Frequency and motives of blood glucose self-monitoring in type 1 diabetes.

AIMS: Recommendations for self-monitoring of blood glucose (SMBG) from the DCCT have not been implemented with the same rigour as recommendations for intensifying insulin therapy. We assessed the frequency of and motives for SMBG and compared SMBG behaviour with clinical, behavioural and demographic characteristics. METHODS: Cross-sectional Danish-British multicentre survey of 1076 consecutive patients with type 1 diabetes, who completed a detailed questionnaire on SMBG and related issues. The key variables were test frequency and motive. RESULTS: SMBG was performed daily by 39% of the patients and less than weekly by 24%. Sixty-seven percent reported to perform routine testing, while the remaining 33% only tested when hypo- or hyperglycaemia was suspected. Age, gender, and level of diabetes-related concern were associated with test pattern. Reported frequencies of mild and severe hypoglycaemia and awareness of hypoglycaemia were independently associated with testing behaviour, whereas the presence of late diabetic complications was not. Lower HbA1c was associated with more frequent testing. CONCLUSION: Patient compliance regarding SMBG is limited. Thus, almost two thirds of the patients do not perform daily SMBG and one third do not perform routine tests.

Prediction of severe hypoglycaemia by angiotensin-converting enzyme activity and genotype in type 1 diabetes.

AIMS/HYPOTHESIS: We have previously shown a strong relationship between high angiotensin-converting enzyme (ACE) activity, presence of the deletion (D) allele of the ACEgene and recall of severe hypoglycaemic events in patients with Type 1 diabetes. This study was carried out to assess this relationship prospectively. METHODS: We followed 171 adult outpatients with Type 1 diabetes in a one-year observational study with the recording of severe hypoglycaemia. Participants were characterised by serum ACE activity and ACE genotype and not treated with ACE inhibitors or angiotensin II receptor antagonists. RESULTS: There was a positive relationship between serum ACE activity and rate of severe hypoglycaemia with a 2.7 times higher rate in the fourth quartile of ACE activity compared to the first quartile (p=0.0007). A similar relationship was observed for the subset of episodes with coma (2.9 times higher rate in fourth quartile compared to first quartile; p=0.048). The impact of serum ACE activity was most pronounced in C-peptide negative subjects (4.2 times higher rate in fourth quartile compared to first quartile; p=0.003), and in this subgroup carriers of the D allele of the ACEgene had higher rates of severe hypoglycaemia compared to the group homozygous for the insertion (I) allele. In a multiple regression analysis high serum ACE activity and impaired awareness of hypoglycaemia were identified as the only significant predictors of severe hypoglycemia. CONCLUSION: High ACE activity and the presence of the D allele of the ACE gene predict a high rate of severe hypoglycaemia in Type 1 diabetes.

Activity of angiotensin-converting enzyme and risk of severe hypoglycaemia in type 1 diabetes mellitus.

BACKGROUND: The insertion (I) allele of the angiotensin-converting-enzyme (ACE) gene occurs at increased frequency in endurance athletes. This association suggests that low ACE activity is favourable for performance in conditions with limited substrate availability. Such conditions occur in endurance athletes during competition and in diabetic patients during insulin-induced hypoglycaemia. Patients rely on preserved functional capacity to recognise hypoglycaemic episodes and avoid progression by self-treatment. We studied whether ACE activity is related to the risk of severe hypoglycaemia in type 1 diabetes. METHODS: Consecutive adult outpatients with type 1 diabetes, untreated with ACE inhibitors or angiotensin-II-receptor antagonists (n=207) reported their experience of mild and severe hypoglycaemia during the previous 1 year and 2 years. The patients were further characterised by diabetes history, degree of hypoglycaemia awareness, measurement of C-peptide, haemoglobin A(1c), and serum ACE concentrations, and determination of ACE genotype. FINDINGS: Patients with the DD genotype had a relative risk of severe hypoglycaemia in the preceding 2 years of 3.2 (95% CI 1.4-7.4) compared with those who had the II genotype. There was a significant relation between serum ACE activity and the rate of severe hypoglycaemia (relative risk per 10 U/L increment 1.4 [1.2-1.6]), corresponding to a 3.5 times higher risk for patients in the highest quartile than for those in the lowest quartile. Multiple regression analysis showed that the effect of the ACE genotype was explained by its influence on serum ACE activity and that the only other significant determinants of the risk of severe hypoglycaemia were the degree of hypoglycaemia awareness, b-cell function, and duration of diabetes of more than 20 years. INTERPRETATION: ACE activity is a clinically significant marker of the risk of severe hypoglycaemia in patients with type 1 diabetes, especially in those with impaired defence against hypoglycaemia. These findings need to be confirmed in prospective studies.

A 6-year nationwide cohort study of glycaemic control in young people with type 1 diabetes. Risk markers for the development of retinopathy, nephropathy and neuropathy. Danish Study Group of Diabetes in Childhood.

The study aimed to identify risk markers (present at the start of the study in 1989) for the occurrence and progression of microvascular complications 6 years later (in 1995) in a Danish nationwide cohort of children and adolescents with Type 1 diabetes (average age at entry 13.7 years). Probabilities for the development of elevated albumin excretion rate (AER), retinopathy, and increased vibration perception threshold (VPT) could then be estimated from a stepwise logistic regression model. A total of 339 patients (47% of the original cohort) were studied. Sex, age, diabetes duration, insulin regimen and dose, height, weight, HbA(1c), blood pressure, and AER were recorded. In addition, information on retinopathy, neuropathy (VPT), and anti-hypertensive treatment was obtained at the end of the study. HbA(1c) (normal range 4.3-5.8, mean 5.3%) and AER (upper normal limit <20 microg min(-1)) in two, timed overnight urine collections were analysed centrally. Eye examination was performed by two-field fundus photography. Determination of VPT was assessed by biothesiometry. Increased AER (> or =20 microg min(-1)) was found in 12.8% of the patients in 1995, and risk markers for this were increased AER and high HbA(1c), in 1989 (both p<0.001). Retinopathy was present in 57.8% of patients in 1995, for which the risk markers were long duration of diabetes (p<0.0001), age (p<0.01), and high HbA(1c) (p<0.0001) in 1989. Elevated VPT (>6.5 V) was found in 62.5% of patients in 1995, for which the risk markers were male sex (p<0.05), age (p<0.0001), and increased AER (p<0.05) in 1989. This study confirms that hyperglycaemia plays a major role for the development of microvascular complications in kidneys and eyes, and emphasises the need for optimal glycaemic control in children and adolescents with Type 1 diabetes.

Cognitive function and mood after profound nocturnal hypoglycaemia in prepubertal children with conventional insulin treatment for diabetes.

OBJECTIVES: To examine the frequency of nocturnal hypoglycaemia, and the effects on cognitive function and mood, in children with insulin dependent diabetes mellitus (IDDM). DESIGN: Two overnight glucose profiles, in the home environment, and assessments of cognitive function and mood the following day. Twenty nine prepubertal patients with IDDM (median age, 9.4 years; range, 5.3-12.9) and 15 healthy controls (single overnight profile), median age 9.5 (range, 5.6-12.1) years were studied. RESULTS: Asymptomatic hypoglycaemia (glucose < 3.5 mmol/l) was observed in 13 of 29 patients studied on night 1: four of these and seven others were hypoglycaemic on night 2. The median glucose nadir was 1.9 (range, 1.1-3.3) mmol/l and the median duration of hypoglycaemia was 270 (range, 30-630) minutes. Hypoglycaemia was related to insulin dose, but not glycosylated haemoglobin (HbA1c) values, and was partially predicted by a midnight glucose of < 7.2 mmol/l. Cognitive performance was not altered after hypoglycaemia but a lowering of mood was observed. CONCLUSIONS: Young children on conventional insulin regimens are at high risk for profound, asymptomatic nocturnal hypoglycaemia, which is difficult to predict. There was no short term effect on cognitive function but mood change was detected.

Human insulin and hypoglycaemia: a literature survey.

Thirty-nine clinical studies and 12 epidemiological reports comparing human insulin and porcine insulin were reviewed. Twenty-five studies (encompassing 338 subjects) showed identical symptoms and physiological response to acute hypoglycaemia overall. Fifteen studies (encompassing more than 1253 patients) showed identical incidence of hypoglycaemia overall and similar symptoms with the two types of insulin. Twelve studies showed identical incidence of hypoglycaemia overall with the two types of insulin. Thus, the overwhelming evidence from a large number of studies including a large number of patients suggests that: (1) human and porcine insulin do not provoke different hormonal responses to hypoglycaemia; (2) they do not cause different symptoms of hypoglycaemia; (3) the incidence of severe hypoglycaemia with human insulin does not differ from that of porcine insulin.

Symptomatic hypoglycaemia in 411 type 1 diabetic patients.

The frequency of symptomatic hypoglycaemic episodes was studied in 411 randomly selected conventionally treated Type 1 diabetic out-patients. Between two consecutive visits to the out-patient clinic each patient filled in a questionnaire at home. The number of hypoglycaemic episodes was then recorded prospectively in a diary for 1 week. From the questionnaires, the (retrospective) frequencies of mild and severe symptomatic hypoglycaemia were 1.6 and 0.029 episodes patient-1 week-1. From the diaries, the (prospective) frequencies of mild and severe hypoglycaemic episodes were 1.8 and 0.027 patient-1 week-1. Symptomatic hypoglycaemia was more frequent on working days than during weekends (1.8:1) and more frequent in the morning than during the afternoon, evening, and night (4.5:2.2:1.4:1). The symptoms of hypoglycaemia were non-specific, heterogeneous, and weakened with increasing duration of diabetes. During their diabetic life, 36% of the patients had experienced hypoglycaemic coma. The frequency of hypoglycaemia was positively, but only weakly, correlated with insulin dose, number of injections, percentage unmodified insulin of the total dose, and HbA1c (mild hypoglycaemia only). The frequency was also negatively, but weakly, correlated with age and HbA1c (episodes with coma only), but not correlated with sex, duration of diabetes, or patients' ratings of worries about mild and severe hypoglycaemia.

The relationship between symptomatic and biochemical hypoglycaemia in insulin-dependent diabetic patients.

The relationship between symptomatic (subjective feelings) and biochemical (blood glucose concentration less than 3 mmol l-1) hypoglycaemia was studied in 66 randomly selected insulin-dependent diabetic out-patients under normal conditions of daily life with conventional insulin injection regimens. The patients (a) collected 7-point diurnal blood glucose profiles at home on three consecutive days and then once weekly for 3 weeks, (b) indicated whether they felt hypoglycaemic at sampling times, and (c) collected extra samples if they felt hypoglycaemic at any time during the study period. The weekly frequencies of symptomatic and biochemical hypoglycaemia were 0.99 and 1.75 per patient, respectively. Biochemical hypoglycaemia was present in 29% of the symptomatic episodes, and symptomatic hypoglycaemia accompanied 16% of the biochemical episodes. Symptomatic hypoglycaemia was experienced at a median blood glucose concentration of 3.4 mmol l-1 (range 1.4-14.9 mmol l-1). Fifty per cent of both symptomatic and biochemical episodes occurred before lunch, while the remainder were evenly distributed throughout the day. The occurrence of biochemical hypoglycaemia, but not of symptomatic hypoglycaemia, was inversely correlated with HbA1c and median blood glucose concentration. Thus symptomatic hypoglycaemia is an unreliable indicator of biochemical hypoglycaemia and of the degree of glycaemic control. Blood glucose measurements are a prerequisite for the diagnosis of hypoglycaemia.

Modeling absorption kinetics of subcutaneous injected soluble insulin.

Absorption of subcutaneously injected soluble insulin deviates markedly from simple first-order kinetics and depends both on the volume and concentration of the injected solution. This paper presents a model of the absorption process in which insulin is presumed to be present in subcutis in a low molecular weight form, a high molecular weight form, and an immobile form where the molecules are bound to the tissue. The model describes how diffusion and absorption gradually reduce the insulin concentrations in the subcutaneous depot and thereby shift the balance between the three forms in accordance with usual laws of chemical kinetics. By presuming that primarily low molecular weight insulin penetrates the capillary walls, the model can account for experimentally observed variations in the absorption rate over a wide range of volumes and of concentrations. The model is used to determine the effective diffusion constant D for insulin in subcutis, the absorption rate constant B for low molecular weight insulin, the equilibrium constant Q between high and low molecular weight insulin, the binding capacity C for insulin in the tissue, and the average life time T for insulin in its bound state. Typical values for a bolus injection in the thigh of fasting type I diabetic patients are D = 0.9 x 10(-4) cm2/min, B = 1.3 X 10(-2)/min, and Q = 0.13 (ml/IU)2. Binding of insulin in the tissue is significant only at small concentrations. The binding capacity is of the order of C = 0.05 IU/cm3 with a typical average life time in the bound state of T = 80.0 min. Combined with a simplified model for distribution and degradation of insulin in the body, the absorption model is used to simulate variations in plasma free insulin concentrations with different delivery schedules, i.e., bolus injection and dosage by means of an infusion pump. The simulations show that a pump repetition frequency of 1-2 per hr is sufficient to secure an almost constant plasma insulin concentration.

Glycaemic threshold for changes in electroencephalograms during hypoglycaemia in patients with insulin dependent diabetes.

The relation between blood glucose concentration, the symptoms and signs of hypoglycaemia, and electroencephalographic changes in diabetic patients is not known. The effect of hypoglycaemia on brain function was studied in 13 patients with insulin dependent diabetes. During a gradual fall in blood glucose concentration induced by a bolus injection of insulin followed by an intravenous infusion of insulin, during 60 minutes of biochemical hypoglycaemia, and after restoration of normoglycaemia with intravenous glucose electroencephalograms were evaluated continuously by period-amplitude analysis; blood samples were taken every 10 minutes throughout. No changes were seen in electroencephalograms when the blood glucose concentration was above 3 mmol/l. At a median blood glucose concentration of 2.0 (95% confidence interval 1.7 to 2.3) mmol/l alpha activity decreased abruptly in the electroencephalograms concomitant with an increase in theta activity, reflecting neuronal dysfunction in the cortex. When the blood glucose concentration was further lowered changes were observed in the electroencephalograms indicating that deeper brain structures were affected. A normal electroencephalogram was re-established at a blood glucose concentration of 2.0 (1.8 to 2.1) mmol/l. There was no significant correlation between the blood glucose concentration at the onset of changes in the electroencephalograms and age, duration of diabetes, insulin dose, haemoglobin A1c concentration, initial blood glucose concentration, rate of fall in blood glucose concentration, and appearance of symptoms and signs of hypoglycaemia. Changes in electroencephalograms during hypoglycaemia appear and disappear at such a narrow range of blood glucose concentrations that the term threshold blood glucose concentration for the onset of such changes seems justified.

Incidence of nocturnal hypoglycaemia in insulin-dependent diabetic patients on intensive therapy.

The frequency of nocturnal hypoglycaemia, i.e. blood glucose concentration (BG) less than 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 less than 3.0 mmol/l during the night. Eleven patients (44%) on CSII had hypoglycaemia (NS). The total number of BGs less than 3.0 mmol/l was higher on CSII, 42 of 225, versus 16 of 207 on MII (p less than 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 = less than 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 MII. HbA1c, BG before bedtime and in the morning might be useful in the evaluation of nocturnal hypoglycaemia.

Cognitive function during hypoglycaemia in type I diabetes mellitus.

Neuropsychological testing was carried out in 16 insulin dependent (type I) diabetic men during four periods when mean blood glucose concentrations were (A) 6.3 (SEM 0.13) mmol/l (113.5 (SEM 2.3) mg/100 ml), (B) 2.9 (0.05) mmol/l (52.3 (0.9) mg/100 ml), and (C) 1.8 (0.03) mmol/l (32.4 (0.05) mg/100 ml), all measured during intravenous insulin infusion, and (D) 6.1 (0.13) mmol/l (109.9 (2.3) mg/100 ml), measured after intravenous glucose. The total neuropsychological test score decreased between periods A and B, A and C, and B and C, whereas improvement occurred between periods C and D (all p less than 0.02). These results were not due to changes in individual subjects alone but were consistent for the whole group. During hypoglycaemia there were changes in the patients' estimates of elapsed time, which were underestimated at period C as compared with the estimates at periods A, B, and D (all p less than 0.05). None of the 16 patients noticed symptoms of hypoglycaemia at period A or B, 12 reported symptoms at C, and one at D. Patients with type I diabetes may show a deterioration in neuropsychological skills during periods of asymptomatic subnormal or hypoglycaemic blood glucose concentrations.

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 less than 0.001). Hypoglycaemia was more frequent pre-prandially than post-prandially (p less than 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 less than 0.0001).

Nocturnal hypoglycaemia in patients receiving conventional treatment with insulin.

The prevalence of nocturnal biochemical hypoglycaemia--that is, blood glucose concentrations below 3 mmol/l (55 mg/100 ml)--was evaluated in a random sample of 58 insulin dependent diabetics receiving twice daily insulin. Seventeen patients had at least one blood glucose value below 3 mmol/l (55 mg/100 ml) and five a value below 2 mmol/l (36 mg/100 ml) during the night. Both bedtime (2300) and fasting morning (0700) blood glucose concentrations were significantly lower in the group with nocturnal hypoglycaemia compared with the group without (p less than 0.00001). If the bedtime blood glucose concentration was below 6 mmol/l (108 mg/100 ml) the risk of nocturnal hypoglycaemia was 80% (95% confidence limits 51-96%). If the bedtime blood glucose concentration was above 6 mmol/l the likelihood of hypoglycaemia not occurring during the night was 88% (74-96%). The mean glycosylated haemoglobin A1c (HbA1c) concentration in the group with nocturnal biochemical hypoglycaemia (8.2 (range 5.0-12.4)%) was significantly lower than that in the group without (9.4(7.0-14.2)%) (p less than 0.02). The prevalence of nocturnal hypoglycaemia in the patients receiving twice daily insulin (29%) was compared with that in 15 patients receiving thrice daily insulin (47%) and was not found to be significantly different. The likelihood of this risk being greater with thrice daily insulin was, however, 88%. No patient with nocturnal biochemical hypoglycaemia woke up during the night with symptomatic hypoglycaemia. Nocturnal biochemical hypoglycaemia is common during twice daily treatment with insulin, and low values of HbA1c might be associated with a higher risk of such hypoglycaemia. The blood glucose concentration at bedtime is a significant predictor of nocturnal biochemical hypoglycaemia, and HbA1c values might be of help in identifying patients at risk.