A Comparative Study of Responses to Acute Hypoglycaemia Induced by Human and Porcine Insulins in Patients with Type 1 Diabetes

The effects of human and porcine insulins on the symptomatic, physiological, and counterregulatory hormonal responses to acute hypoglycaemia were compared in 40 patients with Type 1 diabetes, 20 of whom were newly diagnosed while 20 had been treated for between 5 and 20 years. In a double-blind, cross-over trial all patients were treated with human or porcine insulin, in random order, for two consecutive 3-month periods. At the end of each treatment period they were subjected to an acute episode of experimental hypoglycaemia induced by a continuous intravenous infusion (2.0 mU kg⁻¹ min⁻¹) of the same insulin species. Haemodynamic, sweating, and tremor responses were measured during both studies, symptom scores were recorded and the arterialized plasma glucose thresholds for autonomic activation and the onset of subjective symptoms were identified. In all patients the glycaemic thresholds for the initiation of the autonomic physiological responses to hypoglycaemia and the onset of the symptomatic response were concurrent and did not differ with insulin species (plasma glucose 1.94 vs 1.96 mmol l⁻¹, human vs porcine studies). The onset, temporal pattern, nature, and magnitude of the physiological responses (sweating, heart rate, blood pressure, and tremor) during acute experimental hypoglycaemia were also identical with each insulin species. The magnitude and temporal pattern of the response of counterregulatory hormones (adrenaline, noradrenaline, glucagon, ACTH, and GH) to hypoglycaemia as induced by human and porcine insulins were indistinguishable, as were the total and individual scores of autonomic and neuroglycopenic symptoms. In conclusion, in patients who had newly diagnosed and intermediate duration (5–20 years) of diabetes, the symptomatic, physiological, and counterregulatory hormonal responses to acute insulin-induced hypoglycaemia did not differ between human and porcine insulins, and the plasma glucose thresholds at which the symptomatic and autonomic responses were initiated were identical with both insulin species. This study does not support the hypothesis that treatment with human insulin modifies the symptomatic, physiological, and counterregulatory hormonal responses to acute hypoglycaemia.     

Circadian Blood Pressure Levels in Normotensive Normoalbuminuric Type 1 Diabetic Patients

Increase in blood pressure and its circadian alterations in Type 1 diabetes are usually associated with diabetic nephropathy. To evaluate if diabetes itself could be responsible for the observed increase in blood pressure levels, we studied a group of 17 normotensive, normoalbuminuric Type 1 diabetic patients with a disease duration more than 15 years, with no clinical evidence of autonomic neuropathy or ischaemic heart disease, and without any known determinant of hypertension, and a control group of 17 normal subjects, normotensive, each matched for sex, age, BMI, albumin excretion rate, and clinical blood pressure to a diabetic subject. In both groups an ambulatory blood pressure monitoring was performed through an oscillometric recorder. The mean systolic and diastolic ambulatory blood pressure values were significantly higher in diabetic patients (p <0.001) in the 24-h analysis and during waking and sleeping periods. The night/day ratio of systolic and diastolic blood pressure were not significantly different in patients and controls, as well as heart rate values and heart rate variability. We conclude that mechanism(s) inherent to the diabetic condition other than diabetic nephropathy or autonomic neuropathy could be responsible for blood pressure evaluation in normotensive Type 1 diabetes with normoalbuminuria.     

Hypoglycaemia and Non-cognitive Aspects of Psychological Function in Insulin-dependent (Type 1) Diabetes Mellitus (IDDM)

Hypoglycaemia provokes unpleasant symptoms and sensations in patients with insulin-dependent (Type 1) diabetes mellitus (IDDM). There is much interest in, and information on, the cognitive effects of acute insulin-induced hypoglycaemia. However, the effects of hypoglycaemia on brain function extend to important, non-cognitive aspects of psychological functioning, which are reviewed here. Acute hypoglycaemia induces changes in mood which result in a transient state of ‘tense tiredness’, a decrease in happiness, an increase in tense arousal, and decreased energetic arousal. Appraisals of life problems are affected adversely. Frequent exposure to hypoglycaemia is associated with heightened fear of hypoglycaemia, which can be quantitated in individuals. Personality may also influence behavioural responses to hypoglycaemia and the ability of an individual to cope with diabetes. The adverse effects of hypoglycaemia on mood, behaviour, personality, social function and management of diabetes in individual patients may be profound and need to be identified and addressed appropriately. © 1997 by John Wiley & Sons, Ltd.     

Physiological,Symptomatic and Hormonal Responses to Acute Hypoglycaemia in Type 1 Diabetic Patients with Autonomic Neuropathy

The effects of peripheral autonomic neuropathy on the symptomatic, physiological, and hormonal responses to acute insulin-induced hypoglycaemia were studied in two groups of patients with Type 1 diabetes, matched for age, duration of diabetes, and prevailing glycaemic control. A group of eight patients who gave a history of normal awareness of hypoglycaemia and had normal cardiovascular autonomic function tests were compared to a group of six patients who had symptoms of autonomic dysfunction and gross abnormalities of cardiovascular autonomic function tests. An additional two patients with autonomic neuropathy who also had hypoglycaemia unawareness were studied. Acute hypoglycaemia was induced by intravenous infusion of insulin (2.5 ***mU kg^?1 min^?1) and the onset of the acute autonomic reaction (R) was identified objectively by the sudden rise in heart rate and onset of sweating. Cognitive function and hypoglycaemia symptom scores were estimated serially, and plasma counterregulatory hormones were measured. Acute autonomic activation was observed to occur in all subjects in response to hypoglycaemia and commenced at similar venous plasma glucose concentrations in both groups (neuropathic patients: 1.6 ± 0.2 mmol I^?1 vs non-neuropathic patients 1.6 ± 0.2 mmol I^?1, p = 0.9,). In the neuropathic patients plasma adrenaline responses were significantly lower at all time points from time R until time R + 30 min (MANOVA for repeated measures, F = 19.4, p < 0.001). The total autonomic symptom score at R was slightly lower in the neuropathic patients (12 (8–12) median (range)) but was not significantly different from the non-neuropathic patients (14 (10–26), p = 0.10), and the total neuroglycopenic symptom scores were very similar (neuropathic group: 11 (6–21) vs non-neuropathic group: 11.5 (6–22), p = 0.95). Although some of the autonomic responses were lower, but not significantly so, in the patients with autonomic neuropathy this study suggests that peripheral autonomic neuropathy is not the principal cause of hypoglycaemia unawareness in patients with Type 1 diabetes.     

Diurnal Variation of Blood Pressure in Adolescents with Type 1 Diabetes: Dippers and Non-dippers

The study aimed to determine the prevalence of impaired nocturnal BP fall in adolescents with Type 1 diabetes. Thirty-six normoalbuminuric normotensive adolescents with Type 1 diabetes (19 males, 17 females) aged 14.4 ± 2.1 years (mean ± SD) with duration of 4.0 (2.6–7.5) years (median (25–75th percentile)) and 23 controls (11 males, 12 females) aged 15.0 ± 1.6 years were studied. Day/night BP variation was examined using Ambulatory Accutracker II Monitor (Raleigh, NC). Recordings were made at 30 min intervals during the day and 60 min intervals during the night. Time records were set according to individual diaries. There was no significant difference in day and night systolic or diastolic BP or in mean day/night BP variability between patients with Type 1 diabetes and control subjects. 15/36 patients compared to 3/23 controls (chi squared = 5.43, p < 0.02) were non-dippers defined as a nocturnal fall in either systolic (13/36) or diastolic (6/36) BP or both (4/36) of less than 10 %. These non-dippers had normal day–night ratio of heart rate when compared with the remainder of the patients or controls. In conclusion a significant number of young normotensive normoalbuminuric patients with Type 1 diabetes show an impaired fall in blood pressure at night, predominantly in systolic BP. These changes may be relevant to the long-term development of macrovascular or microvascular disease.     

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.     

Incidence of Nocturnal Hypoglycaemia in Insulin-dependent Diabetic Patients on Intensive Therapy

ABSTRACT The frequency of nocturnal hypoglycaemia, i.e. blood glucose concentration (BG) <3.0 mmol/l, was evaluated in consecutively selected insulin-dependent patients on multiple insulin injections (MII), n =23, or continuous subcutaneous insulin infusions (CSII), n =25. Blood was sampled hourly from 23.00 to 07.00. Seven patients (30%) on MII had at least one BG <3.0 mmol/l during the night. Eleven patients (44%) on CSII had hypoglycaemia (NS). The total number of BGs <3.0 mmol/l was higher on CSII, 42 of 225, versus 16 of 207 on MII (p<0.025). The duration of hypoglycaemia was 2 hours (range 1–6) on MII and 4 hours (range 1–7) on CSII with a maximal prevalence at 4 hours and between 5 and 7 hours, respectively (p=<0.05). The frequency of nocturnal hypoglycaemia is high in patients on intensified insulin regimens. Nocturnal hypoglycaemia occurs later in the night and is of longer duration on CSII than on MIL HbA_1c, BG before bedtime and in the morning might be useful in the evaluation of nocturnal hypoglycaemia.     

动态血压监测探讨体重指数与血压的关系

目的:动态血压监测探讨患者体重指数与血压变化情况。方法:选择门诊和病房住院的患者共691例(其中男性417例,女性274例),年龄范围13~90岁,平均年龄为55岁。所有观察对象测量诊室血压、心率、身高、体重和监测24小时动态血压等指标,按照体重指数分为3组,体重指数<24为正常体重组;24≤体重指数<28为超重组;体重指数≥28为肥胖组。结果:肥胖组患者24小时和白天的平均收缩压/舒张压、夜间平均舒张压以及24小时、白天和夜间心率均高于正常体重组,有显著性差异(P<0.05~0.01)。此外,血压负荷也随着体重指数的增加而增加,有显著性差异(P<0.05~0.01)。结论:体重指数与动态血压和血压负荷有较密切的关系;与正常体重组、超重组比较,肥胖组患者的血压最高、心率最快;动态血压提供的数据信息量大,结论更可靠、准确。     

Randomized Trial Comparing Nicotinamide and Nicotinamide Plus Cyclosporin in Recent Onset Insulin-dependent Diabetes (IMDIAB 1)

A 1-year open randomized controlled multicentre trial was carried out on 90 patients with recent onset (< 4 weeks) insulin-dependent diabetes (IDDM) to compare the effect of nicotinamide (NCT) with the combination NCT and low dose cyclosporin (CyA) on clinical remission and optimization of metabolic control during the first year from diagnosis. Three groups of patients were randomly assigned to receive for 12 months either NCT 25 mg kg^?1 day^?1 (n = 30) or NCT 25 mg kg^?1 day^?1 + CyA 5 mg kg^?1 day^?1 (n = 30), the latter adjusted to maintain 12 whole blood trough levels of 83 nmol l^?1; a third group of patients (n = 30) receiving insulin only acted as a control group for spontaneous remission and metabolic control. Clinical remission (i.e. suspension of insulin therapy with normal metabolic parameters for more than 2 weeks according to the International Diabetes Immunotherapy Group) was achieved at 3 months in 6/30 NCT treated patients and in 1/30 NCT + CyA treated patient (p = 0.05); no remission was observed in control patients. At 6 months the number of patients achieving remission in each group was 4/29, 3/27, and 1/29, respectively (p = NS). One year after diagnosis 4/27 NCT treated, 2/25 NCT+ CyA treated but 0/28 of the control patients were in remission (NCT vs control p = 0.05). Clinical remission lasted longer (7 ± 3 SD months) in NCT treated patients than in NCT+ CyA treated or control patients (p < 0.02). In patients who did not show clinical remission, there were no significant differences in the integrated measures of metabolic control (HbA₁ and C peptide) between the two groups; however, NCT+ CyA treated patients only required significantly less insulin at 12 months compared to control patients (p < 0.02). Side-effects were not observed in patients receiving NCT and were minimal in those treated with the combination of NCT+ CyA. We conclude that nicotinamide alone is a safe and effective adjunct to insulin in the early phase of IDDM to increase the rate of clinical remission and to improve integrated parameters of metabolic control.     

The Cost of Insulin-dependent Diabetes Mellitus (IDDM) in England and Wales

This study estimates the direct health and social care costs of insulin-dependent diabetes mellitus (IDDM) in England and Wales in 1992 to be £96 million, or £1021 per person in a population with IDDM estimated at 94 000 individuals. These costs include insulin maintenance, hospitalization, GP and out-patient consultations, renal replacement therapy, and payments to informal carers. Expenditure is concentrated on younger age groups, with one-third of the total expended on those aged 0–24. Around one-half of the total costs can be directly attributed to IDDM, with the remainder associated with a range of complications of the disease. The single largest area of service expenditure is renal replacement therapy. The cost estimates are most sensitive to incidence rates of IDDM, numbers on dialysis and average duration of dialysis. A further £113 million pounds may be lost each year due to premature deaths resulting in lost productive contributions to the economy. The direct and indirect costs of IDDM are therefore significant. The cost of illness framework presented here should facilitate the economic evaluation of new and existing treatment regimens, which may improve value for money by reducing costs and/or increasing the quality or quantity of life for people with IDDM.     

The Natural Course of Microalbuminuria in Insulin-dependent Diabetes: A 10-year Prospective Study

The purpose of this study was to describe the clinical course in patients followed right from the onset of microalbuminuria to the development of diabetic nephropathy. A 10-year prospective follow-up of 209 consecutive normotensive insulin-dependent diabetic patients with normal urinary albumin excretion (UAE <30 mg 24 h^?1), age 34 (18–50) years and duration of diabetes 17 (10–30) years was performed. Twenty-four-hour urinary albumin excretion was measured every 4 months, glycated haemoglobin and supine blood pressure was measured annually. Two-hundred (96%) patients completed 10 (range 5–10) years follow-up. Twenty-nine (15%) patients developed persistent microalbuminuria (UAE 30–300 mg 24 h^?1). Eight of these have progressed to nephropathy and one had died of diabetic nephropathy. Multiple stepwise logistic regression analysis demonstrated baseline urinary albumin excretion (p = 0.0016) and glycated haemoglobin (p = 0.0014) but not blood pressure as predictors of development of microalbuminuria within the following 10 years. The median annual increase in urinary albumin excretion was 27 (range 17–65)% in the 29 patients developing microalbuminuria. The median duration from onset of microalbuminuria to development of nephropathy was 7 years. The prevalence of patients receiving antihypertensive treatment (BP > 140/90 mmHg) increased from 10% at onset of microalbuminuria to 45% 4 years after onset of microalbuminuria. The prevalence of patients with proliferative retinopathy increased from 7% at onset of microalbuminuria to 28% 4 years after onset of microalbuminuria. The incidence of persistent microalbuminuria in normotensive insulin-dependent diabetic patients is 2% per year, and development of persistent microalbuminuria is a strong predictor of overt nephropathy. Development of hypertension is frequent in the early course of microalbuminuria and treatment modalities for normotensive patients with microalbuminuria are urgently needed.     

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.     

Longitudinal Study of Lipoprotein(a) in Peripubertal Children with Insulin-dependent Diabetes

We aimed to examine the longitudinal relationship between lipoprotein(a) and haemoglobin A_1c, albumin excretion rate, and puberty in peripubertal children with insulin-dependent diabetes. A total of 114 patients aged 11.5 ± 3.6 years (mean (SD)) were followed prospectively for 15.2 ± 2.8 months. Lipoprotein(a), apolipoproteinB-100, haemoglobin A_1c, mean overnight albumin excretion rate and Tanner stage were determined at the beginning and end of the study period. Lipoprotein(a) and apolipoproteinB-100 were measured using nephelometry. This method was correlated with radioimmunoassay and there was no significant change in mean bias during the study. Lipoprotein(a) fell significantly over time (214, (152, 276); 160 (84, 236) mg I^?1 geometric mean (0.95 confidence intervals), p < 0.001); apolipoproteinB-100 did not change. Lipoprotein(a) and apolipoproteinB-100 did not differ in 233 cross-sectional controls of similar age. The change in lipoprotein(a) did not correlate with a small fall in haemoglobin A_1c or with overnight albumin excretion rate, Tanner stage or insulin dose. Separate analysis of male and female patients and prepubertal and pubertal patients continued to show a significant fall in lipoprotein(a) independent of change in haemoglobin A_1c or albumin excretion rate. Likewise, 53 patients with a change in haemoglobin A_1c of greater than 1%, and 20 patients who progressed from normal albumin excretion rate to albumin excretion rate above the 95th centile, showed no relationship between lipoprotein(a) and haemoglobin A_1c or albumin excretion rate. In conclusion, longitudinal changes in lipoprotein(a) do not relate to metabolic control or early changes in albuminuria in young patients with insulin-dependent diabetes.     

Frequency of Daytime Biochemical Hypoglycaemia in Insulin-treated Diabetic Patients: Relation to Daily Median Blood Glucose Concentrations

The frequency and distribution of daytime biochemical hypoglycaemia (capillary blood glucose concentration below 3 mmol/l) was assessed in type 1 diabetic patients on conventional twice daily insulin therapy (n = 79) and on continuous subcutaneous insulin infusion (n = 20). Patients collected and mailed to the hospital blood for seven-point blood glucose profiles. For both treatment regimens the frequency of biochemical hypoglycaemia on individual days was inversely related to the median blood glucose concentration in a curvilinear manner (p < 0.001). Hypoglycaemia was more frequent pre-prandially than post-prandially (p < 0.01), and was evenly distributed during the day in patients on continuous subcutaneous insulin infusion. In patients on conventional therapy, however, pre-lunch hypoglycaemia was four times more frequent than pre-breakfast or pre-dinner hypoglycaemia (p < 0.0001).     

Diabetic Microangiopathy: Lupus Anticoagulant Dependent Thrombotic Tendency in Type 1 (Insulin-dependent) Diabetes Mellitus

Type 1 (insulin-dependent) diabetes mellitus is associated with long-term vascular complications. In addition to metabolic factors, immunological and haemostatic mechanisms may be involved. Lupus anticoagulant (LA), an immunoglobulin which interferes with endothelial cell function, is frequently associated with a high risk of thromboembolic events. LA has been described in several diseases but never in diabetes mellitus. The aim of this study was to evaluate if endothelial dysfunction and unmodulated haemostasis are amplified by the presence of LA in Type 1 diabetic patients. Plasma samples collected from clinically and biochemically well-characterized Type 1 diabetic patients were examined for LA, fibrinogen, prothrombin (PT), PTT, prothrombin degradation products (F1 + 2) and activated protein C (APC). The results revealed significantly decreased APC and increased F1 + 2 plasma concentrations in LA-positive but not in LA-negative patients; 60 % of LA-positive and only 18 % of LA-negative patients had microangiopathy (not significant). No thrombotic episodes in large vessels were found in LA-positive patients. These findings suggest that LA could be considered an additional factor in the onset and/or progression of diabetic complications, acting as a link between the immunological and haemostatic systems in the pathogenesis of diabetic microangiopathy. © 1997 by John Wiley & Sons, Ltd.     

Signal-averaged Electrocardiogram in Patients with Insulin-dependent (Type 1) Diabetes Mellitus With and Without Diabetic Neuropathy

The purpose of this study was to investigate the presence of ventricular late potentials derived from signal-averaged ECG in patients with IDDM with and without diabetic neuropathy. Eighty patients with IDDM but without evidence of cardiac disease and 80 age-matched healthy control subjects were investigated. The corrected QT interval was measured from the standard surface electrocardiogram. Ventricular late potentials were derived from signal-averaged electrocardiogram. Out of the 80 diabetic patients, 20 had an autonomic neuropathy, 20 had an isolated peripheral neuropathy, and 40 had no symptoms of neuropathy. The corrected QT interval was significantly prolonged in patients with an autonomic neuropathy as compared with the control group (436 ± 23 ms^.5 vs 384 ± 23 ms^.5, p < 0.001). In the other patient groups there was no significant prolongation of the corrected QT interval. Ventricular late potentials were present in 3 diabetic patients with an isolated peripheral neuropathy and in 1 control subject (NS). No diabetic patient with an autonomic neuropathy had ventricular late potentials. Our data did not indicate an increased incidence of ventricular late potentials derived from signal-averaged electrocardiogram in diabetic patients independent of a coexisting diabetic neuropathy or a prolonged corrected QT interval. © 1997 by John Wiley & Sons, Ltd.     

HEM-6000手腕式血压计的可靠性

目的 采用美国医疗器械检测协会(AAMI)标准,对HEM-6000手腕式血压计的血压测量精确度进行临床验证研究.方法 入选对象为18岁以上成年人,共91人.腕部测压结果与听诊法比较.每位受试者用2种方法同时各进行3次坐位血压测量,对91人的273对血压测量值用以下2种方法进行统计分析:(1)先计算出2种测压方法得到的血压测量值误差,再求得误差的平均值和标准偏差.(2)先计算出每位受试者用2种测压方法得到的血压平均值的差值,再求得该差值的平均值和标准偏差.结果 根据方法1得到的收缩压(SBP)和舒张压(DBP)的测量误差分别为(0.5±7.1)mm Hg和(-1.6±6.1)mm Hg;根据方法2得到的结果分别(0.5±6.1)mm Hg和(-1.6±5.3)mm Hg.血压值的水平及手腕周长对测量误差无影响.结论 HEM-6000手腕式血压计通过AAMI检验标准,可推荐患者用于家庭自我测压.