Baroreflex sensitivity is depressed in microalbuminuric Type I diabetic patients at rest and during sympathetic manoeuvres

Abstract Aims/hypothesis. To evaluate baroreflex sensitivity (BRS) in microalbuminuric and normoalbuminuric Type I (insulin-dependent) diabetic patients without autonomic neuropathy and in healthy control subjects. Methods. Microalbuminuric Type I diabetic patients (n = 15) were matched for age, sex, body mass index (BMI) and smoking habits with 15 normoalbuminuric patients and with 15 healthy control subjects. All subjects had a blood pressure less than 160/95 mmHg, a BMI less than 30 kg/m² and normal autonomic function on standard tests. Blood pressure and heart rate were measured non-invasively (Finapres) at rest and during sympathetic activation (handgrip, mental stress, standing). The baroreflex sensitivity was defined as the mean gain between blood pressure variability and heart rate variability in the 0.07–0.15 Hz frequency band. Results. Resting baroreflex sensitivity was decreased in the microalbuminuric patients (3.5 ± 0.4 ms/mmHg) compared with the normoalbuminuric patients and the healthy subjects (7.6 ± 1.6 and 9.5 ± 1.1 ms/mmHg, respectively, p < 0.001). The sympathetic tests reduced baroreflex sensitivity similarly in the groups without changing the between group differences. Conclusion/interpretation. Baroreflex sensitivity is reduced in Type I diabetic patients with microalbuminuria but without autonomic neuropathy. A prospective study should indicate whether this early abnormality in cardiovascular reflex function is a risk factor of cardiovascular mortality in these patients. [Diabetologia (1999) 42: 1345–1349] Received: 20 May 1999 and in revised form: 8 July 1999     

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.     

Lipoprotein(a) in Type 1 Diabetic Patients with Renal Disease

Lp(a) was measured in 64 normoalbuminuric, 52 microalbuminuric, and 37 proteinuric Type 1 diabetic patients and 54 healthy subjects. Microalbuminuric and proteinuric Type 1 diabetic patients had higher median Lp(a) values (133 (16–1932) and 169 (17–1149) mg I^?1) than patients with normal AER (73 (15–1078) mg I^?1; p=0.048 and p=0.027). Lp(a) in healthy subjects (110 (15–1630)mg I^?1) did not differ from the diabetic subgroups. The frequency of Lp(a) values in the upper quarter of the normal distribution was similar in the diabetic groups and did not differ between diabetic and control subjects. The cumulative distribution of Lp(a) was similar in all groups. Lp(a) concentrations were not related to AER, age, gender, duration of diabetes, body mass index, glycaemic control, serum creatinine, free insulin or systolic blood pressure. Cholesterol, LDL-cholesterol, triglycerides, and apo B were higher in microalbuminuric and proteinuric than in normoalbuminuric Type 1 diabetic patients. Lp(a) was independently related to diastolic blood pressure, fibrinogen, and macroangiopathy. In conclusion, median Lp(a) concentrations tend to be higher in Type 1 diabetic patients with early and established renal disease, although the differences are small and the overlap between groups large. Lp(a) is related to diastolic blood pressure and fibrinogen, and this association of powerful risk factors suggests that Lp(a) may play a role in the pathogenesis of cardiovascular disease in Type 1 diabetic patients with proteinuria. Whether Lp(a) is an independent determinant of increased cardiovascular risk in these patients needs to be elucidated by prospective studies.     

24-h blood pressure and autonomic function is related to albumin excretion within the normoalbuminuric range in IDDM patients

Summary Significant changes in both blood pressure, autonomic function and kidney ultrastructure are observed in insulin-dependent diabetic (IDDM) patients with microalbuminuria. Intervention strategies are evaluated at even earlier stages of disease. Identification of patients at risk of developing microalbuminuria must be based on a thorough knowledge of the relations between key pathophysiological parameters in patients with normoalbuminuria. The aim of the present study was to characterize the interactions of urinary albumin excretion (UAE), 24-h ambulatory blood pressure (AMBP), and sympathovagal balance in a large group of normoalbuminuric IDDM patients. In 117 normoalbuminuric (UAE < 20 μg/min) patients we performed 24-h AMBP (Spacelabs 90 207), with assessment of diurnal blood pressure and heart rate (HR) variation, and short-term (three times 5 min) power spectral analysis of RR interval oscillations, as well as cardiovascular reflex tests (HR variation to deep breathing, postural HR and blood pressure response). Patients with UAE above the median (4.2 μg/min) had significantly higher 24-h systolic and diastolic AMBP (125 ± 10.1/76 ± 7.2 mmHg) compared to the low normoalbuminuric group (120 ± 8.4/74 ± 5.1 mmHg), p < 0.01 and 0.02, respectively. Patients with UAE above the median had significantly reduced short-term RR interval variability including both the high frequency component (5.47 ± 1.36 vs 6.10 ± 1.43 ln ms²), and low frequency component (5.48 ± 1.18 ln ms² compared to 5.80 ± 1.41 ln ms²), p < 0.02 and p = 0.04 (ANOVA). In addition, patients with high-normal UAE had reduced mean RR level (faster heart rates) 916 ± 108 compared to 963 ± 140 ms, p < 0.04. These differences were not explained by age, duration of diabetes, gender, level of physical activity, or cigarette smoking. HbA_{1 c} was significantly higher (8.6 ± 1.2 vs 8.2 ± 1.0 %, p = 0.03) in the group with high normal UAE. Comparing normoalbuminuric IDDM patients with UAE above and below the median value, we found significantly higher AMBP in combination with significant differences in sympathovagal balance and significantly poorer glycaemic control in the group with high-normal albumin excretion. Our data demonstrate interactions between albumin excretion, blood pressure, autonomic function, and glycaemic status, already present in the normoalbuminuric range and may describe a syndrome indicative of later complications. [Diabetologia (1997) 40: 718–725] Received: 9 January 1997 and in revised form: 12 March 1997     

Indications of Low Sex Hormone Binding Globulin (SHBG) in Young Females with Type 1 Diabetes,and an Independent Association to Microalbuminuria

Sex hormone binding globulin (SHBG) is normally decreased during puberty and inversely related to insulin resistance. Microalbuminuria is rare before puberty in Type 1 diabetes implicating that sex hormones may contribute to its development. We investigated SHBG levels in young females with >5 years of Type 1 diabetes, and the association to microalbuminuria. Ten diabetic females with, and 15 without microalbuminuria, and 17 healthy controls in pubertal stage 4–5 were compared regarding anthropometric data, fasting serum levels of SHBG, testosterone, insulin, insulin-like growth factor-1 (IGF-1), lipids and lipoproteins. Multiple regression analyses were performed to study variables with independent influences on SHBG and albumin excretion rate (AER), respectively, in Type 1 diabetes. SHBG was lower and testosterone/SHBG ratio higher in normoalbuminuric females with diabetes than in controls. This was further emphasized in diabetic patients with microalbuminuria. IGF-1 was lower in Type 1 diabetes than in controls, and significantly decreased in microalbuminuric as compared to normoalbuminuric diabetic patients. IGF-1 was only correlated to SHBG in healthy controls. In Type 1 diabetes, applying stepwise multiple regression analysis, insulin dose, BMI, and HbA_1c had a significant and independent inverse influence on SHBG (r² = 0.77, p < 0.001). With log AER as the dependent variable, low SHBG, low IGF-1, HbA_1c, and age added to the regression (r² = 0.65, p = 0.004), whereas BMI, insulin dose and blood pressure did not. In conclusion, SHBG is decreased in young females with Type 1 diabetes, influenced by increased insulin requirements, BMI and HbA_1c. In turn, low SHBG seems to be independently associated to elevated AER in these patients. Prospective studies are necessary to confirm our results.     

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.     

Glomerular hyperfiltration in microalbuminuric NIDDM patients

Summary Glomerular hyperfiltration and microalbuminuria are both regarded as risk factors for the development of diabetic nephropathy in insulin-dependent diabetic patients. Information on glomerular hyperfiltration is scarse in microalbuminuric non-insulin-dependent diabetic (NIDDM) patients. Therefore, we performed a cross-sectional study of glomerular filtration rate (single i. v. bolus injection of ⁵¹Cr-EDTA, plasma clearance for 4 h) in 158 microalbuminuric NIDDM patients compared to 39 normoalbuminuric NIDDM patients and 20 non-diabetic control subjects. The groups were well-matched with regard to sex, age and body mass index. The uncorrected (ml/min) and the adjusted (ml · min^–1· 1.73 m^–2) glomerular filtration rate were both clearly elevated in the microalbuminuric patients: 139 ± 29 and 117 ± 24 as compared to 115 ± 19 and 99 ± 15; 111 ± 23 and 98 ± 21 in normoalbuminuric NIDDM patients and control subjects, respectively (p < 0.001). The glomerular filtration rate (ml · min^–1· 1.73 m^–2) in NIDDM patients who had never received antihypertensive treatment was also clearly elevated in the microalbuminuric patients (n = 96): 119 ± 22 as compared to 100 ± 14 and 98 ± 21 in normoalbuminuric NIDDM patients (n = 27) and control subjects (n = 20), respectively (p < 0.001). Glomerular hyperfiltration (elevation above mean glomerular filtration rate plus 2 SD in normoalbuminuric NIDDM patients) was demonstrated in 37 (95 % confidence interval 30–45)% of the microalbuminuric patients. Multiple regression analysis revealed that HbA_{1 c}, 24-h urinary sodium excretion, age and known duration of diabetes were correlated with glomerular filtration rate in microalbuminuric NIDDM patients (r ² = 0.21, p < 0.01). Our cross-sectional study indicates that NIDDM patients at high risk of developing diabetic nephropathy are also characterized by an additional putative risk factor for progression, glomerular hyperfiltration. [Diabetologia (1996) 39: 1584–1589]     

Prothrombin Fragment 1 + 2 and Antithrombin III-Thrombin Complex in Microalbuminuric Type 2 Diabetic Patients

In microalbuminuria there is an increased cardiovascular risk not fully explained by the excess of conventional risk factors. To investigate whether or not microalbuminuria is associated with haemostatic abnormalities in Type 2 diabetic patients, we measured the prothrombin fragment 1 + 2, a marker of thrombin generation, and the thrombin-antithrombin complex, a marker of thrombin neutralization. Plasma levels of prothrombin fragment 1 + 2 and thrombin-antithrombin complex were assayed in 17 microalbuminuric patients (albumin excretion rate, AER 20–200 μg min^?1) and in 17 comparable normoalbuminuric (AER < 20 μg min^?1) Type 2 diabetic patients. Plasma prothrombin fragment 1 + 2 was significantly higher in microalbuminuric than in normoalbuminuric patients (1.09 ± 0.06 vs 0.86 ± 0.04 nM, p = 0.003). Individual values of F1 + 2 were above the upper limit of the normal range in 8/17 microalbuminuric and in none of the normoalbuminuric Type 2 diabetic patients. Plasma thrombin-antithrombin complex values were not significantly different in the two groups and were not correlated with AER. These results suggest that microalbuminuria is associated with a prethrombotic state and a relatively defective thrombin neutralization. Coagulation abnormalities might be part of the cardiovascular risk in microalbuminuric patients.     

24-h ambulatory blood pressure and retinopathy in normoalbuminuric IDDM patients

Summary The role of blood pressure elevation in the incidence and progression of diabetic retinopathy is not clearly established and results have been conflicting. Blood pressure and urinary albumin excretion (UAE) are closely related. In order to evaluate the independent relationship between retinopathy and blood pressure elevation, precise information on UAE is essential, as confounding by renal disease (incipient or overt), cannot otherwise be excluded.The aim of the present study was to evaluate the association between diabetic retinopathy and 24-h ambulatory blood pressure (AMBP) in a group of well-characterized normoalbuminuric IDDM patients. In 65 normoalbuminuric (UAE < 20 μg/min) IDDM patients we performed 24-h AMBP (Spacelabs 90 207) with readings at 20-min intervals. Fundus photographs were graded independently by two experienced ophthalmologists. UAE was measured by RIA and expressed as geometric mean of three overnight collections made within 1 week. HbA_{1 c} was determined by HPLC. Tobacco use and level of physical activity were assessed by questionnaire. Fifteen patients had no detectable retinal changes [grade 1], 35 had grade 2 retinopathy; and 15 had more advanced retinopathy [grade 3–6]. Diastolic night blood pressure was significantly higher in patients with diabetic retinopathy compared to patients without retinopathy (68 ± 8 mmHg [grade 3–6] and 65 ± 6 mmHg [grade 2], compared to 61 ± 4 mmHg [grade 1], p = 0.02). Diurnal blood pressure variation was significantly blunted in the patients with retinopathy as indicated by a higher night/day ratio of diastolic blood pressure (84.6 % ± 4 [grade 3–6], and 81.2 % ± 6 [grade 2] compared to 79.1 % ± 4 [grade 1], p = 0.01). Heart rate tended to be higher in patients in group 2 and 3–6 compared to patients without retinopathy with p values of 0.07 and 0.11 for day-time and 24 h values, respectively. Mean HbA_{1 c} increased significantly with increasing levels of retinopathy (p < 0.01). Patients were similar regarding sex, age, tobacco use, and level of physical activity. Notably, UAE was almost identical in the three groups (5.0 × /÷1.7 [grade 1], 3.9 × /÷1.8 [grade 2], and 5.1 × /÷1.6 μg/min [grade 3–6]). In conclusion, night blood pressure is higher and circadian blood pressure variation blunted in patients with retinopathy compared to patients without retinopathy despite strict normoalbuminuria and similar UAE levels in the groups compared. Our data suggest that the association between blood pressure and diabetic retinopathy is present also when coexisting renal disease is excluded. Disturbed diurnal variation of blood pressure is a pathophysiological feature related to the development of both retinopathy and nephropathy in IDDM patients. [Diabetologia (1998) 41: 105–110] Received: 27 May 1997 and in revised form: 5 September 1997     

Increased plasma apolipoprotein B levels and blood hyperviscosity in non-insulin-dependent diabetic patients: Role in the occurrence of arterial hypertension

Summary An association between arterial blood pressure and blood viscosity has been suggested in healthy and in diabetic subjects, and that the hemorheological pattern may be influenced by blood lipid alterations. In diabetic patients a relationship between arterial hypertension and blood lipid changes may therefore be suggested. This study concerns 19 type II diabetics with hyperlipidemia (triglycerides=3.2±1 mmol/l; total cholesterol=6.1±1.2 mmol/l; HDL-cholesterol=0.92±0.27 mmol/l; VLDL=29±5%) (group A), and 19 normolipidemic type II diabetics (triglycerides=1.15±0.5 mmol/l; total cholesterol=5.1±1 mmol/l; HDL-cholesterol =1.25±0.38 mmol/l; VLDL=20±5%) (group B). No differences concerning age, body weight, duration of diabetes and glycemic control were found in hyperlipidemic compared to normolipidemic diabetics. On the contrary, higher systolic and diastolic blood pressure levels were demonstrated in group A (167±14 mmHg and 101±5.2 mmHg, respectively) than in group B (144±15 mmHg, p<0.001 and 87±6.9 mmHg, p<0.001, respectively). An increase of plasma apolipoprotein B level (163±27 mg/dlvs 102±21 mg/dl, p<0.001), of plasma viscosity (1.81±0.08 mPasvs 1.51±0.07 mPas, p<0.001) and of blood viscosity (5.37±0.33 mPasvs 5.07±0.04 mPas, p<0.01, at shear-rate of 90 s⁻¹; 18.4±1 mPasvs 14.1±0.9 mPas, p<0.001 at shear-rate of 2.25 s⁻¹) was found in group A, compared to group B. Moreover several positive correlations (p<0.001) between apolipoprotein B level, plasma and blood viscosity were demonstrated in the hyperlipidemic diabetic patients. These findings suggest that blood changes in diabetes might be involved in the occurrence of blood pressure alterations. This study was presented in part at the 22nd Meeting of the European Association for the Study of Diabetes (EASD), Rome September 16–20, 1986.     

Albumin excretion rate and its relation to kidney disease in non-insulin-dependent diabetes mellitus

Abstract. Objective . To estimate the occurrence of increased albumin excretion rate (AER) and its significance as a marker of diabetic kidney disease in non-insulin-dependent diabetic subjects. Design . Population-based, controlled cross-sectional study. Setting . A primary health care centre in the city of Tampere, south-west Finland. Subjects . Consecutive, recently diagnosed (n = 150) and long-term (n = 146) middle-aged non-insulin-dependent diabetic subjects. Matched non-diabetic control subjects (n = 150). Main outcome measures . Albumin excretion rate, fractional AER, microalbuminuria (AER 30–300 mg 24 h^?1), clinical nephropathy (AER exceeding 300 mg 24 h^?1) and kidney biopsy in diabetic subjects with an AER exceeding 100 mg 24 h^?1. Results . Mean (± standard deviation [SD]) 24-h AER was increased in recently diagnosed diabetic subjects, 54 (111) mg, and long-term diabetic subjects, 134 (479) mg, compared to non-diabetic control subjects, 16 (19) mg. The fractional AER was 7.5 (18.3) × 10^?6 in recent diabetic subjects, 53.1 (306.9) × 10^?6 in long-term diabetic subjects and 2.8 (3.7) × 10^?6 in non-diabetic control subjects. Microalbuminuria was found in 8% of non-diabetic subjects, in 29% of recent and in 27% of long-term diabetic subjects. The prevalence of clinical nephropathy was 7% in long-term and 4% in recent diabetic subjects, whilst no non-diabetic subject had nephropathy. In 12 of 16 eligible kidney biopsies, diabetic glomerulosclerosis was found, in four subjects the finding was normal. Conclusions . The AER is clearly increased in recent non-insulin-dependent diabetic subjects and further increased in diabetic subjects with a mean disease duration of 10 years. An increased AER in non-insulin-dependent diabetic subjects suggests diabetic kidney disease.     

Telomere length and progression of diabetic nephropathy in patients with type 1 diabetes

Abstract. Fyhrquist F, Tiitu A, Saijonmaa O, Forsblom C, Groop P‐H, on behalf of the FinnDiane Study Group (Minerva Institute for Medical Research; Helsinki University Central Hospital; and Folkhälsan Institute of Genetics; Helsinki, Finland). Telomere length and progression of diabetic nephropathy in patients with type 1 diabetes. J Intern Med 2010; 267 : 278–286. Objectives. To determine whether short telomere length of blood leucocytes from patients with type 1 diabetes is associated with or predictive of progression of diabetic nephropathy. Design and methods. Two consecutive DNA samples were obtained from 132 patients from the nationwide Finnish Diabetic Nephropathy Study with type 1 diabetes. Control DNA samples were taken from 44 healthy blood donors. Telomere length was measured by Southern blot. Patients were divided into three groups according to their urinary albumin excretion rate (AER): 48 patients with normoalbuminuria (AER < 20 μg min^?1); seven patients with microalbuminuria (AER ≥ 20 μg min^?1 <200 μg min^?1) and 77 patients with macroalbuminuria (AER ≥ 200 μg min^?1). Progression was defined as a change in albuminuria to a higher level. Results. Progression occurred in 21 patients. Progressors had shorter mean telomere length (8.1 ± 0.7 kb, mean ± SD; P = 0.017) and higher percentage of short telomeres (32.0 ± 8%, P = 0.002) than nonprogressors (8.5 ± 0.7 kb and 27 ± 7.2%, respectively). Thus, both shorter telomeres (HR = 0.190, 95%CI 0.065–0.558, P = 0.0025) and higher proportion of short telomeres (HR = 1.115, 1.039–1.195, P =0.0023) were independent predictors of diabetic nephropathy. Telomere length was not associated with the degree of albuminuria and was not different in patients with type 1 diabetes compared with healthy controls. Conclusions. Short telomeres are independent predictors of progression of diabetic nephropathy in patients with type 1 diabetes.     

Diurnal Variation in Blood Pressure in Insulin-dependent Diabetic Smokers and Non-smokers with and without Microalbuminuria

In subjects with essential hypertension, loss of the normal nocturnal dip in blood pressure is associated with a greater risk of developing end-organ complications. In subjects with diabetes, smoking carries a similar association. To assess whether these factors may have an aetiological and synergistic role in the vascular complications of diabetes, 24-hour blood pressure monitoring was performed in insulin-dependent diabetic (IDDM) patients with normal albumin excretion (n = 19) and microalbuminuria (n = 21) of comparable age and duration of diabetes, and with no evidence of autonomic neuropathy or hypertension. The potential influence of smoking was examined by subdividing the groups, depending on smoking status. Ten of the microalbuminuric group and 9 of the normoalbuminuric group were current smokers, the remaining patients never having smoked. There was a significant difference between mean (±SD) daytime vs nocturnal blood pressure in patients with normal albumin excretion (114 ± 3/70 ± 4 vs 102 ± 3/62 ± 3 mmHg; p < 0.001) and microalbuminuria (109 ± 5/75 ± 5 vs 101 ± 3/65 ± 4 mmHg; p < 0.001) but mean blood pressure values did not differ significantly between the groups. A similar fall in nocturnal blood pressure was found in smokers and non-smokers with and without microalbuminuria (p < 0.001), but there was no difference between the mean blood pressure values in the different subgroups. In conclusion, normotensive IDDM patients, who do not have autonomic neuropathy, retain a significant diurnal variation in blood pressure, irrespective of smoking habit or presence of microalbuminuria. © 1997 by John Wiley & Sons, Ltd.     

Urinary Excretion and Clearance of Insulin in Diabetic and Normal Children and Adolescents

Seventy-two diabetic (38 males) and 86 normal (41 males) children provided timed overnight urine collections. Fourteen of the diabetic and 33 of the normal children had concurrent overnight plasma insulin profiles. Urinary insulin clearance in the diabetic subjects was compared with excretion of albumin, growth hormone, retinol-binding protein, and N-acetyl-β-D -glucosaminidase. In the normal subjects, urinary insulin excretion correlated with mean overnight plasma levels in the boys (r = 0.82, p< 0.001) but not in the girls (r = 0.32), and varied with puberty stage in the boys. Insulin clearance was greater in boys than girls during puberty, and fell in both sexes with advancing puberty. Insulin excretion was greater in diabetic than normal children in both sexes at all puberty stages. Insulin clearance was also greater in diabetic than normal subjects (1.05 ± 0.1 ml min^?1 1.73 m^?2 vs o.48 ± 0.05 ml min^?1 1.73 m^?2, p< 0.001). Insulin excretion as a percentage of the filtered load was also greater in diabetic than normal subjects (1.9 ± 0.27% vs 0.85 ±0.09%, p < 0.01). In the diabetic children, there was a correlation between urinary insulin and growth hormone excretion (r = 0.52, p < 0.02), and retinol-binding protein in those (n = 10) with higher retinol binding protein excretion (r = 0.76, p = 0.01). The value of urinary insulin excretion as a measure of free plasma insulin levels in normal and diabetic children may be limited by sex differences in renal insulin clearance, and by proximal renal tubular dysfunction in children with diabetes.     

Determinants of carotid artery wall thickening in young patients with Type 1 diabetes mellitus

To investigate associations between early atherosclerosis and possible risk factors for it in young patients with established Type 1 diabetes mellitus (DM), we measured the combined intima-media thickness (IMT) of the common carotid arteries with high resolution ultrasound in 310 young patients (age ≤ 40 years, mean 27.9 ± 6.5) with a diabetes duration ≥ 2 years, and in two control groups of similar age (control 1:40 healthy subjects, control 2: 40 Type 1 DM recently diagnosed patients). Albumin excretion rate and lipids (total cholesterol and triglycerides) were measured and retinopathy and hypertension (systolic blood pressure > 140 or diastolic blood pressure > 90 mmHg) sought in the patients. Mean maximum IMT was 0.52 ± 0.06 mm in control group 1 and 0.50 ± 0.05 mm in control group 2 with a mean difference of 0.02 mm (95% CI: −0.01, 0.04). The more established Type 1 DM patients had a significantly greater IMT (0.57 ± 0.13 mm, p < 0.001) than both control groups. In a subgroup analysis, patients with microvascular diabetic complications (n = 99) had a significantly greater IMT (0.63 ± 0.17 vs 0.55 ± 0.10 mm, p < 0.001) than those without (n = 211). In a multiple linear regression analysis with a significance level of ≤ 0.10, the carotid artery IMT of our established diabetic patients was related to age, male gender, triglycerides and nephropathy, suggesting the latter as the main diabetes-specific risk for intima-media thickening in young Type 1 DM patients. © 1998 John Wiley & Sons, Ltd.     

Low Prevalence of Microalbuminuria in Young Italian Insulin-dependent Diabetic Patients with Short Duration of Disease: a Population-based Study

Objectives of this study were to determine the prevalence of microalbuminuria and the level of glycaemic control obtained in a young Italian population-based cohort of subjects with short duration of insulin-dependent diabetes mellitus (IDDM). Out of 298 subjects with onset of IDDM in the period 1984–88, 211 were examined (71 %) in 1991–92 (duration of disease 3–9 years). Microalbuminuria was defined as albumin excretion rate (AER) 20–200 μg min⁻¹ in an overnight urine collection or alb/creat > 2.5 mg mmol⁻¹ in men and >4.5 mg mmol⁻¹ in women in one first morning urine sample. Twelve subjects had AER 20–200 μg min⁻¹ and 4 had elevated alb/creat ratio. Prevalence of microalbuminuria was 7 % (95 % CI 4.0–11.1) in subjects with duration of IDDM 3–9 years and 4 % (0.3–7.7) in subjects with duration 3–5 years. Only 1 microalbuminuric subject was found out of 52 aged ⩽14 years. Duration of IDDM was significantly higher (6.9 ± 1.9 years vs 5.7 ± 1.6, p = 0.007) and HDL-cholesterol lower (1.22 ± 0.21 mM vs 1.42 ± 0.34, p = 0.025) in micro-than in normoalbuminuric subjects, even after adjustment for age, systolic and diastolic blood pressure, BMI, and HbA_1c. In almost 50 % of the cohort, HbA_1c levels were over 9 %, whereas only in 10.9 % HbA_1c levels were lower than 6.6 % (mean + 3 SD). In conclusion, this Italian population-based study showed low prevalence of microalbuminuria in young subjects with short duration of IDDM, even if the glycaemic control obtained was far from ideal.     

Comparison of Platelet Aggregability in Japanese Type 2 Diabetic Patients With and Without Microalbuminuria

Microalbuminuria is associated with higher cardiovascular morbidity and mortality in Type 2 (non-insulin-dependent) diabetic patients. This study was designed to assess whether Type 2 diabetic patients with microalbuminuria (urinary albumin excretion rate (AER) 20–200 μg min^?1) is associated with alterations in platelet aggregability as compared with those with normal urinary albumin excretion (AER < 20 μg min^?1). Platelet aggregability was compared between 21 Japanese Type 2 diabetic patients with microalbuminuria and 21 individually pair-matched (for age, sex, body mass index, treatment, and HbA_1c level) patients with normoalbuminuria. The in vitro platelet aggregation induced by 1.0 and 3.0 μmol I^?1 ADP and 0.5 and 1.0 mg I^?1 collagen was measured using platelet-rich plasma. No significant differences were observed between the two groups in the values for maximum percent platelet aggregation, percent aggregation at 3 min, and aggregation velocities after adding ADP or collagen. Microalbuminuric patients had significantly higher mean values for systolic (p < 0.004) and diastolic (p < 0.02) blood pressures and plasma fibrinogen level (p < 0.03) as compared with the respective mean values in normoalbuminuric patients. The results suggest that Japanese microalbuminuric Type 2 diabetic patients do not differ in the degree of platelet aggregability as compared with normoalbuminuric patients, despite an increase in certain other coronary risk factors.     

Reproducibility of erythrocyte sodium-lithium countertransport activity and ambulatory blood pressure measurements in type 1 diabetes mellitus

We aimed to study the reproducibility of sodium-lithium countertransport [SLCT] activity and ambulatory blood pressure monitoring [ABPM] in type 1 diabetes. We did this by performing repeated measurements of SLCT activity and ABPM in 11 recent-onset diabetic children and in 11 patients with longer duration of diabetes. Both parameters were related to microalbuminuria. In the older group of diabetic children a significant correlation [r = 0.78; P<0.005] in SLCT activity between the first and second study was observed [514.3±186.4 vs 491.0 ± 148.0 μmol/l erythrocytes/h]. Diurnal systolic and diastolic blood pressure were comparable at both time points within the same group of diabetic children [in group 1: 102.6±6.1 vs 108.6±7.6 mmHg N.S.; in group 2: 113.4 ± 10.6 vs 114.0±7.8 mmHg N.S. Diastolic blood pressure in group 1: 57.4±4.8 vs 65.7±6.9 mmHg N.S., in group 2: 70.6±9.1 vs 68.5±5.3 mmHg N.S.]. Moreover, there was a significant correlation in both diurnal and nocturnal systolic blood pressure between the first and second study in the whole diabetic population. Both SLCT activity and blood pressure values obtained by ABPM were found to be reproducible individual characteristic markers in type 1 diabetic children. Received: 22 November 1997 / Accepted in revised form: 30 April 1998     

Combined exercise training reduces blood pressure,arterial stiffness,and insulin resistance in obese prehypertensive adolescent girls

Childhood obesity is strongly linked to pathological processes for cardiovascular diseases in later adulthood. Obese adolescent girls with high blood pressure (BP) are reported to have increased arterial stiffness, which is associated with the development of hypertension and atherosclerosis. The present study sought to examine the impact of combined resistance and aerobic exercise (CRAE) training on BP, brachial-ankle pulse wave velocity (baPWV), insulin resistance (IR), and body composition in obese prehypertensive girls. Forty girls (age, 15 ± 1 years; systolic BP, 132 ± 2 mmHg, diastolic BP, 80 ± 5 mmHg) were randomly assigned to either a combined exercise (EX, n = 20) or no exercise group (CON, n = 20). The EX group performed CRAE for 12 weeks, 3 times per week. BP, baPWV, blood nitrite/nitrate, endothelin-1 (ET-1), homeostasis model assessment for insulin resistance (HOMA-IR), and body composition were measured before and after the exercise intervention. BP (?-7.3 ± 2.67 mmHg), baPWV (?-1.23 ± 0.49 m/s), ET-1 (?-14.35 ± 1.76 μmol/mL), nitrite/nitrate (?0.5 ± 0.09 μM), HOMA-IR (?-1.4 ± 0.07), percent body fat (?-1.35 ± 0.9%), and waist circumference were significantly improved (P < 0.05) in the EX group after 12 weeks of training versus the CON group. These findings indicate that 12 weeks of CRAE improves BP, HOMA-IR, and arterial stiffness and reduces central adiposity in obese adolescent girls with prehypertension. Thus, this study provides evidence that CRAE can be a useful therapeutic treatment for high BP, IR, and central adiposity, thereby reducing the likelihood of pathological development for cardiovascular diseases in later adulthood.     

Is ACE Inhibition with Lisinopril Helpful in Diabetic Neuropathy?

Thirteen diabetic patients with hypertension (mean diastolic blood pressure 96.2 ± 1.1 mmHg) were included in a study to assess the effects of lisinopril (20 mg day^?1) on measures of nerve function. Patients had nerve conduction velocity (NCV), temperature discrimination threshold (TDT), and vibration perception threshold (VPT) measurements. At the end of 12 weeks of treatment with lisinopril, there was a significant improvement in median motor NCV (mean change ± SEM 2.7 ± 0.6 m s^?1, p < 0.0001), median sensory NCV (2.1 ± 0.9 m s^?1, p = 0.03), peroneal motor NCV (1.0 ± 0.4 m s^?1, p = 0.03), and sural sensory NCV (1.9 ± 0.7 m s^?1 p = 0.01) values. There were also significant improvements in warm TDT and VPT. Diastolic BP decreased significantly, but there was no significant change in HbA₁. Double blind controlled studies are now needed to confirm the effect of lisinopril on measures of nerve function.