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To evaluate the influence of duration on the development of autonomic neuropathy (AN) a group of type I diabetic patients (n = 58) who had been diagnosed between the ages of 15 and 25 years was investigated. The duration of diabetes varied from 2 months to 30 years (mean 13 years). AN tests included a deep breathing test (E/I ratio) and an orthostatic test on tilt table (acceleration and brake indices) and the results were corrected for age. A clear correlation between AN test and duration of diabetes was shown only for the E/I ratio (r = -0.44, p less than 0.001). On the other hand, deteriorations in the brake index were unrelated to the duration of diabetes and occurred early; 35% of the patients with a duration of 10 years or less showed an abnormal brake index. Autonomic test deviations were related to other diabetic complications. The E/I ratio and the acceleration index were especially low in patients with retinopathy as well as in patients with symptoms of AN if combined with peripheral neuropathy (PN). The brake index was low in patients with symptoms of AN independent of PN.

Glomerular filtration rate (GFR) measured by the 51Cr-EDTA clearance method, autonomic nerve function evaluated by the heart rate reaction to deep breathing (E/I ratio) and to tilting (acceleration and brake indices), and orthostatic blood pressures were followed up after 5-7 yr in 43 patients with Type 1 diabetes. At follow up, 20 patients showed a decrease in GFR greater than expected. In the first study, these patients showed low E/I ratios and brake indices indicating vagal neuropathy, while the acceleration index fell, indicating sympathetic denervation, between the studies. Accordingly, vagal neuropathy preceded decreases in GFR and sympathetic denervation favoured deteriorations in GFR. The present report provides evidence that sympathetic denervation might be behind the development of diabetic kidney complications.

In cross-sectional studies elevations in growth hormone (GH), factor VIII related antigen (VIIIR:Ag), and plasminogen activator activity (PAA) have been connected with diabetic retinopathy. To evaluate the importance of these factors for the development of retinopathy, we have carried out a prospective study. In a primary study GH, VIIIR:Ag, and PAA were evaluated during a 25 min exercise test in 22 insulin dependent diabetes mellitus (IDDM) patients. After 5-7 years, the patients were re-evaluated and the presence of retinopathy in the follow-up study was correlated to the findings in the primary study. Patients with retinopathy in the primary or the second study (n = 14) showed a significant increase in GH (p less than 0.05) during the first 5 min of exercise compared with patients without retinopathy. Moreover, the 14 retinopathy patients showed further significant elevations in GH (p less than 0.001), VIIIR:Ag (p less than 0.01) and PAA (p less than 0.001) during the remaining 20 min of exercise. In contrast, patients without retinopathy (n = 8) in the follow-up study, did not show significant elevations in GH, VIIIR:Ag, and PAA during exercise. A lack of rise in GH, VIIIR:Ag, and PAA during exercise seems to indicate a resistance to retinopathy in IDDM patients.

The effect of the degree and speed of tilt on the immediate heart rate reaction measuring cardiac autonomic nerve function was evaluated in nine healthy subjects. The results showed that the tilt angle determined the immediate increase in heart rate. The increase in heart rate was maximal when a 90 degrees tilt was performed. After the immediate increase there was a transient decrease in heart rate after rapid tilts (2-5 s). A rapid 90 degrees tilt is preferred when automatic nerve function should be evaluated from the immediate heart rate response.

To evaluate the clinical utility of fructosamine as a mean of monitor glycaemic control, fructosamine and HbA1c were compared in 46 random out-patients visiting a Diabetic Clinic as well as in 25 inpatients admitted to a Diabetes Day Care Unit. In the out-patients, there were a significant correlations between fructosamine and fasting blood glucose (r = 0.75) as well as between fructosamine and HbA1c (r = 0.91). However, when the reference values were considered, interesting differences were found; only 4% of the out-patients showed normal HbA1c values while 39% showed normal fructosamine values. Accordingly, fructosamine and HbA1c evaluate different aspects of glycaemic control. During an admission of 7 days to the Diabetes Day Care Unit no statistical changes in mean blood glucose and fructosamine values occurred. On the other hand, two weeks after discharge from the Unit, not only fructosamine (3.58 +/- 0.16 mmol vs 3.09 +/- 0.08 mmol/l) but also HbA1c (9.52 +/- 0.38% vs 8.33 +/- 0.23%) had improved significantly. Thus HbA1c measures improvements in glycaemic control as early as 3 weeks after changes in treatment. At six weeks after discharge HbA1c (7.63 +/- 0.34%) but not fructosamine (3.02 + 0.14 mmol/l) had improved further. HbA1c is a reliable marker of glycaemic control while the value of fructosamine in clinical practice is unclear.

Autonomic neuropathy (AN) test results (Valsalva manoeuvre, deep breathing, and tilting) are frequently impaired in diabetics without symptoms of AN, particularly in those with peripheral neuropathy (PN). We have investigated 24 asymptomatic diabetics with PN, 17 diabetics with symptoms of AN and 24 healthy controls. The heart rate reactions to the three tests were impaired in both patient groups. The Valsalva manoeuvre could not distinguish between the patient groups. The heart rate reaction to deep breathing, estimated as the expiration/inspiration (E/I) ratio, was slightly more disturbed in patients with AN than those with PN (1.04 vs. 1.09, p less than 0.05) but the frequency of abnormally low E/I ratios was high in both groups (76.5 vs. 54.2%, NS). The immediate heart rate reaction to tilting, estimated as the brake index, clearly separated the patient groups. An abnormally low brake index was shown in 82.3% of AN patients and in 33.3% of PN patients (p less than 0.01). The study shows that the deep breathing test is sensitive for AN but an impaired immediate heart rate reaction to tilting is more specific for symptomatic AN.

Low sodium and potassium adenosine triphosphatase (ATPase) activity has been proposed as a mechanism behind diabetic neuropathy. In this study the platelet ATPase activity and platelet noradrenaline efflux rate were determined in 47 insulin-dependent diabetes mellitus (IDDM) patients and 20 controls. Ulnar motor conduction velocities, tested in a subgroup, were lower in patients than in controls (52.7 +/- 1.3 m s-1 vs. 61.3 +/- 1.4 m s-1; P less than 0.001). Platelet ATPase activity tended to be increased in the patients compared with the controls (29.9 +/- 1.0 x 10(-3) min-1 vs. 26.9 +/- 1.1 x 10(-3) min-1; NS). In ulnar nerve function tested subjects, ATPase activity was higher in patients than in controls (31.2 +/- 1.7 x 10(-3) min-3 vs. 25.9 +/- 1.3 x 10(-3) min-1; P less than 0.01). The platelet noradrenaline efflux rate tended to be higher in patients with lower brake indices, a sign of autonomic neuropathy, than in controls (29.0 +/- 3.0 x 10(-3) min-1 vs. 21.2 +/- 0.9 x 10(-3) min-1; P less than 0.05). The platelet ATPase activity was not decreased in IDDM patients, however, a connection between diabetic autonomic neuropathy and platelet transmittor leakage was indicated.

Bone scintigraphy was performed in 16 men with newly diagnosed prostatic carcinoma before orchiectomy as well as 2 weeks and 2 months after operation. The uptake in the lower thoracic and lumbar vertebrae was registered up to 240 min after injection of 99mTc-MDP and was then calculated for each patient and vertebra. The relative standard deviation in measured uptake due to measuring technique was estimated to be +/- 7%. In eight patients, who had normal bone scintigraphies before orchiectomy, there were no changes in the uptake values after operation. The remaining eight patients had widespread metastatic involvement prior to treatment. Six of these patients showed a so called "flare phenomenon" in the abnormal vertebrae which means an initial increase in uptake after operation followed by a decreased uptake in response to therapy. One patient had a continuously increased uptake in all the abnormal vertebrae which correlated well with the clinical progression of the disease, while in another patient both reactions were seen. Thus, repeated quantitative bone scintigraphies using 99mTc-MDP can be made in a reproducible way and can be a useful tool to follow a patient's response to treatment.

The orthostatic reaction to tilting was studied in 46 diabetics without symptoms of autonomic neuropathy and in 31 age-matched healthy control subjects. After tilting, the diastolic blood pressure rose in the control subject but was unchanged or tended to fall in the diabetics, except in those of short duration without retinopathy. After tilting, the control subjects showed an immediate increase in heart rate with the highest value at 8.4 +/- 1.0 s (mean +/- SEM), followed by a transient decrease with lowest value at 21.2 +/- 0.9 s. The acceleration and brake index measured the changes in heart rate. The brake index was lower in diabetics of short duration with retinopathy (6.9 +/- 1.6) than in those without (14.4 +/- 2.3, P < 0.01) as well as matched control subjects (18.7 +/- 2.5, P 0.01). In the diabetics of long duration no differences were shown between those with or without retinopathy but the accleration (10.3 +/- 1.6 vs 19.9 /!- 2.3, P < 0.05) and the brake index (5.3 +/- 1.4 vs 19.9 +/- 2.3, P < 0.01) were lower in those with vagal neuropathy.

The conventional indirect immunofluorescence test of islet cell antibodies was recently improved by the development of a two-colour immunofluorescence assay using a monoclonal proinsulin antibody to detect islet B cells. The aim of this study was to test whether in this new assay the prevalence and titre of ICA were affected by the time of incubation carried out in the presence of aprotinin (Trasylol) as an inhibitor of proteolysis. The end-point titre of ICA was therefore determined in sera from 70 children aged 0.6 to 15 years with recent onset Type 1 (insulin-dependent) diabetes mellitus, 50 healthy control subjects and 97 non-diabetic siblings of Type 1 diabetic children. In the conventional two-colour assay, ICA was positive in 53/70 (76%) Type 1 diabetic patients, 1/50 control subjects and 2/97 siblings after 30 min incubation. Prolonged incubation for 18 h increased the prevalence of ICA positive samples to 62/70 (89%) in the diabetic patients and to 2/50 in the control subjects, while the prevalence among the siblings was unchanged. Of the ICA positive non-diabetic subjects, one control child has a father with Type 1 diabetes, and one of the siblings subsequently developed Type 1 diabetes. In the diabetic patients the median titre was 1:32 for the 30 min incubation, and it increased to 1:64 for the 18 h incubation (p less than 0.001). A marked prozone effect was seen; 16% of the samples from the Type 1 diabetic children sera were negative at a 1:2 dilution, but were found positive at higher dilutions.(ABSTRACT TRUNCATED AT 250 WORDS)

The pattern of fall in B-cell function measured as plasma and 24 h urinary C-peptide excretion, as well as levels of islet cell antibodies, insulin antibodies and metabolic parameters, were followed for two years in 39 children aged 1-17 years prospectively from clinical onset of Type 1 (insulin-dependent) diabetes. At onset 32/36 patients had measurable plasma C-peptide (median 0.13 nmol/l). Maximum values of fasting and postprandial plasma C-peptide were reached at a median duration of three months. Thereafter both plasma and urinary C-peptide declined linearly. The median value of the rate of fall in postprandial plasma C-peptide was 0.019 nmol.1-1.month-1. Age at onset was positively correlated to the maximum value of postprandial plasma C-peptide in each patient (rs = 0.57, p = 0.0001) and throughout the observation time positively correlated to fasting and postprandial C-peptide and to the 24 h urinary C-peptide excretion (rs range 0.35-0.70, p = 0.03-0.0001). The rate of fall of postprandial C-peptide was unrelated to age at onset and was strikingly parallel in different age groups. Islet cell antibodies were present in 87% of the patients at onset and decreased to 38% at 24 months. Islet cell antibody titres were not correlated to age at onset or to plasma or urinary C-peptide at any single observation. However, islet cell antibody negative patients had significantly higher (p less than 0.05) postprandial plasma C-peptide values at 1, 9, and 12 months of duration, compared to islet cell antibody positive patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The immediate heart rate acceleration, blood pressure reaction, plasma adrenaline (PA), and plasma noradrenaline (PNA) responses to a 90 degrees and 2 sec tilt were evaluated in 13 male patients with type I diabetes. A disturbed immediate acceleration, as measured by a previously described acceleration index (AI), was found in 5 patients. All patients with normal AI but only one of those with abnormal AI showed an increase in PA during the first minute after tilt (p less than 0.02). A late diastolic blood pressure fall occurred in 6 patients and the fall was minor (5 mmHg) in 5 of these. Patients with a late diastolic blood pressure fall showed a significantly lower increase in PNA 1-8 min after tilt than those without (55 +/- 13% versus 163 +/- 24% (mean +/- SE), p less than 0.005). An abnormal immediate acceleration to tilt is associated with an impaired sympatho-adrenal reaction, and even a minor diastolic blood pressure fall indicates peripheral sympathetic denervation.

To find a simple and accurate test of autonomic nervous dysfunction in diabetes mellitus, 41 insulin-dependent diabetics and 25 controls were investigated. The diabetics, none of whom had symptoms of autonomic dysfunction, were tested for retinopathy and sensory neuropathy. Each subject also performed maximal deep-breathing procedures while undergoing electrocardiographic recording: in normal subjects the intervals are shortened during inspiration and prolonged during expiration, and a difference in the heart rate between inspiration and expiration of 10% or less seems to indicate autonomic dysfunction. This difference was calculated as an E:I ratio of the mean of the longest R-R interval during maximal expiration to the mean of the shortest during maximal inspiration. Ten of the 18 patients found to have sensory neuropathy had abnormal E:I ratios, and among those with absent ankle reflexes the proportion was even higher (9 out of 11). The E:I ratio also seemed to be as accurate as traditional tests for autonomic dysfunction and easier to perform. Diabetics with autonomic dysfunction have an increased risk of acute cardiorespiratory death during and after surgery, and maximal deep breathing and calculation of the E:I ratio may be a useful test to perform on diabetics at risk.

Autonomic nerve function was evaluated by deep breathing and tilt table tests in 17 patients with rheumatoid arthritis (RA) and in 24 healthy control subjects. The results showed that all RA patients had increased heart rates at rest, irrespective of the severity of the disease. Patients with severe RA had increased systolic and diastolic blood pressures before and after tilting. Pronounced abnormalities in the immediate heart rate reaction to tilting indicating autonomic neuropathy (AN) were also demonstrated in patients with severe RA. The abnormal immediate reaction to tilting was mainly the result of vagal neuropathy. From the present study it is evident that severe RA may be accompanied by AN and the consequences need to be elucidated.

Sera from 40 Swedish children diagnosed as having Type 1 (insulin-dependent) diabetes mellitus during a one year period along with 40 age and geographically matched control subjects were tested for antibodies to a Mr-64,000 islet protein by immunoprecipitation of 35S-methionine-labelled rat islet amphiphilic proteins. Of the 40 diabetic patients, 29 (73%) were found to be positive whereas all 40 control subjects were negative. Samples were also tested for titres of islet cell cytoplasmic antibodies by indirect immunofluorescence on frozen sections of human pancreas. In the diabetic group, 30 of the 40 patients (75%) were positive for islet cell cytoplasmic antibodies compared with 2 of the 40 control subjects (5%). A comparison of levels of antibodies to the Mr-64,000 protein with islet cell cytoplasmic antibodies revealed a weak (rs = 0.46), but significant (p less than 0.01) correlation between the two tests. There was no effect of age or sex on levels of antibodies to the Mr-64,000 protein. These results in population-based diabetic children and control subjects demonstrate a high frequency of antibodies to the Mr-64,000 protein at the time of clinical onset.

Glucose, fructose, sorbitol and myoinositol concentrations were measured in biopsies of peripheral nerve obtained at above-knee or below-knee amputation. In diabetic patients nerve glucose (median [range]) (5.09 [1.62-12.82] vs 3.12 [1.81-4.01]) p less than 0.001, fructose (0.245 [0.060-1.280] vs 0.150 [0.053-0.385]) p less than 0.05, and sorbitol (0.028 [0.012-0.496] vs 0.016 [0.007-0.059] p less than 0.02, mumol/g wet weight) were significantly higher than in non-diabetic patients. No significant difference was found in myoinositol concentration (1.95 [1.00-3.55] vs 2.09 [1.27-5.40] mumol/g wet weight). Concentrations differed markedly from previously reported values in human nerve obtained at post-mortem.