Effect of hypoglycemia on baroreflex sensitivity in individuals with type 2 diabetes: implications for autonomic control of cardiovascular function in diabetes.

PURPOSE: Hypoglycemia is associated with increased mortality, though the mechanisms underlying this association are not established. Hypoglycemia impairs the counterregulatory hormonal and autonomic responses to subsequent hypoglycemia. It is unknown whether hypoglycemia elicits a generalized impairment in autonomic control of cardiovascular function in individuals with type 2 diabetes. We tested the hypothesis that in individuals with type 2 diabetes, hypoglycemia impairs a key measure of cardiovascular autonomic homeostasis, baroreflex sensitivity. METHODS: Sixteen individuals with well-controlled type 2 diabetes and without known cardiovascular disease were exposed to two 90-min episodes of experimental hypoglycemia (2.8 mmol/L, 50 mg/dL) on the same day. All individuals experienced a hypoglycemic-hyperinsulinemic clamp in the morning (AM clamp) and again in the afternoon (PM clamp). Baroreflex sensitivity was assessed using the modified Oxford method before the initiation of each hypoglycemic-hyperinsulinemic clamp, during the last 30 min of hypoglycemia, and the following morning. A mixed effects model adjusting for sex, age, BMI, and insulin level, demonstrated a significant effect of hypoglycemia on baroreflex sensitivity. The study is registered at ClinicalTrials.gov (NCT03422471). RESULTS: Baroreflex sensitivity during PM hypoglycemia was reduced compared to baseline, during AM hypoglycemia, and the next day. Insulin levels positively correlated with baroreflex sensitivity at baseline and during AM hypoglycemia. CONCLUSION: Exposure to hypoglycemia impairs a key measure of autonomic control of cardiovascular function and, thus, may increase the risk of cardiac arrhythmias and blood pressure lability in individuals with type 2 diabetes. This effect is attenuated in part by increased insulin levels.

Ghrelin does not impact the blunted counterregulatory response to recurrent hypoglycemia in mice.

Introduction: Recurrent episodes of insulin-induced hypoglycemia in patients with diabetes mellitus can result in hypoglycemia-associated autonomic failure (HAAF), which is characterized by a compromised response to hypoglycemia by counterregulatory hormones (counterregulatory response; CRR) and hypoglycemia unawareness. HAAF is a leading cause of morbidity in diabetes and often hinders optimal regulation of blood glucose levels. Yet, the molecular pathways underlying HAAF remain incompletely described. We previously reported that in mice, ghrelin is permissive for the usual CRR to insulin-induced hypoglycemia. Here, we tested the hypothesis that attenuated release of ghrelin both results from HAAF and contributes to HAAF. Methods: C57BL/6N mice, ghrelin-knockout (KO) + control mice, and GhIRKO (ghrelin cell-selective insulin receptor knockout) + control mice were randomized to one of three treatment groups: a "Euglycemia" group was injected with saline and remained euglycemic; a 1X hypoglycemia ("1X Hypo") group underwent a single episode of insulin-induced hypoglycemia; a recurrent hypoglycemia ("Recurrent Hypo") group underwent repeated episodes of insulin-induced hypoglycemia over five successive days. Results: Recurrent hypoglycemia exaggerated the reduction in blood glucose (by ~30%) and attenuated the elevations in plasma levels of the CRR hormones glucagon (by 64.5%) and epinephrine (by 52.9%) in C57BL/6N mice compared to a single hypoglycemic episode. Yet, plasma ghrelin was equivalently reduced in "1X Hypo" and "Recurrent Hypo" C57BL/6N mice. Ghrelin-KO mice exhibited neither exaggerated hypoglycemia in response to recurrent hypoglycemia, nor any additional attenuation in CRR hormone levels compared to wild-type littermates. Also, in response to recurrent hypoglycemia, GhIRKO mice exhibited nearly identical blood glucose and plasma CRR hormone levels as littermates with intact insulin receptor expression (floxed-IR mice), despite higher plasma ghrelin in GhIRKO mice. Conclusions: These data suggest that the usual reduction of plasma ghrelin due to insulin-induced hypoglycemia is unaltered by recurrent hypoglycemia and that ghrelin does not impact blood glucose or the blunted CRR hormone responses during recurrent hypoglycemia.

Automated Insulin Delivery for Hypoglycemia Avoidance and Glucose Counterregulation in Long-Standing Type 1 Diabetes with Hypoglycemia Unawareness.

Objective: Automated insulin delivery (AID) may benefit individuals with long-standing type 1 diabetes where frequent exposure to hypoglycemia impairs counterregulatory responses. This study assessed the effect of 18 months AID on hypoglycemia avoidance and glucose counterregulatory responses to insulin-induced hypoglycemia in long-standing type 1 diabetes complicated by impaired awareness of hypoglycemia. Methods: Ten participants mean ± standard deviation age 49 ± 16 and diabetes duration 34 ± 16 years were initiated on AID. Continuous glucose monitoring was paired with actigraphy to assess awake- and sleep-associated hypoglycemia exposure every 3 months. Hyperinsulinemic hypoglycemic clamp experiments were performed at baseline, 6, and 18 months postintervention. Hypoglycemia exposure was reduced by 3 months, especially during sleep, with effects sustained through 18 months (P ≤ 0.001) together with reduced glucose variability (P < 0.01). Results: Hypoglycemia awareness and severity scores improved (P < 0.01) with severe hypoglycemia events reduced from median (interquartile range) 3 (3-10) at baseline to 0 (0-1) events/person·year postintervention (P = 0.005). During the hypoglycemic clamp experiments, no change was seen in the endogenous glucose production (EGP) response, however, peripheral glucose utilization during hypoglycemia was reduced following intervention [pre: 4.6 ± 0.4, 6 months: 3.8 ± 0.5, 18 months: 3.4 ± 0.3 mg/(kg·min), P < 0.05]. There were increases over time in pancreatic polypeptide (Pre:62 ± 29, 6 months:127 ± 44, 18 months:176 ± 58 pmol/L, P < 0.01), epinephrine (Pre: 199 ± 53, 6 months: 332 ± 91, 18 months: 386 ± 95 pg/mL, P = 0.001), and autonomic symptom (Pre: 6 ± 2, 6 months: 6 ± 2, 18 months: 10 ± 2, P < 0.05) responses. Conclusions: AID led to a sustained reduction of hypoglycemia exposure. EGP in response to insulin-induced hypoglycemia remained defective, however, partial recovery of glucose counterregulation was evidenced by a reduction in peripheral glucose utilization likely mediated by increased epinephrine secretion and, together with improved autonomic symptoms, may contribute to the observed clinical reduction in hypoglycemia.

Pathophysiology and management of hypoglycemia in diabetes.

In the century since the discovery of insulin, diabetes has changed from an early death sentence to a manageable chronic disease. This change in longevity and duration of diabetes coupled with significant advances in therapeutic options for patients has fundamentally changed the landscape of diabetes management, particularly in patients with type 1 diabetes mellitus. However, hypoglycemia remains a major barrier to achieving optimal glycemic control. Current understanding of the mechanisms of hypoglycemia has expanded to include not only counter-regulatory hormonal responses but also direct changes in brain glucose, fuel sensing, and utilization, as well as changes in neural networks that modulate behavior, mood, and cognition. Different strategies to prevent and treat hypoglycemia have been developed, including educational strategies, new insulin formulations, delivery devices, novel technologies, and pharmacologic targets. This review article will discuss current literature contributing to our understanding of the myriad of factors that lead to the development of clinically meaningful hypoglycemia and review established and novel therapies for the prevention and treatment of hypoglycemia.

Experimentally Induced Hypoglycemia-associated Autonomic Failure in Humans: Determinants, Designs, and Drawbacks.

Context: Iatrogenic hypoglycemia remains one of the leading hindrances of optimal glycemic management in insulin-treated diabetes. Recurring hypoglycemia leads to a condition of hypoglycemia-associated autonomic failure (HAAF). HAAF refers to a combination of (i) impaired hormonal counterregulatory responses and (ii) hypoglycemia unawareness to subsequent hypoglycemia, substantially increasing the risk of severe hypoglycemia. Several studies since the 1990s have experimentally induced HAAF, yielding variable results. Objective: The aim of this review was to assess the varying designs, clinical outcomes, potential assets, and drawbacks related to these studies. Method: A systemic literature search was conducted on PubMed and Embase in winter 2021 to include all human studies attempting to experimentally induce HAAF. In different combinations, the search terms used were "hypoglycemia-associated autonomic failure," "HAAF," "hypoglycemia," "recurring," "recurrent," "repeated," "consecutive," and "unawareness," yielding 1565 publications. Inclusion criteria were studies that had aimed at experimentally inducing HAAF and measuring outcomes of hormonal counterregulation and awareness of hypoglycemia. Results: The literature search yielded 27 eligible publications, of which 20 were successful in inducing HAAF while statistical significantly impairing both hormonal counterregulation and impairing awareness of hypoglycemia to subsequent hypoglycemia. Several factors were of significance as regards inducing HAAF: Foremost, the duration of antecedent hypoglycemia should be at least 90 minutes and blood glucose should be maintained below 3.4 mmol/L. Other important factors to consider are the type of participants, insulin dosage, and the risk of unintended hypoglycemia prior to the study. Conclusion: Here we have outlined the most important factors to take into consideration when designing a study aimed at inducing HAAF, including to take into consideration other disease states susceptible to hypoglycemia, thus hopefully clarifying the field and allowing qualified studies in the future.

Hypoglycemic unawareness: challenges, triggers, and recommendations in patients with hypoglycemic unawareness: a case report.

BACKGROUND: Hypoglycemia is a fairly common complication in diabetic patients, particularly in those on insulin therapy. Hypoglycemia symptoms are classified into two types: autonomic and neuroglycopenic symptoms. If a person develops neuroglycopenic symptoms before the appearance of autonomic symptoms or is asymptomatic until blood sugar levels are very low, the patient will develop hypoglycemic unawareness (HU). CASE PRESENTATION: A 25-year-old Iranian woman with HU presented with a severe hypoglycemic episode. This episode was characterized by loss of consciousness and focal neural deficits, which were unusual symptoms in the patient, who was a medical intern with type 1 diabetes and currently being treated with regular and NPH insulin. CONCLUSIONS: Hypoglycemia is a common complication in diabetic patients receiving oral or insulin therapy. A patient who is unaware of their condition may experience severe and potentially fatal episodes. These incidents can negatively affect their daily lives as well as their careers and jobs. Hypoglycemia-associated autonomic failure is a possible cause for patients with multiple episodes of severe hypoglycemia. IThe use of a continuous glucose monitoring device with an alarm, if available, can be an excellent option for these patients.

Falla autonómica asociada a hipoglucemia / Hypoglycemia associated autonomic failure

La hipoglucemia inadvertida (HI) es una complicación del tratamiento de la diabetes mellitus tipo 1 (DM1) y DM2 tratada con insulina o sulfonilureas, que se caracteriza por una capacidad reducida para percibir el inicio de los episodios de hipoglucemia. En general, coexiste con una insuficiente respuesta hormonal contrarreguladora a la hipoglucemia denominada falla autonómica asociada a la hipoglucemia (FAAH). El desarrollo de HI y de falla contrarreguladora a la hipoglucemia aumentan significativamente el riesgo de hipoglucemias severas. Se han desarrollado escalas de puntuación para identificar, en la consulta clínica, a este grupo de personas con elevado riesgo de hipoglucemias severas. La piedra angular del tratamiento consiste en evitar las hipoglucemias mediante una intervención multifactorial de cuidados clínicos y educación estructurada.

Hypoglycemia unawereness is a complication of type 1 diabetes treatment and of type 2 diabetes treatment treated with insulin or sulfonylureas, characterized by a reduced ability to perceive the onset of episodes of hypoglycemia. In general, it coexists with an insufficient counterregulatory hormonal response to hypoglycemia called: hypoglycemia associated autonomic failure (HAAF). The development of hypoglycemia unawereness and counterregulatory failure to hypoglycemia significantly increase the risk of severe hypoglycemia. Scoring scales have been developed to identify this group of people at high risk of severe hypoglycemia in the clinic. The cornerstone of treatment is to avoid hypoglycemia through a multifactorial intervention of clinical care and structured education.

Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure.

BACKGROUND: Recurrent hypoglycemia blunts counter-regulatory responses to subsequent hypoglycemic episodes, a syndrome known as hypoglycemia-associated autonomic failure (HAAF). Since adrenergic receptor blockade has been reported to prevent HAAF, we investigated whether the hypoglycemia-associated rise in plasma epinephrine contributes to pathophysiology and reported interindividual differences in susceptibility to HAAF. METHODS: To assess the role of hypoglycemia-associated epinephrine responses in the susceptibility to HAAF, 24 adult nondiabetic subjects underwent two 2-hour hyperinsulinemic hypoglycemic clamp studies (nadir 54 mg/dL; 0-2 hours and 4-6 hours) on Day 1, followed by a third identical clamp on Day 2. We challenged an additional 7 subjects with two 2-hour infusions of epinephrine (0.03 µg/kg/min; 0-2 hours and 4-6 hours) vs saline on Day 1 followed by a 200-minute stepped hypoglycemic clamp (90, 80, 70, and 60 mg/dL) on Day 2. RESULTS: Thirteen out of 24 subjects developed HAAF, defined by ≥20% reduction in average epinephrine levels during the final 30 minutes of the third compared with the first hypoglycemic episode (P < 0.001). Average epinephrine levels during the final 30 minutes of the first hypoglycemic episode were 2.3 times higher in subjects who developed HAAF compared with those who did not (P = 0.006).Compared to saline, epinephrine infusion on Day 1 reduced the epinephrine responses by 27% at the 70 and 60 mg/dL glucose steps combined (P = 0.04), with a parallel reduction in hypoglycemic symptoms (P = 0.03) on Day 2. CONCLUSIONS: Increases in plasma epinephrine reproduce key features of HAAF in nondiabetic subjects. Marked interindividual variability in epinephrine responses to hypoglycemia may explain an individual's susceptibility to developing HAAF.

A Human Randomized Controlled Trial Comparing Metabolic Responses to Single and Repeated Hypoglycemia in Type 1 Diabetes.

AIMS: Hypoglycemia hinders optimal glycemic management in type 1 diabetes (T1D). Long diabetes duration and hypoglycemia impair hormonal counter-regulatory responses to hypoglycemia. Our study was designed to test whether (1) the metabolic responses and insulin sensitivity are impaired, and (2) whether they are affected by short-lived antecedent hypoglycemia in participants with T1D. MATERIALS AND METHODS: In a randomized, crossover, 2x2 factorial design, 9 male participants with T1D and 9 comparable control participants underwent 30 minutes of hypoglycemia (p-glucose < 2.9 mmol/L) followed by a euglycemic clamp on 2 separate interventions: with and without 30 minutes of hypoglycemia the day before the study day. RESULTS: During both interventions insulin sensitivity was consistently lower, while counter-regulatory hormones were reduced, with 75% lower glucagon and 50% lower epinephrine during hypoglycemia in participants with T1D, who also displayed 40% lower lactate and 5- to 10-fold increased ketone body concentrations following hypoglycemia, whereas palmitate and glucose turnover, forearm glucose uptake, and substrate oxidation did not differ between the groups. In participants with T1D, adipose tissue phosphatase and tensin homolog (PTEN) content, hormone-sensitive lipase (HSL) phosphorylation, and muscle glucose transporter type 4 (GLUT4) content were decreased compared with controls. And antecedent hypoglycemic episodes lasting 30 minutes did not affect counter-regulation or insulin sensitivity. CONCLUSIONS: Participants with T1D displayed insulin resistance and impaired hormonal counter-regulation during hypoglycemia, whereas glucose and fatty acid fluxes were intact and ketogenic responses were amplified. We observed subtle alterations of intracellular signaling and no effect of short-lived antecedent hypoglycemia on subsequent counter-regulation. This plausibly reflects the presence of insulin resistance and implies that T1D is a condition with defective hormonal but preserved metabolic responsiveness to short-lived hypoglycemia.

Potential role of hypothalamic microRNAs in regulation of FOS and FTO expression in response to hypoglycemia.

Hypoglycemia-associated autonomic failure (HAAF) is a serious complication of diabetes which is associated with the absence of physiological homeostatic counter-regulatory mechanisms that are controlled by the hypothalamus and sympathetic nervous system. Identification of biomarkers for early detection of HAAF requires an advanced understanding of molecular signature of hypoglycemia which is yet to be identified. The outcomes of the present study have shown that the viability and the apoptotic rate of the hypothalamic neurons (mHypoE-N39) were decreased significantly due to hypoglycemia in a dose-dependent fashion (p < 0.05). Although there are more than 1000 miRNAs differentially expressed in hypothalamus, only twelve miRNAs (miR-7a, miR-7b, miR-9, miR-29b, miR-29c, miR-30a, miR-30b, miR-30c, miR-101b-3p, miR-181a-5p, miR-378-3p and miR-873-5p) were correlated to two main hypothalamic regulatory proteins, FOS and FTO. Expression of these proteins was very sensitive to hypoglycemia. We demonstrated that hypoglycemia modulates the expression of hypothalamic miRNAs that are related to FOS and FTO.

The hypoglycemia associated autonomic failure triggered by exercise in the patients with "brittle" diabetes and the strategy for prevention.

Exercise is a fundamental component of diabetes management. However, choosing inappropriate type or timing of exercise is associated with mild or severe hypoglycemia either during exercise or several hours after exercise. Several studies have shown that impaired counterregulatory responses triggers hypoglycemia. Therefore, in this investigation, we explored the appropriate intensity and time of exercise in patients with diabetes. The mechanisms of counterregulatory responses and hypoglycemia associated autonomic failure (HAAF), as well as the strategies for preventing episodes of hypoglycemia after exercise were also investigated. In this study, we obtained the following results: 1) High intensity interval exercise is more suitable for diabetic patients. 2) Morning exercise reduces nocturnal hypoglycemia risks compared with midday, afternoon and evening exercise. 3) Hypoglycemia can be prevented by dietary approach, reduction or suspension of insulin dose, use of mini dose glucagon, caffeine, mitigation methods, prediction algorithm, autonomic feedback controlled close-loop insulin delivery, real time continuous glucose monitoring. Based on these results we concluded that exercise may cause severe hypoglycemia or induce blunted response in patients with diabetes. For Diabetes Mellitus (DM) patients, the intensity and time of exercise influence the occurrence of hypoglycemia. This review summarizes the clinical characteristics of different types of exercises and time of exercise that can be potentially used to educate and guide patients regarding the role of exercise in standard of care.

Hypoglycemia-associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes.

Hypoglycemia remains a major barrier to the achievement of target levels of glycemic control for most individuals with insulin-dependent type 1 diabetes (T1D). Both the loss of ß cells and an accompanying defect in the α cell response to hypoglycemia predispose patients with T1D to the development of low blood glucose. Increased glucose variability, exposure to hypoglycemia, and impaired awareness of hypoglycemia all contribute to increased risk of experiencing severe hypoglycemia, which is explained by progressive impairment in epinephrine secretion and autonomic symptom generation in response to hypoglycemia leading to defective glucose counterregulation and hypoglycemia unawareness that characterize hypoglycemia-associated autonomic failure (HAAF). Interruption of HAAF requires interfering with the mechanisms of brain adaptation to low blood glucose that affect central glucose sensing and the autonomic response to hypoglycemia, or avoidance of hypoglycemia that may allow for eventual recovery of counterregulatory and autonomic symptom responses. Strategies for hypoglycemia avoidance that include continuous glucose monitoring may reduce, but do not eliminate, clinically significant hypoglycemia, with ongoing counterregulatory defects and impaired awareness of hypoglycemia. Complete avoidance of hypoglycemia can be achieved following pancreatic islet transplantation and allows for the restoration of counterregulatory and autonomic symptom responses that evidences the potential for reversing HAAF in T1D.

Hypoglycemia: Role of Hypothalamic Glucose-Inhibited (GI) Neurons in Detection and Correction.

Hypoglycemia is a profound threat to the brain since glucose is its primary fuel. As a result, glucose sensors are widely located in the central nervous system and periphery. In this perspective we will focus on the role of hypothalamic glucose-inhibited (GI) neurons in sensing and correcting hypoglycemia. In particular, we will discuss GI neurons in the ventromedial hypothalamus (VMH) which express neuronal nitric oxide synthase (nNOS) and in the perifornical hypothalamus (PFH) which express orexin. The ability of VMH nNOS-GI neurons to depolarize in low glucose closely parallels the hormonal response to hypoglycemia which stimulates gluconeogenesis. We have found that nitric oxide (NO) production in low glucose is dependent on oxidative status. In this perspective we will discuss the potential relevance of our work showing that enhancing the glutathione antioxidant system prevents hypoglycemia associated autonomic failure (HAAF) in non-diabetic rats whereas VMH overexpression of the thioredoxin antioxidant system restores hypoglycemia counterregulation in rats with type 1 diabetes.We will also address the potential role of the orexin-GI neurons in the arousal response needed for hypoglycemia awareness which leads to behavioral correction (e.g., food intake, glucose administration). The potential relationship between the hypothalamic sensors and the neurocircuitry in the hindbrain and portal mesenteric vein which is critical for hypoglycemia correction will then be discussed.

Cerebral glycogen in humans following acute and recurrent hypoglycemia: Implications on a role in hypoglycemia unawareness.

Supercompensated brain glycogen levels may contribute to the development of hypoglycemia-associated autonomic failure (HAAF) following recurrent hypoglycemia (RH) by providing energy for the brain during subsequent periods of hypoglycemia. To assess the role of glycogen supercompensation in the generation of HAAF, we estimated the level of brain glycogen following RH and acute hypoglycemia (AH). After undergoing 3 hyperinsulinemic, euglycemic and 3 hyperinsulinemic, hypoglycemic clamps (RH) on separate occasions at least 1 month apart, five healthy volunteers received [1-13C]glucose intravenously over 80+ h while maintaining euglycemia. 13C-glycogen levels in the occipital lobe were measured by 13C magnetic resonance spectroscopy at ∼8, 20, 32, 44, 56, 68 and 80 h at 4 T and glycogen levels estimated by fitting the data with a biophysical model that takes into account the tiered glycogen structure. Similarly, prior 13C-glycogen data obtained following a single hypoglycemic episode (AH) were fitted with the same model. Glycogen levels did not significantly increase after RH relative to after euglycemia, while they increased by ∼16% after AH relative to after euglycemia. These data suggest that glycogen supercompensation may be blunted with repeated hypoglycemic episodes. A causal relationship between glycogen supercompensation and generation of HAAF remains to be established.

Hypothalamic-Pituitary-Adrenal Axis Programming after Recurrent Hypoglycemia during Development.

Permanent brain injury is a complication of recurrent hypoglycemia during development. Recurrent hypoglycemia also has adverse consequences on the neuroendocrine system. Hypoglycemia-associated autonomic failure, characterized by ineffective glucose counterregulation during hypoglycemia, is well described in children and adults on insulin therapy for diabetes mellitus. Whether recurrent hypoglycemia also has a programming effect on the hypothalamus-pituitary-adrenal cortex (HPA) axis has not been well studied. Hypoglycemia is a potent stress that leads to increased glucocorticoid secretion in all age groups, including the perinatal period. Other conditions associated with exposure to excess glucocorticoid in the perinatal period have a programming effect on the HPA axis activity. Limited animal data suggest the possibility of similar programming effect after recurrent hypoglycemia in the postnatal period. The age at exposure to hypoglycemia likely determines the HPA axis response in adulthood. Recurrent hypoglycemia in the early postnatal period likely leads to a hyperresponsive HPA axis, whereas recurrent hypoglycemia in the late postnatal period lead to a hyporesponsive HPA axis in adulthood. The age-specific programming effects may determine the neuroendocrine response during hypoglycemia and other stressful events in individuals with history of recurrent hypoglycemia during development.

Mechanisms of hypoglycemia unawareness and implications in diabetic patients.

Hypoglycemia unawareness (HU) is defined at the onset of neuroglycopenia before the appearance of autonomic warning symptoms. It is a major limitation to achieving tight diabetes and reduced quality of life. HU occurs in approximately 40% of people with type 1 diabetes mellitus (T1DM) and with less frequency in T2DM. Though the aetiology of HU is multifactorial, possible mechanisms include chronic exposure to low blood glucose, antecedent hypoglycaemia, recurrent severe hypoglycaemia and the failure of counter-regulatory hormones. Clinically it manifests as the inability to recognise impeding hypoglycaemia by symptoms, but the mechanisms and mediators remain largely unknown. Prevention and management of HU is complex, and can only be achieved by a multifactorial intervention of clinical care and structured patient education by the diabetes team. Less know regarding the impact of medications on the development or recognition of this condition in patients with diabetes. Several medications are thought to worsen or promote HU, whereas others may have an attenuating effect on the problem. This article reviews recent advances in how the brain senses and responds to hypoglycaemia, novel mechanisms by which people with insulin-treated diabetes develop HU and impaired counter-regulatory responses. The consequences that HU has on the person with diabetes and their family are also described. Finally, it examines the evidence for prevention and treatment of HU, and summarizes the effects of medications that may influence it.

Posttranscriptional regulation of adrenal TH gene expression contributes to the maladaptive responses triggered by insulin-induced recurrent hypoglycemia.

Acute metabolic stress such as insulin-induced hypoglycemia triggers a counterregulatory response during which the release of catecholamines (epinephrine), the activation of tyrosine hydroxylase (TH) enzyme and subsequent compensatory catecholamine biosynthesis occur in the adrenal medulla. However, recurrent exposure to hypoglycemia (RH), a consequence of tight glycemic control in individuals with type 1 and type 2 diabetes compromises this physiological response. The molecular mechanisms underlying the maladaptive response to repeated glucose deprivation are incompletely understood. We hypothesize that impaired epinephrine release following RH reflects altered regulation of adrenal catecholamine biosynthesis. To test this hypothesis, we compared the effect of single daily (RH) and twice-daily episodes of insulin-induced hypoglycemia (2RH) on adrenal epinephrine release and production in normal rats. Control animals received saline injections under similar conditions (RS and 2RS, respectively). Following 3 days of treatment, we assessed the counterregulatory hormonal responses during a hypoglycemic clamp. Changes in adrenal TH gene expression were also analyzed. The counterregulatory responses, relative TH transcription and TH mRNA levels and Ser40-TH phosphorylation (marker for enzyme activation) were induced to a similar extent in RS, 2RS, and RH groups. In contrast, epinephrine and glucagon responses were attenuated in the 2RH group and this was associated with a limited elevation of adrenal TH mRNA, rapid inactivation of TH enzyme and no significant changes in TH protein. Our results suggest that novel posttranscriptional mechanisms controlling TH mRNA and activated TH enzyme turnover contribute to the impaired epinephrine responses and may provide new therapeutic targets to prevent HAAF.

Avoiding or coping with severe hypoglycemia in patients with type 2 diabetes.

Hypoglycemia is a major barrier to achieving the glycemic goal in patients with type 2 diabetes. In particular, severe hypoglycemia, which is defined as an event that requires the assistance of another person to actively administer carbohydrates, glucagon, or take other corrective actions, is a serious clinical concern in patients with diabetes. If severe hypoglycemia is not managed promptly, it can be life threatening. Hypoglycemia-associated autonomic failure (HAAF) is the main pathogenic mechanism behind severe hypoglycemia. Defective glucose counter-regulation (altered insulin secretion, glucagon secretion, and an attenuated increase in epinephrine during hypoglycemia) and a lack of awareness regarding hypoglycemia (attenuated sympathoadrenal activity) are common components of HAAF in patients with diabetes. There is considerable evidence that hypoglycemia is an independent risk factor for cardiovascular disease. In addition, hypoglycemia has a significant influence on the quality of life of patients with diabetes. To prevent hypoglycemic events, the setting of glycemic goals should be individualized, particularly in elderly individuals or patients with complicated or advanced type 2 diabetes. Patients at high-risk for the future development of severe hypoglycemia should be selected carefully, and intensive education with reinforcement should be implemented.

Avoiding or coping with severe hypoglycemia in patients with type 2 diabetes

Hypoglycemia is a major barrier to achieving the glycemic goal in patients with type 2 diabetes. In particular, severe hypoglycemia, which is defined as an event that requires the assistance of another person to actively administer carbohydrates, glucagon, or take other corrective actions, is a serious clinical concern in patients with diabetes. If severe hypoglycemia is not managed promptly, it can be life threatening. Hypoglycemia-associated autonomic failure (HAAF) is the main pathogenic mechanism behind severe hypoglycemia. Defective glucose counter-regulation (altered insulin secretion, glucagon secretion, and an attenuated increase in epinephrine during hypoglycemia) and a lack of awareness regarding hypoglycemia (attenuated sympathoadrenal activity) are common components of HAAF in patients with diabetes. There is considerable evidence that hypoglycemia is an independent risk factor for cardiovascular disease. In addition, hypoglycemia has a significant influence on the quality of life of patients with diabetes. To prevent hypoglycemic events, the setting of glycemic goals should be individualized, particularly in elderly individuals or patients with complicated or advanced type 2 diabetes. Patients at high-risk for the future development of severe hypoglycemia should be selected carefully, and intensive education with reinforcement should be implemented.

Diabetic autonomic neuropathy.

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.