Platelet spreading in diabetes mellitus

In 162 test persons divided into healthy control persons and diabetics of type I and type II the thrombocyte spreading was investigated according to the method of Breddin. Age, sex, degree of seriousness of retinopathy, duration of diseases, present level of blood sugar and HbA1 concentration were taken into account. Spread thrombocyte forms were increasingly found in old age, in diabetics of both types and a close relation to the extent of retinopathy was evident. As diabetic retinopathy became evident and with growing degree of seriousness, spread forms of thrombocytes were increasingly found, so that the increased spreading capacity may be interpreted as a disturbed metabolic and blood vessel situation in diabetes mellitus.     

Diabetic retinopathy and its association with limited joint mobility

Limited joint mobility (LJM) of the small joints of the hands was studied in 63 adult insulin-dependent diabetics to determine whether LJM might serve as an indicator to the presence of diabetic retinopathy in diabetics of long duration. In 123 non-diabetic controls, and in the 63 diabetics, the prevalence of LJM increased with age. In the diabetics, LJM was not associated with retinopathy, long-term glycaemic control or HLA type. The hypothesis that LJM is useful as a predictor of the development of retinopathy in young diabetics does not extend to older diabetics of long duration. LJM and retinopathy may have a different pathophysiology.     

The influences of islet transplantation on metabolic abnormalities and diabetic complications

To assess the long-term effect of islet transplantation on metabolic abnormalities and chronic complications of diabetic recipients, the long-term follow-up data of 36 type 1 diabetic subjects with functioning islet grafts for more than 1 year were analysed in this article. 36 type 1 diabetics, with mean age of 34.30 +/- 12.05 yr and mean duration of 11.53 +/- 5.29 yr, were followed up for a mean period of 29.39 +/- 9.50 mo after successfully transplanting with short-term cultured islet tissue of human fetal pancreases. The effect of islet transplants was identified as excellent in 13 subjects, good in 12 and fair in 11. The comparative studies were carried out of the mean levels of serum C-peptide, plasma glucose, GHb and GPP, serum lipids, and mean excretion of urine sugar, and the diabetic retinopathy, nephropathy as well as the autonomic neuropathy before transplantation in comparison with those of the present. The results of the study demonstrated that islet transplants could improve the function of islet B cells and the glucose metabolism, and might delay the development of diabetic retinopathy, nephropathy and autonomic neuropathy in successfully transplanted diabetic recipients, but not exert any influences on those of patients in fair group.     

Multivariate analysis for the understanding of typical diabetic hemostasis criteria. 1: Plasma markers]

In 309 patients investigations were made into the functions of blood coagulation with special consideration of numerous metabolic criteria. They referred to 111 healthy control persons and 198 patients with diabetes mellitus, 67 of them being of type I and 131 of type II. From a variety of metabolic characteristics and haemostasis optimal criteria were determined by means of the statistical method of multivariance analysis, which enables a distinction to be made between diabetics of type I, type II and healthy persons. Among those 13 characteristics detected as optimal amount there were thrombin time, thrombin coagulase time as parameter of haemostasis both before and after venous congestion, reptilase time prior to venous congestion and fibrinogen concentration after it. Thus, these coagulation factors indicate a different behaviour in both types of diabetes and in healthy control persons.     

Obesity--a risk factor for diabetic retinopathy in type 2 diabetes?

The aim of the study was to investigate whether obesity, independently or associated with other risk factors, increases the risk for the diabetic retinopathy in type 2 diabetic persons. Data of 156 diabetic persons that have consecutively attended the Outpatient Department in the Vuk Vrhovac Institute in Zagreb during two months period were studied. According to their body mass index (BMI) they were divided into three groups: group 1 (BMI < or = 25; n = 49), group 2 (BMI 26-29.9; n = 52) and group 3 (BMI > or = 30; n = 55). The three groups did not differ in age, duration of diabetes, treatment, cholesterol, HDL-cholesterol and triglycerides. With increase in BMI, we observed a significant deterioration of HbA1c and a significant increase in LDL-cholesterol, systolic and diastolic blood pressure. Statistical analyses shown that the prevalence of retinopathy increased significantly with higher body weight (gr. 1: 40.8%, gr. 2: 63.4%, gr. 3: 63.6%;p < 0.05), but also with correlation to quality of metabolic control (HbA1c) and systolic blood pressure. Therefore, obesity may be, because of its significant correlation to quality of metabolic control (HbA1c) and systolic blood pressure, considered as risk factor for diabetic retinopathy in type 2 diabetic persons.     

Normal tissue plasminogen activator and plasminogen activator inhibitor activity in plasma from patients with type 1 diabetes mellitus.

The fibrinolytic system was investigated in 38 patients (21 males and 17 females) affected by type 1 diabetes mellitus (18 free from complications, 10 with retinopathy, and 10 with autonomic neuropathy) and in 8 healthy controls. Two separate fibrinolysis-stimulating tests were done: standardized venous occlusion and 1-desamino-8-D-arginine vasopressin infusion. Plasma tissue plasminogen activator antigen and activity and plasma plasminogen activator inhibitor activity were measured. All the patients were in good metabolic control (mean HbA1c 7.4%, range 6.1-8.0%). No significant differences were observed either between the diabetic patients and the control subjects, nor among the subgroups of diabetic patients. The fibrinolytic system is probably not involved in type 1 diabetes mellitus.     

Clinical disorders of fibrinolysis: a critical review

Much progress has recently been made in understanding the biochemistry and physiology of endogenous fibrinolysis. As a result, a better understanding of the mechanisms and clinical consequences of disordered fibrinolysis has emerged. Increased fibrinolytic activity is an uncommon but important cause of hemorrhagic disease. Congenital disorders of fibrinolysis which cause bleeding include increased plasma plasminogen activator activity and deficiency of alpha-2 antiplasmin. Acquired disorders associated with increased fibrinolytic activity and bleeding include liver cirrhosis, amyloidosis, acute promyelocytic leukemia, some solid tumors, and certain snake envenomation syndromes. Increased fibrinolysis is important to recognize because epsilon-aminocaproic acid (EACA) may be required to prevent or control bleeding. Diminished fibrinolytic activity has been associated with a variety of thrombotic disorders, but a direct cause-and-effect relationship has yet to be established. Congenital abnormalities of fibrinolysis associated with thrombosis include plasminogen deficiency, decreased endothelial generation of plasminogen activator activity, and certain abnormal fibrinogens. Thrombosis in these disorders is effectively managed with warfarin. Diminished fibrinolysis has also been reported in "idiopathic" venous thrombosis, oral contraceptive-induced and post-operative venous thrombosis, coronary artery disease, cerebrovascular disease, systemic lupus erythematosus, and thrombotic thrombocytopenic purpura, but the significance of abnormal fibrinolysis in these disorders is uncertain. Large, prospective studies of fibrinolytic variables as risk factors for vascular and thrombotic disease are needed to determine whether pharmacologic augmentation of impaired fibrinolysis could be useful in the prevention or treatment of these disorders.     

Visceral fat is a determinant of PAI-1 activity in diabetic and non-diabetic overweight and obese women.

Plasminogen activator inhibitor type 1 (PAI-1), an inhibitor of fibrinolysis and an important and independent cardiovascular risk factor, has been shown to be elevated in obesity and type 2 diabetes. Recent study results have suggested that adipose tissue--visceral fat in particular--could play an important role in the fibrinolytic process.In order to assess the specific role of this fat distribution, we measured PAI-1 activity (AU/ml) and visceral fat (CT-scan at level L4-L5) in 2 groups of 30 overweight and obese diabetic and overweight and obese non-diabetic women. Subjects were matched for age, weight, body mass index, fat mass and total abdominal fat. Visceral adipose tissue and PAI-1 were significantly higher in diabetic women (p = 0.022 and p = 0.004 respectively) than in non-diabetic patients. Visceral fat correlated significantly with PAI-1 activity, even after correction for insulin and triglycerides (r = 0.28, p = 0.034). Stepwise regression analysis showed visceral fat as the most important determinant factor for PAI-1 in the whole group and in the non-diabetic group. In the diabetic group, fasting insulin was the most important determinant. These results show that visceral fat is more important than BMI or total body fat in the determination of PAI-1 levels. Furthermore, the increased amount of visceral fat in type 2 diabetics may contribute to the increase of PAI-1 activity levels and the subsequent increased risk for thrombovascular disease, regardless of BMI and total fatness.     

Multivariate analysis for the understanding of typical diabetic hemostasis criteria. 3. Determination of a typical retinopathy parameter-constellation]

Features of metabolism and haemostasis which are different in diabetics of both types in comparison with normal subjects were covered by the statistical method of multivariance analysis depending on the severity of diabetic retinopathy. In 29 diabetics without retinopathy, 46 patients with stage I or II, and 36 patients with stage III the following parameters could be found as optimal criteria for characterizing the extent of vascular changes: blood sugar concentration, concentration of sialic acid and HDL cholesterol in the serum, serum protein, sialic acid per protein volume, total cholesterol in the serum and capillary fragility and number of large spreading forms of platelets features of hemostasis. Thus, diabetic retinopathy is characterized by a wide spectrum of different features containing the parameters of hemostasis. Thrombocytic vascular interactions are characterized by platelet spreading and capillary fragility which are significant for the development of diabetic retinopathy.     

Red blood cell deformability index in diabetic retinopathy

In order to investigate the relationship between haemorheological disturbances and diabetic microangiopathy we have studied the red blood cell deformability index (RBCD-index) by means of a filtration technique in 69 diabetics, aged 49-83 years, and in 40 non diabetic healthy controls (group A) of respective age and sex. The diabetics were classified into the following groups, according to the findings of a thorough clinical and laboratory investigation. Twenty patients (group B) were free of vascular complications, whereas 9 (group C) suffered from background retinopathy, 27 (group D) background retinopathy and ischaemic cardiopathy or peripheral arterial occlusive disease and 13 (group E) of proliferative retinopathy with diffuse micro- and macroangiopathy. The RBCD-index was significantly (P less than 0.001) decreased in diabetics with retinopathy compared to the diabetic and non diabetic controls. The lowest RBCD-index was observed in diabetics with proliferative retinopathy and in those with diffuse micro- and macrovascular complications (RBCD-index, means +/- SDM ml/min: A 0.68 +/- 0.15; B 0.64 +/- 0.08; C 0.60 +/- 0.08; D 0.49 +/- 0.09; E 0.48 +/- 0.09). These findings suggest that the RBCD is impaired in diabetics with retinopathy, especially in those with severe vascular complications, and that this abnormal rheological behavior of erythrocytes can be found even in the early stages of diabetic microangiopathy.     

Deep venous thrombosis of the arm: a study of coagulation and fibrinolysis.

Sixty consecutive patients with phlebographically verified deep venous thrombosis of the upper arm were studied for disorders of coagulation and fibrinolysis. No appreciable increase in abnormalities of the factor VIII complex, antithrombin III, or inhibitors of activators of fibrinolysis were found. A decreased fibrinolytic defence mechanism, evident either as a deficient release capacity of fibrinolytic activators from the vein during stasis or as decreased fibrinolytic activity in the vein wall as determined histochemically, was found in 26 out of 53 patients studied (49%). It is concluded that deep venous thrombosis of the upper arm is a multifactorial disease. An impaired fibrinolytic defence mechanism is one of the factors that may be of pathogenetic importance.     

Proliferative diabetic retinopathy is associated with a low level of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor. a pilot study.

Retinopathy is the most common microvascular diabetes complication and represents a major threat to the eyesight. The aim of this study was to address the role of pro- and anti-angiogenic molecules in diabetic retinopathy in the aqueous humor of the eye. Aqueous humor was collected at cataract surgery from 19 diabetic patients and from 13 age- and sex-matched normoglycemic controls. Levels of pro-angiogenic vascular endothelial growth factor (VEGF) and angiogenic inhibitor pigment epithelium-derived factor (PEDF) were determined. Angiogenic activity of the aqueous humor was quantified by measuring its effect on the migration of capillary endothelial cells. In the aqueous fluid, VEGF levels were increased in diabetics (mean values: 501 vs. 367 pg/ml; p = 0.05), compared to controls. PEDF was found to be decreased in diabetics (mean values: 2080 vs. 5780 ng/ml; p = 0.04) compared to controls. In seven diabetic patients with proliferative retinopathy, the most profound finding was a significant decrease of the PEDF level (mean value: 237 ng/ml), whereas VEGF levels were comparable to diabetic patients without proliferation (mean value: 3153; p = 0.003). Angiogenic activity in samples of patients from the control group was generally inhibitory due to PEDF, and inhibition was blocked by neutralizing antibodies to PEDF. Likewise, in diabetics without proliferation, angiogenic activity was also blocked by antibodies to PEDF. We will demonstrate here that the level of the natural ocular anti-angiogenic agent PEDF is inversely associated with proliferative retinopathy. PEDF is an important negative regulator of angiogenic activity of aqueous humor. Our data may have implications for the development of novel regimens for diabetic retinopathy.     

Rapid tightening of blood glucose control leads to transient deterioration of retinopathy in insulin dependent diabetes mellitus: the Oslo study.

In a study of retinopathy during one year of tight blood glucose control 45 type I (insulin dependent) diabetics without proliferative retinopathy were randomised to receive either continuous subcutaneous insulin infusion, multiple insulin injections, or conventional insulin treatment (controls). Near normoglycaemia was achieved with continuous infusion and multiple injections but not with conventional treatment. Blind evaluation of fluorescein angiograms performed three monthly showed progression of retinopathy in the control group, transient deterioration in the continuous infusion group, and no change in the multiple injection group. Half the patients receiving continuous infusion and multiple injections developed retinal cotton wool spots after three to six months. These changes regressed in all but four patients after 12 months. Control patients did not develop cotton wool spots. Patients who developed cotton wool spots are characterised by a larger decrement in glycosylated haemoglobin and blood glucose values, more frequent episodes of hypoglycaemia, a longer duration of diabetes, and more severe retinopathy at onset. A large and rapid fall in blood glucose concentration may promote transient deterioration of diabetic retinopathy.     

Serum N-acetyl-beta-D-glucosaminidase (NAG) activity in patients with diabetes mellitus with reference to diabetic microangiopathy]

In 110 diabetics type I and type II and in 30 control subjects the total serum activity of NAG as well as of its isoenzymatic forms A and B was determined. In cases with diabetic nephropathy the GFR and serum creatinine was also analysed. It was found that NAG activity is correlated to the degree of clinical symptoms of diabetic vascular changes. Therefore it could be suggested that NAG plays a role in development of microangiopathy. NAG determination may also serve as an index differentiating the diabetic microangiopathy from other forms of microvessels.     

Low phospholipid arachidonic acid values in diabetic platelets.

Platelet aggregation is enhanced in diabetes mellitus, and platelets may be implicated in the pathogenesis of diabetic angiopathy. Increased platelet aggregation is probably mediated by the production of the proaggregatory prostaglandin thromboxane, which is synthesised from arachidonic acid (C20:4) by the action of the platelet enzymes cyclo-oxygenase and thromboxane synthetase. The fatty acid composition of platelet phospholipid was measured in 20 normal controls, 10 insulin-treated diabetics with no or minimal retinopathy, and 10 insulin-treated diabetics with proliferative retinopathy. The percentage of arachidonic acid was significantly higher in controls (mean 22.6%) than in the diabetics with no or minimal retinopathy (mean 18.5%; p less than 0.025) and the diabetics with proliferative retinopathy (mean 14.6%; p less than 0.001). The percentage of linoleic acid was lower in controls (mean 8.9%) than in the diabetics with no or minimal retinopathy (mean 12.6%; p less than 0.01) and diabetics with proliferative retinopathy (mean 13.1%; p less than 0.001). The mean percentage of linolenic acid was significantly lower in the diabetics with proliferative retinopathy (2.7%) than in the normal control group (4.4%; p less than 0.01). A significant negative correlation was found between the percentages of arachidonic acid and glycosylated haemoglobin (Rs = -0.58; p less than 0.001). A significant positive correlation was found between linoleic acid and the percentage of glycosylated haemoglobin (Rs = 0.51; p less than 0.01). The reciprocal correlation between percentages of arachidonic acid and glycosylated haemoglobin suggests that diabetic control may influence thromboxane release and platelet activity directly and that low percentages of arachidonic acid reflect the increased degree of in-vivo activation.     

Serum angiotensin-converting enzyme in diabetes mellitus: a negative report

Serum angiotensin-converting enzyme (ACE) was measured by a direct photometric method in 78 normotensive diabetic patients and in 34 controls. For comparison, ACE was also assayed in 24 subjects by a radiometric procedure. We found no ACE elevations in diabetics and no significant difference in mean ACE levels between diabetics and normals. Within the diabetic group, enzyme levels were not affected by duration of disease, degree of metabolic control, or presence or not of microangiopathy. Only type I subjects had mean ACE significantly (p less than 0.05) higher than type II, very likely due to their younger age. Serum ACE data from photometric and radiometric methods significantly correlated. ACE measurement seems to be of scarce significance in diabetes mellitus.     

Progression of diabetic retinopathy and changes in serum insulin-like growth factor I (IGF I) during continuous subcutaneous insulin infusion (CSII)

The rise in serum IGF I concentration during continuous subcutaneous insulin infusion (CSII) may be a contributory factor in the deterioration of diabetic retinopathy that sometimes occurs during this treatment but the relation of serum levels to the severity of retinopathy has not been previously studied. In twelve non-obese insulin dependent diabetics (age range: 22-41 yrs) with mean +/- SD duration of diabetes: 14.8 +/- 4.7 yrs, serum IGF I concentration, HbA1 and retinopathy score were estimated prospectively over twelve months following the institution of CSII therapy. After four months of treatment, eight patients showed deterioration of retinopathy by at least one level of severity. Serum IGF I concentration rose from a mean +/- SEM of 155 +/- 17.7 micrograms/l at entry to 199 +/- 23.1 micrograms/l at four months and by twelve months had returned to near initial values 163 +/- 17.4 micrograms/l. There was however, no significant correlation between retinopathy score and serum IGF I level by analysis of variance for the whole group, or in the group of diabetics whose retinopathy deteriorated. The rise in IGF I concentration over the first four months and subsequent decline in IGF I values over the next eight months was inversely related to HbA1 concentration (r = -0.58; P less than 0.05). One patient with early ischaemic retinopathy on entry, experienced a marked rise in serum IGF I corresponding to a rapid tightening of glycaemic control. At four months she developed florid proliferative changes requiring panretinal laser therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oral administration of orinase (tolbutamide); clinical observations of effect on nondiabetic and diabetic humans

Ingestion of tolbutamide (Orinase(R)) by nondiabetic humans brought about a maximum reduction in blood sugar within one to two hours. In diabetic persons taking large doses of insulin, or who needed insulin for control, hyperglycemia, ketosis, and increased excretion of glucose in the urine developed when tolbutamide was substituted for insulin or was used before insulin therapy was begun. The only serious toxic manifestation observed was a skin rash in two patients. Successful control of diabetes with tolbutamide was limited to cases in which the disease was of mild, stable type and the patient was 40 or more years of age, of normal weight, and with a previous insulin requirement of 5 to 30 units per day. It was of benefit in 43.5 per cent of all diabetic patients in the series studied and in about 75 per cent of the group that might be referred to as selected. The duration of the disease and the duration of insulin therapy were unimportant in predicting effectiveness for tolbutamide therapy.     

In-vitro venous prostacyclin production,plasma 6-keto-prostaglandin F1 alpha concentrations,and diabetic retinopathy.

Previous studies have shown that vessels from diabetics produce less prostacyclin in vitro than those from normal controls. To determine whether this decreased production is related to complications elective biopsy of a superficial forearm vein was performed on 12 insulin-dependent male diabetics, six with nil or minimal and six with proliferative retinopathy, and seven male controls. Vein segments from the diabetics and controls produced similar amounts of prostacyclin in vitro (medians 0.11 and 0.19 ng/mg tissue respectively), but the segments from the diabetics with nil or minimal retinopathy produced less than those from the diabetics with proliferative retinopathy (medians 0.09 and 0.18 ng/mg respectively). Preoperative plasma immunoreactive concentrations of 6-keto-prostaglandin F1 alpha were not significantly different between the controls and the diabetics (medians 101 and 116 pg/ml respectively). In a separate study, however, 11 diabetics with duration of disease of over 10 years and nil or minimal retinopathy had significantly lower concentrations than a matched group of 16 with background or proliferative retinopathy (medians 79 and 121 pg/ml respectively). These results do not support an association between reduced prostacyclin production and diabetic retinopathy.     

Reversal of insulin resistance in type I diabetes after treatment with continuous subcutaneous insulin infusion.

Insulin responsiveness was studied with the euglycaemic glucose clamp technique in seven patients with type I diabetes and in six control subjects matched for age and weight. The glucose disposal rate was significantly reduced in the diabetic subjects when they were receiving conventional insulin treatment compared with the control group, showing insulin resistance in the diabetics. The diabetic patients were again studied after eight days of intensified metabolic control achieved with continuous subcutaneous insulin infusion. During the infusion a more physiological insulin regimen was used compared with their regular treatment, less of the total insulin dose being given as continuous infusion and more as bolus doses before meals. The insulin resistance in the diabetics was largely reversed after this improved metabolic control. Dose response studies showed an increased glucose disposal rate at all plasma insulin concentrations, including the maximum insulin concentration, indicating a predominant effect of the continuous infusion regimen at the postreceptor level. The improved insulin effect seen with continuous subcutaneous insulin infusion could be due to the improved metabolic control achieved as well as the more physiological regimen.