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.     

Lower levels of circulating IGF‐I in Type 1 diabetic women with frequent severe hypoglycaemia during pregnancy

Aims Severe hypoglycaemia is a significant problem in pregnant women with Type 1 diabetes. We explored whether frequent severe hypoglycaemia during pregnancy in women with Type 1 diabetes is related to placental growth hormone (GH) and insulin‐like growth factor I (IGF‐I) levels. Methods A prospective, observational study of 107 consecutive pregnant women with Type 1 diabetes. Blood samples were drawn for IGF‐I and placental GH analyses at 8, 14, 21, 27 and 33 weeks. Severe hypoglycaemic events were reported within 24 h. Results Eleven women (10%) experienced frequent severe hypoglycaemia (≥ 5 events), accounting for 60% of all events. Throughout pregnancy, IGF‐I levels were 25% lower in these women (P < 0.005) compared with the remaining women, despite similar placental GH levels. Eighty per cent of the severe hypoglycaemic events occurred before 20 weeks when IGF‐I levels were at their lowest. This finding was not explained by differences in insulin dose, median plasma glucose levels or glycated haemoglobin. History of severe hypoglycaemia the year preceding pregnancy and impaired hypoglycaemia awareness—being the only predictors of frequent severe hypoglycaemia in a logistic regression analysis—were not associated with IGF‐I or placental GH levels at 8 weeks. Conclusions In women with Type 1 diabetes experiencing frequent severe hypoglycaemia during pregnancy, IGF‐I levels are significantly lower compared with the remaining women despite similar placental GH levels. IGF‐I levels are lowest in early pregnancy where the incidence of severe hypoglycaemia is highest. IGF‐I may be a novel factor of interest in the investigation of severe hypoglycaemia in patients with Type 1 diabetes.     

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.     

Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes

Aims Impaired awareness of hypoglycaemia (IAH) is thought to affect approximately 25% of people with Type 1 diabetes. While this estimate was based on retrospective information from patients in several small studies performed several years ago, validated methods of assessment have not been used in a large hospital clinic-based population to ascertain the prevalence in the present era. Methods Five hundred and eighteen people with Type 1 diabetes were recruited by random selection over a 2-year period. Participants completed a questionnaire documenting baseline characteristics and assessment of their awareness status using the method described by Gold et al. The number of episodes of severe hypoglycaemia they had experienced in the preceding year was recorded retrospectively. Results IAH was present in 19.5% of the cohort. Compared to those with normal awareness of hypoglycaemia, those with IAH were significantly older [mean ± standard deviation (sd ); 39.3 ± 12.9 vs. 45.9 ± 13.5 years, P < 0.001], had a longer duration of diabetes [median (interquartile range) 14 (8–22) vs. 23 (14–32) years, P < 0.001], and had a six-fold higher frequency of severe hypoglycaemia in the previous year [0.38 ± 1.04 (25th–75th centile 0–0) vs. 2.36 ± 4.81 (25th–75th centile 0–2) episodes per person, P < 0.001]. Conclusions The present survey of a large hospital-based clinic population has confirmed that a significant proportion of people with Type 1 diabetes (19.5%) continue to have IAH. Despite improvements in insulin therapies, intensification of insulin regimens and innovative patient education, the prevalence of IAH remains high in Type 1 diabetes.     

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.     

Hypoglycaemia and driving in people with insulin-treated diabetes: adherence to recommendations for avoidance.

BACKGROUND: Hypoglycaemia impairs driving performance, so drivers with insulin-treated diabetes should try to avoid hypoglycaemia when driving, and treat it effectively if it occurs. It is not known how many insulin-treated drivers are familiar with, or adhere to, recommended safe practice. METHODS: We surveyed a representative sample of 202 current drivers with insulin-treated diabetes (115 with Type 1 diabetes), using a structured questionnaire. Data were obtained on driving history, estimated frequency of hypoglycaemia, and measures taken to avoid and treat hypoglycaemia when driving. RESULTS: The licensing authority (DVLA) and motor insurance company had been informed by almost all participants. Sixty-four participants (31.7%) had experienced hypoglycaemia while driving, and 27 (13.4%) reported that this had occurred within the preceding year. A minimum blood glucose level of 4.0 mmol/l or higher was considered necessary for driving by 151 drivers (74.8%), and 176 (87.1%) reported always keeping carbohydrate in their vehicle. However, 77 (38.1%) reported never carrying a glucose meter when driving, and 121 (59.9%) that they never test blood glucose before driving, or test only if symptomatic of hypoglycaemia. Most participants (89%) would stop driving to treat hypoglycaemia and would not resume driving immediately, although only 28 (13.9%) would wait longer than 30 min. Almost half of participants were failing to observe at least one essential aspect of safe driving. CONCLUSIONS: Compliance with statutory requirements to inform the licensing authority and motor insurer is good, and drivers' perceptions of the minimum safe blood glucose level for driving are encouraging. However, most drivers rely on symptoms to detect hypoglycaemia while driving, and seldom test blood glucose before driving. Patient education should emphasize the role of blood glucose monitoring in relation to driving, and highlight the potential deterioration in driving performance when blood glucose falls below 4.0 mmol/l.     

A Structural Equation Model for Predictors of Severe Hypoglycaemia in Patients with Insulin-dependent Diabetes Mellitus

There are several predictors of severe hypoglycaemia in patients with insulin-dependent diabetes mellitus (IDDM), many of which are correlated. To assess factors which may be predictive of severe hypoglycaemia, structural equation modelling was used to test specific hypotheses using prospective data. Sixty patients with insulin-dependent diabetes mellitus (IDDM) were studied prospectively for one year during which any episodes of severe hypoglycaemia, asymptomatic biochemical hypoglycaemia, and glycaemic control were documented. Half the patients reported hypoglycaemia unawareness and they were matched for HbA₁ with the rest. Baseline measurements included symptomatic awareness of hypoglycaemia, fear of hypoglycaemia, previous history of hypoglycaemia, glycaemic control, and peripheral autonomic function. Formal structural equation modelling was performed on these variables and a model was constructed that expressed the putative causal associations among the variables. The frequency of severe hypoglycaemia (measured prospectively) correlated significantly with duration of diabetes, awareness of hypoglycaemia, patient’s age, history of previous severe hypoglycaemia and autonomic function scores. HbA₁ did not show significant correlation, possibly because of the narrow range in the subject population. In the structural equation modelling exercise, at least 18 % of the variance of severe hypoglycaemia, measured prospectively, was accounted for by a history of severe hypoglycaemia, the state of awareness of hypoglycaemia, and the autonomic function score. Over 25 % of the variance of ‘worry’ on the hypoglycaemia fear scale was accounted for by a history of previous severe hypoglycaemia. An assessment of multiple risk factors for hypoglycaemia may be of value in advising individual patients about their diabetes care. © 1997 by John Wiley & Sons, Ltd.     

Classification of symptoms of hypoglycaemia in insulin-treated diabetic patients using factor analysis: relationship to hypoglycaemia unawareness.

The allocation of some symptoms of acute hypoglycaemia to autonomic and neuroglycopenic groups has proved problematical, with possible misinterpretation of studies which depend upon the use of diverse symptom questionnaires. Two hundred and ninety-five randomly selected insulin-treated diabetic patients were asked to report the symptoms which they usually experienced and believed to be caused by hypoglycaemia. Sweating, trembling, inability to concentrate, weakness, hunger and blurred vision were the most frequently reported symptoms. To classify symptoms of hypoglycaemia objectively, Factor Analysis was used to identify related symptoms which grouped together. This resulted in five groups or clusters of symptoms, four of which could be denominated as groups with a presumed common aetiology, and were labelled: 'neuroglycopenic', 'general malaise', 'autonomic', 'motor dysfunction', and 'sensory dysfunction'. The groups of symptoms derived by Factor Analysis were assessed in relation to partial or absent symptomatic awareness of hypoglycaemia based on historical evidence from the 295 insulin-treated diabetic patients. Neuroglycopenic symptoms were reported more commonly by the patients who had reported partial awareness of hypoglycaemia (number of symptoms 2.6 +/- 1.8 (mean +/- SD] than by the patients who had reported normal hypoglycaemia awareness (1.4 +/- 1.5 symptoms) (p less than 0.05). By contrast autonomic symptoms were reported less frequently by the patients who had reported absent hypoglycaemia awareness (1.3 +/- 1.4 symptoms) than by those with normal awareness (2.2 +/- 1.4 symptoms) (p less than 0.05), which was similar to the number of autonomic symptoms reported by the patients who had partial hypoglycaemia awareness (2.1 +/- 1.3 symptoms).     

Levofloxacin‐associated hypoglycaemia complicated by pontine myelinolysis and quadriplegia

Background Central pontine myelinolysis (CPM) usually presents in chronic alcoholics and in patients in whom hyponatraemia has been corrected rapidly. However, CPM may occur in other clinical circumstances, including patients with severe hypoglycaemia. We describe the occurrence of CPM and quadriplegia in a patient who experienced fluoroquinolone‐associated severe hypoglycaemia. Case report A 63‐year‐old man with Type 2 diabetes mellitus was admitted to hospital for resection of a large liposarcoma. Renal‐dose levofloxacin was utilized as part of an antimicrobial regimen to treat post‐operative peritonitis. On days 6–8 of levofloxacin therapy, the patient experienced recurrent hypoglycaemia despite total parenteral nutrition, 10% dextrose containing fluids and cessation of insulin therapy 3 days prior to the first hypoglycaemic episode. Hypoglycaemia resolved within 24 h of stopping levofloxacin. After a final and severe hypoglycaemic event, the patient developed quadriplegia and tonic left deviation of gaze. Magnetic resonance imaging revealed a high‐intensity lesion in the central pons consistent with CPM. Conclusions Fluoroquinolones should be considered as a potential cause of hypoglycaemia. Severe hypoglycaemia has the potential to cause white matter lesions in the pons. Putative mechanisms include failure of membrane ion channels, oligodendrocyte apoptosis and oxidative stress of glucose reperfusion. Fluoroquinolone‐associated hypoglycaemia and hypoglycaemia‐induced quadriplegia are both rare and we believe this is the first case report linking the two events.     

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.     

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.     

Prospective assessment of severe hypoglycaemia in diabetic children and adolescents with impaired and normal awareness of hypoglycaemia

Summary To establish whether impaired hypoglycaemic awareness is associated with increased rate of severe hypoglycaemia and to assess clinical predictors of severe episodes without warning symptoms a prospective study of 130 insulin-dependent diabetic children and adolescents was undertaken for 1 year. Using a structured questionnaire, 48 patients reported impaired awareness and 82 reported normal awareness of hypoglycaemia at baseline of the study. The two groups did not differ regarding clinical and metabolic characteristics. Episodes of severe hypoglycaemia were recorded for 1 year. The rate of severe hypoglycaemia was higher in the group with impaired awareness than in the group with normal awareness (p < 0.0001). Of the severe hypoglycaemic episodes, 34.0 % developed without warning symptoms. Patients with impaired awareness experienced more severe episodes without warning symptoms than those with normal awareness (p = 0.0054). Severe hypoglycaemia occurred more frequently in patients with impaired awareness aged 6 years and less (p = 0.0041) than in older counterparts. Impaired awareness reported at baseline [adjusted odds ratio (OR): 5.8; p = 0.0021], age 6 years or less (3.4; p = 0.0121), previous severe episode (4.8; p = 0.0043) and more than 5 % of home blood glucose readings 3.3 mmol/l or less in the preceding month (4.2; p = 0.0211) proved to be independently predictive of severe hypoglycaemic events without warning symptoms. In conclusion, impaired hypoglycaemic awareness is associated with an increased rate of severe hypoglycaemia in diabetic children and adolescents. One third of severe episodes developed without warning symptoms. Impaired awareness, young age and recent biochemical or severe hypoglycaemias are independent risk factors for such episodes. Avoidance of hypoglycaemia should be a priority in pre-school children with diabetes. [Diabetologia (1998) 41: 898–903] Received: 15 December 1997 and in revised form: 5 March 1998     

The effect of an education programme (HyPOS) to treat hypoglycaemia problems in patients with type 1 diabetes

BACKGROUND: In a randomized, prospective multi-centre trial, the effect of a specific training programme (HyPOS) for patients with hypoglycaemia problems was compared with a control group (CG), receiving a standardized education programme aiming at avoidance of hypoglycaemia by optimization of insulin therapy. METHODS: A total of 164 type 1 diabetes patients (age 46.0 +/- 12.5 yrs, HbA(1c) 7.3 +/- 1.0%, 50% male) were randomized. Hypoglycaemia awareness was measured by the hypoglycaemia awareness questionnaire (HAQ) and by a visual analogue scale (VAS). There were no baseline differences. RESULTS: After a 6-month follow-up, hypoglycaemia awareness significantly improved in HyPOS compared to that in the CG (Delta HAQ 0.7 [95% CL 0.1-1.2], p = 0.024, Delta VAS 0.8 [95% CL 0.2 - 1.2], p = 0.015). In HyPOS, the threshold for detection of low blood glucose (Delta 0.2 mmol/L [95% CL 0.03 - 0.04], p = 0.02) and the treatment of low blood glucose (Delta 4.6 g [95% CL 1.6 - 7.6], p = 0.03) increased significantly. The number of undetected hypogylcaemic episodes (Delta - 1.4 episodes per week [95% CL 0.4-2.5], p = 0.01) and the rate of mild hypoglycaemia dropped significantly in HyPOS (Delta 2.1% [95% CL 0.5-5.3], p = 0.015). The numbers of severe (Delta 0.3 events per patient per year [95% CL - 0.04-1.0], p = 0.037) and very severe hypoglycaemic episodes (Delta 0.3 events per patient per year [95% CL - 0.1-0.7], p = 0.09) were lower in HyPOS, but these differences were not significant. CONCLUSION: Compared to the CG, HyPOS demonstrates additional benefits in terms of improving impaired hypoglycaemia awareness, reducing mild hypoglycaemia, detecting low blood glucose, and treating low blood glucose.     

Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection

BACKGROUND: Differences between studies in rates of severe hypoglycaemia in type 1 diabetic cohorts are common and poorly understood. The purpose of this study was to assess the frequency of severe hypoglycaemia in unselected patients treated in different secondary care centres and to evaluate the influence of risk markers, clinical setting and selection. METHODS: Cross-sectional Danish-British multicentre survey of 1076 consecutive adult patients with clinical type 1 diabetes who completed a detailed questionnaire on hypoglycaemia and related issues. Key variable was the self-reported rate of severe hypoglycaemia during the preceding year. RESULTS: The overall rate of severe hypoglycaemia in the preceding year was 1.3 episodes/patient-year and episodes were reported by 36.7% of subjects. The distribution was highly skewed with 5% of subjects accounting for 54% of all episodes. There were no significant differences between countries or centres. Reduced hypoglycaemia awareness, peripheral neuropathy and smoking were the only significant risk markers of severe hypoglycaemia in a stepwise multivariate analysis. In a subgroup selected to be similar to the Diabetes Control and Complications Trial (DCCT) cohort, the rate of severe hypoglycaemia was 0.35 episodes/patient-year and only retinopathy was a significant risk marker together with state of awareness. CONCLUSION: Severe hypoglycaemia remains a significant clinical problem in type 1 diabetes. The rate of severe hypoglycaemia and the influence of risk markers are very sensitive to selection and differences in rates between centres or studies seem to disappear after correction for differences in clinical characteristics. Smoking is a novel overall risk marker of severe hypoglycaemia.     

Severe hypoglycaemia in type 1 diabetes mellitus: underlying drivers and potential strategies for successful prevention

Hypoglycaemia remains an over‐riding factor limiting optimal glycaemic control in type 1 diabetes. Severe hypoglycaemia is prevalent in almost half of those with long‐duration diabetes and is one of the most feared diabetes‐related complications. In this review, we present an overview of the increasing body of literature seeking to elucidate the underlying pathophysiology of severe hypoglycaemia and the limited evidence behind the strategies employed to prevent episodes. Drivers of severe hypoglycaemia including impaired counter‐regulation, hypoglycaemia‐associated autonomic failure, psychosocial and behavioural factors and neuroimaging correlates are discussed. Treatment strategies encompassing structured education, insulin analogue regimens, continuous subcutaneous insulin infusion pumps, continuous glucose sensing and beta‐cell replacement therapies have been employed, yet there is little randomized controlled trial evidence demonstrating effectiveness of new technologies in reducing severe hypoglycaemia. Optimally designed interventional trials evaluating these existing technologies and using modern methods of teaching patients flexible insulin use within structured education programmes with the specific goal of preventing severe hypoglycaemia are required. Individuals at high risk need to be monitored with meticulous collection of data on awareness, as well as frequency and severity of all hypoglycaemic episodes. Copyright © 2013 John Wiley & Sons, Ltd.     

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.     

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 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’.     

Hypoglycaemia and gastric emptying

Hypoglycaemia is arguably the most important complication of insulin therapy in type 1 and type 2 diabetes. Counter-regulation of hypoglycaemia is dependent on autonomic function and frequent hypoglycaemia may lead to reductions in both autonomic warning signals and the catecholamine response, the so-called “impaired awareness of hypoglycaemia”. It is now appreciated that gastric emptying is a major determinant of the glycaemic response to carbohydrate-containing meals in both health and diabetes, that disordered (especially delayed) gastric emptying occurs frequently in diabetes, and that acute hypoglycaemia accelerates gastric emptying substantially. However, the potential relevance of gastric emptying to the predisposition to, and counter-regulation of, hypoglycaemia has received little attention. In insulin-treated patients, the rate of gastric emptying influences the timing of the postprandial insulin requirement, and gastroparesis is likely to predispose to postprandial hypoglycaemia. Conversely, the marked acceleration of gastric emptying induced by hypoglycaemia probably represents an important counter-regulatory response to increase the rate of carbohydrate absorption. This review summarizes the current knowledge of the inter-relationships between hypoglycaemia and gastric emptying, with a focus on clinical implications.