To describe potential factors influencing reporting of severe hypoglycemia in adult patients with type 1 diabetes and to analyze their effect on reported rates of severe hypoglycemia.

Reported rates of severe hypoglycemia defined as need for third party assistance vary between 0.3-3.0 events per patient-year in unselected cohorts, corresponding to a yearly prevalence range of 10-53%. When defined as need for parenteral therapy with glucose or glucagon or need for admission to an emergency unit or hospitalization, incidence and prevalence rates of severe hypoglycemia are 0.02-0.5 events per patient-year and 1-29%, respectively. When subjects with recurrent severe hypoglycemia in the past or suffering from impaired hypoglycemia awareness are excluded from participation in studies, lower rates are reported. Studies applying anonymous reporting or reporting by partners report higher rates of severe hypoglycemia. There is a large variation between studies reporting incidence and prevalence of severe hypoglycemia in patients with type 1 diabetes, mainly explained by definition of severity, methods of reporting, and patient selection. These findings call for consensus about hypoglycemia definition and reporting in future research.

The goal of this pilot study was to assess the effects of acute hypoglycemia on retinal function and contrast sensitivity in individuals with and without diabetes. Hyperinsulinemic hypoglycemic and euglycemic clamp procedures were performed in subjects without diabetes (n=7) and with controlled type 1 diabetes (n=5). Mean age was 28 years, and none had retinal disease. During euglycemia (glucose 95-110 mg/dl) and acute hypoglycemia (glucose 50-55 mg/dl), contrast sensitivity was measured and spatial retinal responses were recorded with multifocal electroretinograms (mfERG), a rapid technique for mapping sensitivity from the foveal, macular and peripheral areas of the retina. During hypoglycemia, retinal responses (mfERG P1 wave) were decreased in both type 1 diabetes subjects and subjects without diabetes. The dominant effect was in the amplitude of the responses in the central macular retina, not in their temporal properties. Responses from the central region, central 10(0), were on average 1.8-fold lower than those from the periphery for both groups. All diabetes subjects and 3/7 without diabetes reported central scotoma. Decreases in mfERG amplitude were accompanied by decreases in contrast sensitivity. These changes were immediately reversed with the restoration of euglycemia. Overall, this study demonstrates that the acute effects of hypoglycemia in the human eye predominantly involve central vision, and these visual effects originate, at least in part, in the retina. The association between low blood glucose levels and impaired central vision underscores the importance of avoiding when possible and promptly treating hypoglycemia, particularly in individuals with diabetes.

Electrocardiographic T wave peak-to-end interval (TpTe) is one parameter of T wave morphology, which contains indicators for hypoglycaemia. This paper shows the corrected TpTe (TpTe(c)) interval as one of the inputs contributing to detect hypoglycaemia. Support vector machine (SVM) and fuzzy support vector machine (FSVM) utilizing radial basis function (RBF) are used as the classification methods in this paper. By comparing with the classification systems using inputs of corrected QT interval (QT(c)) and heart rate only, the results indicate that the inclusion of TpTec in combination with QTc and heart rate performs better in the detection of hypoglycaemia in terms of sensitivity, specificity and accuracy.

In a one-year prospective study in insulin-treated diabetics, 61 episodes of severe hypoglycemia demanding medical assistance were registered in 46 patients. The incidence of severe hypoglycemia was estimated at 0.07 per patient and year. Mean age (50 +/- 16.9 yr), diabetes duration (19 +/- 11.6 yr), HbAlc (7.8 +/- 1.8%) and daily insulin dose (0.63 +/- 0.23 IU/kg) in these patients (SH group) did not differ from a control group matched for sex and age. However, the patients in the SH group were treated with relatively less short-acting insulin than the patients in the control group (25 +/- 13.8% vs. 39 +/- 24.5%; p less than 0.01). This finding may indicate that multiple injection therapy with a higher relative amount of short-acting insulin could reduce the risk of severe hypoglycemia, provided the metabolic control is unaltered.

The main disadvantage of intensive treatment in the Diabetes Control and Complications Trial (DCCT) was an increased risk of hypoglycaemia that was not explained by the difference in HbA(1c) values alone. This study re-analysed DCCT data to establish whether mean blood glucose (MBG) and/or glucose variability add to the predictive value of HbA(1c) for hypoglycaemia risk in type 1 diabetes.

The times to first and subsequent severe hypoglycaemic events were compared with MBG, HbA(1c) and within-day SD of blood glucose using Cox regression after adjusting for other known risk factors for hypoglycaemia.

On its own, the incidence of time to first hypoglycaemic event increased 1.05-fold for each 1 mmol/l decrease in MBG and 1.07-fold for every 1 mmol/l increase in glucose SD. MBG and SD of blood glucose also both added to the ability of HbA(1c) to predict repeated hypoglycaemic events: after adjusting for HbA(1c), a 1 mmol/l increase in SD was associated with a 1.09-fold increased risk of a first event, increasing to a 1.12-fold risk of a fifth event. A 1 mmol/l fall in MBG added a constant 1.02-1.03-fold risk of repeated events. Daytime events were predicted more accurately than nocturnal episodes.

This study has established that HbA(1c), MBG and glucose variability measurements each have an independent role in determining an individual's risk of hypoglycaemia in type 1 diabetes. All three aspects of glycaemic assessment should thus be considered in patients in whom hypoglycaemia is a real or potential problem.

Untreated diabetic rats show impaired counterregulation against hypoglycemia. The blunted epinephrine responses are associated with reduced adrenomedullary tyrosine hydroxylase (TH) mRNA levels. Recurrent hypoglycemia further impairs epinephrine counterregulation and is also associated with reduced phenylethanolamine N-methyltransferase mRNA. This study investigated the adaptations underlying impaired counterregulation in insulin-treated diabetic rats, a more clinically relevant model. We studied the effects of insulin treatment on counterregulatory hormones and adrenal catecholamine-synthesizing enzymes and adaptations after recurrent hypoglycemia. Groups included: normal; diabetic, insulin-treated for 3 wk (DI); and insulin-treated diabetic exposed to seven episodes (over 4 d) of hyperinsulinemic-hypoglycemia (DI-hypo) or hyperinsulinemic-hyperglycemia (DI-hyper). DI-hyper rats differentiated the effects of hyperinsulinemia from those of hypoglycemia. On d 5, rats from all groups were assessed for adrenal catecholamine-synthesizing enzyme levels or underwent hypoglycemic clamps to examine counterregulatory responses. Despite insulin treatment, fasting corticosterone levels remained increased, and corticosterone responses to hypoglycemia were impaired in DI rats. However, glucagon, epinephrine, norepinephrine, and ACTH counterregulatory defects were prevented. Recurrent hypoglycemia in DI-hypo rats blunted corticosterone but, surprisingly, not epinephrine responses. Norepinephrine and ACTH responses also were not impaired, whereas glucagon counterregulation was reduced due to repeated hyperinsulinemia. Insulin treatment prevented decreases in basal TH protein and increased PNMT and dopamine beta-hydroxylase protein. DI-hypo rats showed increases in TH, PNMT, and dopamine beta-hydroxylase. We conclude that insulin treatment of diabetic rats protects against most counterregulatory defects but not elevated fasting corticosterone and decreased corticosterone counterregulation. Protection against epinephrine defects, both without and with antecedent hypoglycemia, is associated with enhancement of adrenal catecholamine-synthesizing enzyme levels.

Epinephrine, norepinephrine, and corticosterone responses to hypoglycemia are impaired in diabetic rats. Recurrent hypoglycemia further diminishes epinephrine responses. This study examined the sympathoadrenal system and hypothalamo-pituitary-adrenal axis for molecular adaptations underlying these defects. Groups were normal (N) and diabetic (D) rats and diabetic rats exposed to 4 days of 2 episodes/day of hyperinsulinemic hypoglycemia (D-hypo) or hyperinsulinemic hyperglycemia (D-hyper). D-hypo and D-hyper rats differentiated effects of hypoglycemia and hyperinsulinemia. Adrenal tyrosine hydroxylase (TH) mRNA was reduced (P < 0.05 vs. N) 25% in all diabetic groups. Remarkably, mRNA for phenylethanolamine N-methyltransferase (PNMT), which converts norepinephrine to epinephrine, was reduced (P < 0.05 vs. all) 40% only in D-hypo rats. Paradoxically, dopamine beta-hydroxylase mRNA was elevated (P < 0.05 vs. D, D-hyper) in D-hypo rats. Hippocampal mineralocorticoid receptor (MR) mRNA was increased (P < 0.05 vs. N) in all diabetic groups. Hippocampal glucocorticoid receptor (GR), hypothalamic paraventricular nucleus (PVN) GR and corticotropin-releasing hormone (CRH), and pituitary GR and proopiomelanocortin (POMC) mRNA levels did not differ. We conclude that blunted corticosterone responses to hypoglycemia in diabetic rats are not due to altered basal expression of GR, CRH, and POMC in the hippocampus, PVN, and pituitary. The corticosterone defect also does not appear to be due to increased hippocampal MR, since we have reported normalized corticosterone responses in D-hypo and D-hyper rats. Furthermore, impaired epinephrine counterregulation in diabetes is associated with reduced adrenal TH mRNA, whereas the additional epinephrine defect after recurrent hypoglycemia is associated with decreases in both TH and PNMT mRNA.

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.

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.

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.

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.

To propose a strategy, applicable on general hospital wards, for prevention of hypoglycemia in hospitalized patients.

Although the mortality rate among hospitalized patients with hypoglycemia has been shown to be 22.2 to 27% in series that included patients with diabetes, some investigators have shown that hypoglycemia is not an independent predictor of mortality. Outside the critical care setting, the comparative risks of hyperglycemia and hypoglycemia and the relationship of hospital hypoglycemia to intensification of glycemic control have not been determined. The reported incidence of hospital hypoglycemia ranges from 1.2% for hospitalized adults to 20% for nonpregnant patients with diabetes admitted without a metabolic emergency. Among patients receiving antihyperglycemic therapy, the literature describes precipitating events--usually a sudden change of caloric exposure-- and predisposing conditions for hypoglycemic episodes.

Hospital hypoglycemia is predictable, and it is preventable by measures other than undertreatment of hyperglycemia. Physician orders for antihyperglycemic therapy should be written and, if necessary, be revised so as to respond to the presence of predisposing conditions for hypoglycemia. A ward-based protocol or hospital-wide policy should establish the appropriate response to triggering events. Within the time frame of action of previously administered antihyperglycemic drugs (after abrupt interruption of caloric exposure), the threshold for preventive intravenous administration of dextrose is a glucose concentration of 120 mg/dL.

Hypoglycemia is a common complication of insulin therapy, particularly in the young. For children and adolescents with diabetes, the risk of hypoglycemia may not only prevent optimal glycemic control but can also add significantly to the psychosocial burden of the disease. Recently, surveys employing prospective monitoring techniques have allowed more precise information to be gained about rates of hypoglycemia, its clinical associations, and the impact of new therapies and technologies. A number of reports have estimated rates of hypoglycemic comas and convulsions to be approximately 20 events per 100 patient years in children on current conventional therapy. There is evidence that the introduction of new analog short- and longer-acting insulins and the more widespread use of continuous subcutaneous infusion therapies may allow improvements in glycemic control to occur without the usual increased rate of severe hypoglycemic episodes. The use of glucose sensor technology has brought into focus the widespread occurrence of asymptomatic hypoglycemia. Asymptomatic hypoglycemia has long been recognized, particularly at night, when the combination of excessive insulin action and suppressed counter-regulatory hormone responses put children at special risk of hypoglycemia. Hypoglycemia unawareness is common in the young and is associated with an increased risk of severe hypoglycemia. Whether episodes of severe hypoglycemia have long-term consequences is controversial. Early studies suggesting that the developing brain is sensitive to permanent neurological damage as a result of hypoglycemia have not been confirmed in more recent reports. Many studies have not found convincing evidence of neurological sequelae of the hypoglycemic events that are an inevitable complication of insulin therapy. The question, however, remains under active investigation. Continued prospective monitoring of hypoglycemia rates and consequences has become an essential component of diabetes management.

To determine the risk of frequent and severe hypoglycemia and the associated demographic and clinical risk factors.

Demographic and diabetes self-management factors were measured in 415 subjects followed prospectively for 4-6.5 years of type 1 diabetes duration as participants in a population-based incident cohort. Blood samples were collected up to three times yearly to test glycosylated hemoglobin (GHb) levels. Reports of frequent (2-4 times/week) and severe (lost consciousness) hypoglycemia as well as other diabetes self-management data were collected by questionnaires.

Frequent hypoglycemia was common (33 and 35% of participants reported this on the 4- and 6.5-year questionnaires, respectively), whereas severe hypoglycemia occurred much less often. Better glycemic control (odds ratio [OR] 1.3 per 2% decrease in GHb, 95% CI 1.1-1.5) and more frequent self-monitored blood glucose (1.5 per blood glucose check, 1.3-1.7) were independently related to frequent hypoglycemia. The association of frequent hypoglycemia with intensive insulin therapy increased with age. Better glycemic control (1.5 per 2% decrease in GHb, 1.2-2.0) and older age were related to severe hypoglycemic reactions. No sociodemographic factors other than age increased the risk of hypoglycemia.

Frequent hypoglycemia was common in a population representing the full range of glycemic control in the community. Intensive insulin management and blood glucose monitoring independently predicted frequent but not severe hypoglycemia. This information may be useful for updating patients such that minor changes in diabetes management might decrease the daily burden of this condition while maintaining intensive insulin therapy.

Hypoglycemia may reach forensic relevance concerning the psychophysical ability of running a car and with respect to a possible imputability. Our retrospective study included anamnesis and clinical symptoms observed in drivers with impaired performance to point out correlations between biochemical parameters and the actual course of the disease and its sequelae on roadworthiness. Clinical-biochemical estimations were performed on glucose, lactic acid and ethanol including a toxicological screening. It is proposed to utilize the estimation of glucose and lactic acid (the so-called combined value) in blood samples taken on behalf of the police as an important hint to the actual state of glucose metabolism. The anamnesis and the symptomatology may complete the biochemical analyses.

The drugs used to treat diabetes mellitus are diverse and involve several classes. However, these drugs can be roughly separated into hypoglycaemic agents, such as insulin and the sulphonylureas, and antihyperglycaemic agents, such as the biguanides, the alpha-glucosidase inhibitors and troglitazone. Reports of insulin overdose are rare. The major effects of insulin overdose are secondary to the insult to the CNS produced by hypoglycaemia. The mainstay of insulin overdose management is glucose replacement therapy. Sulphonylureas are the most commonly used oral antihyperglycaemic agents in the management of type 2 (non-insulin-dependent; NIDDM) diabetes mellitus. Sulphonylureas primarily cause serum glucose reduction by stimulating the release of preformed insulin from the pancreatic islets. The mainstay of sulphonylurea overdose management is glucose replacement therapy, and in severe cases, reduction of insulin release. In the large majority of patients intravenous glucose supplementation will be sufficient to maintain euglycaemia. Repaglinide, a meglitinide analogue, is a new nonsulphonylurea oral hypoglycaemic agent. In overdose, this drug may produce prolonged hypoglycaemia similar to the sulphonylureas. The primary problem with biguanide overdose is the potential for lactic acidosis. The management of biguanide overdose is largely supportive and directed at correcting the metabolic acidosis along with associated complications. The alpha-glucosidase inhibitors, acarbose, voglibose and miglitol competitively and reversibly inhibit the alpha-glucosidase enzymes (glucoamylase, sucrase, maltase and isomaltase) in the brush border in the small intestine, which delays the hydrolysis of complex carbohydrates. They appear unlikely to produce hypoglycaemia in overdose, but abdominal discomfort and diarrhoea may occur. Troglitazone is the first thiazolidinedione antidiabetic drug available. There are no data on overdose, probably because of its very recent introduction. Overdoses with antidiabetic drugs produce major morbidity, with many cases requiring intensive care medicine and prolonged hospital stays. However, fatalities are rare when treatment is initiated early. The management of the hypoglycaemic drugs (insulin and sulphonylureas) is based primarily on restoring and maintaining euglycaemia via intravenous dextrose supplementation. In the case of the sulphonylureas, reduction of insulin secretion via pharmacological intervention may also be necessary. With biguanides the main risk appears to be cardiovascular collapse secondary to profound acidosis. The management focus is on restoring acid-base balance with hyperventilation and the use of insulin to shift the utilisation of glucose from the nonoxidative pathway to the oxidative pathway. Use of haemodialysis has shown equivocal results but may be valuable in metformin overdose.

Hypoglycemia remains a critical problem in the treatment of IDDM and often limits our ability to consistently achieve excellent glycemic control. Ongoing studies will be important to increase our understanding of the factors responsible for its occurrence and the impact that hypoglycemia may have, particularly for the brain. Significant differences have been documented between adults and children in the incidence of this complication of insulin therapy as well as in the counterregulatory hormone responses to hypoglycemia and its effects on the CNS. While children with diabetes still need insulin treatment, the prevention of hypoglycemia will be a central aim of management. This will depend on effective and expert diabetes education and support for the patient and his or her family along with better efforts to achieve more physiological insulin replacement.

The education of diabetic patients, proposed as an essential therapeutic tool since the early 1920s and accepted as such by official medicine only in the 1970s, has generated great enthusiasm over the last decade, with increasing concern for greater effectiveness by improved motivation of both patients and doctors. Structured education depends on the precise definition of agreed, short-term objectives, whose attainment shall be verified. Educational objectives may be set at different levels: knowledge of the disease, skills required for treatment, capacity to integrate therapy in everyday life,... The most relevant objectives however are the therapeutic goals of each individual patient, i.e. most often, prevention of acute complications, near-normoglycemia to prevent late complications and foot care to prevent disabling consequences of the latter. This can only be attained through a global approach to the patient, at once medical, educational and psychological. Medical science has definitively confirmed the importance of near- normoglycemia and proposes more effective insulin regimens and new recommendations for diet and exercise. Education demands a lot from health care providers: specific training, teaching skills, good communication, supportive attitude, readiness to listen and to negotiate. Patients' motivation to learn and adhere to treatment is also greatly influenced by individual factors, both psychological and environmental, that need to be taken into account.

The allocation of hypoglycaemic symptoms to autonomic 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 out-patients and found that 11 key hypoglycaemic symptoms segregated into three clear factors: autonomic (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.

The 1990 Americans with Disabilities Act forbids employers to bar disabled persons from jobs unless employers can show the disabled person cannot perform the tasks. The Federal Highway Administration will not license persons with diabetes mellitus to drive commercial motor vehicles in interstate commerce. These individuals may experience severe hypoglycemia, greatly increasing their risk of losing control of the truck. This prohibition is currently being reexamined. We describe the disease process leading to severe hypoglycemia and its physical manifestations. To quantify the risks of licensing persons with diabetes to use insulin, we first estimate the number of potential insulin-using drivers. We estimate that 1420 insulin-using persons would seek licenses in the United States if they were permitted to do so (920 noninsulin dependent and 500 insulin dependent). Next, we estimate the annual incidence of mild and severe hypoglycemia in these populations. The third step is to estimate the number of hypoglycemic episodes while driving. Estimating the likelihood of a crash due to a mild or severe hypoglycemic episode is the fourth step. We estimate that an additional 42 crashes each year would occur if insulin using persons were licensed to drive commercial motor vehicles in interstate commerce (20 from insulin dependent and 22 from non-insulin dependent drivers).

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-1year-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-1year-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-1year-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-1year-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).(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to evaluate the incidence and causes of hypoglycemia requiring hospitalization of diabetic patients treated with insulin or oral antidiabetic agents. From 1975 to 1989, 20,978 patients were treated in the Department of Gastroenterology and Metabolic Diseases of the Warsaw Medical School; review of their records disclosed that severe hypoglycemia was the cause of admission in 236 cases (1.12%). Two hundred patients (74 older than 60 years) were treated with insulin and 36 (28 older than 60 years) with oral agents. The most frequent cause of hypoglycemia was dietetic error (123 cases), followed by excessive physical effort (55 cases), error in the dose of hypoglycemic drug (22 cases), and alcohol abuse (13 cases). Hypoglycemia was the cause of death in 13 patients (8 aged over 60 years). In another 24 patients (17 aged over 60 years), exacerbation of ischemic heart disease was observed. Serious injuries with bone fracture were experienced by 11 patients (7 aged over 60 years). We conclude that hypoglycemia is still a serious risk for the life and health of diabetic patients treated with insulin or oral agents, especially those in advanced age. For this latter group of patients, more liberal criteria of metabolic control seem to be justified.

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).(ABSTRACT TRUNCATED AT 250 WORDS)

In the clinical setting, the impact of educational efforts on the amount of regular exercise and its effects on diabetes control are unclear. Fifty type 1 diabetic, 50 type 2 diabetic and 70 non-diabetic subjects were evaluated using a questionnaire for type, duration and intensity of exercise to assess weekly energy expenditure. Diabetic subjects did not exercise more than controls: 36% of the type 1, 46% of the type 2 and 46% of the control subjects admitted no physical activity, and those exercising regularly had similar energy expenditure: 1808 +/- 320, 2722 +/- 617, 2523 +/- 304 (mean +/- SEM) kcal/week respectively (P = NS). There was no correlation between the degree of activity and HbA1c levels, or hypoglycaemic events. HbA1c levels were less than 6,8% in 31% of nonactive patients versus 21% of active patients (P = NS). A negative correlation was found between physical activity and daily insulin usage (r = 0.27, P less than 0.05), but differences between patients averaged only 4IU/1000 kcal energy expenditure/day. We conclude that patients' attitude towards exercise was not improved by our educational methods and that physical exercise was not necessarily associated with good blood glucose control.

Hypoglycaemia is possibly the most frequent metabolic emergency, in that insulin-induced hypoglycaemia is a common side-effect of treatment of a common disease. The symptoms are partly sympathetic and related to the release of catecholamines. These symptoms include sweating, tremor, palpitations, sensation of hunger, restlessness and anxiety. Other symptoms are caused by an insufficient supply of glucose to the brain, resulting in neuroglucopenia with symptoms like blurred vision, weakness, slurred speech, vertigo and difficulties in concentration. Symptom recognition is the primary and most effective defence against cerebral dysfunction which is the ultimate consequence of hypoglycaemia. Even in insulin-treated diabetic patients symptom failure might occur. Patients who experience severe episodes of hypoglycaemia do not constitute a special subgroup of patients. However, near-normalization of blood glucose levels have resulted in an increase in the incidence of severe hypoglycaemia. Moreover, the threshold for hormonal counter-regulatory responses in adrenaline, growth hormone and cortisol is lowered after a period of strict metabolic control in insulin-dependent diabetic patients. The glucose level at which the patients become subjectively aware of hypoglycaemia is correspondingly reduced. Other reasons for hypoglycaemia to occur are oral hypoglycaemic agents, especially sulfonylureas which may be potentiated by other drugs. Prolonged hypoglycaemia may be seen after first-order sulfonylureas, and may indicate glucose infusion as treatment. Next to insulin and sulfonylurea, ethanol is the most common cause of hypoglycaemia. In non-diabetics, hypoglycaemia will typically develop 6-24 h after a moderate or heavy intake of ethanol by a person who has had an insufficient intake of food for 1 or 2 days. Insulin-producing tumours, insulinomas and non-islet cell tumours may also be reasons for hypoglycaemia in non-diabetics. Treatment of mild episodes of hypoglycaemia is intake of fast-absorbing carbohydrates. Severe episodes can be treated with either i.v. dextrose or glucagon injected i.m. or i.v. The glycaemic response and recovery of a normal level of consciousness is 1-2 min slower after glucagon than after glucose.

The aims of the present study were to investigate the relationship between severe hypoglycaemia and autonomic dysfunction in diabetic children, and to assess the glycaemic response to an insulin infusion test. In a one year period, 12 of 69 diabetic patients (17%) experienced at least one severe episode of hypoglycaemia, defined as an event which required outside assistance. All patients underwent five cardiovascular autonomic tests. Seven of the hypoglycaemic patients showed three or more abnormal autonomic tests. Among the 57 non-hypoglycaemic diabetics, there was no patient with three or more abnormal tests. In hypoglycaemic diabetics with and without autonomic dysfunction, and in eight healthy age matched subjects an insulin infusion test was performed. A pronounced blood glucose decline and a subnormal increase in heart rate during insulin infusion were obtained in patients with autonomic dysfunction. Thus, severe hypoglycaemia may be due to impaired defence mechanisms against blood glucose decline in diabetic children with autonomic dysfunction.

The present study assessed 106 diabetic patients 2 years after beginning insulin treatment at or after 70 years of age. Ten patients (9%) had had the therapy discontinued after 2-4 months, 26 (25%) had died of causes unrelated to insulin therapy, 12 (11%) were lost to follow-up, and 58 (55%) were still alive and insulin treated. Fifty-one were at home and seven institutionalized for reasons unrelated to insulin therapy. Of these 58 patients, 50 were available for further study. Except for frequency of travel, which had decreased, lifestyle either improved or did not change. Patients' perceptions of the goals of treatment were more appropriate to a younger population of patients, who are less vulnerable to hypoglycaemic reactions. Mean fasting blood glucose was considered by the medical staff to be too low in 42% of cases. Adding insulin to the treatment of the elderly did not negatively affect their lifestyle, and indeed, insulin therapy appeared to create or strengthen the patients' existing social support network. Educational interventions must attempt to extend the effect of the specialized unit outside the hospital, to families, visiting nurses as well as general practitioners.

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

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

The main therapeutic indication for glucagon is the treatment of hypoglycaemia in insulin overdosed Type 1 (insulin-dependent) diabetic patients. We have previously shown that an intranasal spray of 7.5 mg glucagon with deoxycholic acid as surfactant was able to correct an i.v. insulin-induced hypoglycaemia in diabetic patients. However, bioavailability and stability needed to be improved before intranasal glucagon could be introduced into clinical practice. This has now been achieved with a freeze-dried mixture of glucagon (1 mg) and glycocholic acid (1 mg) as a surfactant. Kinetics and efficacy have been controlled by (1) comparing subcutaneous and intranasal glucagon in 12 healthy non-hypoglycaemic subjects; (2) testing intranasal glucagon in six Type 1 diabetic patients in whom hypoglycaemia was induced by an i.v. bolus of insulin and (3) comparing subcutaneous and intranasal glucagon in six Type 1 diabetic patients in whom hypoglycaemia was induced by adding extra subcutaneous regular insulin to their usual morning dosage. Our results show that 1 mg of intranasal glucagon is as effective as 1 mg of subcutaneous glucagon in terms of the rise in blood glucose. Differences in kinetics between the subcutaneous and the intranasal routes may be observed: intranasal glucagon initiates the blood glucose rise earlier than does the subcutaneous form but the effect of the latter is more sustained. Glycocholic acid appears to be a perfectly tolerated agent in acute conditions. The use of intranasal lyophylized glucagon, for the reversal of hypoglycaemia in Type 1 diabetes, seems to be a clinically relevant alternative to its parenteral equivalent and should now be ready to be introduced in the market.

The prevalence of anti-insulin antibodies (AIABs) and their association with clinical parameters, metabolic control and severe hypoglycaemia were investigated in a geographically defined population of insulin-treated diabetic patients. Eighty per cent of the patients (479) delivered venous blood samples and answered a questionnaire on severe hypoglycaemic problems during a 12-month period. Circulating AIABs were demonstrable in 78% of the patients, being more common among those with type 1 diabetes and in long-duration patients. High levels of AIABs were also more frequent in patients in whom insulin treatment had been initiated prior to the era of highly purified insulins. The AIABs did not correlate to metabolic control, insulin dose or severe hypoglycaemia. It is concluded that AIABs is not a risk factor for severe hypoglycaemia in insulin-treated diabetic patients.

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.

A prospective study of symptomatic hypoglycaemia was conducted in 47 children over a 14-week period using a questionnaire completed at home for each episode of hypoglycaemia. Twenty-nine children (62%) experienced 150 episodes during the study. The average incidence was once every 33 days (range 0-5.2 mo-1). Hypoglycaemia occurred more frequently in children with lowest haemoglobin A1 levels. Episodes were not randomly distributed in time; hypoglycaemia occurred significantly more frequently in the evening, in the early morning and around midday. The majority of episodes were judged to be mild but 2 children had nocturnal convulsions and glucagon was used on three occasions. Symptomatic nocturnal hypoglycaemia occurred one or more times in 30% of the children. Daytime episodes were manifested by tremor, feeling weak, dizziness, pallor, and other symptoms and signs. In 46% of cases the cause was not evident to parents or children, but 25% were related to physical activity.

In a 12-month survey on the causes and frequency of hypoglycaemia presenting to an inner-city accident and emergency department, a total of 86 cases were recorded. A missed meal and/or alcohol ingestion accounted for most of the precipitating causes, being 52% and 21% respectively. As 49% of subjects presented with major clinical manifestations of hypoglycaemia (fit or coma), greater emphasis is required in the instruction on regularity of meal and caution with alcohol in high-risk groups such as the diabetic and also in non-diabetic groups.

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.

Plasma glutathione S-transferase basic isoenzyme (GST B1) concentrations have been measured by specific radioimmunoassay in Type 1 diabetic patients and in normal subjects, before and after controlled insulin-induced hypoglycaemia, and in a further group of Type 1 diabetic patients in hypoglycaemic coma. The activities of alanine aminotransferase (ALT), aspartate amino-transferase (AST), and gamma-glutamyl transferase (gamma GT) were also measured. GST B1 concentrations were significantly increased 3 h after controlled insulin-induced hypoglycaemia, both in the diabetic patients (p less than 0.02) and in the normal group (p less than 0.05), but the magnitude of the rise did not differ between these two groups. Four of the 9 patients presenting in hypoglycaemic coma had a GST B1 concentration above the reference range. ALT, AST, and gamma GT activities did not rise following hypoglycaemia in any of the groups.

The course of a diabetic patient who self-administered 2500 U of NPH insulin subcutaneously was examined in detail. Despite resumption of oral intake on day 3, she required iv glucose for 6 days, during which time serum free insulin levels remained elevated. Glucose requirements closely matched those calculated from published euglycemic clamp data on maximal glucose disposal rates during insulin infusion. We postulate that her prolonged course was due to delayed absorption of the subcutaneous insulin. This is the first case of massive insulin overdose studied in such detail, and the results may facilitate management of future cases.

Hypoglycaemia (blood glucose 1.3-2.5 mmol/l) was induced in twenty-eight diabetic children by reduction of their morning meal. Fatigue and pallor were the most common signs of hypoglycaemia. Compared to findings during normoglycaemia, plasma concentrations of adrenalin, noradrenalin and cortisol were significantly higher at glucose nadir. Plasma glucagon concentration at glucose nadir was correlated to the fasting C-peptide concentration and inversely to the duration of diabetes. Children who lacked C-peptide also lacked glucagon response to hypoglycaemia. The parents' opinion of the need to give carbohydrates corresponded to the blood glucose level. The presence of adrenergic signs correlated to the plasma adrenalin and the neuroglucopenic signs to blood glucose. The lowest glucose level correlated inversely to the concentration of free insulin. When facilities for glucose infusion are lacking, a rational step in treating the unconscious hypoglycaemic child seems to be the injection of glucagon, considering the blunted or absent glucagon secretion.

The effect of mild insulin-induced hypoglycaemia on symptoms, physiological changes, and adrenaline responses was assessed in 10 normal subjects and 15 insulin-dependent diabetic patients (5 with reduced awareness of hypoglycaemic symptoms). When blood glucose was maintained at 3.2 mmol/l, reaction time was prolonged in both normal and diabetic subjects and plasma adrenaline levels increased in the normals and some diabetics; there were no other physiological responses. 2 normals and 1 diabetic were aware that their blood glucose was low. When blood glucose was maintained at 2.5 mmol/l for 30 min, 9/10 normals but only 4/15 diabetics recognised hypoglycaemia. Increases in hypoglycaemic symptom score, tremor, and sweating, and falls in diastolic blood pressure were significant only in the normal subjects and the 4 "aware" patients. Adrenaline levels increased in all cases, but were more pronounced in the normals and aware diabetics. Reaction time remained prolonged in all groups. All measurements returned to baseline when blood glucose was raised to 4.5 mmol/l. Impairments in adrenaline response may be common, even in diabetic patients without autonomic neuropathy and in those who do not complain of hypoglycaemic unawareness; consequent failure to recognise a falling blood glucose may predispose to a risk of severe hypoglycaemia.

The effect of insulin-induced hypoglycaemia on cerebral blood flow was examined using the intravenous xenon-clearance technique in 9 patients with Type 1 (insulin-dependent) diabetes (aged 20 to 43 years) and 9 age-matched control subjects before, during and after hypoglycaemia. Cerebral blood flow rose in both groups. The mean basal cerebral flood flow values were not significantly different and during hypoglycaemia mean cerebral blood flow increased by 17% (p = 0.008) in the diabetic patients and by 21% (p = 0.0003) in the control subjects. The results suggest that in young diabetic patients without autonomic neuropathy or microangiopathy cerebral vessels dilate normally in response to hypoglycaemia. The physiological importance of an increase in cerebral blood flow during hypoglycaemia is uncertain; but glucose availability is increased.

The special requirements for implantable glucose sensors which differ from laboratory analysers and in vitro probes include continuous operation without drift, compatibility with in vivo body conditions, electrical and toxicological safety and patient acceptability. We have studied the effect of oxygen tension, operating temperature and pH, and the stability of various potentially implantable amperometric glucose sensors so as to aid the choice of the technologies most suitable for in vivo application.

We analyzed 137 episodes of hypoglycemia (serum glucose less than or equal to 49 mg per deciliter) occurring in 94 adult patients hospitalized during a six-month period at a tertiary care hospital. Forty-five percent of the patients had diabetes mellitus, and administered insulin was implicated in 90 percent of episodes in diabetics. Hypoglycemia in diabetic patients occurred under a variety of circumstances, frequently because of decreased caloric intake related to illness or hospital routine. Insulin-induced hypoglycemia also occurred during treatment of hyperkalemia (eight patients) or during hyperglycemia related to total parenteral nutrition (six patients). Forty-six of the 94 patients had chronic renal insufficiency, and 20 of these 46 had underlying diabetes mellitus. Thus, renal insufficiency unrelated to diabetes mellitus was the second most frequent diagnosis associated with hypoglycemia. The majority of other cases of hypoglycemia were related to liver disease, infections, shock, pregnancy, neoplasia, or burns. Hypoglycemia was not the apparent cause of death in any patient, but the overall hospital mortality was 27 percent and was related to the degree of hypoglycemia and the number of risk factors for hypoglycemia. We conclude that hypoglycemia is a common problem in hospitalized patients, is common in renal insufficiency, is usually iatrogenic, and correlates with high mortality in severely ill patients.