Cognitive dysfunction in adults with Type 1 (insulin-dependent) diabetes mellitus of long duration: effects of recurrent hypoglycaemia and other chronic complications

Summary To examine the long-term effects of recurrent severe hypoglycaemia and other biomedical complications on mental efficiency, a battery of cognitive tests was administered to 142 Type 1 (insulin-dependent) diabetic adult patients (age 33.5±5.6 years; mean ±SD) and 100 demographically similar non-diabetic control subjects. All diabetic subjects had been diagnosed before the age of 17 years. Diabetic subjects with one or more complications (distal symmetrical polyneuropathy; advanced background or proliferative retinopathy; overt nephropathy; one or more episodes of severe hypoglycaemia) performed significantly (p<0.001) more poorly than non-diabetic control subjects on tests requiring sustained attention, rapid analysis of visuospatial detail, and hand eye co-ordination. Regression analyses indicated that the best biomedical predictor of cognitive test performance was a diagnosis of polyneuropathy. Although severe recurrent hypoglycaemia was not associated with performance on any test, the neuropathy × recurrent hypoglycaemia interaction term was significant. These results suggest that in adults with Type 1 diabetes of long duration, recurrent hypoglycaemia does not appear to influence cognitive performance directly, but may interact with neuropathy to exaggerate or otherwise magnify the extent of neurobehavioural dysfunction.     

Regional cerebral blood flow in IDDM patients: Effects of diabetes and of recurrent severe hypoglycaemia

Summary Chronic hyperglycaemia and recurrent severe hypoglycaemia have both been implicated as causing cerebral damage in patients with diabetes. Although cognitive dysfunction and intellectual impairment have been demonstrated in patients with recurrent severe hypoglycaemia, structural correlates have not been described, and it is not known whether specific functional changes occur in the brains of affected patients. Regional cerebral blood flow was estimated by SPECT with ^99mTechnetium Exametazime in 20 patients with IDDM. Ten patients had never experienced severe hypoglycaemia and 10 had a history of recurrent severe hypoglycaemia. Patient results were compared with 20 age- and sex-matched healthy volunteers. We observed differences between the two patient groups and the control group. Tracer uptake was greater in diabetic patients in the superior pre-frontal cortex. This effect was particularly pronounced in the group who had a history of previous severe hypoglycaemia. Patients with a history of recurrent hypoglycaemia also had a relative reduction in tracer uptake to the calcarine cortex. This suggests an alteration in the pattern of baseline regional cerebral blood flow in diabetic patients with frontal excess and relative posterior reduction in cerebral blood flow.Abbreviations IDDM insulin-dependent diabetes mellitus - SPECT single photon emission computed tomography - EEG electroencephalograph - ANOVA analysis of variance     

Cumulative cognitive impairment following recurrent severe hypoglycaemia in adult patients with insulin-treated diabetes mellitus

Summary To examine the hypothesis that episodes of severe hypoglycaemia may cause cumulative cognitive impairment, 100 Type 1 (insulin-dependent) diabetic patients were examined. Their age range was 25–52 years, and the onset of diabetes had occurred after the age of 19 years. Patients with evidence of organic brain disease, including cerebrovascular disease, were excluded. A questionnaire was used to assess the number, frequency and severity of hypoglycaemic episodes experienced during treatment with insulin and the accuracy of this retrospective information was verified from general practice and hospital case-notes. A detailed neuropsychological assessment was undertaken, including tests of pre-morbid and present IQ (Wechsler-Revised), memory and information-processing speed. Significant correlations were observed between the frequency of severe hypoglycaemia and the magnitude of intellectual decline, Performance IQ, inspection time and reaction time (patients with the more frequent hypoglycaemia had poorer performance). Two sub-groups of patients were identified on the basis of their experience of severe hypoglycaemia, and were balanced for pre-morbid IQ, age and duration of diabetes. One sub-group (n=23) had never experienced severe hypoglycaemia (Group A), whilst the other sub-group (n=24) had suffered at least five episodes of severe hypoglycaemia (Group B). Group B had greater intellectual impairment than Group A, and Group B also had a significantly slower mean reaction time and higher reaction time variance when compared with Group A. It is concluded that recurrent severe hypoglycaemia is associated with cumulative cognitive impairment in adult diabetic patients treated with insulin.     

Comparing hormonal and symptomatic responses to experimental hypoglycaemia in insulin‐ and sulphonylurea‐treated Type 2 diabetes

Aims Patients with diabetes rely on symptoms to identify hypoglycaemia. Previous data suggest patients with Type 2 diabetes develop greater symptomatic and hormonal responses to hypoglycaemia at higher glucose concentrations than non‐diabetic controls and these responses are lowered by insulin treatment. It is unclear if this is as a result of insulin therapy itself or improved glucose control. We compared physiological responses to hypoglycaemia in patients with Type 2 diabetes patients treated with sulphonylureas (SUs) or insulin (INS) with non‐diabetic controls (CON). Methods Stepped hyperinsulinaemic hypoglycaemic clamps were performed on 20 subjects with Type 2 diabetes, 10 SU‐treated and 10 treated with twice‐daily premixed insulin, and 10 age‐ and weight‐matched non‐diabetic controls. Diabetic subjects were matched for diabetes duration, glycated haemoglobin (HbA_1c) and hypoglycaemia experience. We measured symptoms, counterregulatory hormones and cognitive function at glucose plateaux of 5, 4, 3.5, 3 and 2.5 mmol/l. Results Symptomatic responses to hypoglycaemia occurred at higher blood glucose concentrations in SU‐treated than INS‐treated patients [3.5 (0.4) vs. 2.6 (0.5) mmol/l SU vs. INS; P = 0.001] or controls [SU vs. CON 3.5 (0.4) vs. 3.0 (0.6) mmol/l; P = 0.05]. They also had a greater increase in symptom scores at hypoglycaemia [13.6 (11.3) vs. 3.6 (6.1) vs. 5.1 (4.3) SU vs. INS vs. CON; P = 0.017]. There were no significant differences in counterregulatory hormone responses or impairment of cognitive function among groups. Conclusions Sulphonylurea‐treated subjects are more symptomatic of hypoglycaemia at a higher glucose level than insulin‐treated subjects. This may protect them from severe hypoglycaemia but hinder attainment of glycaemic goals.     

Severe hypoglycaemia and cognitive impairment in older patients with diabetes: the Fremantle Diabetes Study

Aims/hypothesis  The aim was to investigate the relationship between severe hypoglycaemia and cognitive impairment in older patients with diabetes. Methods  A sample of 302 diabetic patients aged ≥70 years was assessed for dementia or cognitive impairment without dementia in 2001–2002 and a subsample of non-demented patients (n = 205) was followed to assess cognitive decline. A history of severe hypoglycaemia was determined from self-reports, physician assessments and records of health service use for hypoglycaemia (HSH). Prospective HSH was determined up to 2006. Data analysis, including multiple logistic and Cox regression models, was used to determine whether: (1) there were cross-sectional associations between hypoglycaemia and cognitive status, (2) historical hypoglycaemia predicted cognitive decline, and (3) baseline cognitive status predicted subsequent HSH. Results  There were significant cross-sectional associations between both cognitive impairment and dementia and hypoglycaemia. Independent risk factors for future HSH included dementia (hazard ratio 3.00, 95% CI 1.06–8.48) and inability to self-manage medications (hazard ratio 4.17, 95% CI 1.43–12.13). However, there were no significant associations between historical hypoglycaemia, incident HSH and cognitive decline. Conclusions/interpretation  Dementia is an important risk factor for hypoglycaemia requiring health service utilisation. We found no evidence that hypoglycaemia contributes to cognitive impairment in older patients with diabetes.     

Glucose counterregulation in Type 2 diabetes mellitus.

Glucose counterregulatory failure and hypoglycaemia unawareness frequently complicate treatment of Type 1 diabetes mellitus, especially when aiming for intensive metabolic control. Since tight metabolic control reduces microvascular long-term complications in Type 2 diabetes mellitus, the integrity of glucose counterregulation in Type 2 diabetic patients is important. Using a Medline search, we identified 12 studies in which counterregulatory responses to insulin-induced hypoglycaemia were compared between Type 2 diabetic patients and appropriate controls. A review of these studies showed that some patients with Type 2 diabetes mellitus develop mild counterregulatory dysfunction and reduced awareness of insulin-induced hypoglycaemia. Some studies suggested an association between counterregulatory impairment and intensity of metabolic control. We speculate that the relatively low frequency of (severe) hypoglycaemic events in Type 2 diabetes may explain why glucose counterregulation remains unaffected in most patients. We hypothesize that residual beta-cell reserve and insulin resistance provide protection against severe hypoglycaemia and limit impaired counterregulation. Diabet. Med. 18, 519-527 (2001)     

A randomized pilot study in Type 1 diabetes complicated by severe hypoglycaemia, comparing rigorous hypoglycaemia avoidance with insulin analogue therapy, CSII or education alone.

AIM: To determine potential for amelioration of recurrent severe hypoglycaemia without worsening in overall control in individuals with long-standing Type 1 diabetes (T1DM). METHODS: Twenty-one people with T1DM characterized by altered hypoglycaemia awareness and debilitating severe hypoglycaemia were randomized in a pilot 24-week prospective study to optimized analogue therapy (ANALOGUE; lispro/glargine); continuous subcutaneous insulin infusion therapy (CSII; lispro); or re-education with relaxation of blood glucose targets on existing conventional insulin regimen (EDUCATION). Glycaemic profiles and duration of biochemical hypoglycaemia were measured by continuous subcutaneous glucose monitoring and self-monitored blood glucose. RESULTS: Further severe hypoglycaemia was prevented in five participants (71%) in each group (P = 0.06). Incidence of severe hypoglycaemia was: 0.6 (ANALOGUE), 0.9 (CSII), and 3.7 (EDUCATION) episodes per patient year. Restoration of hypoglycaemia awareness was confirmed by validated questionnaire in three (43%) ANALOGUE, four (57%) CSII and five (71%) EDUCATION patients. Glycated haemoglobin (HbA1c) was significantly improved in the ANALOGUE group between weeks 0 and 24 (8.6 +/- 1.1 vs. 7.6 +/- 0.8%; P = 0.04 for change). Non-significant improvement was seen in the CSII group (8.5 +/- 1.9 vs. 7.4 +/- 1.0%; P = 0.06). No change in HbA1c was seen in the EDUCATION group (8.5 +/- 1.1 vs. 8.3 +/- 1.0%; P = 0.54). There were no episodes of diabetic ketoacidosis or any other adverse events in any group. CONCLUSIONS: In this pilot randomized trial comparing optimized ANALOGUE, CSII or EDUCATION alone in unselected individuals with recurrent severe hypoglycaemia, we show potential for restoring hypoglycaemia awareness and preventing further severe hypoglycaemia with concomitant improvement in glycaemic control in ANALOGUE and CSII groups.     

Influence of alcohol on cognitive performance during mild hypoglycaemia; implications for Type 1 diabetes.

AIMS: Alcohol and hypoglycaemia independently affect cognitive function. This may be relevant for insulin-treated diabetic patients who drive motor vehicles. The aim of this study was to examine the effect of mild hypoglycaemia (2.8 mmol/l) with modest alcohol intoxication (levels below UK driving limits) on intellectual performance in patients with Type 1 diabetes. METHODS: A hyperinsulinaemic glucose clamp (60 mU/m2) was used to study 17 subjects [age 35 +/- 8 years, HbA1c 8.1 +/- 1.4% (mean +/- sd)] on four occasions: (A) euglycaemia (4.5 mmol/l) with placebo, (B) euglycaemia with alcohol, (C) hypoglycaemia (2.8 mmol/l) with placebo, and (D) hypoglycaemia with alcohol. Cognitive performance was assessed using four-choice reaction time (4CRT, primary outcome), measurements of general intellectual skills [trail making B (TMB) and digit symbol substitution (DSST)], and visual information processing [visual change detection (VCD)]. A test related to driving performance (hazard perception) was also used. RESULTS: In experiments B and D the average blood alcohol level was 43 mg/dl. This was associated with deterioration in 4CRT [+ 35 ms [95% confidence interval (CI) 20, 50]] and TMB, whereas hypoglycaemia without alcohol increased 4CRT only [+ 39 ms (95% CI 5, 73)]. However, when alcohol was combined with hypoglycaemia, there was marked deterioration in all the cognitive function tests [4CRT 74 ms (95% CI 35, 113), TMB, DSST and VCD]. Hazard perception was not affected. The effect of alcohol was no different in euglycaemia than in hypoglycaemia, i.e. there was no interaction. Whereas hypoglycaemia did not reduce the likelihood that the subjects would drive, alcohol did. CONCLUSIONS: The cumulative effect of alcohol and hypoglycaemia on cognitive function together has implications for driving in patients with Type 1 diabetes. Both independently impair cognitive function and together the effects are additive. Patients with Type 1 diabetes should be educated about hypoglycaemia and driving and should avoid alcohol completely if planning to drive.     

Higher incidence of severe hypoglycaemia leading to hospital admission in Type 2 diabetic patients treated with long-acting versus short-acting sulphonylureas.

AIMS: A comparison of the frequency of severe hypoglycaemia leading to hospital admission in people with Type 2 diabetes mellitus (DM) treated with long vs. short-acting sulphonylureas. METHODS: A community based study over a 12-year period in the population of the city of Basle, Switzerland. The number of diabetic patients treated with oral hypoglycaemic agents was established on the basis of tablet consumption and a defined daily dose, e.g. 7.5 mg for glibenclamide, and 50 mg for glibornuride. RESULTS: Twenty-eight Type 2 diabetic patients were admitted for severe hypoglycaemia, with a median age of 73 years. There were no deaths. Sixteen of these admissions were patients treated with long-acting sulphonylureas and 12 were patients treated with short-acting forms. Only 23.5% of the population with Type 2 DM in Basle were treated with long-acting sulphonylureas. With 30345 person-years of observation, the incidence of severe hypoglycaemia was 2.24 per 1000 person-years for long-acting sulphonylureas vs. 0.75 per 1000 person-year for short-acting forms, odds ratio 3.01 (95% confidence interval 1.35-6.77). Decreased food intake (nine patients) was a major contributing factor. CONCLUSIONS: Severe hypoglycaemia leading to hospital admission is more common in elderly Type 2 diabetic patients treated with long-acting compared to short-acting sulphonylureas. Such long-acting sulphonylureas should be avoided.     

Neuropsychological performance differs between type 1 diabetic and normal men during insulin-induced hypoglycaemia.

Cerebral function was measured with a neuropsychological test battery before, during, and after insulin-induced hypoglycaemia (blood glucose approximately 2.0 mmol l-1) in 10 male Type 1 diabetic patients (age 20-43 years, duration of diabetes 14 (2-30) years) and in 12 normal men. There were no group differences in neuropsychological results at normal glucose levels. Significant effects of hypoglycaemia were found in reaction-time measures (p less than 0.001) and in other tests requiring speed and attention (p less than 0.001), in verbal fluency (p less than 0.05), and short-term memory (p less than 0.001). Significant group effects and interactions (p less than 0.05) revealed that the diabetic patients were generally more affected by hypoglycaemia than the normal subjects. This might have been partly due to the larger absolute decrease in blood glucose level in the diabetic patients, although the rate of glucose decrease was not related to performance in either group. Thus, the diabetic brain might be more vulnerable to hypoglycaemia, perhaps through the persistent impact of repeated hypoglycaemic episodes, although no neuropsychological deficit is demonstrable at normal blood glucose levels.     

Frequency and risk factors of severe hypoglycaemia in insulin-treated Type 2 diabetes: a cross-sectional survey.

AIMS: The reported risk of severe hypoglycaemia in insulin-treated Type 2 diabetes is highly variable and few studies have evaluated the influence of risk factors. We assessed the incidence and the influence of potential risk factors for severe hypoglycaemia in a questionnaire survey in subjects with insulin-treated Type 2 diabetes receiving currently recommended multifactorial intervention. METHODS: Consecutive patients with insulin-treated Type 2 diabetes (n = 401) completed a questionnaire about occurrence of hypoglycaemia in the past, hypoglycaemia awareness and socio-demographic factors. A zero-inflated negative binomial model was used to assess the influence of potential risk factors on the rate of severe hypoglycaemia. RESULTS: The overall incidence of severe hypoglycaemia in the preceding year was 0.44 episodes/person year. Sixty-six (16.5%) patients had experienced at least one event. The risk of any episode of severe hypoglycaemia positively correlated with impaired hypoglycaemia awareness, being married and long duration of diabetes. The risk of repeated episodes of severe hypoglycaemia positively correlated with the presence of peripheral neuropathy, while long duration of diabetes prior to insulin treatment and treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists (ARBs) were associated with reduced risk. C-peptide concentration and HbA1c were not associated with the risk of severe hypoglycaemia. CONCLUSIONS: In this cohort of insulin-treated Type 2 diabetic patients, the incidence of severe hypoglycaemia is higher than reported in most studies, corresponding to about one-third of that in Type 1 diabetes. Impaired hypoglycaemia awareness is the most important risk factor for severe hypoglycaemia.     

Cognitive function, insulin-dependent diabetes and hypoglycaemia.

A series of seven psychometric tests, to evaluate mental concentration and the ability to retain selective attention, lexical fluency, wordlist memorizing and psychomotor speed, was performed on 25 non-diabetic control subjects and 55 insulin-dependent diabetes (IDD) patients of similar social background and professional status. When tested, none of the diabetics was hypoglycaemic and these patients were divided into two groups: Group I: 30 IDD patients unaware of hypoglycaemia, and experiencing frequent and severe episodes of hypoglycaemia. Group II: 25 IDD patients aware of hypoglycaemia. Groups I and II had experienced the disease for the same period of time (17 +/- 13 vs. 14 +/- 11 years, respectively) and they had similar HbA1c levels (7.14 +/- 1.25% vs. 8.6 +/- 1.88%, respectively) and degenerative complications. Compared with the scores of the controls, the Group I scores were lower in four tests: trail-making part A (psychomotor speed; P less than 0.001) and part B (retaining selective attention; P less than 0.01), lexical fluency (P less than 0.01) and Rey auditory-verbal learning test (wordlist learning; P less than 0.05). Group II scores were lower in two tests: trail-making part A (P less than 0.01) and part B (P less than 0.05). In word memorizing, the performance of Group I was inferior to that of Group II (P less than 0.05). In general, these psychometric tests showed that IDD scores were lower than those of the controls, with an average of 67% for Group II and 80% for Group I. Chronic hyperglycaemia and severe hypoglycaemia may have a deleterious effect on cognitive performance. In particular, several severe episodes of hypoglycaemia could be responsible for permanent memory impairment.     

Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes: a population-based study.

AIMS: To ascertain the frequency and identify predictors of self-reported hypoglycaemia in Type 1 and insulin-treated Type 2 diabetes. METHODS: A random sample of 267 people with insulin-treated diabetes were recruited from a population-based diabetes register in Tayside, Scotland. Each subject prospectively recorded the number of mild and severe hypoglycaemic episodes experienced over a 1-month period. Ordinal logistic regression was performed to identify potential predictors of hypoglycaemia. RESULTS: Five hundred and seventy-two hypoglycaemic events were reported by 155 patients. The participants with Type 1 diabetes had a total of 336 hypoglycaemic events with a rate of 42.89 events per patient per year. Of these, nine were severe hypoglycaemic events, with a rate of 1.15 events per patient per year. Participants with insulin-treated Type 2 diabetes experienced a total of 236 hypoglycaemic events with a rate of 16.37 events per patient per year. Of these, five were severe hypoglycaemic events, which would be equivalent to 0.35 events per patient per year. Predictors of hypoglycaemia in Type 1 diabetes were a history of previous hypoglycaemia (P = 0.006) and co-prescribing of any oral drug (P = 0.048). In patients with insulin-treated Type 2 diabetes, a history of previous hypoglycaemia (P < 0.0001) and duration of insulin treatment (P = 0.014) were significant predictors. CONCLUSION: The incidence of self-reported severe hypoglycaemia in insulin-treated Type 2 diabetes is lower than in Type 1 diabetes but does occur more often than previously reported and with sufficient frequency to cause significant morbidity. Duration of insulin treatment is a key predictor of hypoglycaemia in insulin-treated Type 2 diabetes.     

Severe hypoglycaemia in children and adolescents during multiple-dose insulin therapy

Episodes of severe hypoglycaemia, resulting in coma and/or convulsions, were documented in an unselected, population-based group of 376 children and adolescents with Type 1 diabetes mellitus (Type 1 DM) treated at the Aurora Hospital, City of Helsinki. A prospective study in 1994–95 yielded 493 patient-years and a retrospective study in 1990–93, 904 patient-years of data. Of these patients, 77–85 % received insulin in three or more daily doses. During 1990–95, 43 patients had a total of 48 severe hypoglycaemic episodes. For each episode (n = 48), one control Type 1 DM patient who had never experienced any severe hypoglycaemia, matched by age, diabetes duration and puberty, was sought from the study population. Incidence of severe hypoglycaemia was 3.1/100 patient years prospectively and 3.6/100 retrospectively. At the time of the episode, median age was 13.3 (range 2.2–21) years, and median diabetes duration 6.1 (0.5–14.6) years. Rates were similar in different age groups (<6, 6–12.9 and ≥ 13 years). A potential explanation for the hypoglycaemia was found in 79 % of the episodes. Insulin dose was higher (p = 0.04) and HbA_1c lower (p = 0.005) in patients with severe hypoglycaemia than in controls. In conclusion, multiple-dose insulin therapy in young patients with Type 1 DM can be associated with a low rate of severe hypoglycaemia. The majority of such episodes seem to be preventable. © 1998 John Wiley & Sons, Ltd.     

Reversible cognitive deterioration after a single episode of severe hypoglycaemia: a case report.

A case of a male 34-year-old Type 1 diabetic patient who experienced a prolonged severe hypoglycaemic episode is presented. After the hypoglycaemic event, the patient suffered from moderate to severe neuropsychological impairments. On the basis of neuropsychological assessment results, diabetes therapy was modified (less complex insulin regimen, fixed insulin doses and fixed carbohydrate distribution). At a follow-up examination (3 months), presumable complete recovery of cognitive function was observed. This case demonstrates the possible detrimental neuropsychological effects of severe hypoglycaemia, that, in this case, turned out to be reversible. It highlights the clinical implications of impaired cognitive function on self-care and self-management abilities and the usefulness of neuropsychological testing in clinical diabetes care.     

Human insulin: much ado about hypoglycaemia (un)awareness

Summary The biological effects, hypoglycaemic symptoms, endocrine counterregulatory responses and glucose recovery following the injection of purified porcine and human insulin preparations were compared in a number of controlled clinical investigations and prospective clinical trials. In these studies involving healthy volunteers, Type 1 (insulin-dependent) diabetic patients on continuous subcutaneous insulin infusion or intensified conventional insulin therapy and insulin treated Type 2 (non-insulin-dependent) diabetic patients, no differences with regard to biological effects, counterregulatory responses, hypoglycaemic awareness or the long-term incidence of severe hypoglycaemia between porcine and human insulin preparations were identified. These data fail to confirm any specific risk of severe hypoglycaemia attributable to the use of human insulin preparations in the treatment of patients with diabetes mellitus.     

Symptoms of hypoglycaemia in people with diabetes.

The symptoms of hypoglycaemia are fundamental to the early detection and treatment of this side-effect of insulin and oral hypoglycaemic therapy in people with diabetes. The physiology of normal responses to hypoglycaemia is described and the importance of symptoms of hypoglycaemia is discussed in relation to the treatment of diabetes. The symptoms of hypoglycaemia are described in detail. The classification of symptoms is considered and the usefulness of autonomic and neuroglycopenic symptoms for detecting hypoglycaemia is discussed. The many external and internal factors involved in the perception of symptoms are reviewed, and symptoms of hypoglycaemia experienced by people with Type 2 diabetes are addressed. Age-specific differences in the symptoms of hypoglycaemia have been identified, and are important for clinical and research practice, particularly with respect to the development of acquired hypoglycaemia syndromes in people with Type 1 diabetes that can result in impaired awareness of hypoglycaemia. In addition, the routine assessment of hypoglycaemia symptoms in the diabetic clinic is emphasized as an important part of the regular review of people with diabetes who are treated with insulin.     

Attentional functioning is impaired during acute hypoglycaemia in people with Type 1 diabetes.

AIMS: To examine the effects of acute insulin-induced hypoglycaemia on different aspects of attention and on general non-verbal reasoning in people with Type 1 diabetes. METHODS: A hyperinsulinaemic glucose clamp was used to maintain euglycaemia (4.5 mmol/l) or induce hypoglycaemia (2.6 mmol/l) on separate occasions in 16 adults with Type 1 diabetes each of whom were studied on two occasions in a counterbalanced order. During each study condition, the subjects completed parallel tests of cognitive function assessed by the Test of Everyday Attention and the Raven's Progressive Matrices. RESULTS: Hypoglycaemia caused a significant deterioration in tests sensitive to visual and auditory selective attention. During hypoglycaemia, attentional flexibility deteriorated and speed of information processing was delayed. Sustained attention and intelligence scores were preserved during hypoglycaemia. CONCLUSIONS: In people with Type 1 diabetes, hypoglycaemia causes a significant deterioration in attentional abilities, while non-verbal reasoning is preserved. It is likely therefore that many complex cognitive tasks which involve attention will be impaired during moderate hypoglycaemia during everyday life.     

The prevalence of impaired glucose counter-regulation during an insulin-infusion test in insulin-treated diabetic patients prone to severe hypoglycaemia

Summary Among 603 patients over the age of 18, with insulin-treated diabetes mellitus, a questionnaire identified 98 patients who during a 12-month period had experienced severe hypoglycaemia, defined as an event which required the help of another person. Twenty of these patients had repeatedly suffered from such episodes, without any obvious reason, for a period of at least three years. The capacity to counter-regulate a standardized, insulin-infusion test (0.034 U·kg^–1·h^–1 given for 3 h unless severe neuroglucopenia developed) was evaluated in 14 of these patients. In 12, an impaired glucose counter-regulation was registered, defined as blood-glucose values below — 2 SD of healthy subjects. In all but one of these patients, a combined deficiency of glucagon and adrenaline was documented, and was believed to be the likely cause of their inclination towards hypoglycaemia. In patients with severe hypoglycaemia, but not in diabetic patients without severe hypoglycaemia or in healthy subjects, a significant relationship between insulin disappearance and glucose rise was found. It is concluded that in insulin-treated diabetic patients, the prevalence of recurrent attacks of severe hypoglycaemia amounts to about 4%. In such patients, a combined deficiency of adrenaline and glucagon responses to hypoglycaemia is the predominant finding and the disappearance rate of insulin becomes critical for recovery of blood glucose after hypoglycaemia.     

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.