Vicious Cycle Of Recurrent Hypoglycemia Research Articles

Lactate and the Mechanism of Hypoglycemia-Associated Autonomic Failure in Diabetes

Iatrogenic hypoglycemia is a problem for many people with diabetes (1). It causes recurrent morbidity in most people with type 1 diabetes and many with advanced type 2 diabetes and is sometimes fatal. It generally precludes maintenance of euglycemia over a lifetime of diabetes and therefore full realization of the benefits of glycemic control. It impairs defenses against subsequent falling plasma glucose concentrations and causes a vicious cycle of recurrent hypoglycemia. Hypoglycemia in diabetes is typically the result of the interplay of therapeutic insulin excess—caused by treatment with insulin, a sulfonylurea, or a glinide—and compromised physiological and behavioral defenses against falling plasma glucose concentrations (1,2). Compromised physiological defenses include loss of the normal decrease in β-cell insulin secretion and increase in α-cell glucagon secretion and attenuation of the normal increase in adrenomedullary epinephrine secretion during hypoglycemia. The compromised behavioral defense is failure to ingest carbohydrates because of loss of symptoms due to attenuation of the normal increase in sympathoadrenal, largely sympathetic neural, activity. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent hypoglycemia (or sleep or prior exercise) causes both defective glucose counterregulation (by attenuating the epinephrine response in the setting of absent insulin and glucagon responses) and impaired awareness of hypoglycemia (by attenuating sympathoadrenal and the resulting symptomatic responses) and thus a vicious cycle of recurrent hypoglycemia. Although additional intraislet mechanisms may be involved, it is reasonable to attribute both loss of the insulin and of the glucagon responses to hypoglycemia, the prerequisites to HAAF, to β-cell failure. Insulin normally restrains glucagon secretion and a decrease in insulin normally stimulates glucagon secretion during hypoglycemia. In the setting of absolute endogenous insulin deficiency—β-cell failure—there is …

Is there anything positive about iatrogenic hypoglycemia in Type 1 diabetes?

281 ISSN 1758-1907 10.2217/DMT.13.25 © 2013 Future Medicine Ltd Diabetes Manage. (2013) 3(4), 281–283 Iatrogenic hypoglycemia is the most frequent acute complication of insulin therapy. Although the true incidence is difficult to ascertain, it is estimated that patients with Type 1 diabetes experience two to three hypoglycemic events per week and one severe event, requiring third-party assistance, once every 1–2 years [1]. There is substantial interand intra-individual variation in the incidence of hypoglycemic events, ranging from almost none to one or even multiple events per day. Hypo glycemia is considered to be the principal limiting factor to achieve optimal glycemic control in Type 1 diabetes because it is usually unavoidable in the pursuit of near-normal glucose levels [1]. Other factors impacting on the rate of hypoglycemia include (residual) b-cell function, the potency of glucose counter-regulatory function and hypo glycemic awareness. In addition, time of day (daytime versus nighttime), ambient temperature and other environmental factors (e.g., exercise or alcohol use) may play a role in the day-to-day variation. Approximately 25–30% of patients with Type 1 diabetes have severely impaired hypoglycemic awareness, meaning that hypoglycemia does not or only minimally elicits classical warning symptoms, such as sweating, pounding heart or trembling. In these patients, counter-regulatory hormone responses to hypoglycemia are often similarly impaired, meaning that glucose levels may fall more or less unimpeded. Since antecedent hypoglycemia exerts an attenuating effect on the counter-regulatory and symptom responses to subsequent hypoglycemia [2], impairments in both counter-regulatory function and hypoglycemic awareness are thought to result from habituation to recurrent hypoglycemia. The clinical syndrome of severely impaired hypoglycemic awareness thus results from a vicious cycle of recurrent hypoglycemia and progressive counter-regulatory impairments. Patients with this syndrome are at a sixto ten-fold higher risk of severe hypoglycemia compared with those reporting normal hypoglycemic awareness [3]. Severe hypoglycemic events are feared by many patients, relatives and care providers, mainly because of the associated loss of selfcontrol and its potential to cause direct or indirect harm. Extremely low blood glucose levels lasting for several hours may permanently damage the brain and occasionally be fatal. Although such events are extremely rare, a large survey of cause-specific mortality in the UK nevertheless attributed 4% of

Severe Hypoglycemia Predicts Mortality in Diabetes

In this issue of Diabetes Care , McCoy et al. (1) report 3.4-fold higher mortality in patients with diabetes who self-reported severe hypoglycemia (that which required the assistance of another person) 5 years earlier. They suggest that patient-related outcomes such as hypoglycemia would augment risk stratification and management of patients with diabetes. Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes (2). It causes recurrent morbidity in most people with type 1 diabetes and many with advanced type 2 diabetes and is sometimes fatal. It impairs defenses against subsequent hypoglycemia and, thus, causes a vicious cycle of recurrent hypoglycemia. The barrier of hypoglycemia generally precludes maintenance of euglycemia over a lifetime of diabetes and, therefore, full realization of the benefits of glycemic control. Although it can be caused by an episode of marked absolute therapeutic hyperinsulinemia, iatrogenic hypoglycemia is typically the result of the interplay of mild-to-moderate absolute or even relative therapeutic hyperinsulinemia and compromised physiological and behavioral defenses against falling plasma glucose concentrations (2). The compromised physiological defenses include attenuated adrenomedullary epinephrine responses that, in the setting of absent insulin and glucagon responses, cause the clinical syndrome of defective glucose counterregulation with its 25-fold or greater increased risk of severe hypoglycemia during aggressive glycemic therapy. The compromised behavioral defense is the failure to ingest carbohydrates, which results from attenuated sympathoadrenal (largely sympathetic neural) responses that cause the clinical syndrome of hypoglycemia unawareness with its sixfold or greater increased risk of severe hypoglycemia during aggressive glycemic therapy. Defective glucose counterregulation and hypoglycemia unawareness are the components of hypoglycemia-associated autonomic failure (HAAF) in diabetes. HAAF is a form of …

Hypoglycemia unawareness

Iatrogenic hypoglycemia is the limiting factor in the glycemic control of diabetes. It causes recurrent symptomatic and sometimes, at least temporally, disabling episodes in most people with type 1 diabetes, as well as in many with advanced type 2 diabetes. Furthermore, iatrogenic hypoglycemia precludes maintenance of euglycemia during the lifetime of a person with diabetes and thus full realization of the well established benefits of glycemic control. In this article I discuss the clinical problem of hypoglycemia in diabetes from the perspective of pathophysiology. First, the syndromes of defective glucose counterregulation and hypoglycemia without warning symptoms (known as hypoglycemia unawareness) are described, followed by the unifying concept of Hypoglycemia-Associated Autonomie Failure (HAAF). The concept of hypoglycemia-associated autonomie failure in diabetes posits that recurrent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness and thus leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. The clinical relevance of this phenomenon is now well established, but the mechanisms and mediators remain largely unknown. The short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The ultimate goal of lifelong maintenance of euglycemia in patients with diabetes remains elusive because of the pharmacokinetic imperfections of all current glucose-lowering therapies and the resulting barrier of hypoglycemia. Nonetheless, it is now possible both to improve the control of glycemia and to reduce the frequency of hypoglycemia in many people with diabetes. These results can be accomplished by recognizing the problem of hypoglycemia applying the principles of aggressive glycemic therapy and reducing the risk factors of hypoglycemia in people with diabetes.

Exercise-Related Hypoglycemia-Associated Autonomic Failure in Diabetes

Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes (1,2). It causes recurrent morbidity in most people with type 1 diabetes as well as many with advanced type 2 diabetes and is sometimes fatal. It precludes maintenance of euglycemia over a lifetime of diabetes and, therefore, full realization of the benefits of glycemic control. It compromises physiological and behavioral defenses against subsequent falling plasma glucose concentrations and thus causes a vicious cycle of recurrent hypoglycemia. Insight into the pathophysiology of glucose counterregulation will continue to lead to understanding of the frequency and impact of, risk factors for, and prevention of iatrogenic hypoglycemia (1,2). Marked absolute therapeutic hyperinsulinemia can cause isolated episodes of hypoglycemia in people with diabetes. However, episodes of hypoglycemia are more typically the result of the interplay of relative or mild-moderate absolute therapeutic hyperinsulinemia and compromised physiological and behavioral defenses against falling plasma glucose concentrations (1,2) (Fig. 1). The compromised physiological defenses include loss of decrements in β-cell insulin, loss of increments in α-cell glucagon, and, given the latter, attenuation of increments in adrenomedullary epinephrine. The compromised behavioral defense is the failure of carbohydrate ingestion resulting from loss of symptoms, which is largely the result of an attenuated sympathetic neural response. The concept of …

Attenuated Sympathoadrenal Responses, but Not Severe Hypoglycemia, During Aggressive Glycemic Therapy of Early Type 2 Diabetes

Iatrogenic hypoglycemia is a major limiting factor in the strict glycemic management of diabetes (1,2). Hypoglycemia can cause recurrent morbidity in many people with type 1 diabetes and also in some with advanced type 2 diabetes (2,3). Rarely fatal, fear of hypoglycemia precludes maintenance of euglycemia over a lifetime with diabetes and full realization of the vascular benefits of glycemic control. Hypoglycemic events compromise defenses against subsequent falling plasma glucose concentrations and thus cause a vicious cycle of recurrent hypoglycemia. Hypoglycemia in diabetes is fundamentally the result of episodes of therapeutic hyperinsulinemia caused by treatment with an insulin secretagogue or insulin. In general, the incidence of iatrogenic hypoglycemia is a function of the degree of β-cell failure (1,2,4), and risk is predicted by the absence of evidence of endogenous insulin secretion (C-peptide) (5). Incidence of hypoglycemia is lower in people with type 2 diabetes, who are not usually completely insulin deficient, than in those with type 1 diabetes, and this is especially true early in the course of type 2 diabetes. However, the incidence of hypoglycemia increases progressively over time (6), ultimately approximating that in those with type 1 diabetes (7,8), as type 2 diabetic individuals approach the insulin-deficient end of the spectrum. Because type 2 diabetes is ∼20-fold more prevalent than type 1 diabetes and many people with type 2 diabetes ultimately require treatment with insulin, most episodes of iatrogenic hypoglycemia, including severe hypoglycemia, occur in those with type 2 diabetes (1–3,9). The key physiological defenses against falling plasma glucose concentrations are 1 ) a decrease in insulin secretion; 2 ) an increase in glucagon secretion; and, in the absence of the latter, 3 …

The barrier of hypoglycemia in diabetes.

Glycemic control, a worthwhile goal for people with diabetes, is limited by the barrier of iatrogenic hypoglycemia (1). Iatrogenic hypoglycemia 1 ) causes recurrent morbidity in most people with type 1 diabetes and many with advanced type 2 diabetes and is sometimes fatal, 2 ) compromises physiological and behavioral defenses against subsequent falling plasma glucose concentrations and thus causes a vicious cycle of recurrent hypoglycemia, and 3 ) precludes maintenance of euglycemia over a lifetime of diabetes and therefore full realization of the vascular benefits of glycemic control. The premise of this “Perspective in Diabetes” is that insight into the pathophysiology of glucose counterregulation in diabetes leads to understanding of the frequency and impact of, risk factors for, and prevention of iatrogenic hypoglycemia. Partial glycemic control reduces, but does not eliminate, the development of microvascular complications of diabetes (retinopathy, nephropathy, and neuropathy) in type 1 (2) and type 2 (3,4) diabetes. Extrapolation of the Diabetes Control and Complications Trial (DCCT) retinopathy data suggests that long-term maintenance of euglycemia might eliminate those complications (5). Follow-up of the DCCT patients seemingly indicates that a period of earlier partial glycemic control reduces the development of macrovascular complications in type 1 diabetes (6). Aside from the metformin subset of the U.K. Prospective Diabetes Study (4), randomized controlled trials of intensive glycemic therapy have not documented a cardiovascular mortality benefit in type 2 diabetes (3,7,8). However, those trials do not exclude a cardiovascular benefit if glycemic control, or even partial glycemic control, could be maintained over a longer period of time. In any event, given its documented microvascular benefit, maintenance of euglycemia over a lifetime of diabetes would be in the best interest of people with diabetes if that could be accomplished safely. Unfortunately, maintenance of euglycemia over a lifetime of diabetes …

Mechanisms of Hypoglycemia-Associated Autonomic Failure and Its Component Syndromes in Diabetes

Iatrogenic hypoglycemia is a problem for people with diabetes. It causes recurrent morbidity, and sometimes death, as well as a vicious cycle of recurrent hypoglycemia, precluding maintenance of euglycemia over a lifetime of diabetes. Improved therapeutic approaches that will minimize both hypo- and hyperglycemia will be based on insight into the pathophysiology of glucoregulation, specifically glucose counterregulation, in insulin-deficient (type 1 and advanced type 2) diabetes. In such patients, hypoglycemia is the result of the interplay of relative or absolute therapeutic insulin excess and compromised physiological (the syndrome of defective glucose counterregulation) and behavioral (the syndrome of hypoglycemia unawareness) defenses against falling plasma glucose concentrations. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing epinephrine responses to a given level of subsequent hypoglycemia in the setting of absent decrements in insulin and absent increments in glucagon) and hypoglycemia unawareness (by reducing sympathoadrenal and the resulting neurogenic symptom responses to a given level of subsequent hypoglycemia) and thus a vicious cycle of recurrent hypoglycemia. The clinical impact of HAAF is well established in type 1 diabetes; it also affects those with advanced type 2 diabetes. It is now known to be largely reversible, by as little as 2-3 weeks of scrupulous avoidance of hypoglycemia, in most affected patients. However, the mechanisms of HAAF and its component syndromes are largely unknown. Loss of the glucagon secretory response, a key feature of defective glucose counterregulation, is plausibly explained by insulin deficiency, specifically loss of the decrement in intraislet insulin that normally signals glucagon secretion as glucose levels fall. Reduced neurogenic symptoms, a key feature of hypoglycemia unawareness, are largely the result of reduced sympathetic neural responses to falling glucose levels. The mechanism by which hypoglycemia shifts the glycemic thresholds for sympathoadrenal activation to lower plasma glucose concentrations, the key feature of both components of HAAF, is not known. It does not appear to be the result of the release of a systemic mediator (e.g., cortisol, epinephrine) during antecedent hypoglycemia or of increased blood-to-brain glucose transport (although increased transport of alternative fuels is conceivable). It is likely the result of alterations of brain metabolism. Although there is an array of clues, the specific alteration remains to be identified. While the research focus has been largely on the hypothalamus, hypoglycemia is now known to activate widespread brain regions, including the medial prefrontal cortex. The possibility that HAAF could be the result of posthypoglycemic brain glycogen supercompensation has also been raised. Finally, there appear to be diverse causes of HAAF. In addition to recent antecedent hypoglycemia, these include exercise- and sleep-related HAAF. Clearly, a unifying mechanism of HAAF would need to incorporate these causes as well. Pending the prevention and cure of diabetes, critical fundamental, translational, and outcomes research is needed if we are to eliminate hypoglycemia from the lives of people affected by diabetes.

Hypoglycemia in diabetes.

Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes and many with type 2 diabetes, and it is sometimes fatal. The barrier of hypoglycemia generally precludes maintenance of euglycemia over a lifetime of diabetes and thus precludes full realization of euglycemia's long-term benefits. While the clinical presentation is often characteristic, particularly for the experienced individual with diabetes, the neurogenic and neuroglycopenic symptoms of hypoglycemia are nonspecific and relatively insensitive; therefore, many episodes are not recognized. Hypoglycemia can result from exogenous or endogenous insulin excess alone. However, iatrogenic hypoglycemia is typically the result of the interplay of absolute or relative insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors that normally prevent or rapidly correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation. Reduced sympathoadrenal responses cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. Thus, short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The clinical approach to minimizing hypoglycemia while improving glycemic control includes 1) addressing the issue, 2) applying the principles of aggressive glycemic therapy, including flexible and individualized drug regimens, and 3) considering the risk factors for iatrogenic hypoglycemia. The latter include factors that result in absolute or relative insulin excess: drug dose, timing, and type; patterns of food ingestion and exercise; interactions with alcohol and other drugs; and altered sensitivity to or clearance of insulin. They also include factors that are clinical surrogates of compromised glucose counterregulation: endogenous insulin deficiency; history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se, as evidenced by lower HbA(1c) levels, lower glycemic goals, or both. In a patient with hypoglycemia unawareness (which implies recurrent hypoglycemia) a 2- to 3-week period of scrupulous avoidance of hypoglycemia is advisable. Pending the prevention and cure of diabetes or the development of methods that provide glucose-regulated insulin replacement or secretion, we need to learn to replace insulin in a much more physiological fashion, to prevent, correct, or compensate for compromised glucose counterregulation, or both if we are to achieve near-euglycemia safely in most people with diabetes.

Hypoglycemia-associated autonomic failure in diabetes.

Hypoglycemia is the limiting factor in the glycemic management of diabetes. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response to falling glucose levels in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic and the resulting neurogenic symptom responses) and thus a vicious cycle of recurrent hypoglycemia. Perhaps the most compelling support for HAAF is the finding that as little as 2-3 wk of scrupulous avoidance of hypoglycemia reverses hypoglycemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected individuals. Insight into this pathophysiology has led to a broader view of the clinical risk factors for hypoglycemia to include indexes of compromised glucose counterregulation and provided a framework for the study of the mechanisms of iatrogenic hypoglycemia and, ultimately, its elimination from the lives of people with diabetes.

Hypoglycemia risk reduction in type 1 diabetes.

Hypoglycemia is the limiting factor in the glycemic management of diabetes because it generally precludes maintenance of euglycemia. Improving glycemic control while minimizing hypoglycemia in type 1 diabetes mellitus (T1 DM) involves both application of the principles of aggressive therapy--patient education and empowerment, frequent self monitoring of blood glucose, flexible insulin regimens, individualized glycemic goals and ongoing professional guidance and support--and implementation of hypoglycemia risk reduction. Iatrogenic hypoglycemia is the result of the interplay of therapeutic insulin excess and compromised physiological and behavioral defenses against falling plasma glucose concentrations in T1 DM. Relative or absolute insulin excess occurs when insulin doses are excessive, ill-timed or of the wrong type, when exogenous glucose delivery, endogenous glucose production or insulin clearance are decreased or when insulin-independent glucose utilization or sensitivity to insulin are increased. But these conventional risk factors explain only a minority of episodes of severe hypoglycemia. More potent risk factors include absolute insulin deficiency, a history of severe hypoglycemia and aggressive therapy per se as evidenced by lower glycemic goals, lower hemoglobin A1c levels, or both. These are clinical surrogates of compromised glucose counterregulation, the clinical syndromes of defective glucose counterregulation (the result of absent decrements in insulin and absent increments in glucagon with attenuated increments in epinephrine) and hypoglycemia unawareness (the result of reduced autonomic [sympathochromaffin] activation causing reduced warning symptoms of developing hypoglycemia). The unifying concept of hypoglycemia-associated autonomic failure in T1 DM posits that: (1) Periods of relative or absolute therapeutic insulin excess in the setting of absent glucagon responses lead to episodes of hypoglycemia. (2) These episodes, in turn, cause reduced autonomic (including adrenomedullary) responses to falling glucose concentrations on subsequent occasions. (3) These reduced autonomic responses result in both reduced symptoms of developing hypoglycemia (i.e., hypoglycemia unawareness) and--because epinephrine responses are reduced in the setting of absent glucagon responses--impaired physiological defenses against developing hypoglycemia (i.e., defective glucose counterregulation). Thus a vicious cycle of recurrent hypoglycemia is created and perpetuated. Hypoglycemia risk reduction includes, first, addressing the issue of hypoglycemia--the patient's awareness of and concerns about it, its frequency, severity, timing and clinical settings--in every patient contact. Then it requires application of the principles of aggressive therapy, consideration of both the conventional risk factors and those indicative of compromised glucose counterregulation and appropriate regimen adjustments including a two to three week period of scrupulous avoidance of hypoglycemia in patients with hypoglycemia-associated autonomic failure. With this approach the goals of improving glycemic control and minimizing hypoglycemia are not incompatible.