Left Ventricular Hypertrophy in Non-insulin-dependent Diabetic Patients With and Without Diabetic Nephropathy

The aim of our cross-sectional case–control study was to evaluate putative mechanisms of the increased cardiac morbidity and mortality in NIDDM patients with or without diabetic nephropathy. Fifty-one NIDDM patients with diabetic nephropathy (38 males, age 61 ± 8 years, group 1), 53 NIDDM patients with normoalbuminuria (42 males, 61 ± 7 years, group 2), and 22 non-diabetic control subjects (15 males, 58 ± 8 years, group 3) were investigated. Previous antihypertensive treatment was withdrawn 2 weeks before the study. Left ventricular mass index (LVMI) and systolic function were determined by echocardiography. LVMI was elevated, mean ± SE, in group 1: 157 ± 6 g m⁻², and in group 2: 139 ± 7 g m⁻², as compared with group 3: 95 ± 5 g m⁻² (p < 0.001, for both), and in group 1 as compared with group 2 (p = 0.05). The prevalence of left ventricular hypertrophy (LVH) (LVMI > 131 g m⁻² in men and > 100 g m⁻² in women) was much higher in group 1: 75 % (95 % CI, 60–86), and group 2: 51 % (95 % CI, 37–65), as compared with group 3: 9 % (95 % CI, 1–29) (p < 0.001, for both), and in group 1 as compared with group 2 (p < 0.01). Shortening fraction of the left ventricle, % ± SE, was relatively reduced in group 1: 32.5 ± 1.1 %, and group 2: 33.4 ± 1.1 %, as compared with group 3: 41.2 ± 1.2 % (p < 0.01, for both). In a subgroup of 26 normoalbuminuric normotensive NIDDM patients, LVMI was higher than in 14 normotensive non-diabetic control subjects: 137 ± 10 g m⁻² vs 96 ± 7 g m⁻², respectively (p < 0.005). The prevalence of LVH was 42 % (95 % CI, 23–63) and 14 % (95 % CI, 2–43) (p = 0.07) in these two groups, respectively. In conclusion, normotensive and hypertensive NIDDM patients with and without diabetic nephropathy frequently suffer from LVH and relatively reduced systolic function which may constitute independent risk factors for fatal and non-fatal cardiac events. © 1997 John Wiley & Sons, Ltd.     

Enhancement of soluble CD23 serum levels and cell-surface CD23-expression in subjects at increased risk of Type 1 diabetes mellitus and in diabetic patients

The low affinity receptor for IgE, CD23, is expressed on lymphocytes among other cell types. The purpose of the present study was to assess serum sCD23 levels and CD23 expression on peripheral blood mononuclear cells (PBMC) in people at increased risk of developing Type 1 diabetes mellitus and in diabetic patients. Serum sCD23 levels were significantly higher in first-degree relatives of Type 1 patients (median: 3.2 U ml⁻¹) (p < 0.001) and in newly diagnosed (median: 3.3 U ml⁻¹) (p < 0.001) and long-standing (median: 2.5 U ml⁻¹) (p = 0.01) Type 1 diabetic patients than in controls (median: 1.2 U ml⁻¹). Newly diagnosed patients showed higher levels than those with long-standing disease (p = 0.026). Moreover the percentage of B cells expressing CD23 were significantly higher in first-degree relatives (median: 48.6 %) (p < 0.001) and in newly diagnosed (median: 58 %) (p < 0.001) and long-standing (median: 44.8 %) (p = 0.03) Type 1 diabetic patients than in controls (median: 28.5 %). The increased sCD23 levels and the increased number of cells expressing CD23 observed in subjects at increased risk of Type 1 diabetes and diabetic patients may be indicators of Th2 activity in Type 1 diabetes. © 1998 John Wiley & Sons, Ltd.     

Formation of plasma advanced glycosylation end products (AGEs) has no influence on plasma viscosity

Plasma viscosity is mainly determined by large non-spherical proteins. In Type 1 diabetes mellitus, plasma viscosity increases with deterioration of diabetic control. Since protein glycation and formation of advanced glycosylation end products (AGEs) alter the structural and functional properties of proteins, AGEs might influence the rheological properties of plasma proteins. Therefore, we investigated the influence of plasma-AGEs on plasma viscosity in 34 normoalbuminuric diabetic patients (17 Type 1, 17 Type 2) with normal renal and liver function. In an additional experiment, 6 ml plasma of 9 healthy volunteers were incubated under sterile conditions for 14 days at 37.5 °C in the presence of 5.2 and 32.9 mmol l⁻¹ glucose. In diabetic patients, plasma-AGE levels were not correlated with plasma viscosity. Plasma-AGE levels in healthy controls (246 ± 37 U ml⁻¹, mean ± SD) were raised significantly (p<0.001) after the incubation at 37.5 °C (392 ± 57 U ml⁻¹ and 552 ± 58 U ml⁻¹, respectively). However, no difference was found in plasma viscosity pre- and post-incubation (pre-incubation: 1.25 ± 0.04 mPas, post-incubation: 1.23 ± 0.03 and 1.24 ± 0.03, respectively). We conclude that there is no influence of plasma-AGEs on plasma viscosity. © 1997 John Wiley & Sons, Ltd.     

Atrial natriuretic peptide in Type 2 diabetes mellitus: response to a physiological mixed meal and relationship to renal function

Relatively few data exist on atrial natriuretic peptide (ANP) characteristics in Type 2 diabetes mellitus (DM). Therefore, plasma immunoreactive ANP concentrations were measured before and for 4 h following the ingestion of a physiological mixed meal in 8 newly diagnosed, normotensive, normoalbuminuric, patients with Type 2 DM and 6 normotensive, non-diabetic controls. In patients with Type 2 DM, basal plasma ANP concentrations were 4.0 ± 2.0 and not significantly changed following ingestion of the meal, with peak levels of 4.9 ± 2.8 pmol l⁻¹. Non-diabetic controls had higher basal plasma ANP concentrations, 8.7 ± 3.4 pmol l⁻¹ (p < 0.05), significantly increasing to a peak of 11.9 ± 6.3 pmol l⁻¹ at 30 min post meal. Extracellular fluid volume (ECV) was not different between diabetic patients and controls (15877 ± 2679 vs 13668 ± 1792 ml³). Glomerular filtration rate (GFR) (isotopic clearance corrected for body surface area) was elevated in diabetic patients (mean ± SD) 130 ± 39 vs 98 ± 10 ml min⁻¹, p < 0.05). For the DM subjects, basal ANP levels were negatively correlated with GFR (r_s − 0.74, p < 0.05) and effective renal plasma flow (ERPF) (r_s − 0.8, p < 0.05). We conclude that patients with Type 2 DM demonstrate reduced basal plasma ANP concentrations which are inversely correlated to renal function. In contrast to non-diabetic controls, ANP in Type 2 DM does not rise in response to feeding. © 1998 John Wiley & Sons, Ltd.     

Fibrinolytic measurements in Type 2 diabetic patients with acute cerebral infarction

The aim of this study was to investigate disturbances in fibrinolytic components in Type 2 diabetes patients with acute ischaemic stroke. Levels of plasminogen activator inhibitor-1 (PAI-1) activity and tissue PA (t-PA) antigen were measured in Type 2 diabetes subjects with (n=40) and without (n=80) acute stroke compared to non-diabetic subjects with (n=80) and without (n=80) acute ischaemic stroke. Diabetes was defined by WHO criteria and absence of diabetes by blood glucose <7.8 mmol⁻¹ and HbA_IC <6 % (reference range for assay 4.5–6.5 %). Levels of t-PA antigen were lower in healthy controls (9.2 ng ml⁻¹) than in either stroke group (non-diabetic stroke patient: 12.6 ng ml⁻¹; diabetic patient with stroke: 13.5 ng ml⁻¹ (each at p<0.05)) and intermediate in diabetic patients without stroke (11.1 ng ml⁻¹, ns). In a regression model levels of t-PA were related to stroke, BMI and age but not to diabetes or sex. Diabetic subjects without stroke had higher PAI-1 activity levels than either non-diabetic group (17.7 Uml⁻¹ vs 12.1 U ml⁻¹ and 9.2 U ml⁻¹ (each at p<0.05)). Levels were intermediate in diabetic subjects with stroke (12.8 U ml⁻¹, ns). In a regression model levels of PAI-1 were related to Type 2 diabetes, female sex, and body mass index but not stroke or age. These data suggest that further suppression of fibrinolysis does not occur with ischaemic stroke in Type 2 diabetes. The findings contrast with the importance of impaired fibrinolysis in coronary artery disease previously reported in both Type 2 diabetic patients and non-diabetic subjects. © 1998 John Wiley & Sons, Ltd.     

Immunochemical quantification of crossline as a fluorescent advanced glycation endproduct in erythrocyte membrane proteins from diabetic patients with or without retinopathy

Crossline is a novel advanced glycation endproduct (AGE) which has both a crosslink and fluorescence similar to AGE-protein in vivo. To assess the association of AGEs to the development of diabetic retinopathy we developed a sensitive and specific enzyme-linked immunosorbent assay (ELISA) for crossline in blood samples and investigated the association of the development of retinopathy and erythrocyte membrane protein (EMP)-crossline concentrations in patients with Type 2 diabetes mellitus (Type 2 DM). Crossline formation in EMP exceeded that in haemoglobin and was detectable in normal EMP samples without pretreatment by this ELISA system. Mean (±SE) EMP crossline levels were elevated 1.6-fold in diabetic patients without retinopathy (7.6 ± 0.5 pmol mg⁻¹, p < 0.005), 2.2-fold in diabetic patients with non-proliferative retinopathy (10.5 ± 0.6 pmol mg⁻¹, p < 0.001) and 2.6-fold in diabetic patients with proliferative retinopathy (12.0 ± 0.6 pmol mg⁻¹, p < 0.001) compared with healthy control subjects (4.7 ± 0.5 pmol mg⁻¹). Type 2 DM patients with retinopathy had significantly higher EMP-crossline levels than those without retinopathy (p < 0.005). Our data suggest that elevated EMP-crossline concentrations are associated with the presence of retinopathy in patients with Type 2 DM and EMP-crossline measured by our ELISA may provide a useful marker for assessing the role of glycation in the development of diabetic retinopathy. © 1998 John Wiley & Sons, Ltd.     

Influence of hypertension on serum concentration of type IV collagen antigens in streptozotocin-diabetic and non-diabetic rats

Summary The serum concentration of 7S collagen was measured radioimmunologically as a marker of basement membrane type IV collagen synthesis in diabetic and nondiabetic rats with Goldblatt hypertension. In non-diabetic rats the 7S collagen level was significantly raised after induction of hypertension (51%; p<0.001), and showed a positive correlation with relative heart weight as an integral parameter of hypertension (r= 0.63; p<0.01). In diabetic rats, which displayed a 7S collagen concentration roughly 2.5 times as high as the metabolically normal animals, the 7S collagen level was 27% higher in the hypertensive animals (p<0.01). There was no correlation with blood pressure or heart weight, but only a positive correlation with blood glucose (r=0.51; p<0.05). The results indicate that haemodynamic alterations may alter basement membrane collagen metabolism. However, type IV collagen metabolism in diabetes is influenced to a greater extent by metabolic than by haemodynamic factors.     

Reduced capillary hydraulic conductivity in skeletal muscle and skin in Type I diabetes: a possible cause for reduced transcapillary fluid absorption during hypovolaemia

Aims/hypothesis. Patients with Type I (insulin-dependent) diabetes mellitus have a reduced transcapillary fluid absorption from skeletal muscle and skin and thus defective plasma volume regulation during hypovolaemia. Our aim was to find whether a defective capillary filtration coefficient or impaired transcapillary driving force are aetiologic factors for this reduction. Methods. We investigated 11 diabetic patients (diabetes duration 6.9 ± 1.1 years, age 26 ± 1 years), without complications and 12 control subjects (26 ± 1 years). Their capillary filtration coefficient was measured in the upper arm using a volumetric technique at rest and during lower body negative pressure (LBNP). We calculated the driving force for transcapillary fluid transfer. Results. The increase in heart rate and the decrease in systolic blood pressure during lower body negative pressure were similar in diabetic and control subjects. The resting capillary filtration coefficient was decreased in the diabetic subjects, 0.033 ± 0.003 vs 0.051 ± 0.007 ml · 100 ml^–1· min^–1· mmHg^–1 (p < 0.05). During lower body negative pressure, the capillary filtration coefficient increased 35 % in both groups compared with resting capillary filtration coefficient and was still decreased in diabetes; 0.046 ± 0.004 compared with 0.069 ± 0.006 ml · 100ml^–1· min^–1· mmHg^–1 (p < 0.01). The established driving force during lower body negative pressure was 1.37 ± 0.11 vs 1.30 ± 0.15 mmHg (NS) in diabetic and control subjects, respectively. Conclusions/interpretation. Our study indicates that a reduced capillary filtration coefficient rather than defective regulation of transcapillary driving force, is the reason for the reduced transcapillary fluid absorption during hypovolaemic circulatory stress found in Type I diabetic patients. [Diabetologia (2000) 43: 1178–1184] Received: 28 January 2000 and in revised form: 8 May 2000     

Plasminogen Activator Inhibitor (PAI-1) Activity is Elevated in Asian and Caucasian Subjects with Non-insulin-dependent (Type 2) Diabetes but not in Those with Impaired Glucose Tolerance (IGT) or Non-diabetic Asians

In order to study the plasminogen activator inhibitor activity (PAI-1) in subjects at different risk of non-insulin-dependent diabetes and ischaemic heart disease we examined 89 subjects with diet controlled NIDDM (49 Caucasian, 40 Asian), 29 with impaired glucose tolerance (IGT) (13 Caucasian, 16 Asian), and 149 with normal glucose tolerance (67 Caucasian, 82 Asian). Diabetes was diagnosed by WHO criteria and highly specific, monoclonal antibody-based assays were used to measure insulin, intact proinsulin, and des 31,32 proinsulin. Subjects with NIDDM were significantly more obese, had more central distribution of obesity, higher fasting plasma specific insulin concentrations (NIDDM median 74 pmol l⁻¹ vs IGT 41 pmol l⁻¹, p < 0.01 and vs normals 34 pmol l⁻¹, p < 0.001) and higher PAI-1 activity than normals and those with IGT (NIDDM 23.0 ± 6.9 vs IGT 16.8 ± 5.0, p < 0.001 and vs normals 17.1 ± 6.9 AU ml⁻¹, p < 0.001). However, PAI-1 activity was not significantly different between Asian and Caucasian normals (17.5 ± 7.3 vs 16.5 ± 6.4 AU ml⁻¹, p = ns) and diabetic (22.8 ± 7.3 vs 23.1 ± 6.6 AU ml⁻¹, p = ns) subjects. In addition to relationships with obesity and plasma triglyceride, PAI-1 activity, after controlling for age, sex, body mass index, and waist–hip ratio, was related to fasting insulin (partial r = 0.22, p < 0.001), intact proinsulin (partial r = 0.36, p < 0.001), and des 31,32 proinsulin concentrations (partial r = 0.33, p < 0.001) as measured by highly specific assays. The association of PAI-1 with diabetes was weakened but remained statistically significant (p = 0.042) after controlling for age, sex, ethnicity, obesity, plasma triglyceride, and all insulin-like molecules. We conclude that, although PAI-1 activity is raised in subjects with diet-treated NIDDM, it is normal in subjects with IGT and non-diabetic Asians, populations at high risk of NIDDM and ischaemic heart disease. Raised PAI-1 activity may play an important role in the pathogenesis of macrovascular disease in subjects with NIDDM, but is unlikely to explain excess risk of ischaemic heart disease in Asians and those with impaired glucose tolerance.     

Diurnal blood pressure variations in normoalbuminuric type 1 diabetic patients

Abstract. Objective. To test the hypothesis that normoal-buminuric type 1 diabetic patients segregate into groups with normal and elevated ambulatory blood pressure. To evaluate diurnal variation of blood pressure assessed by individual or fixed night-time periods. Design. Cross-sectional study. Setting. Tertiary referral centre. Subjects. Inclusion criteria for type 1 diabetic patients (n = 33): normal urinary albumin excretion (UAE age < 45 < 20 μg min^?1), diabetes duration ≤ 20 years, age 45 years. Healthy controls (n = 33) were matched for sex and age. Main outcome measure. Twenty-four hour, day-time, night-time and night/day ratio of ambulatory blood pressure. Results. Twenty-four-hour blood pressure in diabetic patients did not differ significantly from a normal distribution. The 24-h systolic blood pressure was higher in diabetic patients than in healthy controls (difference: 6 mmHg, 95% confidence interval (CI) from 1 to 10 mmHg, P < 0.05), while no significant differences were found for diastolic values. The 24-h systolic blood pressure in diabetic patients with UAE above the median value (5.8 μg min^?1) was higher than for those with lower UAE (difference: 7 mmHg, 95% CI from 0.5 to 13 mmHg, P < 0.05). The night/day ratio of diastolic blood pressure based on individual informations of the night period was (mean ± SD) 80 ± 6% in diabetic patients and 78 ± 8% in controls (difference: 2%, 95% CI from ?1 to 5%, not significant [NS]). This ratio increase significantly (P < 0.00001) to 90 ± 5% in diabetes and to 84 ± 7% in controls if a fixed night period from 22.30 hours to 06.30 hours was assumed. Conclusions. It was not possible to identify a well-separated group of normoalbuminuric type 1 diabetic patients with elevated ambulatory blood pressure. Values of UAE above the median in diabetic patients are associated with higher ambulatory blood pressure. Assessment of the night/day variation from fixed time-points should be abandoned because this leads to a serious underestimation of the nocturnal reduction in blood pressure.     

Abnormal Response to Exercise in Middle-aged NIDDM Patients with and without Autonomic Neuropathy

The cardiovascular response to exercise in middle-aged non-insulin-dependent diabetes mellitus (NIDDM) patients and the potential role of clinical characteristics and autonomic function were evaluated. One hundred and eight NIDDM patients, aged 40–65 years, were compared with a control group of 112 subjects, matched by age, sex, physical fitness, and presence of hypertension. All subjects performed a maximal exercise test. The diabetic patients completed cardiovascular autonomic neuropathy (CAN) tests: deep breathing, postural hypotension and lying to standing. There were no significant differences in total work capacity, heart rate, and blood pressure, either at rest or at peak exercise between the two groups. Diabetic patients showed significantly lower values of systolic and diastolic blood pressure during exercise, significantly slower recovery of heart rate (at 5th minute the average values were 102.7 ± 14.1 beats min⁻¹ vs 91.9 ± 11.1, p < 0.001); and significantly higher proportion of blunted increase of heart rate (9.2 % vs 0.9 %, p < 0.001) and systolic blood pressure (9.2 % vs 0.7 %, p < 0.001) during exercise. No correlation between the exercise results and the main clinical characteristic (presence of hypertension, BMI, duration of diabetes, treatment, microalbuminuria, total score of CAN) was observed. These findings suggest that the cardiovascular response to exercise could be impaired also in the absence of signs of CAN. This impairment was higher in patients showing a dysfunction of orthosympathetic activity.     

Normalization of fasting glycaemia by intravenous GLP-1 ([7-36 amide] or [7-37]) in Type 2 diabetic patients

Intravenous GLP-1 [7-36 amide] can normalize fasting hyperglycaemia in Type 2 diabetic patients. Whether GLP-1 [7-37] has similar effects and how quickly plasma glucose concentrations revert to hyperglycaemia after stopping GLP-1 is not known. Therefore, 8 patients with Type 2 diabetes (5 female, 3 male; 65 ± 6 years; BMI 34.3 ± 7.9 kg m⁻²; HbA_1c 9.6 ± 1.2 %; treatment with diet alone (n = 2), sulphonylurea (n = 5), metformin (n = 1)) were examined twice in randomized order. GLP-1 [7-36 amide] or [7-37] (1 pmol kg⁻¹min⁻¹) were infused intravenously over 4 h in fasted subjects. Plasma glucose (glucose-oxidase), insulin and C-peptide (ELISA) was measured during infusion and for 4 h thereafter. Indirect calorimetry was performed. Fasting hyperglycaemia was 11.7 ± 0.9 [7-36 amide] and 11.3 ± 0.9 mmol l⁻¹ [7-37]. GLP-1 infusions stimulated insulin secretion approximately 3-fold (insulin peak 168 ± 32 and 156 ± 47 pmol l⁻¹, p < 0.0001 vs basal; C-peptide peak 2.32 ± 0.28 and 2.34 ± 0.43 nmol l⁻¹, p < 0.0001, respectively, with GLP-1 [7-36 amide] and [7-37]). Four hours of GLP-1 infusion reduced plasma glucose (4.8 ± 0.4 and 4.6 ± 0.3 mmol l⁻¹, p < 0.0001 vs basal values), and it remained in the non-diabetic fasting range after a further 4 h (5.1 ± 0.4 and 5.3 ± 0.4 mmol l⁻¹, for GLP [7-36 amide] and [7-37], respectively). There were no significant differences between GLP-1 [7-36 amide] and [7-37] (glucose, p = 0.99; insulin, p = 0.99; C-peptide, p = 0.99). Neither glucose oxidation nor lipid oxidation (or any other parameters determined by indirect calorimetry) changed during or after the administration of exogenous GLP-1. In conclusion, GLP-1 [7-36 amide] and [7-37] normalize fasting hyperglycaemia in Type 2 diabetic patients. Diabetes therapy (diet, sulphonyl ureas or metformin) does not appear to influence this effect. In fasting and resting patients, the effect persists during administration of GLP-1 and for at least 4 h thereafter, without rebound. Significant changes in circulating substrate concentrations (e.g. glucose) are not accompanied by changes in intracellular substrate metabolism. © 1998 John Wiley & Sons, Ltd.     

Decline of Renal Function Is Associated with Proteinuria and Systolic Blood Pressure in the Morning in Diabetic Nephropathy

The aim of this study was to investigate a significance of increased proteinuria in the morning and the effects of antihypertensive treatment on proteinuria and arterial blood pressure in the progression of chronic renal insufficiency in type 2 diabetic patients with hypertension and nephropathy. In three 24-hr urine samples and blood pressure monitoring, separated into a night-and daytime and spot urine in the morning, variation in protein-creatinine ratio (g/g) and blood pressure were assessed in 24 (58 ± 3 years old; M/F: 17/7) diabetic patients with hypertension and nephropathy. Furthermore, the effects of antihypertensive therapy of combinations of angiotensin converting enzyme (ACE) inhibitor, calcium antagonists, diuretics, and α1 blocker were evaluated in 3 years. Home blood pressure measurement was carried out every month and 24-hr urine was collected every 2 months. The baseline urine excretion of protein-creatinine ratio and blood pressure were (1.22 ± 0.13 g/g creatinine: 154/96 ± 6/5 mmHg) in daytime and (1.39 ± 0.13: 168/88 ± 15/7) in the morning. At the end of the study, significant associations among a decline of 24-hr creatinine clearance and both of the urine excretion of protein-creatinine ratio (r = 0.47, p < .01) and the levels of systolic blood pressure (r = 0.46, p < .01) and between the levels of systolic blood pressure and the urine excretion of protein-creatinine ratio in the morning (r = 0.57, p < .001) were demonstrated. However, there were no significant associations among other variables. Analysis of patients who had systolic blood pressure in the morning less than 140 mmHg revealed that 65% of these patients received doxazosin-averaged doses of 4.8 ± 1.5 mg daily. The levels of both blood pressure and proteinuria-creatinine ratio in the morning mainly associate with progression of renal function in diabetic patients with hypertension and nephropathy.     

Prandial Glycaemia After a Carbohydrate-rich Meal in Type I Diabetic Patients: Using the Rapid Acting Insulin Analogue [Lys(B28), Pro(B29)] Human Insulin

The time–action profile of the insulin analogue insulin lispro ([Lys(B28), Pro(B29)] human insulin) with its rapid onset and short duration of action might be more suitable to limit hyperglycaemic excursions after a meal rich in rapidly absorbable carbohydrates in comparison to regular human insulin. A randomized, double-blind study was performed in 10 Type I diabetic patients with good metabolic control (HbA_1c 7.0 ± 0.5 %). After a baseline period of 3 h (blood glucose clamped at 6.7 mmol l⁻¹, i.v. insulin infusion of 0.2 mU kg⁻¹ min⁻¹ throughout the study), the patients ate a pizza, drank a cola and had a carbohydrate-rich dessert (total carbohydrate content 140 g). Immediately before the meal 15.4 ± 3.5 U of either insulin preparation were injected subcutaneously. Blood glucose concentrations were monitored continuously thereafter. Following the injection of insulin lispro the area under the blood glucose curve after the meal was 78 % of that of regular insulin (1.76 ± 0.34 vs 2.26 ± 0.68 mol l⁻¹ *240 min⁻¹; p < 0.01). Maximal blood glucose excursions were higher and were reached later after regular insulin as compared to insulin lispro (11.9 ± 2.8 vs 9.9 ± 1.4 mmol l⁻¹; p < 0.05; 66 ± 37 vs 41 ± 7 min; p < 0.05). Maximal individual differences in the blood glucose excursions (regular human insulin minus insulin lispro) were 4.8 ± 2.2 mmol l⁻¹ (p < 0.0001 against zero) after 110 ± 37 min. In Type I diabetic patients prandial blood glucose excursions after a carbohydrate rich meal were reduced after preprandial injection of insulin lispro in comparison to human regular insulin.     

Prolonged Anti-Hypertensive Effects of Oral Sitaxsentan, a Selective ETA Endothelin Receptor Antagonist, in Spontaneoulsy Hypertensive Hamsters

Introduction The purpose of this study was to determine whether prolonged oral therapy with sitaxsentan, a potent selective ET_A endothelin receptor antagonist, normalizes systolic blood pressure in spontaneously hypertensive hamsters, a new rodent model of high-renin genetic hypertension. Materials and Methods Spontaneously hypertensive hamsters received either oral sitaxsentan (15 mg kg⁻¹ day⁻¹) dissolved in high purity water or saline for 7 weeks. Systolic blood pressure was monitored in lightly anesthetized animals using the leg-cuff method. Results We found that sitaxsentan elicited a significant decrease in systolic blood pressure in spontaneously hypertensive hamsters from 175 ± 6 mmHg at baseline to 109 ± 7 mmHg after 7 weeks (p < 0.05). Although treatment of spontaneously hypertensive hamsters with saline was also associated with a significant decrease in systolic blood pressure from baseline, the magnitude of response was significantly less than that observed with sitaxsentan (p < 0.05). Discussion Collectively, these proof-of-principle data indicate that prolonged oral sitaxsentan therapy normalizes systolic blood pressure in spontaneously hypertensive hamsters. We suggest that selective ET_A endothelin receptor blockade could be beneficial in the treatment of essential hypertension associated with high renin plasma levels.     

Glomerular size-and charge selectivity in Type 2 (non-insulin-dependent) diabetic patients with diabetic nephropathy

Summary In an attempt to evaluate the mechanisms of proteinuria in diabetic kidney disease, we measured the renal clearances of albumin, total IgG, and IgG4 in 20 male Type 2 (non-insulin-dependent) diabetic patients with diabetic glomerulosclerosis (biopsy proven), in 10 male Type 2 diabetic patients without nephropathy (urinary albumin excretion rate ≤ 30 mg/24 h), and in 10 healthy male subjects. The fractional clearance of albumin was increased in patients with nephropathy: 659 (42–4355) · 10^–6 (median (range)), compared to 2.6 (0.2–14.2) · 10^–6 in patients without nephropathy, and 2.3 (0.4–4.2) · 10^–6 in healthy subjects. The fractional clearance of total IgG (neutral) and of IgG4 (anionic) was 40–50 times higher in patients with nephropathy compared to the two other groups. The IgG/IgG4 selectivity index was not significantly different in the three groups, being: 1.12 (0.06–5.65), 1.16 (0.45–3.72) and 1.35 (0.65–3.34) in patients with nephropathy, patients without nephropathy, and healthy subjects, respectively. The IgG/albumin selectivity index was decreased in patients with nephropathy: 0.27 (0.01–1.26) compared to 1.29 (0.07–2.67) (p<0.05) and 1.23 (0.76–7.84) (p<0.001) in patients without nephropathy and healthy subjects, respectively. No significant change in IgG/albumin selectivity index was observed between patients without nephropathy and healthy subjects. The systolic blood pressure was elevated in the patients with nephropathy: 164±21 mm Hg (mean ± SD) compared to patients without nephropathy: 145±20 mm Hg (p<0.05) and to healthy subjects: 133±19 mm Hg (p<0.005). The diastolic blood pressure was higher in patients with and without nephropathy: 92±7 vs 90±10 mm Hg compared to 79±8 mm Hg (p<0.005) in healthy subjects. Our cross-sectional study suggests that impaired barrier size selectivity, probably due to an increase in large pore area (“shunt pathway”) in the glomerular capillary wall and systemic hypertension are the major pathogenic mechanisms of proteinuria in Type 2 diabetic patients with diabetic nephropathy. [Diabetologia (1994) 37: 195–201] Received: 7 June 1993 and in revised form: 25 August 1993     

Thrombomodulin Levels in Insulin-dependent Diabetic Patients with Microalbuminuria

Thrombomodulin (TM) plays an important role in the regulation of blood coagulation at the endothelial surface. TM is also present in plasma, where an increase of its level seems to reflect endothelial damage. Since microalbuminuria is associated with an increased atherothrombotic risk and is considered an expression of widespread vascular damage, we evaluated plasma thrombomodulin levels, blood pressure, and plasma lipid values in Type 1 diabetic patients with micro- and normoalbuminuria. Thrombomodulin was measured in 12 microalbuminuric (albumin excretion rate 20–200 μg min^?1 in 2 of 3 overnight urine collections) and in 12 normoalbuminuric (albumin excretion rate < 20 μg min^?1) Type 1 diabetic patients matched for age, sex, body mass index, smoking habits, diabetes duration, and glycated haemoglobin. Mean thrombomodulin was significantly higher in micro- than in normalbuminuric group (59.34 ± 3.58 vs 43.56 ± 3.52 ng ml^?1 p < 0.01). Systolic and diastolic blood pressure were significantly higher in micro- than in normoalbuminuric group (p < 0.05). There was a positive correlation between plasma thrombomodulin and albumin excretion rate (p = 0.013, r = 0.49), and between thrombomodulin and diastolic blood pressure (p = 0.023, r = 0.46) in diabetic patients as a whole but not in the individual groups. These findings suggest the presence of an endothelial injury in microalbuminuric patients.     

Genetic Variation of a Collagen IV α1-Chain Gene Polymorphism in Danish Insulin-dependent Diabetes Mellitus (IDDM) Patients: Lack of Association to Nephropathy and Proliferative Retinopathy

In insulin-dependent (Type 1) diabetes mellitus (IDDM) the development of nephropathy is partly due to genetic susceptibility. Previously one study has demonstrated a relationship between a HindIII restriction polymorphism of the collagen IV α1-chain gene and diabetic nephropathy. The aim of the present study was to evaluate such as association in a case–control study including 207 Danish IDDM patients: 116 with nephropathy (urinary albumin excretion rate (AER) > 300 mg 24 h⁻¹) and 91 without nephropathy (AER < 30 mg 24 h⁻¹). Using genomic DNA, HindIII restriction fragment length analysis revealed a bi allele polymorphism visualized by Southern hybridization with a cDNA probe recognizing the collagen IV α1-chain gene. No differences in genotype frequencies or allele frequencies were demonstrated comparing patients with and without nephropathy: p = 0.39 and p = 0.96, respectively. Neither were there any difference in genotype frequencies or allele frequencies when the patients were stratified according to the presence of proliferative retinopathy: p = 0.44 and p = 0.84, respectively. Pooling the diabetic groups revealed genotype frequencies and allele frequencies comparable to those found in 57 healthy unrelated Danish individuals. We conclude that in a Danish IDDM population a HindIII restriction polymorphism of the collagen IV α1-chain gene is not associated with diabetic nephropathy, diabetic retinopathy or with diabetes per se. © 1997 by John Wiley & Sons, Ltd.     

The Effect of the Non-ionic Contrast Medium Iohexol on Glomerular and Tubular Function in Diabetic Patients

The effect of the non-ionic contrast medium iohexol (Omnipaque^®) on renal function was investigated in diabetic patients with signs of peripheral ischaemia. Forty-six patients, 70 ± 11 years (mean±SD) old, age at diabetes diagnosis 53±17 years, and with varying degrees of diabetic nephropathy were studied before, 1, 2, and 30 days after aortobifemoral arteriography. Serum creatinine, creatinine clearance, urinary excretion of immunoglobulin G, albumin, collagen IV (NC1), kappa and lambda chains, alpha-1-microglobulin and Tamm-Horsfall protein were evaluated. Within 1 month before and 30 days after arteriography, the glomerular filtration rate was measured by clearance of iohexol. The acute effect of the radiocontrast medium was an increase in the serum creatinine level in 41 (89 %) patients, with a more than 25 % increase in 12 (26 %) patients. The excretion rates of immunoglobulin G and albumin decreased, whereas the proximal and distal tubular function and the excretion of collagen IV did not change. The increment in serum creatinine was associated with the preangiographic renal function (p<0.05), a history of heart failure (p<0.01), but not with age, duration and type of diabetes, gender, systolic or diastolic blood pressure, glycated haemoglobin (HbA_lc) or blood glucose levels. The increase of serum creatinine was associated with a pre-existing proximal tubular dysfunction and a worsening of distal tubular function. No changes in the parameters measured persisted 30 days after angiography. In summary, a transient increment in serum creatinine level after arteriography occurred in 89 % of diabetic patients. It was associated with the preangiographic renal function, a history of heart failure and signs of preexisting proximal tubular dysfunction and worsening of distal tubular function. However, these changes were reversible.     

Assessment of baroreceptor-cardiac reflex sensitivity using time domain analysis in patients with IDDM and the relation to left ventricular mass index

Summary Autonomic dysfunction in insulin-dependent diabetic (IDDM) patients has been associated with abnormalities of left ventricular function and an increased risk of sudden death. A group of 30 patients with IDDM and 30 age, sex and blood pressure matched control subjects underwent traditional tests of autonomic function. In addition, baroreceptor-cardiac reflex sensitivity (BRS) was assessed using time domain (sequence) analysis of systolic blood pressure and pulse interval data recorded non-invasively using the Finapres beat-to-beat blood pressure recording system. ’Up BRS' sequences–increases in systolic blood pressure associated with lengthening of R-R interval, and ’down BRS' sequences–decreases in systolic blood pressure associated with shortening of R-R interval were identified and BRS calculated from the regression of systolic blood pressure on R-R interval for all sequences. We also assessed heart rate variability using power spectral analysis and, after expressing components of the spectrum in normalised units, assessed sympathovagal balance from the ratio of low to high frequency powers. IDDM subjects underwent 2-D echocardiography to assess left ventricular mass index. Standard tests of autonomic function revealed no differences between IDDM patients and control subjects, but dramatic reductions in baroreceptor-cardiac reflex sensitivity were detected in IDDM patients. ’Up BRS' when supine was 11.2 ± 1.5 ms/mmHg (mean ± SEM) compared with 20.4 ± 1.95 in control subjects (p < 0.003) and when standing was 4.1 ± 1.9 vs 7.6 ± 2.7 ms/mmHg (p < 0.001). Down BRS when supine was 11.5 ± 1.2 vs 22 ± 2.6 (p < 0.001) and standing was 4.4 ± 1.9 vs 7.3 ± 2.5 ms/mmHg (p < 0.003). There were significant relations between impairment of the baroreflex and duration of diabetes (p < 0.001) and poor glycaemic control (p < 0.001). From a fast Fourier transformation of supine heart rate data and using a band width of 0.05–0.15 Hz as low-frequency and 0.2–0.35 Hz as high frequency total spectral power of R-R interval variability was significantly reduced in the IDDM group for both low-frequency (473 ± 62.8 vs 746.6 ± 77.6 ms² p = 0.002) and high frequency bands 125.2 ± 12.9 vs 459.3 ± 89.8 ms² p < 0.0001. When the absolute powers were expressed in normalised units the ratio of low frequency to high frequency power (a measure of sympathovagal balance) was significantly increased in the IDDM group (2.9 ± 0.53 vs 4.6 ± 0.55, p < 0.002 supine: 3.8 ± 0.49 vs 6.6 ± 0.55, p < 0.001 standing). Thus, time domain analysis of baroreceptor-cardiac reflex sensitivity detects autonomic dysfunction more frequently in IDDM patients than conventional tests. Impaired BRS is associated with an increased left ventricular mass index and this abnormality may have a role in the increased incidence of sudden death seen in young IDDM patients. [Diabetologia (1996) 39: 1385–1391] Received: 9 April 1996 and in revised form: 19 July 1996