Morphometric studies of the peripheral glomerular basement membrane in early juvenile diabetes I. Development of initial basement membrane thickening

Summary An extension of a previously reported quantitative electronmicroscopic study of the glomerular basement membrane in juvenile diabetes is presented. The initial phase in the development of basement membrane thickening in diabetic glomeruli has also been studied. — Measurements of the basement membrane were obtained from photomontages of glomerular cross sections produced from electron micrographs. A total of 16 glomeruli from five non-diabetics and 83 glomeruli from diabetics were measured. — The results showed that the peripheral glomerular basement membrane is normal at the onset of acute, juvenile diabetes, but a thickening is demonstrable in patients with a duration of the disease of about 2 years. — These findings support the hypothesis that diabetic angiopathy is a consequence of the metabolic derangement in diabetics.Supported by grants from: Statens lægevidenskabelige forskningsråd, Michaelsen fonden, Novo fonden, Rask Ørsted fonden.     

Indirect measurement of systolic blood pressure by strain gauge technique at finger,ankle and toe in diabetic patients without symptoms of occlusive arterial disease

Summary The systolic blood pressure has been measured at the first finger, ankle and first toe, using the strain gauge technique, in 22 diabetic patients aged 40 to 59 years, with diabetes of 11 to 42 years duration, and in 14 non-diabetics in the same age group — all without clinical evidence of occlusive arterial disease in the legs and with palpable pulses in the feet. — The mean systolic gradients (arm-finger, arm-ankle, arm-toe) were equal in the diabetics and nondiabetics. Using mean ± 2.5 x S.D. as normal limits, a significantly elevated systolic blood pressure at the given sites was found in 12 observations among 6 diabetics; 5 of these patients had arterial calcification shown by radiography. In only one observation, a significant pressure drop suggesting arterial stenosis was demonstrated.     

Morphometric studies of the peripheral glomerular basement membrane

Summary Glomerular basement membrane thickness has been estimated by quantitative electron-microscopic study in control subjects and in juvenile diabetics at onset and with short-term diabetes. — The juxta-mesangial part of the basement membrane as well as basement membranes located close to the vascular pole were considered separately and their thickness compared with the remainder of the basement membrane of the same cross section. — It was found that basement membrane, both close to mesangial regions and to the vascular pole, showed greater variation in thickness than the remainder of the glomerular basement membrane. The deviations were, however, small. — The initial thickening occurring in diabetic patients after a few years of the disease was shown to take place as a generalized phenomenon over the entire cross section and did not primarily affect the basement membrane close to mesangial regions or the vascular pole.     

Residual B-cell function in insulin-dependent (type I) diabetics with and without retinopathy

Summary In order to evaluate if residual B-cell function is a protecting factor against the development of diabetic retinopathy in type I diabetics we measured C-peptide levels before and after glucagon stimulation (1 mg i.v.) in 74 type I diabetics. In all patients retinopathy was assessed by fluorescein angiography and retinal lesions were classified as: grade 0, normal; grade 1, background retinopathy; grade 2, proliferative retinopathy. We then correlated the degree of retinopathy to sex, age, duration of diabetes, smoking, percentage of ideal body weight, systolic and diastolic blood pressure, serum cholesterol, triglycerides, creatinine and C-peptide by means of multiple linear regression analysis. Twenty-three out of 74 type I diabetics had retinopathy. In all 7 subjects with proliferative retinopathy duration of diabetes exceeded 10 years. There was significant correlation between retinopathy and duration of diabetes (r=0.373, p<0.001). No correlation was found between retinopathy and all the other variables, in particular between retinopathy and basal C-peptide or C-peptide increment (Δ). An inverse correlation was found between the increment of C-peptide and duration of diabetes (r=−0.404, p<0.01). Our data show that residual B-cell function cannot be considered a protecting factor against the development of diabetic retinopathy.     

Echocardiographic-determined Left Ventricular Wall Characteristics in Insulin-dependent Diabetic Patients

Abstract. Left ventricular wall mass, thickness and movement were investigated by echocardiography in 80 insulin-dependent diabetic patients with no signs of ischaemic heart disease and in 40 healthy controls. In diabetics with a disease duration of >30 yr, urinary albumin excretion rate >200 μg/min (clinical nephropathy), proliferative retinopathy or autonomic neuropathy, both the posterior wall thickness and the septal thickness were increased compared to controls. The posterior wall thickness and the septal thickness were positively correlated to blood pressure (p<0.001), disease duration (p<0.001), urinary albumin excretion rate (p<0.001), and negatively correlated to the heart variation during deep respiration (p<0.01). The left ventricular wall mass was correlated to both blood pressure (p<0.01) and urinary albumin excretion rate (p<0.01). By multiple regression analysis urinary albumin excretion rate, disease duration and heart rate variation during deep respiration did not add significantly to the correlation between left ventricular wall mass/wall thickness and blood pressure. The septal movement was reduced in diabetics with proliferative retinopathy or clinical nephropathy. In conclusion, left ventricular wall thickness and wall mass were closely related to blood pressure in insulin-dependent diabetics. Signs of impaired cardiac function, such as reduced septal movement, were seen only in patients with severe microvascular disease.     

Diabetic neuropathy is closely associated with arterial stiffening and thickness in Type 2 diabetes

Aims Interaction of vascular and metabolic factors appears to contribute to the pathogenesis of diabetic neuropathy. The aim of the study was to assess the impact of arterial stiffening and thickness on diabetic neuropathy in Type 2 diabetes. Methods In 294 patients with Type 2 diabetes, neuropathy was assessed by four components: the presence of neuropathic symptoms, the absence of ankle tendon reflexes, perception of vibration scores and heart rate variation. We measured intima‐media thickness (IMT) of carotid arteries to assess arterial thickening, and brachial–ankle pulse‐wave velocity (PWV) and brachial pulse pressure (PP) which reflect arterial stiffening. Results Diabetic neuropathy, defined as ≥ two of the four components, was significantly associated with age, duration, glycated haemoglobin (HbA_1c), systolic blood pressure, diastolic blood pressure, PP, hypertension, retinopathy, urinary albumin excretion rate, nephropathy stages, PWV and IMT. PWV and PP were significantly associated with neuropathy independent of conventional cardiovascular risk factors. Multiple logistic regression analysis revealed that PWV, retinopathy, age, and HbA_1c, were significant independent determinants of neuropathy. Conclusions The present cross‐sectional study indicates that markers for vascular wall properties such as PWV, IMT and PP are significantly associated with diabetic neuropathy. PWV and PP are significant determinants of neuropathy independent of conventional cardiovascular risk factors. Multifactorial intervention to inhibit progression of the atherosclerotic process may slow progression of neuropathy.     

Echocardiographic analysis of the left ventricle in patients with type II diabetes mellitus

Left ventricular involvement in type II diabetes mellitus is poorly understood. We performed a cross-sectional, M-mode and pulsed Doppler echocardiographic study on 27 diabetic patients and 27 controls accurately matched for age, sex, weight and height. All subjects also underwent 24-hour non-invasive ambulatory blood pressure monitoring. Left ventricular wall thicknesses and dimensions in diastole and systole, left ventricular mass index (82.7 g/m2 vs 78.4 g/m2) and the echocardiographic indices of left ventricular contractility did not show any statistical differences between diabetics and controls. Clinic and 24-hour ambulatory blood pressure did not show important differences between diabetics and controls. Doppler parameters for transmitral flow velocity (including peak A and peak E velocity and their ratio, pressure half time and pressure half slope) were the same in diabetics and controls. A stepwise multivariate regression analysis showed a significant positive independent relationship of peak A/peak E ratio with age (peak A/peak E = 0.0087 + 0.20 x age; F = 18.7; p = 0.0001), but not with diabetes or glycosylated haemoglobin (Hb 1 AC). Compared with non-diabetics, diabetics showed a slight increase in aortic peak flow velocity (0.83 m/sec vs. 0.70 m/sec; p = 0.011) and a very slight increase in peak aortic gradient. Peak aortic velocity showed a highly significant positive independent relation with the duration of diabetes (Vmax = 0.572 + 0.0028* diabetes duration (months); F = 92.6; p less than 0.0001), but not with age, systolic or diastolic blood pressure of HB 1 AC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of age on carotid arterial intima-media thickness in childhood

To investigate relationships between carotid arterial intima-media thickness (IMT) and age in childhood, we performed high-resolution carotid arterial ultrasonography in 60 healthy children (27 boys, 33 girls; age range, 5–14 years) determined by screening to have no dyslipidemia or hypertension. No plaque formation was found, and irregularity of IMT (root mean square roughness of IMT) did not correlate with age. Mean IMT increased in a linear manner with age [IMT in millimeters = (0.009 × age in years) + 0.35] (r = 0.39, P = 0.002). This correlation remained significant after adjustment for gender, parental smoking, systolic and diastolic blood pressure, body mass index, and serum concentrations of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. None of these known cardiovascular disease risk factors in adults had a significant relationship with age-adjusted IMT in children. While circumferential wall stress and diastolic blood pressure were not correlated with age, mean IMT and lumen diameter showed significant positive relationships with circulating blood volume, which was calculated as the function of height and weight. These data suggested that age-dependent physiologic thickening of arterial walls begins in childhood.     

Arterial Wall Changes in Type 2 Diabetic Subjects

Arterial ultrasonic appearances using high resolution ultrasound were studied in 97 subjects with Type 2 diabetes and age- and sex-matched controls. The intima-media thickness of both common carotid arteries was measured 2 cm proximal to the bifurcation and the presence or absence of plaque on both common and femoral bifurcations was recorded. The mean intima-media thickness in subjects with diabetes was 0.82 ± 0.22 mm while in the controls 0.66 ± 0.13 mm (p < 0.001). Multiple regression in diabetic subjects only showed no correlation between age, sex, body mass index, smoking, duration of diabetes, systolic or diastolic blood pressure, cholesterol, HDL, LDL, triglycerides, HbA, and the common carotid artery intima-media thickness. Type 2 diabetes is associated with increased intima-media thickness which has been found to be a marker of cardiovascular events in the general population.     

Arterial pressure in clinically apparent diabetics.

The relationship between arterial blood pressure and clinically apparent diabetes mellitus was examined by measuring blood pressure, under standardised conditions, in 735 ambulant diabetic patients attending St. Mary's and King's College Hospital, London. Other biometric, clinical and family data were also systematically collected. A large proportion of first degree relatives of the diabetics and a control group of first degree relatives of non-diabetics were also seen and examined; they were also tested for the presence of unsuspected diabetes. Blood pressure in diabetics was evaluated in two ways. Mean pressures (systolic and diastolic) were calculated by age and sex and compared with similar data from two British non-diabetic populations. In addition, age and sex adjusted blood pressure "scores" were derived for each of the diabetic propositi and for the relatives by calculating the degree to which their pressures deviated from the mean of a corresponding age/sex group of non-diabetics. These deviations were then made comparable by standardising them for the systematic change in variance with age and sex. Using both "raw pressures" and "adjusted scores" the influence of age, sex, obesity, arm girth, response to diagnosis and ethnic, obstetric and anamnestic features were examined. Analysis of the influence of various characteristics of the diabetic state on blood pressure was made; this included mode of presentation, known duration; insulin dose and degree of metabolic control. Finally the relationship of blood pressure levels to the long-term sequels of diabetes was analysed with special reference to renal disease, eye changes, neuropathy and arterial disease. No systematic difference between arterial blood pressure in diabetics and a suitable control population was detected. Younger patients, females more than males, tended to have somewhat higher mean diastolic pressures but these were balanced by rather lower mean pressures in older diabetics. There was evidence of raised pressure levels at the time of diagnosis of diabetes, particularly in older patients, which "settled" with time for reasons which were not clear. The relationship of arterial pressure with adiposity was comparable to that in non-diabetics. After allowance for age and sex, blood pressures and scores were not related to the mode of onset of the diabetes. In the youngest onset group, however, known duration of diabetes appeared to correlate positively with arterial pressure in excess of the effect of age. Insulin dose and metabolic characteristics of the diabetes showed little clear association with arterial pressure but, as expected, patients with evidence of renal disease had higher mean pressures. However, cause-effect relationship between raised pressure and renal disease in diabetics may operate in both directions. Some elements of retinopathy were positively correlated with blood pressure; others were not. The role of co-existing renal disease in determining this association was examined...     

The cardiac anatomical and functional changes in a group of young type-1 diabetics without microangiopathy]

We study 71 type I diabetics and 25 controls, trying to analyze the anatomical and functional changes due to diabetes. The diabetics, with a mean age of 18.4 +/- 8.2 years, were strictly selected excluding any disease and treatment besides insulin. In 66, and echocardiographic M mode and 2D study was done to calculate wall thickness, cavity dimensions and systolic function indexes; in all, Eco-Doppler analyzing 9 diastolic function indexes. The results showed an increase in septal thickness in diabetics (p less than 0.01 in diastole and less than 0.001 in systole). There was no difference in systolic function or posterior wall thickness, having the diabetics a significant increase of the T 1/2 (p less than 0.001), a decrease of the deceleration of E and the ratio E/A (p less than 0.001). As a group, 12.5% of the diabetics had anatomical abnormalities, and 18.3% diastolic abnormalities at least in two indexes. The only significant correlation was established between the evolution time and the T 1/2 (p less than 0.01). We conclude that in this group of selected diabetics, the anatomical and functional abnormalities found were only imputable to the diabetic abnormality.     

Echocardiographic features of impaired ventricular function in diabetes mellitus.

In order to study left ventricular diastolic function in diabetes mellitus, simultaneous echo- and phonocardiograms were recorded in 142 diabetics (free from heart disease), 20 normal subjects, and 16 patients with coronary artery disease. The resultant traces were digitised, and left ventricular relaxation and the rate and duration of cavity dimension increase and wall thinning were determined. Diastolic variables of left ventricular function were normal in 12 young diabetics with no complications. Significantly delayed mitral valve opening relative to minimum dimension and aortic valve closure was found in all other groups of diabetics. Forty-four diabetics with severe microvascular complications had significantly reduced peak rate and prolonged duration of wall thinning and dimension increase. The abnormalities were unlike those found in subjects with coronary artery disease. The extent of microvascular complications was significantly correlated to most variables of diastolic function. This relation was maintained in 31 diabetics with significant cavity dimension increase during isovolumic relaxation (incoordinate relaxation). In 42 juvenile onset patients there was good correlation between the duration of diabetes and most variables of diastolic function. These studies show that the primary cardiac abnormality in diabetic micro-angiography is a prolonged duration and reduced rate of posterior wall thinning with impaired left ventricular dimension increase, reflecting abnormal myocardial properties.     

Factors Contributing to Left Ventricular Diastolic Dysfunction in Long-term Type I Diabetic Subjects

ABSTRACT Although non-invasive studies in type I diabetic subjects indicate left ventricular (LV) diastolic dysfunction, the contribution of borderline or mild hypertension to such changes is obscure. Thus, digitized M-mode echocardiograms were obtained in 32 (18 men) young (<50 years) normotensive controls and 32 (21 men) long-term (≥12 years) type I diabetics with blood pressures ranging from normal to hypertensive. All diabetics were without clinical heart disease, none were previously treated for hypertension or using cardioactive drugs. Heart rate, systolic and diastolic blood pressures were higher in diabetic than control subjects. Their LV end-diastolic dimension was smaller, whereas wall thickness, LV mass index and fractional shortening were similar to controls. In diabetics, however, the normalized peak filling rate was decreased and the rapid filling period fraction of diastole increased. In multivariate analysis, diabetes and LV mass independently and inversely influenced the normalized peak filling rate, while fractional shortening did so positively. Furthermore, diabetes and systolic blood pressure independently influenced the rapid filling period fraction of diastole. This study is the first to demonstrate systolic blood pressure and LV mass as independent contributors to subclinical LV diastolic abnormalities in diabetics. These findings may therefore indicate the need to treat even mild hypertension in diabetics in an effort to delay the development of cardiopathy.     

Prevalence of diabetic autonomic neuropathy measured by simple bedside tests

Summary To investigate the prevalence of diabetic autonomic neuropathy, five simple bedside tests, beat-to-beat variation during quiet respiration, beatto-beat variation during forced respiration, heart rate and blood pressure response to standing, heart rate response to exercise, and heart rate response to Valsalva's manoeuvre were applied to 75 male insulindependent diabetics, mean age 40 years, (range 30–49 years). The subjects were subdivided into three groups according to duration of diabetes, which was between 0 and 40 years. Twenty-eight healthy age-matched male controls were also studied. The prevalence of diabetic autonomic neuropathy in the whole diabetic population indicated by abnormal response in beat-to-beat variation during forced respiration was 27%. Diabetic autonomic neuropathy increased in frequency with duration of disease. Patients with nephropathy or proliferative retinopathy had a significantly higher prevalence of diabetic autonomic neuropathy as indicated by abnormal beat-to-beat variation during forced respirations (p<0.01) than patients without these complications.     

Is Exercise-induced Blood Pressure Rise Predictive of Nephropathy in Insulin-dependent Diabetes?

ABSTRACT A follow-up study was performed in 48 male diabetics and 17 age-matched male controls, who in 1963 and 1971 participated in an exercise study to evaluate if the results could predict later development of diabetic nephropathy. The inclusion criteria were: Type I (insulin-dependent) diabetes with age below 40, onset of diabetes before age of 30, duration of diabetes more than 7 years and no proteinuria at the time for the first study. The diabetics demonstrated higher systolic blood pressure (BP) at work but as good physical condition as the controls. Thirteen developed nephropathy after 23 years (range 15–36) of diabetes duration. It was found that exercise-induced, abnormally raised systolic BP was not associated with later development of diabetic nephropathy.     

Effects of type 1 diabetes mellitus on cardiac function: a study of monozygotic twins.

OBJECTIVE--To investigate left ventricular size and function in type 1 diabetes and their relation with diabetes duration, glycaemic control, autonomic dysfunction, and complications of diabetes. DESIGN--Cross sectional study using a pulsed wave Doppler echocardiogram to assess left ventricular dimensions, wall thickness, and transmitral blood flow velocity signals. PATIENTS--40 monozygotic twin pairs (23 male, mean age 26 years) discordant for type 1 diabetes and 40 non-diabetic singleton controls with no clinical evidence of cardiac ischaemia. RESULTS--For all Doppler echocardiographic measurements there were strong correlations between monozygotic twins but not between twins and control subjects. Left ventricular dimensions, wall thickness and systolic function, peak E velocity, and the velocity integrals of early left ventricular filling were similar in all three groups. Peak A velocity and the velocity integrals of late ventricular filling (mean (SD)) were greater in diabetic twins (45 (12) v 38 (8) cm/s, P = 0.002; and 32 (11) v 26 (6), P = 0.0002). Diabetic twins had lower E/A ratio (1.59 (0.39) v 1.83 (0.39), P < 0.001), greater atrial filling fraction to total diastolic filling (28 (6) v 25 (5)%, P = 0.002), and prolonged isovolumic relaxation time (72 (12) v 63 (9) ms, P < 0.001). The differences in Doppler findings between diabetic and non-diabetic twins were related to disease duration whereas the prolongation of the isovolumic relaxation time was related to cardiac autonomic dysfunction. CONCLUSIONS--These results show that twins with type 1 diabetes have left ventricular diastolic dysfunction related to diabetes duration and cardiac autonomic dysfunction but not to glycaemic control or microvascular complications. In addition, genetic factors contribute to left ventricular dimension and function.     

Glomerular size and structure in diabetes mellitus

Summary The present electron microscopic study shows that the kidney hyperfunction in early diabetes can be due to a significant morphological change: an increased glomerular filtration surface. Applying standard stereological methods, the area of the peripheral wall of the glomerular capillaries was measured in biopsy specimens obtained from 7 patients with early diabetes and 7 controls. — An 80 per cent enlargement of the capillary wall (the surface of the peripheral basement membrane) was found in the diabetics (2 p=0.0096). Also the total area of the interface between the tuft and the urinary space was increased by 70 per cent (2 p=0.029). Since the thickness of the peripheral basement membrane is known to be unchanged in patients with early diabetes the finding of an increased area of the membrane implies that an increased quantity of basement membrane material is present in these patients. The significance of this phenomenon for the understanding of the metabolism of the basement membrane is discussed, and a working hypothesis is advanced for the pathogenesis of the diabetic microangiopathy.     

Isoamylases in diabetes mellitus

Summary We have evaluated the relationship between diabetes mellitus and exocrine pancreatic insufficiency in diabetic subjects by measuring a specific isoamylase arising from the pancreas. The pancreatic- and salivary-type isoamylase activity in serum and urine were evaluated and related to duration of disease, sex, age, weight, blood glucose level and glycosuria in 153 diabetics. In the insulin-dependent diabetics diagnosed between 15 and 24 years of age, a significant decrease in pancreatic isoamylase activity was found in serum and urine (means with 2 SD range, 50 U/l, 19–137 U/l, and 47 U/l, 4–607 U/l, respectively), as compared with control subjects (79 U/l, 45–140 U/l, and 183 U/l, 43–789 U/l, respectively). In this group of patients a low stimulated output of amylase into the duodenum was also observed (mean with range, 537 U, 87–1808 U), compared with controls (the lower limit of normal 2183 U). A significant positive correlation was found between stimulated output of amylase into the duodenum and pancreatic isoamylase activity in serum (r = 0.84, p < 0.01). In the non-insulin dependent diabetics, a significant negative correlation was found between blood glucose levels and pancreatic isoamylase activity in serum (r = -0.46, p < 0.01). In the diet-treated non-insulin dependent diabetics the pancreatic isoamylase activity in serum was increased compared with controls (mean and 2 SD range, 102 U/l, 49–211 U/l). In patients with blood glucose level above 12 mmol/l, however, a lowered pancreatic isoamylase activity in serum, and no apparent rise in serum immunoreactive insulin in glucose loading test was observed. The results suggest that production of pancreatic amylase is related to endocrine pancreatic function in diabetes mellitus.     

Ambulatory blood pressure monitoring and echocardiographic left ventricular wall thickness and mass

In a highly select group of stable hypertensive patients, we have assessed the strength of association between various blood pressure measurements (24 h average automated ambulatory blood pressure, 4 h automated ambulatory morning average blood pressure, multiple office visit average blood pressure, and a single office visit average blood pressure) and various echocardiographic indices of hypertensive cardiac target organ damage (left atrial diameter, left ventricular end diastolic diameter, posterior wall thickness, combined wall thickness, relative wall thickness, left ventricular mass and mass index, and combined wall thickness/left ventricular diastolic diameter ratio). These data demonstrated that a single 24 h average diastolic blood pressure by automatic noninvasive ambulatory monitoring was a significantly better predictor of echocardiographic posterior wall thickness, combined wall thickness or relative wall thickness than the multiple office or single office average diastolic blood pressure. Also there were highly significant correlations between both 24 h average systolic and diastolic blood pressure and these echocardiographic parameters (in descending order of correlation coefficient): combined wall thickness, posterior wall thickness, combined wall thickness/left ventricular diastolic diameter, left ventricular mass index, relative wall thickness, and left ventricular mass. Left ventricular end diastolic dimension did not linearly correlate with any systolic or diastolic blood pressure measurement. Left atrial dimension demonstrated only a significant association with 24 h average diastolic blood pressure. Single office average blood pressure did not linearly correlate with any echocardiographic parameter.(ABSTRACT TRUNCATED AT 250 WORDS)     

Microalbuminuria in Long-term Insulin-dependent Diabetes Mellitus

ABSTRACT Albumin excretion rate was determined by radioimmunoassay in overnight urine from 102 normotensive patients with insulin-dependent diabetes mellitus of more than 10 years' duration. Based on two samples, 16 patients (16%) exhibited microalbuminuria, defined as a mean excretion rate >20 μg/min. Microalbuminuric patients were significantly younger at onset of diabetes but did not differ from normoalbuminuric patients concerning age or duration of diabetes. Nonetheless, diastolic and mean arterial blood pressures were significantly higher in the microalbuminuric group. The existing glycemic control, assessed by glycosylated hemoglobin (HbA_1C) was better in normoalbuminurics, but not significantly so. The albumin excretion rate in microalbuminuric patients correlated significantly (p<0.01) to diastolic (r=0.69) and to mean arterial blood pressure (r=0.69), but did not correlate to HbA_1C. Thus, it is concluded that even normotensive patients with signs of early diabetic nephropathy, i.e. microalbuminuria, exhibit small, but significant increases in blood pressure.