Hypoglycaemia unawareness in type 1 diabetes: a lower plasma glucose is required to stimulate sympatho-adrenal activation.

To investigate the relationship between awareness of symptoms and the autonomic reaction of hypoglycaemia, acute hypoglycaemia was induced with intravenous insulin (2.5 mU kg-1 min-1) in diabetic and non-diabetic subjects, all of whom had normal cardiovascular autonomic function tests. Three groups were studied: (1) nine patients with Type 1 diabetes with loss of awareness of hypoglycaemia; (2) eight patients who had normal awareness of hypoglycemia, matched for duration of diabetes and blood glucose control; (3) eleven non-diabetic volunteers. The onset of the acute autonomic reaction was identified objectively by the sudden and rapid responses of heart rate and sweating. Cognitive function and hypoglycaemia symptom scores were estimated serially. Acute autonomic activation was observed to occur in all subjects in response to hypoglycaemia. In the 'unaware' diabetic patients, onset of the reaction occurred at a significantly lower plasma glucose (1.0 +/- 0.1 mmol l-1) than in the 'aware' diabetic patients (1.6 +/- 0.2 mmol l-1) (p less than 0.05) or in the non-diabetic control group (1.4 +/- 0.1 mmol l-1) (p less than 0.05). Obvious neuroglycopenia was observed only in the 'unaware' diabetic group and developed when plasma glucose had declined to approximately 1.4 +/- 0.1 mmol l-1, and thus preceded the reaction (p less than 0.02 vs the autonomic threshold). The maximal rise in plasma adrenaline was of similar magnitude in all three groups but a lower plasma glucose was required to stimulate this hormonal response in the 'unaware' patients, in whom the plasma adrenaline concentration was lower at the time of the reaction. Thus, the plasma glucose at which activation of the autonomic reaction was observed was lower in the diabetic patients with unawareness of hypoglycaemia.     

Unawareness of hypoglycaemia in insulin-treated diabetic patients: prevalence and relationship to autonomic neuropathy

Three-hundred and two insulin-treated diabetic patients were questioned about hypoglycaemia using a structured questionnaire interview. Two-hundred and twenty-six patients (75%) had normal symptomatic awareness, 48 (16%) had partial awareness, 21 (7%) had absent awareness of hypoglycaemia, and 7 (2%) denied ever experiencing hypoglycaemia. Patients with complete loss of awareness of hypoglycaemia had diabetes of longer duration; none had a HbA1 concentration within the non-diabetic range. Loss of awareness of hypoglycaemia was associated with an increased incidence of severe hypoglycaemia, 19 (91%) of the patients with absent awareness, and 33 (69%) with partial awareness of hypoglycaemia experiencing severe hypoglycaemia over 1 year compared with only 41 (18%) of patients with normal awareness of hypoglycaemia (p less than 0.001). Cardiovascular autonomic function tests were performed in 226 (75% of the whole group). Of the patients who had diabetes for more than 15 years, 54% (n = 39) with normal awareness of hypoglycaemia, compared with 59% (n = 10) with absent awareness of hypoglycaemia, had evidence of cardiovascular autonomic impairment (NS). Seven (41%) of the 17 patients with absent awareness of hypoglycaemia and diabetes of greater than 15 years duration had no evidence of autonomic dysfunction. Loss of hypoglycaemia awareness is a common problem in patients with insulin-treated diabetes of long duration, is associated with an increased incidence of severe hypoglycaemia, but is not invariably associated with abnormal cardiovascular autonomic function tests.     

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.     

Nocturnal electroencephalogram registrations in Type 1 (insulin-dependent) diabetic patients with hypoglycaemia

Summary Eight Type 1 (insulin-dependent) diabetic patients with no diabetic complications were studied overnight for two consecutive and one subsequent night with continuous monitoring of electroencephalogram and serial hormone measurements. The aims were: 1) to evaluate the influence of spontaneous and insulin-induced hypoglycaemia on nocturnal electroencephalogram sleep-patterns and, 2) to evaluate counter-regulatory hormone responses. Spontaneous hypoglycaemia occurred on six nights (38%) with blood glucose concentrations <3.0 mmol/l and on four nights <2.0 mmol/l. All the patients experienced insulin-induced hypoglycaemia with a blood glucose nadir of 1.6 (range 1.4–1.9) mmol/l. The electroencephalogram was analysed by a new method developed for this purpose in contrast to the traditional definition of delta-, theta-, alpha- and beta-activity. The blood glucose concentration could be correlated to the rank of individual electroencephalogram-patterns during the whole night, and specific hypoglycaemic amplitude-frequency patterns could be assigned. Three of the eight patients showed electroencephalogram changes at blood glucose levels below 2.0 (1.6–2.0) mmol/l. The electroencephalogram classes representing hypoglycaemic activity had peak frequencies at 4 and 6 Hz, respectively, clearly different from the patients' delta- and theta-activity. The changes were not identical in each patient, however, they were reproducible in each patient. The changes were found equally in all regions of the brain. The three patients with electroencephalogram changes during nocturnal hypoglycaemia could only be separated from the other five patients by their impaired glucagon responses. Against this background the possibility of protection by glucagon, against neurophysiologic changes in the brain during hypoglycaemia may be considered.     

Predictors of hypoglycaemia in insulin-treated type 2 diabetes patients in primary care: A retrospective database analysis

AimsTo investigate the frequency and predictors (diabetes care and treatment, comorbidity) of documented hypoglycaemia in primary care patients with insulin-treated type 2 diabetes.MethodsData from 32,545 patients (mean age: 70 (SD 11) years, 50.3% males) from 1072 practices were retrospectively analyzed (Disease Analyzer database Germany: 09/2011–08/2012). Logistic regression (≥1 documented hypoglyemia) was used to adjust for confounders (age, sex, practice characteristics, diabetes treatment regimen).ResultsThe prevalence of patients (12 months) with at least one reported hypoglycaemia was 2.2% (95% CI: 2.0–2.4%). The adjusted odds of having hypoglycemia were increased for renal failure (OR; 95% CI: 1.26; 1.16–1.37), autonomic neuropathy (1.34; 1.20–1.49), and adrenocortical insufficiency (3.08; 1.35–7.05). Patients with mental disorders including dementia (1.49; 1.31–1.69), depression (1.24; 1.13–1.35), anxiety (1.18; 1.01–1.37), and affective disorders (1.80; 1.36–2.38) also showed an increased odds of having hypoglycemia. Location of the practice in an urban area was associated with a lower odds ratio (0.74; 0.68–0.80).ConclusionsBoth individual patient characteristics (e.g. comorbidity) and regional factors (practice location) have a substantial impact on hypoglycaemia in primary care patients with insulin therapy.     

Frequency and Symptoms of Hypoglycaemia Experienced by Patients with Type 2 Diabetes Treated with Insulin

This study ascertained the prevalence of severe hypoglycaemia and loss of awareness of hypoglycaemia in patients with Type 2 diabetes treated with insulin. One hundred and four sequentially selected Type 2 diabetic patients were compared with 104 patients with Type 1 diabetes who were matched for duration of insulin therapy. The patients were interviewed using a standardized questionnaire. During treatment with insulin, 18 Type 2 patients had experienced fewer than two episodes of hypoglycaemia, while 86 had experienced two or more episodes; 80 (93%) reported normal awareness, six (7%) reported partial awareness, and none had absent awareness of hypoglycaemia. All 86 Type 1 diabetic patients matched to the 86 Type 2 patients had experienced multiple episodes of hypoglycaemia; 71 (83%) had normal awareness, 14 (16%) had partial awareness and one patient (1%) reported absent awareness of hypoglycaemia. The Type 1 patients who had altered awareness of hypoglycaemia had longer duration of diabetes and insulin therapy (normal awareness: 5 (1–17) years (median (range)) vs partial awareness: 9 (3–18) years, p < 0.01). Similarly, Type 2 patients with altered awareness had longer duration of diabetes (normal awareness: 11 (2–25) years vs partial awareness: 19 (8–24) years, p < 0.02) and had received insulin for longer (normal awareness: 3 (1–18) years vs partial awareness: 12 (6–17) years, p < 0.001). Severe hypoglycaemia in the preceding year had occurred with a similar prevalence in the Type 2 patients (9 (10%)) and Type 1 patients (14 (16%)), but was more frequent in those patients with partial awareness both in Type 1 patients (normal awareness: 3 (4%) vs partial awareness: 11 (73%), p < 0.001) and in Type 2 patients (normal awareness: 3 (4%) vs partial awareness: 6 (100%), p < 0.001). Although the symptoms of hypoglycaemia were idiosyncratic in individual Type 2 patients, the range and prevalence of specific symptoms were similar to those described by the patients with Type 1 diabetes.     

Permanent neuropsychological impairment after recurrent episodes of severe hypoglycaemia in man

Summary Seventeen Type 1 (insulin-dependent) diabetic patients with a history of recurrent and severe hypoglycaemia and Type 1 diabetic patients with no severe hypoglycaemia were compared as regarded performances in tests of neuropsychological functioning. To test the hypothesis that recurrent severe hypoglycaemia gives rise to permanent cognitive impairment, the study group was selected among those patients who had met with repeated attacks over the last three years or more as identified by a questionnaire among almost 600 insulin-treated diabetic patients. The comparison group without known severe reactions were comparable to the study group with respect to type of diabetes, sex, age, age at onset, duration of diabetes, socio-economic parameters, and prevalence of neuropathy and retinopathy. The results indicate that Type 1 diabetic patients with recurrent severe hypoglycaemia scored lower than those without severe hypoglycaemia in tests of motor ability, short-term and associative memory and visuospatial tasks assessing ability in general problem-solving. Type 1 diabetic patients with severe hypoglycaemia also displayed a higher frequency of perspective reversals suggesting frontal-lobe involvement. These data can be interpreted in two ways. One interpretation implies that the cognitive impairment of Type 1 diabetic patients with severe hypoglycaemia reflects a selection factor, the other that recurrent episodes of severe hypoglycaemia result in permanent cognitive impairment.     

Effects of acute insulin-induced hypoglycaemia on psychomotor function: people with type 1 diabetes are less affected than non-diabetic adults

AIMS/HYPOTHESIS: We examined the effects of acute insulin-induced hypoglycaemia on psychomotor function in non-diabetic volunteers and in adults with type 1 diabetes. METHODS: Non-diabetic adults (n = 20) and adults with type 1 diabetes mellitus (n = 16) each underwent a euglycaemic-hyperinsulinaemic glucose clamp on two separate occasions. Arterialised blood glucose was maintained for 1 h at either 4.5 mmol/l (euglycaemia) or 2.5 mmol/l (hypoglycaemia). During this time participants underwent neuropsychological tests to assess psychomotor function. RESULTS: During hypoglycaemia the non-diabetic participants showed a significant deterioration in the following: (1) four-choice reaction time (p = 0.008); (2) grooved pegboard (a test of manual dexterity; p = 0.004); (3) hand steadiness (p = 0.003); (4) pursuit rotor (a test of fine motor function, attention and coordination; p = 0.018); and (5) test of total body coordination (p = 0.004). No significant differences were observed between euglycaemia and hypoglycaemia in hand-grip (p = 0.897) and line tracing time (p = 0.480) tests. In type 1 diabetes mellitus patients, only four-choice reaction time (p = 0.023) and pursuit rotor (p = 0.045) were impaired significantly during hypoglycaemia. CONCLUSIONS/INTERPRETATION: Although acute hypoglycaemia caused significant impairment of several psychomotor functions in non-diabetic adults, a lower magnitude of impairment was observed in those with type 1 diabetes. The mechanism underlying this discrepant effect of hypoglycaemia on psychomotor function remains unknown, but may be related to the difference in sympathoadrenal activation observed between the groups. People with type 1 diabetes may also have had a behavioural advantage of over non-diabetic participants derived from their previous exposure to hypoglycaemia or potentially the disparate results arose from hypoglycaemia-induced cerebral adaptation.     

Exercise in Type 1 (insulin-dependent) diabetic patients treated with continuous subcutaneous insulin infusion

Summary The study was performed to investigate the effects of mild to moderate exercise on blood glucose levels, metabolite concentrations and responses of counterregulatory hormones in tightly controlled Type 1 (insulin-dependent) diabetic patients treated by continuous subcutaneous insulin infusion, and to quantify the measures necessary to prevent acute and late exercise-induced hypoglycaemia. Seven male patients started a 60 min exercise period 90 min after an insulin bolus and a standard breakfast; they were monitored during a post-exercise resting period of 5 h 30 min. Different basal and premeal insulin infusion rates were applied. (Near)normoglycaemia prevailed throughout the study during the control protocol when the subjects did not exercise and received their usual insulin dose. When they exercised without changing the insulin dose, four patients were forced to stop due to hypoglycaemia. This effect of exercise could be attenuated but not completely avoided if the basal infusion rate of insulin was discontinued during the exercise period. The pronounced increase in catecholamine and growth hormone concentrations during exercise were not sufficient to prevent hypoglycaemic reactions. Hypoglycaemia during exercise could only be prevented when the premeal insulin bolus was reduced by 50% in addition to the discontinuation of the basal insulin infusion during exercise. In order to reduce late hypoglycaemic reactions after exercise the best measure proved to be a reduction of the basal insulin infusion rate by 25% during post-exercise hours. Administration of only 50% of the basal insulin infusion rate during this time was associated with blood glucose levels being raised up to 8 mmol/l. In conclusion, Type 1 diabetic patients treated with continuous subcutaneous insulin infusion at (near)normoglycaemia need to reduce their insulin dosage before, during, and after mild to moderate endurance exercise in order to minimize the risk of acute and late hypoglycaemia.     

Changes in brainstem auditory evoked potentials during insulin-induced hypoglycaemia in type 1 diabetic patients.

To determine whether the central and peripheral auditory pathways are disturbed during hypoglycaemia, brainstem auditory evoked potentials were measured in 16 Type 1 diabetic patients aged 17-55 years during intravenous insulin infusion. Within 60 min mean blood glucose declined from 5.0 mmol l-1 to a nadir at 1.7 mmol l-1 followed by an increase to 2.8 mmol l-1 30 min after the insulin infusion had been discontinued. The latency of wave I of brainstem auditory evoked potentials remained unchanged during hypoglycaemia. However, latencies of waves III and V and interpeak latencies I-III, III-V, and I-V were significantly prolonged at average blood glucose levels of 1.7 or 2.1 mmol l-1 when compared with baseline: III 3.96 +/- 0.03 (+/- SE) vs 4.01 +/- 0.04 ms; V 5.69 +/- 0.07 vs 5.81 +/- 0.07 ms; I-III 2.30 +/- 0.05 vs 2.37 +/- 0.05 ms; III-V 1.73 +/- 0.06 vs 1.83 +/- 0.07 ms; and I-V 4.01 +/- 0.05 vs 4.14 +/- 0.06 ms (all p less than 0.05). When blood glucose was allowed to increase to 2.8 mmol l-1, these conduction delays were no longer demonstrable. The depression of the brainstem was approximately paralleled by the activation of counter-regulatory hormones and development of hypoglycaemic symptoms. We conclude that hypoglycaemia results in a rapidly reversible delay of the transmission time in the brainstem but not in the auditory nerve. The dysfunction in the brainstem suggests that not only cortical centres are involved in response to hypoglycaemia in Type 1 diabetic patients.     

Effects of previous glycaemic control on the onset and magnitude of cognitive dysfunction during hypoglycaemia in Type 1 (insulin-dependent) diabetic patients

Summary To determine whether the degree of previous glycaemic control may modify cognitive responses to hypoglycaemia, the glycaemic thresholds for, and magnitude of cognitive dysfunction as assessed by P300 event-related potentials as well as subjective and hormonal responses during hypoglycaemia were evaluated. Hypoglycaemia was induced by intravenous insulin infusion in 18 Type 1 (insulin-dependent) diabetic patients, 7 of whom were strictly controlled (HbA_1c: 6.3±0.3%; mean±SEM; Group 1) and 11 of whom were poorly controlled (HbA_1c: 9.1±0.4%; Group 2). Within 60 min, mean blood glucose declined from 5.6 and 5.7 mmol/l (baseline) to a nadir of 1.6 and 1.8 mmol/l followed by an increase to 5.6 and 4.3 mmol/l after 120 min in Group 1 and 2, respectively. There was no significant difference between the groups in regard to P300 latency at baseline, but between 50 and 70 min a significant prolongation of this component was noted in Group 2 as compared with Group 1 at blood glucose levels between 1.6 and 2.3 mmol/l (p<0.05). The glycaemic thresholds at which a significant increase of P300 latency over baseline was first noted were 1.6±0.2 mmol/l in Group 1 and 3.5±0.2 mmol/l in Group 2 (p<0.05). The glucose thresholds at which this prolongation was no longer demonstrable were 1.9±0.1 mmol/l in Group 1 and 3.8±1.4 mmol/l in Group 2, respectively (p<0.05). The glycaemic threshold at which the P300 amplitude was first significantly reduced was 2.2 mmol/l in Group 2, whereas no such reduction was observed in Group 1. The glycaemic thresholds for the perception of subjective symptoms were 1.7±0.2 mmol/l in Group 1 and 2.5±0.2 mmol/l in Group 2 (p<0.05), and those for the first significant rise of the counter-regulatory hormones were 2.3±0.1 and 1.6±0.2 mmol/l in Group 1 as well as 2.8±0.1 mmol/l in Group 2 (p<0.05). Thus, the glycaemic threshold for and magnitude of, cognitive dysfunction during hypoglycaemia are reduced in strictly-controlled as compared with poorly-controlled Type 1 diabetic patients. In the latter group, cognitive impairment may precede the onset of counter-regulatory hormone responses and symptom awareness. These findings support the concept of cerebral adaptation to previous low blood glucose levels.     

Symptomatic hypoglycaemia in childhood diabetes: a population-based questionnaire study

The occurrence of severe and mild hypoglycaemic attacks and their symptoms and signs were studied in 92 insulin-dependent diabetic children, 7-18 years old. A questionnaire was distributed to all families and they were interviewed by an experienced nurse. Severe attacks, for which the help of an adult was needed, were reported by 44% of the children during a 12-month period. Thirty-seven per cent of the attacks occurred in the mornings, most often attributed to extra physical exercise, but equally often without any obvious cause. They were more common in children with strict blood glucose control measured as HbA1c. Fast-acting carbohydrates, given by parents, relieved the attack in most children, but 15% needed a glucagon injection and 12% intravenous glucose. In all, 16% were admitted to hospital. Mild events occurred in 97% of the children, at least once per week in 53% of the children, and were not related to blood glucose control. They were often attributed to extra physical exercise and occurred mainly between breakfast and lunch. Initial symptoms were tremor and hunger; during the whole event tremor and sweating were most common. Parents noted pallor as the most common sign. The frequency of severe or mild attacks could not be correlated to the age of the child, duration of diabetes, daily dose or number of insulin injections.     

Assessment of hypoglycaemia awareness using continuous glucose monitoring.

AIMS: To investigate the possibility of assessing hypoglycaemia awareness in patients with Type 1 diabetes using continuous glucose monitoring. METHODS: Twenty patients with Type 1 diabetes were investigated. Ten patients with Type 1 diabetes and strongly impaired hypoglycaemia awareness were compared with 10 patients with intact hypoglycaemia awareness regarding quality of hypoglycaemia perception (number of undetected hypoglycaemic episodes per 24 h, glucose level < 3.3 mmol/l). Hypoglycaemia detection was assessed using the event function of the Continuous Glucose Monitoring System (CGMS; Medtronic MiniMed, Northridge, CA, USA). Patients were instructed to enter an event upon suspecting being hypoglycaemic. RESULTS: Satisfactory CGMS performance could be achieved [mean r = 0.893 between calibration measurements and CGMS data, mean absolute difference (MAD) = 20.6%], although artefacts were observable and had to be controlled. Hypoglycaemia unaware patients showed a significantly higher total number of hypoglycaemic episodes (P < 0.05), number of undetected hypoglycaemic episodes (P < 0.01), and mean glucose levels (P < 0.05). Even in aware patients, undetected hypoglycaemia was observable. No significant differences regarding occurrence of nocturnal hypoglycaemia were observable. CONCLUSIONS: The possibility of direct assessment of hypoglycaemia awareness using continuous glucose monitoring was demonstrated. Its application in clinical practice could be of use for assessing hypoglycaemia perception and evaluating the impact of treatment changes on hypoglycaemia awareness.     

The impact of insulin type on severe hypoglycaemia events requiring inpatient and emergency department care in patients with type 2 diabetes

Aims

To evaluate the risk from different insulin types on severe hypoglycaemia (SHG) events requiring inpatient (IP) or emergency department (ED) care in patients with type 2 diabetes.

Methods

Type 2 diabetes patients newly started on insulin in a large commercial claims database were evaluated for SHG events. Patients were classified into an insulin group based on their most frequently used insulin type. Multivariable Cox models assessed the association between insulin type and the risk of SHG events.

Results

We identified 8626 patients (mean age 53.5 years; 55% female) with type 2 diabetes followed for an average of 4.0 years after insulin initiation. Of these, 161 (1.9%) had a SHG event at an average of 3.1y after insulin initiation. Patients with SHG events were slightly older (56.4 vs. 53.4 years), used a similar number of OADs (1.1 vs. 1.2) but had more co-morbidities compared with those without SHG events. In multivariate Cox models, premixed insulin (HR 2.12; p < 0.01), isophane insulin (NPH) (HR 2.02; p < 0.01), and rapid acting insulin (HR 2.75; p < 0.01) had significantly higher risks of SHG events compared with glargine. No statistically significant difference in SHG events was seen with detemir (HR 1.20; p = 0.73).

Conclusions

Among patients with type 2 diabetes, the use of newer basal insulin analogues was associated with lower rates of SHG events requiring IP or ED care compared with users of other insulin formulations. Future research should examine the impact of hypoglycaemia events of different severity levels.     

An Analysis of the Glucagon Response to Hypoglycaemia in Patients with Type 1 Diabetes and in Healthy Subjects

The study aimed to analyse the glucagon response during hypoglycaemia in relation to gender, level of hypoglycaemia, and hyperinsulinaemia as well as its relation to other counterregulatory hormones in patients with Type 1 diabetes and in nondiabetic subjects. Mild hypoglycaemia was induced by an i.v. insulin infusion (244 pmol kg^?1h^?1) for 180 min in 43 Type 1 diabetic patients and 22 nondiabetic subjects. Venous blood glucose, plasma free insulin, glucagon, adrenaline, noradrenaline, growth hormone, and cortisol were measured every 15–30 min. The hormonal responses during hypoglycaemia were evaluated from the incremental areas under their respective curves. There was a linear correlation between the glucagon response and the decremental area of blood glucose (p < 0.005), but the slope of the regression line in the diabetic group was less steep than in the controls (p < 0.5), and, in spite of the deeper hypoglycaemia in the diabetic groups, their glucagon response was diminished (p < 0.05). Plasma, adrenaline, growth hormone and cortisol all increased during hypoglycaemia. The glucagon response correlated with the responses of growth hormone and cortisol in both groups, while it was positively correlated with the adrenaline response (p < 0.001) and inversely with the plasma insulin (p < 0.001) only in the diabetic patients. Although the insulin infusion rate was identical, the female diabetic patients had a lower metabolic clearance rate of insulin as compared with the males (p < 0.05). There was no statistical difference in the counterregulatory hormone responses between males and females in neither of the groups. In conclusion, this study suggests that the glucagon response to hypoglycaemia in Type 1 diabetic patients, may be suppressed by circulating insulin within its therapeutic range, and stimulated by the simultaneously secreted adrenaline. Furthermore, female Type 1 diabetic patients have a lower metabolic clearance rate of insulin than males, yielding a more pronounced hypoglycaemia in response to the same dose of insulin, although this study does not provide evidence of a gender difference in the responsiveness of counterregulatory hormones to hypoglycaemia.     

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.     

Attenuated neutrophil respiratory burst following acute hypoglycaemia in diabetic patients and normal subjects

The effects of insulin-induced hypoglycaemia on the neutrophil respiratory burst were investigated in six patients with type 1 diabetes and six non-diabetic control subjects. Plasma glucose reached similar nadirs in control subjects (0.9±0.1 mmol l^–1; mean±SEM) and diabetic patients (1.2±0.2 mmol l^–1) (NS). The resting neutrophil respiratory burst was similar in control subjects (1.26±0.15 mV) and diabetic patients (1.03±0.18 mV) (NS). The neutrophil respiratory burst fell following hypoglycaemia in control subjects and diabetic patients to 0.38±0.05 mV (P<0.001) and 0.54±0.09 mV (P<0.05), respectively. This fall was significantly greater in control subjects (ANOVA; P<0.001). Resting neutrophil counts were not significantly different in control subjects (3.2±0.3×10⁹ l^–1) and diabetic patients (6.1±1.5×10⁹ l^–1). Following hypoglycaemia, neutrophil numbers increased in control subjects and diabetic patients to 11.5±1.4×10⁹ l^–1 (P<0.01) and 9.7±1.7×10⁹ l^–1 (P<0.05), respectively. This increase was significantly greater in control subjects (ANOVA; P<0.001). These results suggest that the neutrophil respiratory burst is suppressed in response to hypoglycaemia and that this phenomenon is more pronounced in non-diabetic subjects. Received: 28 March 1997 / Accepted in revised form: 31 July 1997     

Intranasal glucagon treatment relieves hypoglycaemia in children with Type 1 (insulin-dependent) diabetes mellitus

Summary The aim of the present study was to compare intranasal glucagon with subcutaneous glucagon as a treatment of insulin-induced hypoglycaemia in 11 children, 7–12 years old, with Type 1 (insulin-dependent) diabetes mellitus. Hypoglycaemia (1.6±0.1 vs 1.8±0.2 mmol/l) was induced twice in each child by continuous insulin and variable glucose infusions. One milligram of intranasal glucagon or 0.5 mg of subcutaneous glucagon was given in a randomized order. At 15 min after the administrations of either intranasal or subcutaneous glucagon, the blood glucose concentration increased by 1.5±0.2 mmol/l or 1.7±0.2 mmol/l above the glucose nadir, respectively. After nasal administration, the maximal rise in blood glucose was seen after 25 min. Subcutaneous injections induced higher and more sustained plasma glucagon concentrations but the children suffered more often from nausea than when they were treated intranasally. In conclusion, treatment with intranasal glucagon seems to be efficient and results in a rapid correction of insulin-induced hypoglycaemia with few side-effects.     

Hypertension in diabetic clinic patients and their siblings

Summary The prevalence of hypertension was investigated in a systematically chosen sample of patients attending a diabetic clinic. One hundred ninety-one patients were classified as Type 1 (insulin-dependent), 183 were classified as Type 2 (non-insulin-dependent) and 12 were deemed unclassifiable. Two hundred fifty-five control subjects attending non-medical out-patient clinics were also examined under similar conditions. Hypertension was significantly (p<0.001) more common among Type 2 patients (38%) than among Type 1 patients (15%) or control subjects (16%). The difference between Type 2 patients and control subjects, but not between Type 2 and Type 1 patients, persisted when the influences of age and body mass index were controlled. We also investigated the prevalence of hypertension among the siblings of the hypertensive patients identified, together with a matched normotensive group. One hundred eighty-eight siblings were examined and historical details were obtained for a further 451 siblings. When age and body mass index were controlled for in examined siblings, the risk of hypertension was greater in those with a hypertensive proband than in those with a normotensive proband, in the control (p<0.06) and Type 1 (p<0.02) groups. Among the siblings of Type 2 probands, however, the risk of hypertension in those with a normotensive proband Was at least as great as in those with a hypertensive proband, and greater than in those with a normotensive proband in the control (p<0.10) or Type 1 (p<0.05) groups. The prevalence of cardiovascular deaths was also similar in the siblings of normotensive and hypertensive Type 2 probands. We conclude that in our diabetic clinic there is an excess of hypertension among Type 2 patients. There may also be an excess of hypertension among the siblings of Type 2 patients.     

Further evidence for a high incidence of nocturnal hypoglycaemia in IDDM: no effect of dose for dose transfer between human and porcine insulins

We tested the hypothesis that transfer from porcine to human insulin causes a fall in nocturnal blood glucose and an increase in the frequency of hypoglycaemic episodes. Twenty IDDM patients (age 19–55, duration 3–36 years) used Velosulin and Insulatard twice daily for 12 weeks, double-blinded to species (human (H) or porcine (P)) in a randomized crossover study. Species was changed after 4 weeks’ run-in and 4 weeks later, with insulin doses unchanged on transfer. Ten patients underwent each sequence (H/P/H or P/H/P) and were admitted on the first and eighth night after transfer for hourly blood glucose measurement (22.00–07.00). Biochemical hypoglycaemia (<3.5 mmol l⁻¹) was observed on 39 of the 80 patient-nights studied (48.75 %). The number of episodes were similar during each night (H1 8, H8 10, P1 10, P8 11, p = 0.83). Total reported symptomatic episodes (H 51 vs P 73, p = 0.85), total HbA₁ (H 9.8 ± 0.3 %, P 10.0 ± 0.3 %, p = 0.32) and daily insulin doses (H 0.63 ± 0.04 units kg⁻¹ day⁻¹ vs P 0.63 ± 0.05 units kg⁻¹ day⁻¹, p = 0.54) were not different. Despite an apparent fall in blood glucose levels from night 1 to 8 on transfer to human (AUC 82.3 ± 7.8 vs 61.4 ± 5.3 mmol.h l⁻¹, p < 0.05) but not porcine insulin (AUC 70.7 ± 7.2 vs 70.1 ± 7.5 mmol.h l⁻¹, p = 0.74), there was no difference when all 4 nights were considered together (p = 0.30). We conclude that dose for dose transfer to human insulin does not increase numbers of episodes of nocturnal or reported hypoglycaemia. © 1997 by John Wiley & Sons, Ltd.