Brian M. Frier

Is type II diabetes associated with an increased risk of cognitive dysfunction? A critical review of published studies.

Type II (non-insulin-dependent) diabetes may be associated with impaired cognitive function. A detailed search of the literature has identified 19 controlled studies in which cognitive function in type II diabetes has been examined. The studies vary widely with respect to the nature of the diabetic populations studied and the psychological tests used. Thirteen studies demonstrated that the diabetic individuals performed more poorly in at least one aspect of cognitive function. The most commonly affected cognitive ability was verbal memory. Psychomotor ability and frontal lobe function were affected less consistently. The remaining six studies showed no differences in cognitive ability between subjects with type II diabetes and nondiabetic control subjects, but none had adequate statistical power to detect a between-group difference in cognitive ability of 0.5 of a standard deviation (a medium effect size). These findings are consistent with type II diabetes being associated with an increased risk of cognitive dysfunction. However, the widespread differences in methodology between the studies should lead to a cautious interpretation of their conclusions. The etiology of any cognitive decrement in type II diabetes is likely to result from an interaction between metabolic abnormalities intrinsic to diabetes, diabetes-specific complications, and other diabetes-related disorders.

Frequency of Severe Hypoglycemia in Patients With Type I Diabetes With Impaired Awareness of Hypoglycemia

OBJECTIVE To determine the frequency of hypoglycemia in patients with type I diabetes and impaired awareness of hypoglycemia by prospective assessment. RESEARCH DESIGN AND METHODS A prospective study was undertaken for 12 months in 60 patients with type I diabetes: 29 had impaired awareness of hypoglycemia and 31 retained normal awareness of hypoglycemia. The two groups of patients were matched for age, age at onset of diabetes, duration of diabetes, and glycemic control. Episodes of severe hypoglycemia were recorded within 24 h of the event and verified where possible by witnesses. RESULTS During the 12 months, 19 (66%) of the patients with impaired awareness had one or more episodes of severe hypoglycemia with an overall incidence of 2.8 episodes · patient–1 ·year–1. By comparison, 8 (26%) of the patients with normal awareness experienced severe hypoglycemia (P < 0.01) with an annual incidence of 0.5 episode · patient–1 · year–1 (P < 0.001). Severe hypoglycemia occurred at different times of the day in the two groups: patients with impaired awareness experienced a greater proportion of episodes during the evening (P = 0.03), and patients with normal awareness experienced a greater proportion in the early morning (P = 0.05). An assessment of fear of hypoglycemia revealed that patients with impaired awareness of hypoglycemia worried more about hypoglycemia than did patients with normal awareness (P = 0.008), but did not modify their behavior accordingly. CONCLUSIONS This prospective evaluation demonstrated that impaired awareness of hypoglycemia predisposes to a sixfold increase in the frequency of severe hypoglycemia, much of which occurred at home during waking hours.

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.

Diabetes and cognitive dysfunction

Cognitive dysfunction in type 1 and type 2 diabetes share many similarities, but important differences do exist. A primary distinguishing feature of type 2 diabetes is that people with this disorder often (but not invariably) do poorly on measures of learning and memory, whereas deficits in these domains are rarely seen in people with type 1 diabetes. Chronic hyperglycaemia and microvascular disease contribute to cognitive dysfunction in both type 1 and type 2 diabetes, and both disorders are associated with mental and motor slowing and decrements of similar magnitude on measures of attention and executive functioning. Additionally, both types are characterised by neural slowing, increased cortical atrophy, microstructural abnormalities in white matter tracts, and similar, but not identical, changes in concentrations of brain neurometabolites. Disconcertingly, the rapid rise in obesity and type 2 diabetes in all age groups might result in a substantial increase in prevalence of diabetes-related cognitive dysfunction.

Frequency of thyroid dysfunction in diabetic patients: value of annual screening.

A randomly selected group of 1310 adult diabetic patients attending a diabetic outpatient clinic received annual screening for thyroid disease, by estimating serum free thyroxine and TSH concentrations. The overall prevalence of thyroid disease was found to be 13.4%, and was highest (31.4%) in Type 1 diabetic females, and lowest in Type 2 diabetic males (6.9%). As a direct result of screening, new thyroid disease was diagnosed in 6.8% (89 patients) of the population screened; the commonest diagnosis was subclinical hypothyroidism (4.8%), followed by hypothyroidism (0.9%), hyperthyroidism 0.5%), and subclinical hyperthyroidism (0.5%). Female patients with Type 1 diabetes had the highest annual risk of developing thyroid disease (12.3%), but all patient groups had a higher incidence of thyroid dysfunction, compared to that reported in the general population. This study suggests that thyroid function should be screened annually in diabetic patients to detect asymptomatic thyroid dysfunction which is increased in frequency in a diabetic population.

Vascular disease and diabetes : is hypoglycaemia an aggravating factor?

Acute hypoglycaemia provokes profound physiological changes affecting the cardiovascular system and several haematological parameters, principally as a consequence of sympatho‐adrenal activation and counter‐regulatory hormonal secretion. Many of these responses have an important role in protecting the brain from neuroglycopenia, through altering regional blood flow and promoting metabolic changes that will restore blood glucose to normal. In healthy young adults the cardiovascular effects are transient and have no obvious detrimental consequences. However, some of the effected changes are potentially pathophysiological and in people with diabetes who have developed endothelial dysfunction, they may have an adverse impact on a vasculature that is already damaged. The acute haemodynamic and haematological changes may increase the risk of localized tissue ischaemia, and major vascular events can certainly be precipitated by acute hypoglycaemia. These include myocardial and cerebral ischaemia and occasionally infarction. Established diabetic retinopathy often deteriorates after strict glycaemic control is instituted, the latter being associated with a threefold increase in frequency of severe hypoglycaemia, and enhanced exposure to mild hypoglycaemia. The possible mechanisms underlying these hypoglycaemia‐induced effects include haemorrheological changes, white cell activation, vasoconstriction, and the release of inflammatory mediators and cytokines. The concept that acute hypoglycaemia could aggravate vascular complications associated with diabetes is discussed in relation to evolving comprehension of the pathogenesis of atherosclerosis and blood vessel disease. Copyright

Frequency and Morbidity of Severe Hypoglycaemia in Insulin‐treated Diabetic Patients

To estimate the frequency and morbidity of insulin‐induced hypoglycaemia, a retrospective survey was undertaken of the frequency of severe hypoglycaemia in 600 randomly selected patients with insulin‐treated diabetes who were attending a large diabetic outpatient clinic in a teaching hospital. The resulting morbidity (hypoglycaemia‐related injuries, convulsions, and road traffic accidents) was ascertained in 302 patients. One hundred and seventy‐five (29.2%) of the 600 patients reported a total of 964 episodes of severe hypoglycaemia in the preceding year, giving an overall frequency for the group of 1.60 episodes patient−1 year−1. The frequency of severe hypoglycaemia which was documented in 544 Type 1 (ketosis prone) diabetic patients was double that observed in a subgroup of 56 Type 2 diabetic patients who were being treated with insulin (1.70 vs 0.73 episodes patient−1 year−1). In the subset of 302 patients, those who had experienced severe hypoglycaemia had greater morbidity associated with an estimated rate of injury of 0.04 injuries person−1 year−1. Twenty (6.6%) patients reported a total of 37 convulsions associated with hypoglycaemia, 5 of which had occurred in the preceding year (0.02 convulsions person−1 year−1). Five patients reported road traffic accidents in the preceding year which had been caused by hypoglycaemia. The only reliable predictors of severe hypoglycaemia were a history of previous severe hypoglycaemia (p < 0.001), a history of hypoglycaemia‐related injury (p < 0.001) or convulsion (p < 0.001), and the duration of insulin therapy (p < 0.001). Those patients with a history of severe hypoglycaemia had been treated with insulin for longer (17.4 vs 14.3 years, p < 0.02) and tended to have a lower mean glycated haemoglobin concentration. This study confirmed that severe hypoglycaemia is common and demonstrated that it is associated with significant morbidity in a conventionally treated, insulin‐requiring, diabetic population. The multifactorial aetiology of severe hypoglycaemia confounds attempts to predict the individual patient ‘at risk’.

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

SummaryTo 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.

Partitioning the symptoms of hypoglycaemia using multi-sample confirmatory factor analysis.

SummaryThe allocation of hypoglycaemic symptoms to autonomie or neuroglycopenic groups tends to occur on an a priori basis. In view of the practical need for clear symptom markers of hypoglycaemia more scientific approaches must be pursued. Substantial evidence is presented from two large scale studies we performed which support a three factor model of hypoglycaemic symptomatology, based on the statistical associations discovered among symptoms reported by diabetic patients. Study 1 involved 295 insulin-treated outpatients and found that 11 key hypoglycaemic symptoms segregated into three clear factors: autonomie (sweating, palpitation, shaking and hunger) neuroglycopenic (confusion, drowsiness, odd behaviour, speech difficulty and incoordination), and malaise (nausea and headache). The three factors were validated on a separate group of 303 insulin-treated diabetic out-patients. Confirmatory factor analyses showed that the three factor model was the optimal model for explaining symptom covariance in each group. A multi-sample confirmatory factor analysis tested the rigorous assumptions that the relative loadings of symptoms on factors across groups were equal, and that the residual variance for each symptom was identical across groups. These assumptions were successful, indicating that the three factor model was replicated in detail across these two large samples. It is suggested that the results indicate valid groupings of symptoms that may be used in future research and in clinical practice.

Hypoglycemia and Cardiovascular Risks

Although hypoglycemia is the most common side effect of insulin therapy in diabetes and its morbidity is well known, for many years, the potentially life-threatening effects of hypoglycemia on the cardiovascular (CV) system have either been overlooked or have been dismissed as inconsequential to people with insulin-treated type 2 diabetes. This scenario may possibly be a consequence of the persisting misconception that this population is seldom exposed to severe hypoglycemia, defined as any episode that requires external assistance for recovery, whereas self-treated events are classified as “mild” (1). This myth was firmly repudiated by the findings of the large prospective study by the U.K. Hypoglycemia Study Group (2), which demonstrated that severe hypoglycemia is a common problem in insulin-treated type 2 diabetes and that the incidence increases with duration of insulin therapy. However, evidence for CV morbidity associated with hypoglycemia has been predominantly hypothetical and anecdotal (1,3). The potential dangers of intensive treatment regimens and strict glycemic control in people with type 2 diabetes who have CV disease (CVD) have now been highlighted by the disconcerting outcomes of recent studies (4–6), in which hypoglycemia was implicated in the excess mortality that was observed in some of these trials. It is therefore timely to review the effects of hypoglycemia on the CV system, how this major metabolic stress could precipitate major vascular events such as myocardial infarction and stroke, and its potential role in these recent clinical studies. In the adult human, acute hypoglycemia causes pronounced physiological responses as a consequence of autonomic activation, principally of the sympatho-adrenal system, and results in end-organ stimulation and a profuse release of epinephrine (adrenaline). This profound autonomic stimulus provokes hemodynamic changes, the important consequences of which are to maintain the supply of glucose to the brain and promote the hepatic …