Activation of coagulation in diabetes mellitus in relation to the presence of vascular complications.

To examine the relationship between diabetic vascular disease and haemostasis, a set of sensitive assays has been used to assess in vivo activation of coagulation in 62 diabetic patients (41 Type 1 and 21 Type 2), aged 19-68 years, who had been screened for the presence of complications. Fibrinopeptide A, an index of thrombin activity, was significantly increased in diabetic patients compared with control subjects (p less than 0.05), in both plasma (with complications mean 8.04 +/- 11.87 (+/- SD); without complications 7.21 +/- 10.13; control subjects 2.11 +/- 1.40 micrograms l-1) and urine (with complications mean 1.48 +/- 0.74; without complications 1.35 +/- 0.62; control subjects 0.98 +/- 0.39 micrograms l-1). Activated factor VII (VIIa ratio 1.21 +/- 0.39; 1.13 +/- 0.23; 1.01 +/- 0.11) and fibrinogen (3.15 +/- 0.59; 3.11 +/- 0.69; 2.70 +/- 0.57 g l-1) were also elevated in diabetic patients with and without complications (VIIa p less than 0.05, fibrinogen p less than 0.01). The only difference between Type 1 and Type 2 patients was in fibrin degradation products (Type 1 0.28 +/- 0.18; Type 2 0.40 +/- 0.18 mg l-1, p less than 0.01). Plasma levels of fibrin degradation products were elevated in diabetic patients (p less than 0.05 vs control subjects), and correlated with age (r = 0.44, p less than 0.01) but were unrelated to the presence of complications. There were no significant differences in any coagulation variables between diabetic patients with and without complications.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood rheology and cardiovascular risk factors in type 1 diabetes: relationship with microalbuminuria.

Whole blood and plasma viscosity, erythrocyte aggregation and deformability, plasma fibrinogen, lipids, lipoproteins, apolipoproteins, and measures of blood glucose control were compared between 21 Type 1 diabetic patients with microalbuminuria (overnight albumin excretion rate 30-200 micrograms min-1) and 21 patients with albumin excretion below this range matched for age, sex, and duration of diabetes. Patients with microalbuminuria had significantly higher glycosylated haemoglobin (9.4 +/- 1.6 (+/- SD) vs 7.9 +/- 1.8% (normal range 5.0 to 7.6%)), total-cholesterol (5.6 +/- 1.1 vs 4.6 +/- 1.3 mmol l-1), apolipoprotein B (0.82 +/- 0.21 vs 0.66 +/- 0.14 g l-1), and apolipoprotein B:A1 ratio (0.58 +/- 0.18 vs 0.50 +/- 0.15) than those without microalbuminuria (all p less than 0.05). HDL-cholesterol was also raised (1.71 +/- 0.46 vs 1.43 +/- 0.37 mmol l-1, p less than 0.05). Lipoprotein(a) concentration was possibly higher in the microalbuminuric group (median (95% Cl) 105 (82-140) vs 72 (52-114) mg l-1, p = 0.06). No differences were seen in any of the rheological measurements. These results confirm the presence of potentially atherogenic lipoprotein changes in Type 1 diabetic patients with microalbuminuria, but suggest that altered blood rheology does not predate the development of nephropathy.     

von Willebrand factor and early diabetic retinopathy: no evidence for a relationship in patients with Type 1 (insulin-dependent) diabetes mellitus and normal urinary albumin excretion

Summary High plasma levels of von Willebrand factor, an indicator of endothelial cell dysfunction, have been reported in both diabetic retinopathy and nephropathy. It is unclear, however, whether von Willebrand factor is related to diabetic retinopathy in the absence of diabetic nephropathy. The relationship between retinal status and plasma von Willebrand factor concentration was investigated in a cohort of 17 patients with Type 1 (insulin-dependent) diabetes mellitus who were followed-up for a median of 42 months. The patients were examined three times. They were selected for having had normal urinary albumin excretion and no evidence of retinopathy (on fundoscopy) at the first and second examination. They were then divided into two groups, according to absence (Group A;n=9) or presence (Group B;n=8) of retinopathy on fundoscopy or fluorescein angiography at the third examination. Urinary albumin excretion remained normal in all patients. Plasma von Willebrand factor levels were similar in both groups: (median) 128 vs 123 %, 164 vs 132% and 159 vs 130 % (first, second and third examination, respectively). Median changes in plasma von Willebrand factor were also similar: +7 vs +9 % and +5 vs +1 % (first-second and second-third examination). Patients in whom the plasma von Willebrand factor concentration increased had higher systolic blood pressure at the third examination (150±30 vs 130±12 mmHg,p=0.02) when compared to those in whom plasma von Willebrand factor did not increase, but were of similar age and had similar diabetes duration, retinal status, diastolic blood pressure, glycated haemoglobin and serum cholesterol concentration. These data do not support the hypothesis that increases in plasma von Willebrand factor concentration reflect retinal endothelial injury in Type 1 diabetic patients with normal urinary albumin excretion. In these patients, high or increasing plasma von Willebrand factor levels may be related to systolic blood pressure.     

Blood glycogen and metabolic control in diabetes mellitus

The relationship between metabolic control and leukocyte glycogen content in diabetes mellitus was re-evaluated, blood glycogen being measured by an enzymatic procedure. In 30 healthy subjects, fasting blood glycogen averaged 50.6 +/- 2.8 mg l-1 or 7.45 +/- 0.42 ng 10(3)-cells-1, the latter value being unaffected during a 60-min period of induced hyperglycaemia. Comparable levels were found in 18 Type 1 insulin-treated diabetic patients (blood glycogen 50.4 +/- 4.6 mg l-1, leukocyte glycogen 6.92 +/- 0.50 ng 10(3)-cells-1), 6 insulin-treated diabetic patients presenting with chronic pancreatitis (blood glycogen 62.2 +/- 9.3 mg l-1, leukocyte glycogen 6.69 +/- 0.70 ng 10(3)-cells-1) and 12 Type 2 insulin-treated patients (blood glycogen 53.7 +/- 4.3 mg l-1, leukocyte glycogen 7.51 +/- 0.44 ng 10(3)-cells-1). In severely ketotic patients, leukocyte counts and blood glycogen (160.8 +/- 29.6 mg l-1, p less than 0.01 vs stable diabetic patients) were increased, but the leukocytic glycogen content was not significantly affected either before or during intensive insulin therapy and rehydration. The leukocyte glycogen content was abnormally low, however, in 9 untreated Type 2 diabetic patients (5.29 +/- 0.39 ng 10(3)-cells-1, p less than 0.02 vs healthy subjects) and abnormally high (10.77 +/- 0.65 ng 10(3)-cells-1, p less than 0.005 vs healthy individuals) in 30 Type 2 patients treated by sulphonylurea, alone or in combination with insulin. No correlation was found between leukocyte glycogen and either fasting plasma glucose or HbA1c.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contrasting fibrinolytic responses in type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes.

To study fibrinolysis in relation to microvascular diabetic complications, 20 control subjects were compared with 50 Type 1 (insulin-dependent) diabetic patients of similar age, 20 with no complications, 17 with laser-treated retinopathy, and 13 with neuropathy and retinopathy. None were smokers, hypertensive or had macrovascular disease. Pre- and post-venous occlusion blood samples for tests of fibrinolysis were taken. Median (interquartile range) basal tissue plasminogen activator (t-PA) activity was lower in control subjects (100 (less than 100-100) IU l-1) than diabetic patients (uncomplicated 145 (100-280) IU l-1, p = 0.015; retinopathy 180 (100-228) IU l-1, p = 0.037; neuropathy 210 (125-310) IU l-1, p = 0.004, respectively). Basal t-PA inhibition (PAl-1 activity) was higher in control subjects (5.9 (4.5-9.5) kIU l-1) than diabetic patients (uncomplicated 4.0 (3.3-5.0) kIU l-1, p = 0.001; retinopathy 4.5 (3.1-6.3) kIU l-1, p = 0.058; neuropathy 4.0 (3.0-5.4) kIU l-1, p = 0.015, respectively). Post-venous occlusion t-PA antigen was higher in control subjects (10.2 (7.3-15.1) micrograms l-1) than neuropathic patients (5.5 (4.9-7.3) micrograms l-1, p = 0.004). Other tests showed a consistent, but non-significant, trend towards increased basal fibrinolysis in the Type 1 diabetic patients. The results indicate that Type 1 diabetic patients have enhanced basal fibrinolysis. The diminished response to venous occlusion in neuropathic patients is consistent with an endothelial cell defect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of intensive dietary treatment on insulin-stimulated skeletal muscle glycogen synthase activation and insulin secretion in newly presenting type 2 diabetic patients

Ten newly presenting, untreated, Europid Type 2 diabetic patients were studied before and after 8 weeks treatment with intensive diet alone. Nine normal control subjects were also studied. The degree of activation of skeletal muscle glycogen synthase (GS) was used as an intracellular marker of insulin action, prior to and during a 240-min insulin infusion (100 mU kg-1 h-1). Fasting blood glucose decreased from 12.1 +/- 0.9 (+/- SE) to 9.2 +/- 0.8 mmol l-1 (p less than 0.01), but there was no change in fasting insulin concentrations, 9.9 +/- 2.3 vs 9.3 +/- 2.1 mU l-1. Fractional GS activity did not increase in the Type 2 diabetic patients during the insulin infusion either at presentation (change -1.5 +/- 1.9%) or after treatment (change +0.9 +/- 1.8%), and was markedly decreased compared with the control subjects (change +14.5 +/- 2.8%, both p less than 0.001). Glucose requirement during the clamp was decreased in the Type 2 diabetic patients at presentation (2.2 +/- 0.7 vs 7.3 +/- 0.6 mg kg-1 min-1, p less than 0.001), and despite improvement following dietary treatment to 3.3 +/- 0.6 mg kg-1 min-1 (p less than 0.01) remained lower than in the control subjects (p less than 0.001). Fasting plasma non-esterified fatty acid (NEFA) concentrations were elevated at presentation (p less than 0.05), and failed to suppress normally during the insulin infusion. After treatment fasting NEFA concentrations decreased (p less than 0.05) and suppressed normally (p less than 0.05). Insulin secretion was assessed following an intravenous bolus of glucose (0.5 g kg-1) at euglycaemia before and after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Free radical activity in type 2 diabetes

Free radical activity has been implicated in the development of diabetic vascular complications in Type 1 diabetes. The aim of the present study was to investigate the levels of free radical scavengers, particularly erythrocyte superoxide dismutase, plasma and erythrocyte lysate thiol, and caeruloplasmin in 22 Type 2 diabetic patients clinically free of complications, and 15 comparable non-diabetic control subjects. The concentration (median (range] of both superoxide dismutase (23 (10-39) vs 45 (25-75) mumol l-1; p less than 0.001) and plasma thiol (374 (172-523) vs 460 (386-595) mumol l-1; p less than 0.01) were reduced in the diabetic group. There were no significant differences in the concentration of erythrocyte lysate thiol (199 (114-520) vs 188 (114-328) mumol l-1) or plasma caeruloplasmin (18 (9-31) vs 24 (6-50) mumol l-1) between the groups. This reduction in superoxide dismutase and the imbalance in the redox status of the plasma and lysate thiol demonstrated is consistent with an increase in free radical activity in Type 2 diabetes.     

Beneficial effect of a low glycaemic index diet in type 2 diabetes.

Low glycaemic index foods produce low blood glucose and insulin responses in normal subjects, and improve blood glucose control in Type 1 and well-controlled Type 2 diabetic patients. We studied the effects of a low glycaemic index diet in 15 Type 2 diabetic patients with a mean fasting blood glucose of 9.5 mmol l-1 using a randomized, crossover design. Patients were given pre-weighed diets (59% energy as carbohydrate, 21% fat, and 24 g 1000-kcal-1 dietary fibre) for two 2-week periods, with a diet glycaemic index of 60 during one period and 87 during the other. On the low glycaemic index diet, the blood glucose response after a representative breakfast was 29% less than on the high glycaemic index diet (874 +/- 108 (+/- SE) vs 204 +/- 112 mmol min l-1; p less than 0.001), the percentage reduction being almost identical to the 28% difference predicted from the meal glycaemic index values. After the 2-week low glycaemic index diet, fasting serum fructosamine and cholesterol levels were significantly less than after the high glycaemic index diet (3.17 +/- 0.12 vs 3.28 +/- 0.16 mmol l-1, p less than 0.05, and 5.5 +/- 0.4 vs 5.9 +/- 0.5 mmol l-1, p less than 0.02, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasopressin secretion during insulin-induced hypoglycaemia: exaggerated responses in people with type 1 diabetes

Insulin hypoglycaemia causes a rise in plasma vasopressin concentrations in man and the rat, and vasopressin stimulates glucagon secretion and increases hepatic glucose output in man. Vasopressin has also been suggested to have an important synergistic role with corticotrophin releasing factor in the release of adrenocorticotrophin hormone, and a counter-regulatory role for the hormone has been proposed. As diminished anterior pituitary hormone responses to hypoglycaemia have been reported in diabetes mellitus, we studied the plasma vasopressin responses to insulin-induced hypoglycaemia in 10 patients with established Type 1 diabetes and 10 matched control subjects. Blood glucose fell from 4.5 +/- 0.3 to 1.6 +/- 0.1 mmol l-1 (p less than 0.001) in the diabetic group and from 4.6 +/- 0.2 to 1.5 +/- 0.2 mmol l-1 (p less than 0.001) in control subjects, with delayed blood glucose recovery in the diabetic patients. Plasma vasopressin rose in the diabetic patients from 0.9 +/- 0.2 to 6.9 +/- 2.8 pmol l-1 (p less than 0.001), a significantly greater rise (p less than 0.05) than in the control subjects, 0.8 +/- 0.1 to 2.4 +/- 1.0 pmol l-1 (p less than 0.001). Plasma osmolalities remained unchanged and haemodynamic changes were similar in both groups. There is an exaggerated rise in plasma vasopressin concentrations in diabetic patients in response to insulin-induced hypoglycaemia. The putative mechanisms and potential significance of the exaggerated rise are discussed.     

Impaired vascular function during short-term poor glycaemic control in Type 1 diabetic patients.

AIM: To study the effects of short-term poor glycaemic control on vascular function in Type 1 diabetic patients. METHODS: Ten Type 1 diabetic patients, with diabetes duration of less than 10 years and normal urinary albumin excretion and ophthalmoscopy, were studied. All patients were examined after 48 h of good vs. poor glycaemic control within a 3-week period. Blood glucose was measured seven times daily for 2 days before each examination. External ultrasound was used to measure the dilatory response of the brachial artery to post-ischaemic increased blood flow (endothelium-dependent dilation) and to nitroglycerin (endothelium-independent dilation). Plasma concentration of von Willebrand factor antigen, adhesion molecules, vascular endothelial growth factor, homocystein and cholesterol were also measured. RESULTS: The median blood glucose levels in the 48 h before the examinations were [median (range), good vs. poor control]: 6.3 (5.0-7.6) vs. 15.9 (11.3-17.8) (mmol/l). The flow-associated vasodilation (% of baseline) was reduced during poor control: 102.7 (94.7-110.8) vs. 104.0 (99.6-118.5) (P < 0.05) as were the nitroglycerin-induced dilation (% of baseline): 114.5 (103.3-127.9) vs. 120.2 (106.8-148.0) (P < 0.05). P-von Willebrand factor antigen was high during poor control (kIU/l): 1.14 (0.73-1.84) vs. 0.86 (0.72-1.39) (P < 0.05) and so was P-vascular endothelial growth factor (ng/l): 288 (133-773) vs. 254 (90-383) (P < 0.05). CONCLUSIONS: Short-term (48 h) hyperglycaemia in Type 1 diabetic patients may disturb vascular function, possibly mediated through smooth muscle cell dysfunction as well as endothelial dysfunction. We suggest that prolonged and repeated episodes of hyperglycaemia could possibly lead to permanent vascular dysfunction and thereby development and progression of vascular complications in diabetes.     

Efficacy and acceptance of two intensified conventional insulin therapy regimens: a long-term cross-over comparison

The efficacy and acceptability of multiple daily insulin injections (three preprandial injections of short-acting insulin (NovoPen) plus once daily extended-acting insulin) were compared with those of twice daily injections of short- and intermediate-acting insulin. Sixteen Type 1 diabetic patients participated in a cross-over study (6-month treatment periods). Total areas under 24-h plasma free insulin curves, assessed at the end of each study period, were not significantly different, but a greater area under this curve was found for the pen-injector regimen from 1200 to 1600 h (150 +/- 15 (SE) vs 106 +/- 7 mU l-1 h, p less than 0.01). Home blood glucose profiles showed significantly lower values with pen-injector therapy after lunch (7.1 +/- 0.6 vs 8.4 +/- 0.4 mmol l-1, p = 0.05) and before and after dinner (6.4 +/- 0.6 vs 8.8 +/- 0.5 mmol l-1, p less than 0.005, and 7.5 +/- 0.7 vs 9.4 +/- 1.1 mmol l-1, p less than 0.05). Mean daily blood glucose concentration was also lower (7.1 +/- 0.4 vs 8.2 +/- 0.5 mmol l-1, p less than 0.05). HbA1, fructosamine, hypoglycaemic reactions, and body weight were not significantly different. Thirteen patients decided to continue with pen-injector therapy at the end of the study.     

The relationship of oxidative stress to thrombotic tendency in type 1 diabetic patients with retinopathy.

Increased free radical activity may contribute to thrombosis via effects on platelet aggregation and the prostanoid balance. To investigate this further we studied 15 Type 1 diabetic patients with retinopathy, matched with uncomplicated Type 1 patients for age, duration of diabetes and HbA1, together with matched healthy non-diabetic control subjects. The oxidative effects of free radicals as total diene conjugates and lipid peroxides were measured, together with redox status extracellularly as plasma albumin-thiols and intracellularly as erythrocyte superoxide dismutase activity. Platelet count, aggregation of platelets in whole blood to collagen, thromboxane B2, and prostacyclin stimulating factor (PGI2SF) were also assessed. Free radicals measured as lipid peroxides were significantly higher (9.6 (8.1-11.6) mumol l-1 (median and interquartile range) in diabetic patients with retinopathy than in control subjects (8.1 (7.4-9.2) mumol l-1; p less than 0.05). There were also significant reductions in redox status both extracellularly as plasma albumin thiols (408 (383-473) vs 490 (456-517) mumol l-1, p less than 0.001) and intracellularly as erythrocyte superoxide dismutase activity (34 (27-41) vs 44 (36-51) g l-1, p less than 0.05) between patients with retinopathy and control subjects. Platelet counts were increased in diabetic patients with retinopathy (p less than 0.05), as was collagen-induced platelet aggregation (p less than 0.01). Prostacyclin stimulating factor was reduced in patients with retinopathy (p less than 0.05) and correlated within the plasma with lipid peroxides (r = -0.53, p less than 0.04) and albumin thiols (r = 0.64, p less than 0.01). The results suggest that diabetic patients, particularly with retinopathy, are under oxidative stress and have an increased thrombotic tendency with increased platelet reactivity and a reduction in prostacyclin stimulating factor.     

The use of low glycaemic index foods improves metabolic control of diabetic patients over five weeks.

The aim of the present study was to determine whether any benefit might occur from lowering the glycaemic index of diet in the medium term in diabetic patients. Eighteen well-controlled diabetic patients (12 Type 1 and 6 Type 2 non-insulin-treated), were assigned to either a high mean glycaemic index or low mean glycaemic index diet for 5 weeks each in a random order using a cross-over design. The two diets were equivalent in terms of nutrient content and total and soluble fibre content. The glycaemic indices were 64 +/- 2 (mean +/- SD) % and 38 +/- 5% for the two diets. The high glycaemic index diet was enriched in bread and potato and the low glycaemic index diet in pasta, rice, and legumes. At the end of the study periods, the following variables were improved on the low compared to the high glycaemic index diet: fructosamine (3.9 +/- 0.9 vs 3.4 +/- 0.4 mmol l-1, p less than 0.05); fasting blood glucose (10.8 +/- 2.8 vs 9.6 +/- 2.7 mmol l-1, p less than 0.02); 2-h postprandial blood glucose (11.6 +/- 2.9 vs 10.3 +/- 2.5 mmol l-1, p less than 0.02); mean daily blood glucose (12.0 +/- 2.5 vs 10.4 +/- 2.7 mmol l-1, p less than 0.02); serum triglycerides (1.5 +/- 0.9 vs 1.2 +/- 0.6 mmol l-1, p less than 0.05). No significant differences were found in body weight, HbA1C, insulin binding to erythrocytes, insulin and drug requirements, and other circulating lipids (cholesterol, HDL-cholesterol, phospholipids, Apolipoprotein A1, Apolipoprotein B). Thus the inclusion of low glycaemic index foods in the diet of diabetic patients may be an additional measure which slightly but favourably influences carbohydrate and lipid metabolism, requires only small changes in nutritional habits and has no known deleterious effects.     

Double-blind placebo-controlled study of the effects of bezafibrate on blood lipids, lipoproteins, and fibrinogen in hyperlipidaemic type 1 diabetes mellitus

The effects of bezafibrate 400 mg day-1 or placebo administered for 3 months, were compared in 36 patients with stable Type 1 diabetes and hypercholesterolaemia and/or hypertriglyceridaemia. Baseline characteristics of the 17 bezafibrate- and 19 placebo-treated patients were comparable in most respects with the exception of concentrations of fasting serum triglycerides and blood glucose which were lower (NS) and plasma fibrinogen which were higher (p less than 0.05), in those later treated with bezafibrate. Serum cholesterol concentrations decreased after 3 months bezafibrate treatment (from 7.1(0.2) (SE) to 6.3 (0.3) mmol l-1, p less than 0.05), predominantly due to a reduction in low density lipoprotein (LDL) cholesterol (from 4.8(0.3) to 4.2(0.3) mmol l-1, p less than 0.05). Over the same period bezafibrate reduced serum triglycerides from 1.78 (95% Cl 1.23-2.57) to 1.26(1.02-2.09) mmol l-1 (p less than 0.05), and plasma fibrinogen from 4.1(0.2) to 2.9(0.2) g l-1, p less than 0.001. Serum apolipoprotein B and apolipoprotein (a) showed no statistically significant changes. Overall there was no change in high density lipoprotein (HDL) cholesterol. However, in patients who were initially hypertriglyceridaemic there was significant increase in the cholesterol content of HDL and the HDL2-cholesterol subfraction (both p less than 0.05). After 3 months treatment with bezafibrate, fasting blood glucose levels were reduced from 8.5(1.1) to 6.4(0.7) mmol l-1, p less than 0.05, without any change in glycosylated haemoglobin (9.2(0.4) to 9.1(0.5)%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired vascular reactivity is present despite normal levels of von Willebrand factor in patients with uncomplicated Type 2 diabetes.

BACKGROUND: Type 2 diabetes is associated with an increased risk of cardiovascular disease. Endothelial dysfunction is thought to be an early marker of atherosclerosis. The purpose of this study was to assess whether endothelial function, judged by measurements of flow-mediated vasodilatation (FMD) and nitroglycerine (NTG)-induced vasodilatation as well as serum levels of von Willebrand factor, was affected in patients with uncomplicated Type 2 diabetes and normal levels of urinary albumin excretion (UAE). SUBJECTS AND METHODS: Twenty-three patients with Type 2 diabetes, normal UAE and no vascular complications were examined. Twenty-three healthy subjects matched for age, gender, body mass index and resting vessel size served as controls. All participants were non-smokers. Endothelial function was assessed by high-resolution ultrasound which measures changes in diameter of the brachial artery during flow-mediated and NTG-induced vasodilatation. We also measured serum levels of von Willebrand factor. RESULTS: In Type 2 diabetic patients FMD (3.2 +/- 0.5% vs. 4.8 +/- 0.5%, P = 0.019) as well as NTG-induced vasodilatation (15.9 +/- 0.6% vs. 18.5 +/- 0.9%, P = 0.021) were significantly reduced compared with controls. Levels of von Willebrand factor were not different between groups (0.88 +/- 0.07 vs. 0.88 +/- 0.07 in patients and controls, respectively) and were not correlated to FMD or NTG-induced vasodilatation. CONCLUSION: Impaired vascular reactivity is present in uncomplicated Type 2 diabetes and seems to be a more sensitive marker of vascular dysfunction than von Willebrand factor.     

Co-occurrence of hypercalciuria and hypouricaemia in type 2 diabetic patients

The relationship between the urinary excretion of calcium (Ca2+) and uric acid was investigated in 151 Type 2 diabetic patients and 48 normal subjects. In the diabetic patients, uric acid clearance/creatinine clearance (Clurate/Clcr) was higher and the serum level of uric acid was lower than in the normal subjects (Clurate/Clcr: 10.9 +/- 5.8 vs 8.1 +/- 2.6%, p less than 0.001; serum uric acid: 3.4 +/- 86 vs 357 +/- 89 mumol l-1, p less than 0.001). Calcium clearance/Clcr (Clca/Clcr) also increased in the diabetic patients, as did urinary excretion rate, but the serum Ca2+ level was not different to normal control subjects (Clca/Clcr: 2.29 +/- 1.59 vs 1.56 +/- 0.98%, p less than 0.001; Ca2+ excretion rate: 2.24 +/- 1.67 vs 1.63 +/- 1.11 mmol day-1, p less than 0.01; serum Ca2+ level: 2.34 +/- 0.11 vs 2.33 +/- 0.08 mmol l-1). In the diabetic patients, Clcr positively and the serum uric acid negatively correlated with the urinary excretion of Ca2+ (p less than 0.001 for both correlations in the multivariate regression analysis). These data suggest that the diabetic patients have increased fractional excretion of both Ca2+ and uric acid.     

Double-blind crossover study of acarbose in type 1 diabetic patients.

The addition of acarbose to insulin treatment was evaluated in 14 Type 1 (insulin-dependent) diabetic patients assessed conventionally (blood glucose profile and HbA1c measurement) and with an artificial B-cell. Their metabolic control was poor, fasting blood glucose 10.7 +/- 0.3 (+/- SE) mmol l-1, mean daily blood glucose 9.7 +/- 0.3 mmol l-1, and HbA1c 9.6 +/- 0.2% (normal range 5.0-6.1%). They were of normal body weight (body mass index 22.5 +/- 0.3 kg m-2), and were C-peptide deficient (fasting 0.08 +/- 0.02 nmol l-1). In addition to their usual insulin therapy (46.9 +/- 3.5 U day-1 in three pre-meal injections), they received 100 mg acarbose or placebo three times a day for 6 weeks in a randomized double-blind crossover design. On the last day of either acarbose or placebo treatment, the usual insulin therapy was discontinued and an artificial B-cell was used for insulin delivery, programmed for euglycaemia. Placebo or acarbose was continued before meals. Acarbose reduced mean daily blood glucose concentrations (8.5 +/- 0.3 vs 9.7 +/- 0.3 mmol l-1, p = 0.002) and HbA1c levels (8.3 +/- 0.1 vs 9.6 +/- 0.2%, p less than 0.001). A significant reduction in insulin requirement after meals was found with the artificial B-cell, 25.1 +/- 2.5 (first treatment acarbose) and 24.1 +/- 2.9 U (first treatment placebo) with acarbose and 40.0 +/- 2.5 and 35.6 +/- 2.9 U with placebo (p less than 0.001). These results suggest that acarbose could usefully be administered to Type 1 diabetic patients to ameliorate glucose control and reduce insulin requirement.     

Thrombogenic and endothelial damage markers in patients with ischemic systolic impairment

INTRODUCTION: Anticoagulation is rarely indicated in patients with left ventricular dysfunction who show an increased risk for thromboembolism. In theory, the three arms of the Virchow' triad may be present: abnormal blood flow, endothelial damage and prothrombotic markers. The aim of this study was to identify the last two arms. PATIENTS AND METHOD: We studied 82 consecutive patients with demonstrated ischaemic heart disease and sinus rhythm, and compared them with a control group comprised of 32 healthy subjects matched for age and sex. None or the patients had had an acute coronary event or hemodynamic decompensation within the 3 months prior to inclusion in the study. The plasma concentration or von Willebrand factor and fibrin d-dimer and fibrinogen were determined as endothelial damage and prothrombotic markers, respectively. A fractional shortening less than 29% by echography was defined as ventricular systolic dysfunction. RESULTS: The patients showed significantly higher levels of von Willebrand factor with respect to the control group (109.2 31.9 vs 85.5 32.6%, p < 0.01), with no differences in fibrinogen and fibrin d-dimer values. Twenty-six patients fulfilled criteria of left ventricular systolic dysfunction. Patients with left ventricular dysfunction showed higher fibrinogen (386 118 vs 322 102 mg/dl, p = 0.03) and fibrin d-dimer (0.36 0.22 vs 0.26 0.10 g/ml; p = 0.04) levels, with no differences in von Willebrand factor levels. CONCLUSIONS: After acute coronary events, patients with ischaemic heart disease show markers of endothelial damage. However, patients with left ventricular dysfunction show a hypercoagulable state.     

Metabolic control may influence the increased superoxide generation in diabetic serum.

Superoxide anion (O2-) generation in serum from 10 Type 1 diabetic patients and 10 normal subjects was measured ex vivo. The amount of O2- production was significantly increased in diabetic serum 0.41 +/- 0.04 (+/- SD) vs 0.14 +/- 0.04 mumol l-1 min-1, p less than 0.001) and correlated with fasting plasma glucose and glycosylated protein levels in both diabetic (r = 0.72, p less than 0.01, and r = 0.62, p less than 0.05) and normal r = 0.75, p less than 0.01 and r = 0.64, p less than 0.05) subjects. Improved metabolic control in the diabetic patients was associated with a reduction of serum O2- production (0.28 +/- 0.06 mumol l-1 min-1, p less than 0.01), but the correlation between O2- levels and fasting plasma glucose and glycosylated protein concentrations was retained (r = 0.86 and r = 0.72, respectively, both p less than 0.01).     

Hyperglycaemic siblings of Type II (non-insulin-dependent) diabetic patients have increased PAI-1, central obesity and insulin resistance compared with their paired normoglycaemic sibling

AIMS/HYPOTHESIS: First-degree relatives of Type II (non-insulin-dependent) diabetic patients in cross-sectional studies have increased insulin resistance, associated cardiovascular risk factors and abnormalities of fibrinolysis and coagulation. To minimise between-family genetic and environmental confounders, we investigated within-family relationships between early hyperglycaemia and risk factors. METHODS: Thirteen age and gender matched sibling pairs of Type II (non-insulin-dependent) diabetic patients, one hyperglycaemic, one normoglycaemic (fasting plasma glucose at screening 6.0-7.7 mmol.l(-1) and < 6.0 mmol.l(-1), respectively) were assessed for plasminogen activator inhibitor antigen (PAI-1), tissue plasminogen activator antigen (t-PA), fibrinogen, Factor VII and Factor VIII/von Willebrand factor antigen. Fasting lipid profiles, blood pressure and HOMA insulin sensitivity (%S) were also measured in siblings and in matched subjects without family history of diabetes. RESULTS: Hyperglycaemic and normoglycaemic siblings (7 female, 6 male) were aged, mean (SD) 56.8 (8.7) and 55.8 (8.4) years. Hyperglycaemic siblings had increased PAI-1 antigen, geometric mean (i.q.r.): 26.3 (15.1-45.6) vs 11.1 (2.1-23.3) ng/ml, p=0.0002, similar t-PA antigen, mean (SD) 9.5 (4.3) vs 7.4 (2.5) ng/ml, p=0.2 and fibrinogen 2.2 (0.3) vs 2.3 (0.6) g/l, p=0.5, and reduced %S 66.3 (30.5) vs 82.9 (25), p=0.04. PAI-1 correlated negatively with %S ( r=-0.55, p=0.005). No significant differences were found in blood pressure or fasting lipids. CONCLUSION/INTERPRETATION: A minor increase in plasma glucose in non-diabetic sibling pairs of Type II (non-insulin-dependent) diabetic patients was associated with reduced insulin sensitivity, increased central adiposity and a doubling of PAI-1 antigen concentration, suggesting impaired fibrinolysis. It is possible that this could contribute to increased cardiovascular risk in these subjects.