Challenging perspectives in diabetic management. Chairmen's introduction.
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Adult↗
Biomedical subjects
D Tschöpe
Publications and source records attributed to D Tschöpe.
Role of oxygen derived radicals for vascular dysfunction in the diabetic heart: prevention by alpha-tocopherol?
The evidence that the generation of reactive oxygen intermediates (ROI) plays an important role for the increased cardiovascular risk in diabetes is summarised. In addition to the well known parameters of oxidative stress as lipid hydroperoxides and thiobarbituric acid substances (TBARS), recent observations indicate that isoprostanes which can be taken as a more specific parameter of oxidative stress, are generated in higher amounts by diabetic patients. This increased formation of isoprostanes can be inhibited by an installment of a close metabolic control or the supplementation with tocopherol. The cause for the elevated oxidative stress is not yet fully understood, however the autoxidation of glucose, the formation of advanced glycation endproducts and the activation of NADPH-oxidase seem to be relevant processes. Since ROI are able to quench nitric oxide and to inhibit the synthesis of prostacyclin, the antithrombotic, vasodilating and antiatherosclerotic properties of endothelium are impaired in diabetes. Additionally, the balance of endothelial mediators released by endothelium is shifted to angiotensin II and endothelin, compounds which enhance the proliferation of smooth muscle cells and may limit the coronary reserve of myocardium. The activation of the transcription factor NF-kappa B by glucose and its autoxidative products is regarded as a key event in the transformation of the vasculature in diabetes. Epidemiological observations and very recent clinical studies underlie the impact of ROI for the development of cardiovascular complications in diabetes and suggest that an antioxidative treatment might be helpful to reduce the cardiac risk in diabetes.
Animals↗
[Arachnoid cyst as the differential diagnosis of ischemic optic neuropathy in type-II diabetes].
HISTORY AND CLINICAL FINDINGS: A 71-year-old woman, a diabetic (type IIb) for 27 years, developed bilateral hemianopsia over a period of about 2 years. A few weeks before hospital admission the defect in her visual fields increased more rapidly and double vision occurred intermittently. The hemianopsia was demonstrated by finger perimetry. There was no evidence of heart failure or peripheral vascular disease. Muscle reflexes were normal, but there was a decrease in vibratory sensation in both feet. The cause of the visual disturbance was at first thought to be an ischaemic optic neuropathy. INVESTIGATIONS: Biochemical tests showed an HbA1 of 12.8%, blood sugar levels were between 230 and 359 mg/dl, and there was increased intravascular platelet activation. Ophthalmological examination confirmed bitemporal hemianopsia and early retinopathy. Magnetic resonance imaging of the skull revealed an intra- and suprasellar cystic space-occupying lesion extending to the right optic chiasma. These findings, taken together, indicated an arachnoidal cyst. TREATMENT AND COURSE: After the diabetic metabolic state had been normalized with insulin treatment (average of 30 IU of an intermediary insulin) and dietary measures, the cyst was evacuated stereotactically. The hemianopsia quickly improved markedly and the patient was discharged 4 days after the operation with her vision nearly fully restored.
Aged↗
Adhesive proteins in platelet-endothelial interactions.
Adhesion molecules mediate the interaction between endothelium and platelets as well as other blood cells and the endothelium. The structure and function of some of these molecules will be reviewed and discussed. The expression of these molecules is largely affected by disease states such as hypertension, diabetes, and cardiac failure. Determination of adhesion molecules expressed on the surface of endothelial cells and platelets by cytoflowmetry enables a new approach to estimate the activity state of these cells and might be helpful to identify patients with an increased thrombotic risk.
Blood Platelets↗
Prevalence of gastrointestinal symptoms in diabetic patients and non-diabetic subjects.
To determine the frequency of gastrointestinal symptoms in diabetic patients, 190 patients, consecutively referred to the Diabetes Research Institute, reported their gastrointestinal symptoms on a standardized symptom list. One hundred and eighty non-diabetic healthy subjects served as (matched) controls. Finally, 75 patients with Type 1 (insulin-dependent) diabetes mellitus (33 male, 43 female; age 34,1 (18-60) yrs, diabetes duration: 11,1 (0,3-41) yrs) and 68 patients with Type 2 (non-insulin-dependent) diabetes mellitus (31 male, 37 female, age: 61,4 (37-88) yrs, diabetes duration: 10,7 (0,3-40) yrs) were studied and compared with two cohorts of controls of the same size. There were no differences in prevalence of symptoms referrable to the upper and lower GI-tract in type 1 diabetic patients as compared with controls. Among patients with type 2 diabetes the main gastrointestinal complaint was constipation (22,1% vs 10,3%; p < 0.05). Upper gastrointestinal symptoms were also more frequent among Type 2 diabetic subjects (nausea 11,8% vs 2,9%, p < 0.05). There was a tendency for an increased symptom prevalence with higher age in both type 1 and type 2 diabetes. Presence of peripheral neuropathy was associated with a higher symptom prevalence in type 1 diabetes. After stratification, diabetes duration and glycaemic control (HbA1c) did not influence the frequency of symptoms. Thus, gastrointestinal symptoms occur frequently among both diabetic patients and non-diabetic subjects. However, significant differences were found only in type 2 (non-insulin-dependent) diabetes, the commonest symptom being constipation. These findings support the need of a nondiabetic control group in epidemiological studies evaluating symptom prevalence in diabetes mellitus.
Adolescent↗
Platelets deficient in glycoprotein IIIb aggregate normally to collagens type I and III but not to collagen type V.
The aggregation of platelets induced by collagens is considered an important step in primary hemostasis. Glycoprotein (GP) IIIb (GPIIIb, GPIV, CD36) has been proposed as a blood platelet receptor for collagen. Platelets from three healthy blood donors were shown to be clearly deficient in GPIIIb. These platelets aggregated normally in response to type I and III collagens. In addition, platelet factor 4, beta-thromboglobulin, and adenosine triphosphate (ATP) secretion in response to type I and III collagens was normal. The findings indicate that GPIIIb is not the major, essential collagen receptor for type I and III collagens. This would explain why all individuals with GPIIIb-deficient platelets examined so far are healthy and, in particular, show no apparent evidence of hemostatic problems. However, in contrast to control platelets, no aggregation and impaired platelet factor 4, beta-thromboglobulin, and ATP secretion was observed in response to type V collagen. Therefore, it is postulated that for type V collagen-induced aggregation both GPIa/IIa and GPIIIb are essential.
Adult↗
White cell and thrombocyte disorders. Standardized, self-learning flow cytometric list mode data classification with the CLASSIF1 program system.
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Autoanalysis↗
[Optic neuropathy in type-1 diabetes and acetylsalicylic acid-refractory thrombocyte activation].
A 26-year-old female with severe complications from type I diabetes mellitus of 17 years' duration (proliferative retinopathy, nephropathy with renal failure and nephrotic syndrome) developed rapid deterioration of vision in the right eye to 6/60 over a period of several weeks. There were no other neurological signs. Ophthalmological examination showed no worsening of the diabetic retinopathy, but the presence of bilateral optic atrophy, confirmed by visual evoked potentials. CT scan did not reveal any retrobulbar process, and MR scans of both the optic nerves and the visual pathways were unremarkable. The clinical features and the investigations pointed towards ischaemic optic atrophy. Detailed platelet studies showed intravascular platelet activation and an ADP-inducible increase in aggregation, although thromboxane formation was almost absent because of cyclooxygenase inhibition by acetylsalicylic acid. These findings suggest that the ischaemia was due to microcirculatory disturbances secondary to diabetic microangiopathy and platelet hyperreactivity.
Adult↗
Enhancement of spontaneous fibrinolytic activity in diabetic retinopathy.
The fibrinolytic system was studied in 96 patients with type I diabetes mellitus. Patients were grouped according to their degree of retinopathy; 38 patients with no evidence of retinopathy, 28 patients with background retinopathy and 30 patients with proliferative retinopathy. Thirty healthy individuals served as controls. The basal fibrinolytic activity as measured by clot lysis time and t-PA activity was increased in diabetic patients. This was associated with low levels of plasminogen activator inhibitor. Increased levels of D-dimer in diabetic patients further indicate enhanced in vivo fibrinolysis. The increase in fibrinolytic activity was highest in diabetics without retinopathy, and decreased with increasing retinopathy. Endothelial release of t-PA after venous occlusion was not different between controls and all diabetic groups. These findings suggest that in type I diabetics the fibrinolytic system is in an activated state. With worsening of retinopathy this increase in fibrinolytic activity diminishes.
Adolescent↗
Increased GPIIB/IIIA expression and altered DNA-ploidy pattern in megakaryocytes of diabetic BB-rats.
Hyperactive platelets contribute to angiopathic complications in diabetes mellitus. It is unclear whether the increased platelet function is a primary pathogenetic factor in diabetes or follows vascular injury. Increased platelet size and numbers of glycoprotein receptors on diabetic platelets suggest that thrombopoiesis is altered in diabetes mellitus. For further support of this hypothesis we studied whether megakaryocytes are changed with regard to the DNA-ploidy pattern and the GPIIB/IIIA expression in 10 acute diabetic (AD) and 24 insulin treated diabetic (ITD) BB rats in comparison with 22 diabetes resistant (ND) BB rats. In the AD group megakaryocyte size (P = 0.035) and the modal DNA-ploidy distribution dropped (P = 0.0001) concomitant with increased TNF-alpha activity (P = 0.001). GPIIB/IIIA expression and the peripheral platelet status were unchanged. After 4 weeks of insulin substitution metabolic parameters (glucose, cholesterol, triglycerides) were lowered, but remained still elevated. As compared to the AD group the modal DNA-ploidy pattern reversed, but the relative percentage of 64n megakaryocytes increased 2.3-fold and GPIIB/IIIA expression increased 1.6-fold. Simultaneously, the peripheral platelet count and size increased. From these results we conclude that alterations of the megakaryocyte compartment occur at early onset of diabetes. These changes could reflect a response to increased systemic cytokine production during inflammatory islet cell destruction. The peripheral platelet thrombotic potency increased with insulin treatment. This was associated with an increase of 64n-megakaryocytes with upregulated GPIIB/IIIA expression and could reflect a mitogenic effect of insulin upon the endomitotic cycle of the megakaryocytes.
Animals↗
[Diabetic cardiopathy. Pathophysiologic concepts and therapeutic approaches].
Epidemiological data reviewed suggest that diabetes itself increases the cardiac risk of diabetics (types I and II), independently from the development of coronary heart disease and in addition to other risk factors (hypertension, hypercholesterolemia, hypertriglyceridemia, smoking and others), presumably by a specific myocardial disease called "diabetic cardiopathy", or according to the recommendations of the WHO, "diabetic heart muscle disease." Disturbances of the left and right ventricular function as well as the autonomic function of the heart can be understood as signs of this specific cardiopathy. The pathophysiological mechanisms underlying this disease are not yet fully known; however, recent evidence is presented that diabetes leads to a facet of metabolic dysfunctions regarding glucose and energy metabolism, calcium homeostasis and the expression of specific proteins that diminish the ability of the heart to respond to increased workload and increase the vulnerability of the heart in diabetes. Since preliminary experimental data indicate that inhibitors of the angiotensin-converting enzyme can protect the heart in diabetes, it is intriguing to suggest that increased release of angiotensin II plays a significant role in the change from reduced adaptability to irreversible damage of the heart in diabetes.
Angiotensin-Converting Enzyme Inhibitors↗
Thrombospondin binds normally to glycoprotein IIIb deficient platelets.
Glycoprotein IIIb (GPIV, CD36) has been proposed as the platelet receptor for thrombospondin (TSP). We found two healthy blood donors, whose platelets were shown to be GPIIIb deficient. These platelets expressed endogeneous TSP as control platelets and their binding capacity for exogeneous TSP was the same. These results indicate that GPIIIb is not the major TSP receptor on platelets. However, it is not yet possible to exclude that in GPIIIb-deficient platelets other proteins may substitute for GPIIIb in TSP binding.
Adult↗
Increase in the cytosolic concentration of calcium in platelets of diabetics type II.
The intracellular concentration of calcium (Cai) was measured in platelets of healthy control subjects and diabetics type II. Cai was elevated in platelets of diabetics type II under basal conditions, after stimulation by collagen, in the presence and absence of calcium in the incubation medium. The increase in Cai after stimulation by collagen was inhibited by nitrendipine in both kinds of platelets, however Cai remained elevated in platelets of diabetics. Our data and findings of others may be understood as indications of disturbances in the handling of Cai in diabetes.
Aged↗
Circulating activated platelets in myeloproliferative disorders.
Platelet activation in patients with myeloproliferative disorders is often suggested by increased platelet alpha-granule secretion and an acquired storage pool defect of dense granules. To determine whether activated platelets circulate in patients with chronic myeloproliferative disorders, we evaluated the binding of monoclonal antibodies against activation-dependent epitopes on resting platelets (P 12, CD 63, and CD 62) in 12 patients with prominent megakaryocytic proliferation (8 patients with essential thrombocythemia, 2 with chronic myeloid leukemia, and 2 patients with polycythemia rubra vera). In addition, platelet aggregation in response to collagen, adenosine diphosphate, platelet activating factor, and agglutination with ristocetin was investigated. In 3 patients there was an increased percentage of platelets binding at least 1 activation marker. In 2 other patients, a trend towards increased antibody binding was observed. Binding of the antibody to thrombospondin (P 12) was related to expression of the GMP 140 protein (CD 62, r = 0.76, p = 0.004). There was no correlation of platelet aggregation defects in vitro to increased expression of platelet activation markers or to thrombohaemorrhagic complications. However, circulating activated platelets were detected in three out of five patients with a history of bleeding or thrombotic complications. The results of this preliminary study suggest that some but not all patients with myeloproliferative disorders showed increased amounts of circulating activated platelets. The relation of bleeding and thrombotic complications to the expression of activation-dependent epitopes on platelets in myeloproliferative disorders requires further investigation.
Adult↗
Epidemiology of faecal incontinence in selected patient groups.
It is known that only a minority of patients with faecal incontinence report these symptoms to their physicians. Epidemiological estimates based on medical chart data, therefore, may contain a detection bias. To evaluate such bias in epidemiological data, we evaluated prospectively the presence of faecal incontinence in selected patient groups with a proven high incidence of such symptoms and compared it to the incidence in a group of healthy controls. If the patient acknowledged faecal incontinence in the questionnaire, the medical chart was checked to see if these symptoms had been noted during previous work-up; this was used to estimate the number of unregistered cases if the epidemiological estimate is based on medical chart data. The incidence of incontinence was significantly elevated in all patient groups as compared to the controls, but only up to 5% of patients with faecal incontinence, regardless of the underlying mechanism, had these incontinence symptoms noted in the medical charts. We conclude that for the estimation of the prevalence and incidence of faecal incontinence, data from medical charts contain a detection bias which systematically underestimates the real presence of faecal incontinence.
Adult↗
Decreased expression of adhesion molecules on monocytes in recent onset IDDM.
The expression of adhesion molecules in monocytes of patients with recent onset type I diabetes was analysed. Monocytes were identified as CD14-positive cells by flow cytometry. The percentage of monocytes expression LFA-1 alpha, ICAM-1 and HLA-DR was slightly lower in recent onset type I diabetes (n = 13) compared to normal subjects (n = 15) and was significantly decreased after activation of cells with lipopolysaccharide and interferon-gamma for 5-24 hr. Receptor densities on adhesion molecule-positive monocytes and the expression of LFA-1 beta were normal. These data indicate that monocyte trafficking is abnormal in recent onset type 1 diabetes.
Adolescent↗
Determination of platelet activation by assaying filamentous actin and detecting membrane alterations.
Thrombin stimulation of human gel-filtered platelets in an unstirred system (without aggregation) results in actin polymerisation. Concomitantly with actin polymerisation the activation markers (CD 63--glycoprotein 53, a 53 kD lysosomal protein and CD 62--GMP 140, a 140 kD alpha granule protein) increase on the platelet membrane as well as the specific binding of monoclonal antibodies to thrombospondin (P 10). Consequently, both assays run in parallel and indicate sensitively platelet activation. Our data also indicate that exposure of subcellular structures following granule fusion is a very early event when platelets are challenged by thrombin and involve a reorganisation of cytoskeletal structures. Cytochalasin E inhibits completely the thrombin-induced actin polymerisation and the platelet aggregation but only partially the thrombin-induced exposure of CD 63. The activation markers CD 62 and P 10 were not influenced.
Actins↗
[Acute effects of extracorporeal LDL cholesterol and fibrinogen elimination on blood rheology and microcirculation].
Long-term intermittent heparin-induced extracorporeal low-density lipoprotein (LDL)-cholesterol precipitation was performed in three men - aged 32, 52 and 56 years - with severe familial hypercholesterolaemia and angiographically demonstrated coronary heart disease. This significantly lowered by 65-70% their LDL-cholesterol concentration and by 48-54% their fibrinogen concentration. Fibrinogen elimination reduced plasma viscosity by 13-14% and clearly raised the transcutaneously measured partial pressure of oxygen by 33-50%. Clinically the improved microcirculation achieved a decrease in angina symptoms: the walking distance of the 52-year-old man increased from about 100 m to 4000 m, the daily need of glyceryl trinitrate falling from an average of 12 to 4 aerosol doses.
Adult↗