Effects of Intranasal Naloxone on Hypoglycemia-Associated Autonomic Failure (HAAF) in Susceptible Individuals.

CONTEXT: Hypoglycemia-associated autonomic failure (HAAF), defined as blunting of counter-regulatory hormone and symptom responses to recurrent hypoglycemia, remains a therapeutic challenge in diabetes treatment. The opioid system may play a role in HAAF pathogenesis since activation of opioid receptors induces HAAF. Blockade of opioid receptors with intravenous naloxone ameliorates HAAF experimentally, yet is not feasible therapeutically. OBJECTIVE: To investigate the effects of opioid receptor blockade with intranasal naloxone on experimentally-induced HAAF. DESIGN: Randomized, double-blinded, placebo-controlled crossover study. SETTING: Academic research center. PARTICIPANTS: Healthy non-diabetic volunteers. INTERVENTIONS: Paired two-day studies, 5-10 weeks apart, each consisting of three consecutive hypoglycemic episodes (hyperinsulinemic hypoglycemic clamps, glucose nadir: 54 mg/dL): two on day 1 with administration of intranasal naloxone vs. placebo, followed by the third episode on day 2. MAIN OUTCOME MEASURES: Differences in counter-regulatory hormones responses and hypoglycemia symptoms between first and third hypoglycemic episodes in naloxone vs. placebo studies. RESULTS: Out of 17 participants, 9 developed HAAF, confirming variable inter-individual susceptibility. Among participants susceptible to HAAF, naloxone maintained some hormonal and symptomatic responses to hypoglycemia and prevented the associated requirement for increased glucose infusion. Unexpectedly, naloxone reduced plasma epinephrine and growth hormone responses to the first hypoglycemic episode but prevented further reduction with subsequent hypoglycemia. CONCLUSIONS: This is the first study to report that intranasal naloxone, a widely used opioid receptor antagonist, may ameliorate some features of HAAF. Further investigation is warranted into mechanisms of variable inter-individual susceptibility to HAAF and the effects of intranasal naloxone in people with diabetes at risk for HAAF.

Lesion of NPY Receptor-expressing Neurons in Perifornical Lateral Hypothalamus Attenuates Glucoprivic Feeding.

Glucoprivic feeding is one of several counterregulatory responses (CRRs) that facilitates restoration of euglycemia following acute glucose deficit (glucoprivation). Our previous work established that glucoprivic feeding requires ventrolateral medullary (VLM) catecholamine (CA) neurons that coexpress neuropeptide Y (NPY). However, the connections by which VLM CA/NPY neurons trigger increased feeding are uncertain. We have previously shown that glucoprivation, induced by an anti-glycolygic agent 2-deoxy-D-glucose (2DG), activates perifornical lateral hypothalamus (PeFLH) neurons and that expression of NPY in the VLM CA/NPY neurons is required for glucoprivic feeding. We therefore hypothesized that glucoprivic feeding and possibly other CRRs require NPY-sensitive PeFLH neurons. To test this, we used the ribosomal toxin conjugate NPY-saporin (NPY-SAP) to selectively lesion NPY receptor-expressing neurons in the PeFLH of male rats. We found that NPY-SAP destroyed a significant number of PeFLH neurons, including those expressing orexin, but not those expressing melanin-concentrating hormone. The PeFLH NPY-SAP lesions attenuated 2DG-induced feeding but did not affect 2DG-induced increase in locomotor activity, sympathoadrenal hyperglycemia, or corticosterone release. The 2DG-induced feeding response was also significantly attenuated in NPY-SAP-treated female rats. Interestingly, PeFLH NPY-SAP lesioned male rats had reduced body weights and decreased dark cycle feeding, but this effect was not seen in female rats. We conclude that a NPY projection to the PeFLH is necessary for glucoprivic feeding, but not locomotor activity, hyperglycemia, or corticosterone release, in both male and female rats.

Hypoglycaemia.

In health hypoglycaemia is rare and occurs only in circumstances like extreme sports. Hypoglycaemia in type 1 Diabetes (T1D) and advanced type 2 Diabetes (T2D) are the result of interplay between absolute or relative insulin access and defective glucose counterregulation. The basic mechanism is, failure of decreasing insulin and failure of the compensatory increasing counterregulatory hormones at the background of falling blood glucose. Any person with Diabetes on anti-diabetic medication who behaves oddly in any way whatsoever is hypoglycaemic until proven otherwise. Hypoglycaemia can be a terrifying experience for a patient with Diabetes. By definition, hypoglycaemic symptoms are subjective and vary from person to person and even episode to episode in same person. Fear of iatrogenic hypoglycaemia is a major barrier in achieving optimum glycaemic control and quality of life which limits the reduction of diabetic complications. Diabetes patients with comorbidities especially with chronic renal failure, hepatic dysfunction, major limb amputation, terminal illness, cognitive dysfunction etc. are more vulnerable to hypoglycaemia. In most cases, prompt glucose intake reverts hypoglycaemia. Exogenous insulin in T1D and insulin treated advanced T2D have no control by pancreatic regulation. Moreover, failure of increase of glucagon and attenuated secretion in epinephrine causes the defective glucose counterregulation. In this comprehensive review, I will try to touch all related topics for better understanding of hypoglycaemia.

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia.

The impaired ability of the autonomic nervous system to respond to hypoglycemia is termed "hypoglycemia-associated autonomic failure" (HAAF). This life-threatening phenomenon results from at least two recent episodes of hypoglycemia, but the pathology underpinning HAAF remains largely unknown. Although naloxone appears to improve hypoglycemia counterregulation under controlled conditions, hypoglycemia prevention remains the current mainstay therapy for HAAF. Epinephrine-synthesizing neurons in the rostroventrolateral (C1) and dorsomedial (C3) medulla project to the subset of sympathetic preganglionic neurons that regulate peripheral epinephrine release. Here we determined whether or not C1 and C3 neuronal activation is impaired in HAAF and whether or not 1 wk of hypoglycemia prevention or treatment with naloxone could restore C1 and C3 neuronal activation and improve HAAF. Twenty male Sprague-Dawley rats (250-300 g) were used. Plasma epinephrine levels were significantly increased after a single episode of hypoglycemia (n = 4; 5,438 ± 783 pg/ml vs. control 193 ± 27 pg/ml, P < 0.05). Repeated hypoglycemia significantly reduced the plasma epinephrine response to subsequent hypoglycemia (n = 4; 2,179 ± 220 pg/ml vs. 5,438 ± 783 pg/ml, P < 0.05). Activation of medullary C1 (n = 4; 50 ± 5% vs. control 3 ± 1%, P < 0.05) and C3 (n = 4; 45 ± 5% vs. control 4 ± 1%, P < 0.05) neurons was significantly increased after a single episode of hypoglycemia. Activation of C1 (n = 4; 12 ± 3%, P < 0.05) and C3 (n = 4; 19 ± 5%, P < 0.05) neurons was significantly reduced in the HAAF groups. Hypoglycemia prevention or treatment with naloxone did not restore the plasma epinephrine response or C1 and C3 neuronal activation. Thus repeated hypoglycemia reduced the activation of C1 and C3 neurons mediating adrenal medullary responses to subsequent bouts of hypoglycemia.

Resting metabolic rate in muscular physique athletes: validity of existing methods and development of new prediction equations.

Estimation of resting metabolic rate (RMR) is an important step for prescribing an individual's energy intake. The purpose of this study was to evaluate the validity of portable indirect calorimeters and RMR prediction equations in muscular physique athletes. Twenty-seven males (n = 17; body mass index (BMI): 28.8 ± 2.0 kg/m2; body fat: 12.5% ± 2.7%) and females (n = 10; BMI: 22.8 ± 1.6 kg/m2; body fat: 19.2% ± 3.4%) were evaluated. The reference RMR value was obtained from the ParvoMedics TrueOne 2400 indirect calorimeter, and the Cosmed Fitmate and Breezing Metabolism Tracker provided additional RMR estimates. Existing RMR prediction equations based on body weight (BW) or dual-energy X-ray absorptiometry fat-free mass (FFM) were also evaluated. Errors in RMR estimates were assessed using validity statistics, including t tests with Bonferroni correction, linear regression, and calculation of the standard error of the estimate, total error, and 95% limits of agreement. Additionally, new prediction equations based on BW (RMR (kcal/day) = 24.8 × BW (kg) + 10) and FFM (RMR (kcal/day) = 25.9 × FFM (kg) + 284) were developed using stepwise linear regression and evaluated using leave-one-out cross-validation. Nearly all existing BW- and FFM-based prediction equations, as well as the Breezing Tracker, did not exhibit acceptable validity and typically underestimated RMR. The ten Haaf and Weijs (PLoS ONE, 9: e1084602014 (2014)) and Cunningham (1980) (Am. J. Clin. Nutr. 33: 2372-2374 (1980)) FFM-based equations may produce acceptable RMR estimates, although the Cosmed Fitmate and newly developed BW- and FFM-based equations may be most suitable for RMR estimation in male and female physique athletes. Future research should provide additional external cross-validation of the newly developed equations to refine the ability to predict RMR in physique athletes.

Naltrexone for treatment of impaired awareness of hypoglycemia in type 1 diabetes: A randomized clinical trial.

AIMS: Impaired awareness of hypoglycemia (IAH) is a limiting factor in the treatment of type 1 diabetes (T1D) and is a challenging condition to reverse. The objective of this study was to test the hypothesis that naltrexone therapy in subjects with T1D and IAH will improve counterregulatory hormone response and recognition of hypoglycemia symptoms during hypoglycemia. METHODS: We performed a pilot randomized double blind trial of 4weeks of naltrexone therapy (n=10) or placebo (n=12) given orally in subjects with T1D and IAH. Outcome measures included hypoglycemia symptom scores, counterregulatory hormone levels and thalamic activation as measured by cerebral blood flow using MRI during experimental hypoglycemia in all subjects before and after 4weeks of intervention. RESULTS: After 4weeks of therapy with naltrexone or placebo, no significant differences in response to hypoglycemia were seen in any outcomes of interest within each group. CONCLUSIONS: In this small study, short-term treatment with naltrexone did not improve recognition of hypoglycemia symptoms or counterregulatory hormone response during experimental hypoglycemia in subjects with T1D and IAH. Whether this lack of effect is related to the small sample size or due to the dose, the advanced stage of study population or the drug itself should be the subject of future investigation.

Koch-Haaf reaction of adamantanols in an acid-tolerant hastelloy-made microreactor.

The Koch-Haaf reaction of adamantanols was successfully carried out in a microflow system at room temperature. By combining an acid-tolerant hastelloy-made micromixer, a PTFE tube, and a hastelloy-made microextraction unit, a packaged reaction-to-workup system was developed. By means of the present system, the multigram scale synthesis of 1-adamantanecarboxylic acid was achieved in ca. one hour operation.

A model of self-treatment behavior, glucose variability, and hypoglycemia-associated autonomic failure in type 1 diabetes.

BACKGROUND: Type 1 diabetes patients face a lifelong behaviorally controlled optimization problem: maintaining strict glycemic control without increasing the risk of hypoglycemia. Because internal insulin secretion in type 1 diabetes (T1DM) is practically absent, this optimization is entirely dependent on the interplay among (i) self-treatment behavior, (ii) interaction between exogenous insulin and carbohydrates utilization, and (iii) internal defenses against hypoglycemia. This article presents a mathematical model and a computer simulation of the relationship among self-treatment in T1DM, blood glucose (BG) variability, and hypoglycemia-associated autonomic failure (HAAF). METHOD: A stochastic behavioral self-control process was coupled with a dynamical system simulation of the dampening effect of counterregulation on BG oscillations. The resulting biobehavioral control system was compared to data from a field clinical trial (85 T1DM patients, 21-62 years old, T1DM of at least 2 years duration, and at least two documented severe hypoglycemia episodes during the previous year). RESULTS: The mathematical simulation was able to reproduce characteristics of hypoglycemic events observed during a field clinical trial, such as temporal clustering of hypoglycemic episodes associated with HAAF and occurrence of severe hypoglycemia as a result of periods of HAAF augmented by increased BG variability. CONCLUSION: This investigation offers a mathematical model of HAAF-the primary barrier to intensive insulin treatment. This combined modeling/computer simulation/data analysis approach explains the temporal relationship among behaviorally induced hypoglycemia, glucose variability, and autonomic failure in T1DM. This explanation is valuable not only because it indicates that signs of HAAF can be detected in patients' natural environment via self-monitoring or continuous glucose monitoring, but also because it allows for tracking of the risk of severe hypoglycemia over time.