed)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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| 4. |
- Agardh, Elisabet, et al.
(author)
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Severe retinopathy in type 1 diabetic patients is not related to the level of plasma homocysteine
- 2000
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In: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 60:3, s. 169-174
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Journal article (peer-reviewed)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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| 5. |
- Hultberg, Björn, et al.
(author)
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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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In: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 51:3, s. 277-282
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Journal article (peer-reviewed)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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| 6. |
- Hultberg, Björn, et al.
(author)
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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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In: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 55:8, s. 723-728
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Journal article (peer-reviewed)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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| 7. |
- Lindholm, Eero, et al.
(author)
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The -374 T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy and retinopathy in type 1 diabetic patients.
- 2006
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:Sep 13, s. 2745-2755
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Journal article (peer-reviewed)abstract
- Aims/hypothesis The receptor for AGE (RAGE) is considered to be mainly an intracellular signal-transducer or pro-inflammatory peptide of possible importance for inflammation and autoimmune diseases. Our aim was to study whether the -374 T/A polymorphism in the gene encoding RAGE (AGER) is associated with diabetes type and presence of diabetic complications. Methods The AGER -374 T/A polymorphism was genotyped in 867 type 1 diabetic patients, 2,467 type 2 diabetic patients and 205 non-diabetic control subjects of Scandinavian origin. Results AGER polymorphism was related to different HLA-DQB1 genotypes and the presence of diabetic complications. Type 1 diabetic patients had a higher frequency of the AGER -374 A/A or T/A genotypes than type 2 diabetic patients (51.1 vs 44.9%, p=0.002) and control subjects (51.1 vs 47.6%, p=0.0006). The RAGE -374 T/A polymorphism was associated with HLA-DQB1 genotypes; patients with HLA risk genotypes had a higher frequency of the A/A or T/A genotypes than patients with other HLA-DQB1 genotypes (60.3 vs 40.3%, p < 0.000001). In type 1 diabetic patients, the frequency of the A/A or T/A genotypes was higher in patients with diabetic nephropathy than without (61.1 vs 46.8%, p=0.006) and with sight-threatening retinopathy than without (56.1 vs 47.6%, p=0.03). In type 2 diabetic patients with HbA(1c) values below the median, the T/T genotype was more frequent in patients with diabetic nephropathy than without (54.3 vs 38.2%, p=0.02). Conclusions/interpretation Our results show an association between the AGER -374 T/A polymorphism and type 1 diabetes. This association was HLA-DQB1-dependent. The polymorphism was associated with diabetic nephropathy in both type 1 and type 2 diabetes, in an HbA(1c)-dependent manner in the latter group, and also with sight-threatening retinopathy in type 1 diabetic patients.
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| 8. |
- Agardh, Elisabet, et al.
(author)
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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
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In: Journal of Internal Medicine. - 1365-2796. ; 235:4, s. 353-358
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Journal article (peer-reviewed)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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| 9. |
- Agardh, Elisabet, et al.
(author)
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The prevalence of retinopathy and associated medical risk factors in type I (insulin-dependent) diabetes mellitus
- 1989
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In: Journal of Internal Medicine. - 1365-2796. ; 226:1, s. 47-52
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Journal article (peer-reviewed)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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| 10. |
- Torffvit, Ole, et al.
(author)
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Albuminuria and associated medical risk factors: a cross-sectional study in 451 type II (noninsulin-dependent) diabetic patients. Part 2
- 1991
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In: Journal of Diabetic Complications. - 0891-6632. ; 5:1, s. 29-34
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Journal article (peer-reviewed)abstract
- The association between urinary albumin concentration (UAC) in a morning urine sample and medical risk factors was evaluated in a cross-sectional study of 451 type II (noninsulin-dependent) diabetic patients. The following four groups of patients were created according to their urinary albumin levels: A) normal (less than 12.5 mg/L); B) high normal (12.5-30 mg/L); C) microalbuminuria, ie, incipient nephropathy (31-299 mg/L); and D) clinical nephropathy (greater than or equal to 300 mg/L). The patients with high normal levels had higher HbA1c and systolic blood pressure levels than patients with values within normal limits. The prevalence of incipient and clinical diabetic nephropathy was 20 and 7%, respectively. Incipient nephropathy was associated with higher blood pressures and body weights. Patients with clinical nephropathy had even further increases in these parameters, were older, and had longer duration of diabetes. In both groups of nephropathy, men were preponderant. Thirty six percent of all patients and 73% of patients with clinical nephropathy were treated for hypertension; 55% were treated with insulin. The insulin-treated patients had poorer metabolic control, but there were no differences in blood pressure or serum creatinine levels as compared with those of patients not receiving insulin treatment. The proportion of patients with severe retinopathy increased with the degree of albuminuria, although 22% of the patients with clinical nephropathy continued to be nonretinopathic.
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