Patients with type 1 diabetes mellitus (T1DM) experience multiple episodes of hypoglycemia, resulting in dysfunctional counter-regulatory responses with time. The recent experimental study by Jin et al explored the role of intestinal glucagon-like peptide-1 (GLP-1) in impaired counter-regulatory responses to hypoglycemia. They identified intestinal GLP-1 along with GLP-1 receptor (GLP-1R) as the new key players linked with impaired counter-regulatory responses to hypoglycemia in type 1 diabetic mice. They also demonstrated that excessive expression of GLP-1 and GLP-1R was associated with attenuated sympathoadrenal responses and decreased glucagon secretion. The study has enormous clinical relevance as defective counter regulation and hypoglycemia unawareness negatively impacts the intensive glycemic management approach in this group of patients. However, the physiological processes must be validated in dedicated human studies to comprehensively understand the pathophysiology of this complex relationship, and to clarify the true extent of impaired hypoglycemia counter regulation by intestinal GLP-1. For now, following the results of the index study and other similar studies, GLP-1 analogues usage in T1DM must be carefully monitored, as there is an inherent risk of worsening the already impaired counter-regulatory responses in these patients. Further studies in the future could identify other key players involved in this clinically relevant interaction.

Maintenance of plasma glucose (PG) homeostasis is due to a complex network system. Even a minor fall in PG activates multiple neuroendocrine actions promoting hormonal, metabolic and behavioral responses, which prevent and ultimately recover hypoglycemia, primarily neuroglycopenia. Among these responses, gastric emptying (GE) plays an important role by coordinated mechanisms which regulate transit and absorption of nutrients through the small intestine. A bidirectional relationship between GE and glycemia has been established: GE may explain the up to 30-40 % variance in glycemic response following a carbohydrate-rich meal. In addition, acute and chronic hyperglycemia induce deceleration of GE after meals. Hypoglycemia accelerates GE, but its role in counterregulation has been poorly investigated. The role of GE as a counterregulatory mechanism has been confirmed in pathophysiological conditions, such as gastroparesis or following recurrent hypoglycemia. Therefore, it could represent an "ancestral" mechanism, highly conservative and effective in all individuals, conditions and clinical contexts. Recent guidelines recommend GLP-1 receptor agonists (GLP-1RAs) either as the first injectable therapy for type 2 diabetes mellitus or in combination with insulin. Considering the potential impact on GE, it would be important to study subjects on GLP-1 RAs during hypoglycemia, to establish whether a possible deceleration of GE impairs glucose counterregulation.

Hypoglycemia is a common acute complication of type 1 diabetes (T1D), which may cause seizure, loss of consciousness, and temporary motor or sensory impairment. Glucagon administration is an effective way of treating severe hypoglycemia, especially in a free-living setting. Nonetheless, families have difficulties in managing severe hypoglycemia due to their anxiety and challenges with current glucagon administration techniques. The aim of the current study was to explore the associations between parental fear of hypoglycemia (FoH) and their general anxiety level, and in particular, their attitudes towards and thoughts on glucagon administration.

Parents of children with T1D completed questionnaires assessing background and clinical information, FoH, generalized anxiety disorder (GAD) and parental anxiety for glucagon administration (PAGA).

Sixty-eight parents participated. Positive correlations were found between parental GAD-7 score and both FoH and the number of night-time blood glucose measurements and there was a negative correlation with the child’s age. Parents mean self-evaluation score of their competence in glucagon administration was 6 (standard deviation±2.9) on a scale of 0 to 10. Unsurprisingly, this score was negatively correlated with the PAGA scores. There was no significant difference between children using continuous glucose monitoring system and self-monitoring of blood glucose in terms of parental FoH, anxiety and misconceptions about glucagon administration.

The results showed that parents of children with T1D had anxiety and fear connected with hypoglycemia and glucagon administration. Structured and practical training should be implemented to increase parents’ self-confidence including annual refresher training for home glucagon administration.

Impaired awareness of hypoglycemia (IAH) is a reduction in the ability to recognize low blood glucose levels that would otherwise prompt an appropriate corrective therapy. Identified in approximately 25% of patients with type 1 diabetes, IAH has complex pathophysiology, and might lead to serious and potentially lethal consequences in patients with diabetes, particularly in those with more advanced disease and comorbidities. Continuous glucose monitoring systems can provide real-time glucose information and generate timely alerts on rapidly falling or low blood glucose levels. Given their improvements in accuracy, affordability and integration with insulin pump technology, continuous glucose monitoring systems are emerging as critical tools to help prevent serious hypoglycemia and mitigate its consequences in patients with diabetes. This review discusses the current knowledge on IAH and effective diagnostic methods, the relationship between hypoglycemia and cardiovascular autonomic neuropathy, a practical approach to evaluating cardiovascular autonomic neuropathy for clinicians, and recent evidence from clinical trials assessing the effects of the use of CGM technologies in patients with type 1 diabetes with IAH.

Hypoglycemia is the major limiting factor in the glycemic management of type 1 diabetes. Severe hypoglycemia puts patients at risk of injury and death. Recurrent hypoglycemia leads to impaired awareness of hypoglycemia and this increases the risk of severe hypoglycemia. Recent studies have reported rates for severe hypoglycemia of 35% in type 1 diabetic patients.

To assess the prevalence of severe hypoglycemia in type 1 diabetes mellitus patients and to evaluate the relationship between this and impaired awareness of hypoglycemia according to the Clarke test.

The following data were collected from a cohort of type 1 diabetic patients: age, gender, duration of type 1 diabetes, treatment (multiple daily insulin injection or continuous subcutaneous insulin infusion), glycemia self-control, HbA1c, episodes of severe hypoglycemia and impaired awareness of hypoglycemia.

Of the participants, 39.8% had had at least one episode of severe hypoglycemia (in the previous 6 months), 11.4% with loss of consciousness (in the previous 12 months). According to the Clark test, 40.9% had impaired awareness of hypoglycemia. Older age and longer duration of diabetes were associated with a higher prevalence of severe hypoglycemia with unconsciousness; older age and a lower level of HbA1c were associated with impaired awareness of hypoglycemia.

Our study allows us to confirm the high rate of severe hypoglycemia and impaired awareness of hypoglycemia in patients with type 1 diabetes.

Diabetes is a metabolic disease afflicting millions of people worldwide. A substantial fraction of world's total healthcare expenditure is spent on treating diabetes. Hypoglycemia is a serious consequence of anti-diabetic drug therapy, because it induces metabolic alterations in the brain. Metabolic alterations are one of the central mechanisms mediating hypoglycemia-related functional changes in the brain. Acute, chronic, and/or recurrent hypoglycemia modulate multiple metabolic pathways, and exposure to hypoglycemia increases consumption of alternate respiratory substrates such as ketone bodies, glycogen, and monocarboxylates in the brain. The aim of this review is to discuss hypoglycemia-induced metabolic alterations in the brain in glucose counterregulation, uptake, utilization and metabolism, cellular respiration, amino acid and lipid metabolism, and the significance of other sources of energy. The present review summarizes information on hypoglycemia-induced metabolic changes in the brain of diabetic and non-diabetic subjects and the manner in which they may affect brain function.

Cerebral ischemia is a serious possible manifestation of diabetic vascular disease. Recurrent hypoglycemia (RH) enhances ischemic brain injury in insulin-treated diabetic (ITD) rats. In the present study, we determined the role of ischemic acidosis in enhanced ischemic brain damage in RH-exposed ITD rats.

Diabetic rats were treated with insulin and mild/moderate RH was induced for 5 days. Three sets of experiments were performed. The first set evaluated the effects of RH exposure on global cerebral ischemia-induced acidosis in ITD rats. The second set evaluated the effect of an alkalizing agent (Tris-(hydroxymethyl)-aminomethane: THAM) on ischemic acidosis-induced brain injury in RH-exposed ITD rats. The third experiment evaluated the effect of the glucose transporter (GLUT) inhibitor on ischemic acidosis-induced brain injury in RH-exposed ITD rats. Hippocampal pH and lactate were measured during ischemia and early reperfusion for all three experiments. Neuronal survival in Cornu Ammonis 1 (CA1) hippocampus served as a measure of ischemic brain injury.

Prior RH exposure increases lactate concentration and decreases pH during ischemia and early reperfusion when compared to controls. THAM and GLUT inhibitor treatments attenuated RH-induced increase in ischemic acidosis. GLUT inhibitor treatment reduced the RH-induced increase in lactate levels. Both THAM and GLUT inhibitor treatments significantly decreased ischemic damage in RH-exposed ITD rats.

Ischemia causes increased acidosis in RH-exposed ITD rats via a GLUT-sensitive mechanism. Exploring downstream pathways may help understand mechanisms by which prior exposure to RH increases cerebral ischemic damage.

Clear health benefits are associated with intensive glucose control in type 1 diabetes mellitus (T1DM). However, maintaining near-normal glycemia remains an elusive goal for many patients, in large part owing to the risk of severe hypoglycemia. In fact, recurrent episodes of hypoglycemia lead to 'hypoglycemia-associated autonomic failure' (HAAF), characterized by defective counter-regulatory responses to hypoglycemia. Extensive studies to understand the mechanisms underlying HAAF have revealed multiple potential etiologies, suggesting various approaches to prevent the development of HAAF. In this review, we present an overview of the literature focused on pharmacological approaches that may prevent the development of HAAF. The purported underlying mechanisms of HAAF include: 1) central mechanisms (opioid receptors, ATP-sensitive K+(KATP) channels, adrenergic receptors, serotonin selective receptor inhibitors, γ-aminobuyric acid receptors, N-methyl D-aspartate receptors); 2) hormones (cortisol, estrogen, dehydroepiandrosterone (DHEA) or DHEA sulfate, glucagon-like peptide-1) and 3) nutrients (fructose, free fatty acids, ketones), all of which have been studied vis-à-vis their ability to impact the development of HAAF. A careful review of the current literature reveals many promising therapeutic approaches to treat or reduce this important limitation to optimal glycemic control.

Vital nerve cell functions, including maintenance of transmembrane voltage and information transfer, occur at high energy expense. Inadequate provision of the obligate metabolic fuel glucose exposes neurons to risk of dysfunction or injury. Clinical hypoglycemia rarely occurs in nondiabetic individuals but is an unfortunate regular occurrence in patients with type 1 or advanced insulin-treated type 2 diabetes mellitus. Requisite strict glycemic control, involving treatment with insulin, sulfonylureas, or glinides, can cause frequent episodes of iatrogenic hypoglycemia due to defective counter-regulation, including reduced glycemic thresholds and diminished magnitude of motor responses. Multiple components of the body's far-reaching energy balance regulatory network, including the hindbrain dorsal vagal complex, provide dynamic readout of cellular energetic disequilibrium, signals that are utilized by the hypothalamus to shape counterregulatory autonomic, neuroendocrine, and behavioral outflow toward restoration of glucostasis. The ovarian steroid hormone 17β-estradiol acts on central substrates to preserve nerve cell energy stability brain-wide, thereby providing neuroprotection against bio-energetic insults such as neurodegenerative diseases and acute brain ischemia. The current review highlights recent evidence implicating estrogen in gluco-regulation in females by control of hindbrain metabolic sensor screening and signaling of hypoglycemia-associated neuro-energetic instability. It is anticipated that new understanding of the mechanistic basis of how estradiol influences metabolic sensory input from this critical brain locus to discrete downstream regulatory network substrates will likely reveal viable new molecular targets for therapeutic simulation of hormone actions that promote positive neuronal metabolic state during acute and recurring hypoglycemia.

Diabetes mellitus is the commonest cause of an autonomic neuropathy in the developed world. Diabetic autonomic neuropathy causes a constellation of symptoms and signs affecting cardiovascular, urogenital, gastrointestinal, pupillomotor, thermoregulatory, and sudomotor systems. Several discrete syndromes associated with diabetes cause autonomic dysfunction. The most prevalent of these are: generalized diabetic autonomic neuropathy, autonomic neuropathy associated with the prediabetic state, treatment-induced painful and autonomic neuropathy, and transient hypoglycemia-associated autonomic neuropathy. These autonomic manifestations of diabetes are responsible for the most troublesome and disabling features of diabetic peripheral neuropathy and result in a significant proportion of the mortality and morbidity associated with the disease.

Optimized glycemic control prevents and slows the progression of long-term complications in patients with type 1 and type 2 diabetes. In healthy individuals, a decrease in plasma glucose below the physiological range triggers defensive counterregulatory responses that restore euglycemia. Many individuals with diabetes harbor defects in their defenses against hypoglycemia, making iatrogenic hypoglycemia the Achilles heel of glycemic control. This Profile in Progress focuses on the seminal contributions of Philip E. Cryer, MD, to our understanding of hypoglycemia and glucose counterregulation, particularly his discovery of the syndrome of hypoglycemia-associated autonomic failure (HAAF).

Hypoglycemia continues to be a significant problem for patients with diabetes. The incidence remains high but patients may also be under-reporting hypoglycemic events for various reasons, including hypoglycemia unawareness and deliberate non-reporting. This restricts the ability of healthcare professionals to manage treatment effectively. The aim of this article is to focus specifically on the issues associated with hypoglycemia unawareness and undisclosed hypoglycemia. The article provides general practice teams with an overview of these problems and, through patient narratives, suggests ways to mitigate them.

Hypoglycemia remains a common problem for patients with diabetes and is associated with substantial morbidity and mortality. This article summarizes our current knowledge of the epidemiology, pathogenesis, risk factors, and complications of hypoglycemia in patients with diabetes and discusses prevention and treatment strategies.

To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice.

Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report.

The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions.

Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association's Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society's Clinical Affairs Core Committee in October 2012 and by Council in November 2012.

The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.

To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice.

Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report.

The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions.

Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association's Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society's Clinical Affairs Core Committee in October 2012 and by Council in November 2012.

The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.

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.

We tested the hypothesis that an increase in insulin per se, i.e., in the absence of zinc, suppresses glucagon secretion during euglycemia and that a decrease in insulin per se stimulates glucagon secretion during hypoglycemia in humans.

We measured plasma glucagon concentrations in patients with type 1 diabetes infused with the zinc-free insulin glulisine on three occasions. Glulisine was infused with clamped euglycemia (∼95 mg/dl [5.3 mmol/l]) from 0 to 60 min on all three occasions. Then, glulisine was discontinued with clamped euglycemia or with clamped hypoglycemia (∼55 mg/dl [3.0 mmol/l]) or continued with clamped hypoglycemia from 60 to 180 min.

Plasma glucagon concentrations were suppressed by -13 ± 3, -9 ± 3, and -12 ± 2 pg/ml (-3.7 ± 0.9, -2.6 ± 0.9, and -3.4 ± 0.6 pmol/l), respectively, (all P < 0.01) during zinc-free hyperinsulinemic euglycemia over the first 60 min. Glucagon levels remained suppressed following a decrease in zinc-free insulin with euglycemia (-14 ± 3 pg/ml [-4.0 ± 0.9 pmol/l]) and during sustained hyperinsulinemia with hypoglycemia (-14 ± 2 pg/ml [-4.0 ± 0.6 pmol/l]) but increased to -3 ± 3 pg/ml (-0.9 ± 0.9 pmol/l) (P < 0.01) following a decrease in zinc-free insulin with hypoglycemia over the next 120 min.

These data indicate that an increase in insulin per se suppresses glucagon secretion and a decrease in insulin per se, in concert with a low glucose concentration, stimulates glucagon secretion. Thus, they document that insulin is a β-cell secretory product that, in concert with glucose and among other signals, reciprocally regulates α-cell glucagon secretion in humans.

Iatrogenic hypoglycemia, typically the result of the interplay of therapeutic hyperinsulinemia and compromised defenses resulting in hypoglycemia-associated autonomic failure (HAAF) in diabetes, is a problem for people with type 1 diabetes mellitus (T1DM). It causes recurrent morbidity is sometimes fatal, leads to recurrent hypoglycemia, and precludes euglycemia over a lifetime of T1DM. Risk factors include those that result in relative or absolute insulin excess and those indicative of HAAF in diabetes. Elimination of hypoglycemia from the lives of people with T1DM will likely be accomplished by new treatment methods that provide plasma glucose-regulated insulin replacement or secretion.

Hypoglycemia in young children with type 1 diabetes is an acute complication of intensive insulin therapy and is commonly observed in the absence of signs or symptoms. The effect of intensive treatment and patient age on sympathoadrenal responses has not been established in youth with type 1 diabetes because of difficulties in testing procedures.

We developed a standardized inpatient continuous subcutaneous insulin infusion protocol to produce a progressive fall in plasma glucose concentrations in insulin pump-treated patients. Plasma glucose and counterregulatory hormone concentrations were measured in 14 young children (3 to <8 years, A1C 7.7 +/- 0.6%) vs. 14 adolescents (12 to <18 years, A1C 7.6 +/- 0.8%).

Plasma glucose decreased to similar nadir concentrations in the two groups. Four young children and four adolescents never had an epinephrine response. In the four young children and five adolescents who had a modest epinephrine response, this only occurred when plasma glucose fell to <60 mg/dl. In evaluating symptom scores, 29% of parents of young children felt that their child looked hypoglycemic, even at the lowest plasma glucose concentrations. Adolescents were better able to detect symptoms of hypoglycemia. In comparison with our data, epinephrine response to hypoglycemia in 14 nondiabetic adolescents studied at the Children's Hospital of Pittsburgh was higher.

These data suggest that even young children and adolescents with type 1 diabetes are prone to develop hypoglycemia-associated autonomic failure regardless of duration. Whether these abnormalities can be reversed using continuous glucose monitoring and closed-loop insulin delivery systems awaits further study.

To review the prevalence of, risk factors for, and prevention of hypoglycemia from the perspective of the pathophysiologic aspects of glucose counterregulation in diabetes.

This review is based on personal experience and research and the relevant literature.

Although it can result from insulin excess alone, iatrogenic hypoglycemia is generally the result of the interplay of therapeutic insulin excess and compromised defenses against declining plasma glucose concentrations. Failure of beta-cells of the pancreas -- early in patients with type 1 diabetes mellitus but later in those with type 2 diabetes mellitus (T2DM) -- causes loss of the first 2 physiologic defenses: a decrease in insulin and an increase in glucagon. Such patients are critically dependent on epinephrine, the third physiologic defense, and neurogenic symptoms that prompt the behavioral defense (carbohydrate ingestion). An attenuated sympathoadrenal response to declining glucose levels -- caused by recent antecedent hypoglycemia, prior exercise, or sleep -- causes hypoglycemia-associated autonomic failure (HAAF) and thus a vicious cycle of recurrent hypoglycemia. Accordingly, hypoglycemia is infrequent early in T2DM but becomes increasingly more frequent in advanced (absolutely endogenous insulin-deficient) T2DM, and risk factors for HAAF include absolute endogenous insulin deficiency; a history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se.

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 both to improve glycemic control and to minimize the risk of hypoglycemia in many patients.

The aim is to provide guidelines for the evaluation and management of adults with hypoglycemic disorders, including those with diabetes mellitus.

Using the recommendations of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, the quality of evidence is graded very low (plus sign in circle ooo), low (plus sign in circle plus sign in circle oo), moderate (plus sign in circle plus sign in circle plus sign in circle o), or high (plus sign in circle plus sign in circle plus sign in circle plus sign in circle).

We recommend evaluation and management of hypoglycemia only in patients in whom Whipple's triad--symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised--is documented. In patients with hypoglycemia without diabetes mellitus, we recommend the following strategy. First, pursue clinical clues to potential hypoglycemic etiologies--drugs, critical illnesses, hormone deficiencies, nonislet cell tumors. In the absence of these causes, the differential diagnosis narrows to accidental, surreptitious, or even malicious hypoglycemia or endogenous hyperinsulinism. In patients suspected of having endogenous hyperinsulinism, measure plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and circulating oral hypoglycemic agents during an episode of hypoglycemia and measure insulin antibodies. Insulin or insulin secretagogue treatment of diabetes mellitus is the most common cause of hypoglycemia. We recommend the practice of hypoglycemia risk factor reduction--addressing the issue of hypoglycemia, applying the principles of intensive glycemic therapy, and considering both the conventional risk factors and those indicative of compromised defenses against falling plasma glucose concentrations--in persons with diabetes.

Hypoglycemia, the limiting factor in the glycemic management of diabetes, is the result of the interplay of therapeutic insulin excess and compromised glycemic defenses. The key feature of the latter is an attenuated sympathoadrenal response to hypoglycemia that typically follows an episode of recent antecedent iatrogenic hypoglycemia, a phenomenon termed hypoglycemia-associated autonomic failure (HAAF) in diabetes. We investigated the role of cerebral mechanisms in HAAF by measuring regional brain activation during recurrent hypoglycemia with attenuated counterregulatory responses and comparing it with initial hypoglycemia in healthy individuals.

We used [(15)O]water and positron emission tomography to measure regional cerebral blood flow as a marker of brain synaptic activity during hyperinsulinemic hypoglycemic clamps (55 mg/dl [3.0 mmol/l]) in the naïve condition (day 1) and after approximately 24 h of interval interprandial hypoglycemia (day 2) in nine healthy adults.

Interval hypoglycemia produced attenuated sympathoadrenal, symptomatic, and other counterregulatory responses to hypoglycemia on day 2, a model of HAAF. Synaptic activity in the dorsal midline thalamus during hypoglycemia was significantly greater on day 2 than day 1 (P = 0.004).

Greater synaptic activity associated with attenuated counterregulatory responses indicates that the dorsal midline thalamus plays an active inhibitory role in reducing sympathoadrenal and symptomatic responses to hypoglycemia when previous hypoglycemia has occurred, the key feature of HAAF in diabetes.

Animal and in vitro studies indicate that a decrease in beta-cell insulin secretion, and thus a decrease in tonic alpha-cell inhibition by intraislet insulin, may be an important factor for the increase in glucagon secretion during hypoglycemia. However, in humans this role of decreased intraislet insulin is still unclear.

We studied glucagon responses to hypoglycemia in 14 nondiabetic subjects on two separate occasions. On both occasions, insulin was infused from 0 to 120 min to induce hypoglycemia. On one occasion, somatostatin was infused from -60 to 60 min to suppress insulin secretion, so that the decrement in intraislet insulin during the final 60 min of hypoglycemia would be reduced. On the other occasion, subjects received an infusion of normal saline instead of the somatostatin.

During the 2nd h of the insulin infusion, when somatostatin or saline was no longer being infused, plasma glucose ( approximately 2.6 mmol/l) and insulin levels ( approximately 570 pmol/l) were comparable in both sets of experiments (both P > 0.4). In the saline experiments, insulin secretion remained unchanged from baseline (-90 to -60 min) before insulin infusion and decreased from 1.20 +/- 0.12 to 0.16 +/- 0.04 pmol . kg(-1) . min(-1) during insulin infusion (P < 0.001). However, in the somatostatin experiments, insulin secretion decreased from 1.18 +/- 0.12 pmol . kg(-1) . min(-1) at baseline to 0.25 +/- 0.09 pmol . kg(-1) . min(-1) before insulin infusion so that it did not decrease further during insulin infusion (-0.12 +/- 0.10 pmol . kg(-1) . min(-1), P = 0.26) indicating the complete lack of a decrement in intraislet insulin during hypoglycemia. This was associated with approximately 30% lower plasma glucagon concentrations (109 +/- 7 vs. 136 +/- 9 pg/ml, P < 0.006) and increments in plasma glucagon above baseline (41 +/- 8 vs. 67 +/- 11 pg/ml, P < 0.008) during the last 15 min of the hypoglycemic clamp. In contrast, increases in plasma growth hormone were approximately 70% greater during hypoglycemia after somatostatin infusion (P < 0.007), suggesting that to some extent the increases in plasma glucagon might have reflected a rebound in glucagon secretion.

These results provide direct support for the intraislet insulin hypothesis in humans. However, the exact extent to which a decrement in intraislet insulin accounts for the glucagon responses to hypoglycemia remains to be established.

Spontaneous hypoglycemia is uncommon in the general (nondiabetic) population, but iatrogenic hypoglycemia is rife in patients with type 1 diabetes mellitus, among whom hypoglycemia constitutes a barrier to optimal glycemic control. The obligate dependence on exogenous insulin, together with the current imperfection in insulin therapies, generates degrees of blood glucose fluctuations that often exceed physiological boundaries in these patients. Downward swings in blood glucose levels, if sustained, result in hypoglycemia and significant morbidity and mortality. Hypoglycemia in type 1 diabetes indicates an imbalance between caloric supply and glucose use in response to insulin or exercise. Counterregulatory mechanisms that auto-correct iatrogenic hypoglycemia often become progressively impaired in these patients. This defective counterregulation, together with the imperfections in insulin delivery, set the stage for significant morbidity from iatrogenic hypoglycemia. Recurrent episodes of iatrogenic hypoglycemia induce a state of hypoglycemia unawareness and defective counterregulation, which defines the syndrome of hypoglycemia-associated autonomic failure (HAAF). The reduced awareness of, and counterregulatory responses to, hypoglycemia in patients with HAAF lead to worsening episodes of severe hypoglycemia. Approaches to the prevention of hypoglycemia include glucose monitoring, patient education, meal planning, and medication adjustment. In patients with HAAF, scrupulous avoidance of iatrogenic hypoglycemia may restore the symptomatic and counterregulatory responses to hypoglycemia. Behavioral training focusing on recognition of the more subtle symptoms and signs of evolving hypoglycemia may be beneficial to some patients with HAAF. A methodical search for the pattern and etiology of iatrogenic hypoglycemia is a prerequisite for the identification of the best preventive approach. With proper education, patients with type 1 diabetes and their physicians can learn to prevent or minimize the risk of hypoglycemia while pursuing excellence in glycemic control.

The active cognitive-motor demands of driving may have a significant metabolic demand that could contribute to the development of hypoglycemia. Conversely, symptoms caused by the stress of driving may be confused with hypoglycemia and lead to false alarms. This study examined the metabolic demand and the physiological stress of driving on type 1 diabetes mellitus (T1DM) drivers.

Forty-three T1DM drivers were placed on a constant insulin infusion/variable dextrose infusion to maintain euglycemia for 30 min while either watching a driving video or actually driving a simulator, in a counterbalanced crossover design. Dextrose infusion, heart rate, epinephrine, and subjective symptom ratings were measured every 5 min. Additionally, subjects were monitored for self-treatment (drinking soda).

While blood glucose (BG) levels were equivalent across both conditions, actual driving was associated with a higher dextrose infusion rate (p = 0.02), more autonomic symptoms (p < 0.05), increased heart rate (p < 0.001), a trend (p = 0.09) for greater epinephrine release, and more frequent hypoglycemic self-treatment (p < 0.001).

Driving is a task with a significant metabolic demand, which may lower BG, and also that driving stress may be associated with symptoms similar to those of hypoglycemia. Physicians should discuss with their T1DM patients hypoglycemia and driving, and encourage measuring blood glucose before driving and during long drives.

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.

Defective glucose counterregulation and hypoglycemia unawareness are both well-recognized risk factors for recurrent episodes of severe hypoglycemia in patients with type I diabetes. At present, no conventional therapy is available to routinely overcome these acquired impairments in long-standing diabetes.

To test the hypothesis that successful intraportal islet transplantation could improve this syndrome, hormonal counterregulatory responses and symptoms were studied during stepped hypoglycemic clamp tests before and after intraportal islet transplantation in three patients with type I diabetes who were prone to severe hypoglycemia.

As compared with matched nondiabetic control subjects, before islet transplantation, glucagon responses were absent while epinephrine and cortisol responses were either markedly decreased or absent in all diabetic subjects. One patient also had decreased norepinephrine and growth hormone responses. Autonomic warning symptoms were absent in all patients during hypoglycemia. One month after successful islet transplantation, there was no improvement in the glucagon response. However, glycemic thresholds and/or peak incremental responses of epinephrine, norepinephrine, and cortisol improved in all patients. Moreover, all patients had developed autonomic warning symptoms so that glycemic thresholds were detectable within the examined range.

We conclude that intraportal islet transplantation does not restore hypoglycemia-induced glucagon secretion, but it improves the responses of most counterregulatory hormones and hypoglycemic warning symptoms even in long-standing type I diabetes.

Hypoglycaemia unawareness, is a major risk factor for severe hypoglycaemia and a contraindication to the therapeutic goal of near-normoglycaemia in IDDM. We tested two hypotheses, first, that hypoglycaemia unawareness is reversible as long as hypoglycaemia is meticulously prevented by careful intensive insulin therapy in patients with short and long IDDM duration, and that such a result can be maintained long-term. Second, that intensive insulin therapy which strictly prevents hypoglycaemia, can maintain long-term near-normoglycaemia. We studied 21 IDDM patients with hypoglycaemia unawareness and frequent mild/severe hypoglycaemia episodes while on "conventional" insulin therapy, and 20 nondiabetic control subjects. Neuroendocrine and symptom responses, and deterioration in cognitive function were assessed in a stepped hypoglycaemia clamp before, and again after 2 weeks, 3 months and 1 year of either intensive insulin therapy which meticulously prevented hypoglycaemia (based on physiologic insulin replacement and continuous education, experimental group, EXP, n = 16), or maintenance of the original "conventional" therapy (control group, CON, n = 5). At entry to the study, all 21 IDDM-patients had subnormal neuroendocrine and symptom responses, and less deterioration of cognitive function during hypoglycaemia. After intensive insulin therapy in EXP, the frequency of hypoglycaemia decreased from 0.5 +/- 0.05 to 0.045 +/- 0.02 episodes/patient-day; HbA1c increased from 5.83 +/- 0.18 to 6.94 +/- 0.13% (range in non-diabetic subjects 3.8-5.5%) over a 1-year period; all counterregulatory hormone and symptom responses to hypoglycaemia improved between 2 weeks and 3 months with the exception of glucagon which improved at 1 year; and cognitive function deteriorated further as early as 2 weeks (p < 0.05). The improvement in responses was maintained at 1 year. The improvement in plasma adrenaline and symptom responses inversely correlated with IDDM duration. In contrast, in CON, neither frequency of hypoglycaemia, nor neuroendocrine responses to hypoglycaemia improved. Thus, meticulous prevention of hypoglycaemia by intensive insulin therapy reverses hypoglycaemia unawareness even in patients with long-term IDDM, and is compatible with long-term near-normoglycaemia. Because carefully conducted intensive insulin therapy reduces, not increases the frequency of moderate/severe hypoglycaemia, intensive insulin therapy should be extended to the majority of IDDM patients in whom it is desirable to prevent/delay the onset/progression of microvascular complications.

Little is known about the receptor and post receptor mechanisms of sympathoadrenal signal transmission in type I diabetes mellitus. Therefore, we examined the maximum binding of granulocyte beta 2-adrenoceptors and the in vitro c-AMP accumulation in lymphocytes of 24 children and adolescents with diabetes mellitus and 14 similarly aged healthy subjects. The number of high affinity beta 2-adrenoceptors on granulocytes correlated significantly with unstimulated (r = 0.6, P < 0.004) and with isoproterenol stimulated c-AMP values in lymphocytes (r = 0.68, P < 0.0007) showing the proportional changes of beta 2-adrenoceptors and c-AMP in two different cells. The number of beta 2-adrenoceptors on granulocytes was significantly reduced in diabetic as compared to healthy children (median 1397, range 599-3405 vs. 2205, 825-3200 beta 2-adrenoceptors per granulocyte, P = 0.014). Moreover, the percentage in vitro stimulation of c-AMP by isoproterenol in lymphocytes was significantly reduced in diabetic children as compared to healthy individuals (120%, 39%-278% vs. 225%, 66%-500%, P = 0.012). These results indicate a decreased sympathoadrenergic signal transmission in peripheral blood cells as a model for the liver probably contributing to severe hypoglycaemia in diabetic children.

We hypothesize that in patients with insulin-dependent diabetes mellitus (IDDM), recent antecedent iatrogenic hypoglycemia is a major cause of hypoglycemia-associated autonomic failure, a disorder distinct from classical diabetic autonomic neuropathy (CDAN), and that hypoglycemia-associated autonomic failure, by reducing both symptoms of and defense against developing hypoglycemia, results in recurrent iatrogenic hypoglycemia, thus creating a vicious cycle. We used the hyperinsulinemic (12.0 pmol.kg-1.min-1) stepped hypoglycemic clamp technique to assess autonomic and symptomatic responses to hypoglycemia and the insulin infusion test (4.0 pmol.kg-1.min-1) to assess defense against hypoglycemia on mornings before and after clamped afternoon hypoglycemia (approximately 2.8 mmol/liter) and hyperglycemia (approximately 11.1 mmol/liter) in patients with IDDM. Compared with nondiabetic subjects, IDDM with or without CDAN exhibited reduced epinephrine (P = 0.0222 and 0.0040) and pancreatic polypeptide (P = 0.0083 and 0.0056) responses to hypoglycemia. After afternoon hypoglycemia, lower plasma glucose concentrations were required to elicit autonomic and symptomatic responses during morning hypoglycemic clamps in patients without CDAN. At the 2.8 mmol/liter step, mean (+/- SE) epinephrine levels were 1,160 +/- 270 and 2,040 +/- 270 pmol/liter (P = 0.0060), pancreatic and total symptom scores were 22 +/- 3 and 41 +/- 7 (P = 0.0475) after afternoon hypoglycemia and hyperglycemia, respectively. During morning insulin infusion tests after afternoon hypoglycemia, nadir plasma glucose concentrations were 2.6 +/- 0.2 mmol/liter compared with 3.3 +/- 0.3 mmol/liter (P < 0.001) at the corresponding time points after afternoon hyperglycemia. Thus, we conclude: (a) elevated glycemic thresholds for autonomic responses to hypoglycemia are a feature of IDDM per se, not classical diabetic autonomic neuropathy; and (b) a single episode of afternoon hypoglycemia results in both elevated glycemic thresholds for autonomic and symptomatic responses to hypoglycemia and impaired physiological defense against hypoglycemia the next morning in IDDM.

The prevention or correction of hypoglycemia in humans is the result of both dissipation of insulin and activation of glucose counterregulatory (glucose-raising) systems. Whereas insulin is the dominant glucose-lowering factor, there are redundant glucose counterregulatory factors. Furthermore, there is a hierarchy among the glucoregulatory factors. The first defense against a decrement in plasma glucose is decreased insulin secretion; this occurs with glucose decrements within the physiological range at a glycemic threshold of 4.6 +/- 0.2 mmol/l. However, biological glucose recovery from hypoglycemia can occur despite mild (approximately 2-fold) peripheral hyperinsulinemia and can occur in the absence of portal hypoinsulinemia. Thus additional (glucose counterregulatory) factors must be involved. Critical glucose counterregulatory systems are activated at glycemic thresholds of approximately 3.8 mmol/l (the level at which brain glucose uptake is first measurably reduced), well above the thresholds for symptoms of hypoglycemia (approximately 3.0 mmol/l) and those for cognitive dysfunction resulting from neuroglycopenia (approximately 2.7 mmol/l). Among the glucose counterregulatory factors, glucagon plays a primary role. Indeed, it may be that hypoglycemia does not occur if the secretion and actions of both glucagon and insulin, among the glucoregulatory hormones, are normal. Epinephrine is not normally critical, but it becomes critical to glucose counterregulation when glucagon is deficient. Because hypoglycemia develops or progresses when both glucagon and epinephrine are deficient and insulin is present, these three hormones stand high in the hierarchy of redundant glucoregulatory factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Pancreatic transplantation was performed in three patients with insulin-dependent diabetes mellitus in whom recurrent and severe episodes of hypoglycaemia had been found to be due to defective glucose counterregulation. Thus in these patients the spontaneous blood glucose recovery after insulin-induced hypoglycaemia (0.1 U kg-1 h-1 i.v. insulin until blood glucose levels fell below 2.8 mmol l-1) was delayed, and the responses of glucagon, epinephrine and growth hormone (GH) were absent or diminished. After pancreas transplantation the patients exhibited essentially normal blood glucose control. When the insulin infusion test was repeated 3 months after the transplantation, the blood glucose level recovered rapidly after insulin withdrawal. The glucagon response was restored, and the responses of epinephrine and GH were improved. Plasma C-peptide was suppressed by approximately 50%, which is less than is observed in normal subjects. It is concluded that glucose counterregulation improves after pancreas transplantation. This appears to be mainly due to an improvement in the hypoglycaemia-induced glucagon response, but an amelioration of sympatho-adrenal and hypothalamic-pituitary regulatory mechanisms may also be involved. The apparent failure to suppress completely the insulin release from the denervated pancreas transplant indicates that inhibition of beta-cell secretion during insulin-induced hypoglycaemia may be partly under neural control.

To assess the counterregulatory role of glucagon and to test the hypothesis that catecholamines can largely compensate for an impaired glucagon response, four studies were performed in seven normal volunteers. In all studies, insulin was infused subcutaneously (15 mU.m-2.min-1) and increased circulating insulin approximately twofold to levels (26 +/- 1 microU/ml) observed with intensive insulin therapy. In study 1, plasma glucose fluxes (D-[3-3H]glucose) and plasma substrate and counterregulatory hormone concentrations were simply monitored; plasma glucose decreased from 87 +/- 2 mg/dl and plateaued at 51 +/- 2 mg/dl for 3 h. In study 2 [pituitary-adrenal-pancreatic (PAP) clamp], secretion of insulin and counterregulatory hormones (except for catecholamines) was prevented by somatostatin (0.5 mg/h i.v.) and metyrapone (0.5 g/4 h per os), and glucagon, cortisol, and growth hormone were reinfused to reproduce the concentrations of study 1. In study 3 (lack of glucagon response), the PAP clamp was performed with maintenance of plasma glucagon at basal levels, and glucose was infused whenever needed to reproduce plasma glucose concentration of study 2. Study 4 was identical to study 3, but exogenous glucose was not infused. The PAP clamp (study 2) reproduced glucose concentrations and fluxes observed in study 1. In studies 3 and 4, isolated lack of glucagon response did not affect glucose utilization but caused an early and persistent decrease in hepatic glucose production (approximately 60%) that caused plasma glucose to decrease to 38 +/- 2 mg/dl (P less than 0.01 vs. control 62 +/- 2 mg/dl), despite compensatory increases in plasma epinephrine. We conclude that, in a model of clinical hypoglycemia, glucagon's effect on hepatic glucose production is a dominant counterregulatory factor in humans and that its absence cannot be compensated for by increased epinephrine secretion.

In 114 subjects with Type 1 (insulin-dependent) diabetes mellitus the nocturnal insulin requirements to maintain euglycaemia were assessed by means of i.v. insulin infusion by a Harvard pump. The insulin requirements decreased after midnight to a nadir of 0.102 +/- 0.03 mU.kg-1.min-1 at 02.40 hours. Thereafter, the insulin requirements increased to a peak of 0.135 +/- 0.06 mU.kg-1.min-1 at 06.40 hours (p less than 0.05). The dawn phenomenon (increase in insulin requirements by more than 20% after 02.40 hours lasting for at least 90 min) was present in 101 out of the 114 diabetic subjects, and its magnitude (% increase in insulin requirements between 05.00-07.00 hours vs that between 01.00-03.00 hours) was 19.4 +/- 0.54% and correlated inversely with the duration of diabetes (r = -0.72, p less than 0.001), but not with age. The nocturnal insulin requirements and the dawn phenomenon were highly reproducible on three separate nights. In addition, glycaemic control, state of counterregulation to hypoglycaemia and insulin sensitivity all influenced the magnitude of the dawn phenomenon as follows. In a subgroup of 84 subjects with Type 1 diabetes, the multiple correlation analysis showed that not only duration of diabetes (t = -9.76, p less than 0.0001), but also % HbA1 significantly influenced the magnitude of the dawn phenomenon (t = 2.03, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)