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Hypoglycemia unawareness can occur in diabetic as well as nondiabetic individuals. A single causative mechanism for its occurrence is not yet apparent. It is likely to be multifactorial but current evidence favors a major role for some type of CNS adaptation. Certainly in some instances, classic autonomic neuropathy could be a contributory factor in patients with longstanding diabetes. Most, if not all, individuals with this condition have reduced plasma epinephrine and/or norepinephrine responses during mild hypoglycemia. Although it may be difficult to distinguish between mere reductions in the magnitude of a response and a true alteration in the threshold to initiate that response, four studies (44, 59, 65, 86) have provided evidence for an increase in the threshold (greater hypoglycemia required) for activation of counterregulatory hormone secretion associated with reduced awareness of hypoglycemia; in one study (44), diabetic patients had developed abnormalities with improved glycemic control after intensive insulin therapy; in another study (59), diabetic patients had recurrent hypoglycemia but did not differ in glycemic control (as assessed by glycosylated hemoglobin values) from subjects aware of hypoglycemia. In the two other studies, patients with impaired counterregulatory hormone responses and hypoglycemia unawareness had lower glycosylated hemoglobin levels than the other patients (65, 86). Altered tissue sensitivity to catecholamines seems unlikely to provide a primary explanation since not all symptoms are adrenergic and since, as mentioned earlier, most patients with this condition have reduced or delayed catecholamine responses to hypoglycemia, which in themselves could explain reduced awareness of hypoglycemia. Furthermore, patients with diabetic autonomic neuropathy have been reported to have increased sensitivity to catecholamines (143). One frequent observation, dating back to the early descriptions of hypoglycemia unawareness (17-19), is that patients with this condition have had frequent episodes of hypoglycemia. Although it is easy to envision how reduced warning symptoms could result in development of severe hypoglycemia, it is quite possible that frequent episodes of hypoglycemia themselves might initiate the process. For example, as depicted in Fig. 4, episodes of mild hypoglycemia occurring in insulinoma patients, diabetic patients undergoing intensive insulin therapy, or patients with longstanding diabetes complicated by autonomic neuropathy and impaired glucagon secretion could lead to CNS adaptation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hypoglycemia unawareness. 176 Sep 93

Hypoglycaemia is a severe complication of insulin-dependent diabetes mellitus, especially when it is not preceded by warning signs. A patient unaware of a low blood glucose concentration may not take any remedial action, becomes severely hypoglycaemic and may lapse into a potentially fatal coma. Hypoglycaemic unawareness is associated particularly with good glycaemic control. Hypoglycaemia unawareness was first related to diabetic autonomic neuropathy. Subsequently it emerged that well controlled diabetic patients suffered from hypoglycaemia unawareness more often than poorly controlled patients. Next to autonomic neuropathy and good glycaemic control, the transfer of more slowly resorbed beef and porcine insulin to more rapidly resorbed human insulin has been incriminated as causing an increased incidence of hypoglycaemia unawareness. Reviewing the scientific literature concerning the connection between hypoglycaemia unawareness and the use of human insulin, there is no rationale for supporting the hypothesis that human insulin leads to hypoglycaemia unawareness any longer. While the pathophysiology of hypoglycemia unawareness remains unclear in patients with insulin-dependent diabetes mellitus of long duration, it may well be related to impaired adrenaline secretion. The cause of this impaired adrenaline secretion during hypoglycaemia is unknown and it does not seem to be a result of diabetic autonomic neuropathy.
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PMID:Hypoglycaemia unawareness. 802 94

Hypoglycemia unawareness--loss of the neurogenic (autonomic) warning symptoms of developing hypoglycemia--is one of three hypoglycemia-associated clinical syndromes that exemplify hypoglycemia-associated autonomic failure in IDDM. Reduced awareness of developing hypoglycemia (an elevated glycemic threshold for symptoms) is a feature not only of hypoglycemia unawareness but also of the syndromes of defective glucose counterregulation, elevated glycemic thresholds for symptoms, and activation of glucose counterregulatory systems during effective intensive therapy. These syndromes are major risk factors for severe iatrogenic hypoglycemia in individuals with IDDM. Their pathogenesis is unknown and likely multifactorial. Recent antecedent iatrogenic hypoglycemia may be one factor, perhaps a major factor, that, by reducing both the symptoms of and defenses against developing hypoglycemia, results in recurrent iatrogenic hypoglycemia, thus creating a vicious cycle. On the other hand, treatment with human compared with animal insulin does not appear to be an important factor.
Diabetes Care 1993 Dec
PMID:Hypoglycemia unawareness in IDDM. 829 77

To elucidate neurophysiological characteristics in hypoglycaemia unawareness, we investigated the relationship between electroencephalography (EEG) parameters of vigilance and awareness of various symptom categories early in response to hypoglycaemia in intensively treated diabetic patients with different degrees of hypoglycaemia unawareness. Hypoglycaemia (venous plasma glucose below 2.2 mmol/1) was induced with an intravenous insulin bolus in seven patients with insulin-dependent diabetes mellitus (IDDM) with a history of hypoglycaemia unawareness and repeated severe hypoglycaemia, as well as in a group of seven IDDM patients with good awareness of hypoglycaemia. Both groups were comparable in age, treatment strategy, glycaemic control and level of late complications. Basic cognitive performance and other symptom categories were estimated serially during a period of 2 h following the insulin bolus. A vigilance-controlled EEG was recorded continuously; its automatic analysis included the evaluation of vigilance indices. In the baseline prehypoglycaemic state, hypoglycaemia unaware patients showed higher initial vigilance (p = .05) than the aware group. Unaware patients reported fewer neurogenic (p = .002, mainly cholinergic, p = .009) hypoglycaemia symptoms during hypoglycaemia, and developed an impairment in cognitive performance over time (p = .002). EEG analysis indicated a more rapid decrease in vigilance after the hypoglycaemic stimulus for unaware patients than for aware patients. The lowering of plasma glucose to 3.06-3.89 mmol/l already induced a significant increase in delta and theta, as well as a decrease in alpha relative power only in the unaware group. Differences between groups with regards to the degree of deceleration were most pronounced early, during only slight hypoglycaemia, and topographically spread over central and parietal brain regions. Further lowering of plasma glucose induced an even more pronounced, abrupt increase in slow waves in unaware patients at higher plasma glucose levels than in hypoglycaemia aware subjects (for delta waves at 2.41 +/- 0.16 vs. 1.96 +/- 0.1 mmol/l, p = .04). This preceded the worsening of cognitive performance during hypoglycaemia in unaware patients by 19 +/- 3 min. Hypoglycaemia unawareness associated with previous unconsciousness is associated with- and may be the result of-an early hypoglycaemia-induced reduction in vigilance and an early EEG deceleration, which seems to be a teleologically effective measure for delaying eventual cerebral energy failure in hypoglycaemia.
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PMID:Severe hypoglycaemia unawareness is associated with an early decrease in vigilance during hypoglycaemia. 881 28

Hypoglycaemia unawareness, a frequent syndrome in insulin-dependent diabetes mellitus (IDDM), involves a decrease or absence of perception of specific symptoms which normally inform the subject that plasma glucose is decreasing to dangerous levels leading to neuroglycopenia. Without warning symptoms, IDDM patients are unable to take measures (e.g. eating) to prevent severe neuroglycopenia (unconsciousness). As hypoglycaemia unawareness is associated with impaired glucose counterregulation, especially reduced adrenaline responses, it can lead to severe hypoglycaemia. Various studies in animals and humans have indicated that hypoglycaemia unawareness is largely, if not entirely, secondary to increased brain glucose transport due to recurrent or chronic hypoglycaemia. In fact, meticulous prevention of hypoglycaemia largely restores the warning symptoms and adrenaline responses, at least in short-term IDDM. In long-term IDDM, recovery is less complete. Diabetologists and IDDM patients need to be familiar with hypoglycaemia unawareness and how to prevent or treat it. Intensive therapy strictly for normoglycaemia may actually increase the frequency of hypoglycaemia and hypoglycaemia unawareness. However, if intensive therapy is combined with a hypoglycaemia prevention programme, the percentage of HbA1c can be maintained below risk values for the onset or progression of complications, and the frequency of hypoglycaemia can be kept low. Under these conditions, IDDM patients can maintain the warning symptoms and adrenaline response to hypoglycaemia, ensuring a vital backup system for safe intensive therapy of IDDM.
Diabetes Metab 1997 Sep
PMID:Hypoglycaemia unawareness. 934 40

Maintenance of long-term near-normoglycemia by intensive therapy largely, if not fully, prevents the onset of microangiopathic complications and delays progression of complications in type 1 diabetic patients. However, intensive therapy has been reported to increase the frequency of severe hypoglycemia. In addition, a number of experimental studies have shown that a few episodes of mild, recurrent hypoglycemia blunt the symptom and hormonal responses to hypoglycemia over the next few days. At present, the critical "post-DCCT" (Diabetes Control and Complications Trial) questions are: is it possible to maintain long-term HbA1c < 7.0%, first, without increasing the frequency of severe hypoglycemia, and second, without increasing the frequency of mild, recurrent hypoglycemia? The answer is yes. The key factors are use of a physiological model of insulin replacement and the education of patients to appropriate the decision of insulin dose based on blood glucose monitoring and eating patterns. Hypoglycemia unawareness should be suspected whenever HbA1c is < 6.0 (upper normal limit 5.5%) and the patient does not report autonomic symptoms when their blood glucose level is < 3.0 mmol/l. The unaware patients should be treated with a short-term program of meticulous prevention of hypoglycemia, which reverses the abnormalities of responses of symptoms, hormonal counterregulation, and brain cognitive function. In turn, reversal of these abnormalities decreases the risk for severe hypoglycemia. Importantly, a program of meticulous prevention of hypoglycemia does not result in loss of long-term near-normoglycemia, i.e., it is compatible with the glycemic targets of intensive therapy.
Diabetes Care 1999 Mar
PMID:How to ameliorate the problem of hypoglycemia in intensive as well as nonintensive treatment of type 1 diabetes. 1009 99

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.
Pediatr Diabetes 2003 Sep
PMID:Hypoglycemia in children with type 1 diabetes: current issues and controversies. 1465 73

Recent evidence suggests that the brain has a key role in the control of energy metabolism, body fat content and glucose metabolism. Neuronal systems, which regulate energy intake, energy expenditure, and endogenous glucose production, sense and respond to input from hormonal and nutrient-related signals that convey information regarding both body energy stores and current energy availability. In response to this input, adaptive changes occur that promote energy homeostasis and the maintenance of blood glucose levels in the normal range. Defects in this control system are implicated in the link between obesity and type 2 diabetes mellitus. The central nervous system may be considered the conductor of an orchestra involving many peripheral organs involved in these homeostatic processes. However, the brain is mainly a glucose-dependent organ, which can be damaged by both hypoglycaemia and hyperglycaemia. Hypoglycaemia unawareness is a major problem in clinical practice and is associated with an increased risk of coma. Stroke is another acute complication associated with diabetes mellitus, especially in elderly people, and the control of glucose level in this emergency situation remains challenging. The prognosis of stroke is worse in diabetic patients and both its prevention and management in at-risk patients should be improved. Finally, chronic diabetic encephalopathies, which may lead to cognitive dysfunction and even dementia, are also recognized. They may result from recurrent hypoglycaemia and/or from chronic hyperglycaemia leading to cerebral vascular damage. Functional imaging is of interest for exploring diabetes-associated cerebral abnormalities. Thus, the intimate relationship between the brain and diabetes is increasingly acknowledged in both research and clinical practice.
Diabetes Metab 2010 Oct
PMID:Central nervous system: a conductor orchestrating metabolic regulations harmed by both hyperglycaemia and hypoglycaemia. 2121 33

OBJECTIVE Hypoglycemia unawareness (HU) affects ~25% of people with type 1 diabetes. People with HU are often reliant on family to detect hypoglycemia and treat severe episodes. We explored the impact of HU on family members' lives, their involvement in preventing and managing hypoglycemia, and their information and support needs. RESEARCH DESIGN AND METHODS This study employed an exploratory, qualitative design comprising in-depth interviews with 24 adult family members of persons with type 1 diabetes and HU. RESULTS Family members described restricting their lives so that they could help the person with HU detect and treat hypoglycemia. Some described being very physically afraid of their partner/relative when they had a hypoglycemic episode due to their aggressive and argumentative behavior and personality changes; this could also make treatment administration difficult. Family members also reported feeling anxious and worried about the safety of the person with HU, particularly when they were left unsupervised. These concerns were often precipitated by traumatic events, such as discovering the person with HU in a coma. Family members could neglect their own health and well-being to care for the person with HU and resentment could build up over time. Family members highlighted extensive, unmet needs for information and emotional support; however, some struggled to recognize and accept their own need for help. CONCLUSIONS Our findings reveal a caregiver group currently "in the shadow of the patient" and in urgent need of information and emotional support. Raising awareness among health care professionals is essential, and developing proactive support for family should be considered.
Diabetes Care 2014
PMID:Experiences, views, and support needs of family members of people with hypoglycemia unawareness: interview study. 2399 May 15

The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent hypoglycemia, as well as sleep or prior exercise, causes both defective glucose counterregulation (by attenuating the adrenomedullary epinephrine response, in the setting of absent insulin and glucagon responses) and hypoglycemia unawareness (by attenuating the sympathoadrenal, largely the sympathetic neural, response) and thus a vicious cycle of recurrent hypoglycemia. Albeit with different time courses, the pathophysiology of defense against hypoglycemia - no decrease in therapeutic insulin, no increase in glucagon and an attenuated increase in sympathoadrenal activity - is the same in type 1 diabetes and advanced type 2 diabetes. Hypoglycemia unawareness is reversible by 2-3 weeks of scrupulous avoidance of hypoglycemia in most affected patients. The pathophysiology of HAAF in diabetes explains why the incidence of hypoglycemia increases as patients approach the absolute endogenous insulin deficient end of the disease, provides a comprehensive set of risk factors including those indicative of HAAF, and leads logically to the practice of hypoglycemia risk factor reduction. Because of the risk of hypoglycemic mortality, presumably from cardiac arrhythmias, glycemic goals in diabetes should be individualized, based in part on the risk of hypoglycemia. By practicing hypoglycemia risk reduction - addressing the issue, applying the principles of aggressive glycemic therapy and considering both the conventional risk factors and those indicative of HAAF - it is possible to both improve glycemic control and reduce the risk of hypoglycemia in many patients with diabetes.
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PMID:Hypoglycemia-associated autonomic failure in diabetes. 2409 33


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