Sarah S. Farabi

Fear of hypoglycemia in adults with type 1 diabetes: impact of therapeutic advances and strategies for prevention - a review.

PURPOSE This review summarizes the current state of the science related to fear of hypoglycemia (FOH) in adults with type 1 diabetes. Fear of hypoglycemia is a critical deterrent to diabetes self-management, psychological well-being, and quality of life. We examine the influence of contemporary treatment regimens, technology, and interventions to identify gaps in knowledge and opportunities for research and practice. BASIC PROCEDURES A literature search was conducted of MEDLINE, PsycINFO, and EMBASE. Fifty-three studies that examined fear of hypoglycemia were included. MAIN FINDINGS Fear of hypoglycemia influences diabetes management and quality of life. Gender and age differences exist in experiences and responses. Responses vary from increased vigilance to potentially immobilizing distress. Fear of hypoglycemia is greater at night and may contribute to poor sleep quality. Strategies to reduce fear of hypoglycemia have had varying success. Newer technologies hold promise but require further examination. CONCLUSIONS Fear of hypoglycemia remains a problem, despite advances in technology, insulin analogs, and evidence-based diabetes management. Clinical care should consistently include assessment for its influence on diabetes self-management and psychological health. Further research is needed regarding the influence of newer technologies and individualized strategies to reduce fear of hypoglycemia while maintaining optimal glucose control.

Innovative treatments for adults with obstructive sleep apnea

Obstructive sleep apnea (OSA) affects one in five adult males and is associated with significant comorbidity, cognitive impairment, excessive daytime sleepiness, and reduced quality of life. For over 25 years, the primary treatment has been continuous positive airway pressure, which introduces a column of air that serves as a pneumatic splint for the upper airway, preventing the airway collapse that is the physiologic definition of this syndrome. However, issues with patient tolerance and unacceptable levels of treatment adherence motivated the exploration of other potential treatments. With greater understanding of the physiologic mechanisms associated with OSA, novel interventions have emerged in the last 5 years. The purpose of this article is to describe new treatments for OSA and associated complex sleep apnea. New approaches to complex sleep apnea have included adaptive servoventilation. There is increased literature on the contribution of behavioral interventions to improve adherence with continuous positive airway pressure that have proven quite effective. New non-surgical treatments include oral pressure devices, improved mandibular advancement devices, nasal expiratory positive airway pressure, and newer approaches to positional therapy. Recent innovations in surgical interventions have included laser-assisted uvulopalatoplasty, radiofrequency ablation, palatal implants, and electrical stimulation of the upper airway muscles. No drugs have been approved to treat OSA, but potential drug therapies have centered on increasing ventilatory drive, altering the arousal threshold, modifying loop gain (a dimensionless value quantifying the stability of the ventilatory control system), or preventing airway collapse by affecting the surface tension. An emerging approach is the application of cannabinoids to increase upper airway tone.

Impact of dronabinol on quantitative electroencephalogram (qEEG) measures of sleep in obstructive sleep apnea syndrome.

STUDY OBJECTIVES To determine the effects of dronabinol on quantitative electroencephalogram (EEG) markers of the sleep process, including power distribution and ultradian cycling in 15 patients with obstructive sleep apnea (OSA). METHODS EEG (C4-A1) relative power (% total) in the delta, theta, alpha, and sigma bands was quantified by fast Fourier transformation (FFT) over 28-second intervals. An activation ratio (AR = [alpha + sigma] / [delta + theta]) also was computed for each interval. To assess ultradian rhythms, the best-fitting cosine wave was determined for AR and each frequency band in each polysomnogram (PSG). RESULTS Fifteen subjects were included in the analysis. Dronabinol was associated with significantly increased theta power (p = 0.002). During the first half of the night, dronabinol decreased sigma power (p = 0.03) and AR (p = 0.03), and increased theta power (p = 0.0006). At increasing dronabinol doses, ultradian rhythms accounted for a greater fraction of EEG power variance in the delta band (p = 0.04) and AR (p = 0.03). Females had higher amplitude ultradian rhythms than males (theta: p = 0.01; sigma: p = 0.01). Decreasing AHI was associated with increasing ultradian rhythm amplitudes (sigma: p < 0.001; AR: p = 0.02). At the end of treatment, lower relative power in the theta band (p = 0.02) and lower AHI (p = 0.05) correlated with a greater decrease in sleepiness from baseline. CONCLUSIONS This exploratory study demonstrates that in individuals with OSA, dronabinol treatment may yield a shift in EEG power toward delta and theta frequencies and a strengthening of ultradian rhythms in the sleep EEG.

Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes

The soluble receptor for advanced glycation end products (sRAGE) may be protective against inflammation associated with obesity and type 2 diabetes (T2DM). The aim of this study was to determine the distribution of sRAGE isoforms and whether sRAGE isoforms are associated with risk of T2DM development in subjects spanning the glucose tolerance continuum. In this retrospective analysis, circulating total sRAGE and endogenous secretory RAGE (esRAGE) were quantified via ELISA, and cleaved RAGE (cRAGE) was calculated in 274 individuals stratified by glucose tolerance status (GTS) and obesity. Group differences were probed by ANOVA, and multivariate ordinal logistic regression was used to test the association between sRAGE isoform concentrations and the proportional odds of developing diabetes, vs. normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). When stratified by GTS, total sRAGE, cRAGE, and esRAGE were all lower with IGT and T2DM, while the ratio of cRAGE to esRAGE (cRAGE:esRAGE) was only lower (P < 0.01) with T2DM compared with NGT. When stratified by GTS and obesity, cRAGE:esRAGE was higher with obesity and lower with IGT (P < 0.0001) compared with lean, NGT. In ordinal logistic regression models, greater total sRAGE (odds ratio, 0.91; P < 0.01) and cRAGE (odds ratio, 0.84; P < 0.01) were associated with lower proportional odds of developing T2DM. Reduced values of sRAGE isoforms observed with both obesity and IGT are independently associated with greater proportional odds of developing T2DM. The mechanisms by which each respective isoform contributes to obesity and insulin resistance may reveal novel treatment strategies for diabetes.

Physiology of Sleep

IN BRIEF Far from a simple absence of wakefulness, sleep is an active, regulated, and metabolically distinct state, essential for health and well-being. In this article, the authors review the fundamental anatomy and physiology of sleep and its regulation, with an eye toward interactions between sleep and metabolism.

Impact of exercise on diurnal and nocturnal markers of glycaemic variability and oxidative stress in obese individuals with type 2 diabetes or impaired glucose tolerance

Objective: We measured the effects of a single bout of exercise on diurnal and nocturnal oxidative stress and glycaemic variability in obese subjects with type 2 diabetes mellitus or impaired glucose tolerance versus obese healthy controls. Methods: Subjects (in random order) performed either a single 30-min bout of moderate-intensity exercise or remained sedentary for 30 min at two separate visits. To quantify glycaemic variability, standard deviation of glucose (measured by continuous glucose monitoring system) and continuous overlapping net glycaemic action of 1-h intervals (CONGA-1) were calculated for three 12-h intervals during each visit. Oxidative stress was measured by 15-isoprostane F2t levels in urine collections for matching 12-h intervals. Results: Exercise reduced daytime glycaemic variability (ΔCONGA-1 = −12.62 ± 5.31 mg/dL, p = 0.04) and urinary isoprostanes (ΔCONGA-1 = −0.26 ± 0.12 ng/mg, p = 0.04) in the type 2 diabetes mellitus/impaired glucose tolerance group. Daytime exercise-induced change in urinary 15-isoprostane F2t was significantly correlated with both daytime standard deviation (r = 0.68, p = 0.03) and with subsequent overnight standard deviation (r = 0.73, p = 0.027) in the type 2 diabetes mellitus/impaired glucose tolerance group. Conclusion: Exercise significantly impacts the relationship between diurnal oxidative stress and nocturnal glycaemic variability in individuals with type 2 diabetes mellitus/impaired glucose tolerance.

Type 1 Diabetes and Sleep.

IN BRIEF In people with type 1 diabetes, sleep may be disrupted as a result of both behavioral and physiological aspects of diabetes and its management. This sleep disruption may negatively affect disease progression and development of complications. This review highlights key research findings regarding sleep in people with type 1 diabetes.

ID: 83: PRODUCTION OF SOLUBLE RECEPTOR FOR ADVANCED GLYCATION END-PRODUCTS FOLLOWING ACUTE AEROBIC EXERCISE IS GENDER SPECIFIC

The Receptor for Advanced Glycation End Products (RAGE) is a transmembrane receptor that initiates a self-propagating inflammatory cascade and has been implicated in the onset of complications involved with aging, diabetes and neuroinflammation. Soluble RAGE (sRAGE) inhibits this inflammatory signaling by competitively binding to RAGE ligands without stimulating downstream effectors. Evidence from our lab demonstrates chronic aerobic exercise increases the cleaved isoform of sRAGE (sRAGEc). However, the effects of acute aerobic exercise on sRAGEc production have not been comprehensively examined. Furthermore, recent data suggests that estrogen may play a role in exacerbating RAGE signaling and perturbing sRAGE production in diabetic women. Therefore, the primary objective of this study was to investigate changes in plasma sRAGE with acute aerobic exercise in both lean healthy (LH) and obese insulin resistant (OB-IR) individuals. A secondary objective of the study was to compare exercise responses between men and women. 8 LH participants (4 M, 4 F) and 14 OB-IR participants (4 M, 10 F) were recruited for the study. VO2max was determined via treadmill test and participants returned to the lab on a separate day following an overnight fast and exercised at 65% VO2max for 30 minutes. Blood samples were collected before and following exercise after participants rested in seated position for 30 minutes. Quantification of plasma sRAGE and endogeonous secretory RAGE were determined via ELISA and sRAGEc was calculated by subtraction. Between-group comparisons were made via independent T Test and the effect of gender was analyzed via two-way ANOVA. At baseline the OB-IR group was older (41±3 y vs. 26±1 y, p<.001), more obese (BMI 35.1±0.9 vs. 22.2±0.9 kg . m−2, p<.001) and less aerobically fit (VO2max 27.8±1.8 vs. 50.2±2.9 mL/kg−1. min−1, p<.001) compared the LH group. There was no main effect of group (OB-IR vs. LHC) on change in sRAGE or sRAGEc in response to exercise (ΔsRAGE 20.3±53.2 vs. 13.8±34.4 pg/mL, p=.93), (ΔsRAGEc 28.7±47.1 vs. 14.4±34.8 pg/mL, p=.33). However there was an effect of gender on the response to acute exercise. Males in both groups saw a significantly greater increase in plasma sRAGE (131.49±46.46 vs. −46.94±39.23 pg/mL, p<.05) and plasma sRAGEc (127.73±47.04 vs. −36.08±34.13 pg/mL, p<.05) compared to females. This study is the first to show that young healthy women and obese/insulin resistant women have an impaired ability to increase sRAGE plasma levels with acute aerobic exercise. Recent data has suggested that estrogen can exacerbate RAGE signaling as well as inhibit sRAGE production although the precise mechanism for this interaction is unclear and warrants further investigation.

EEG power and glucose fluctuations are coupled during sleep in young adults with type 1 diabetes

OBJECTIVE To determine the coupling between brain activity and glucose variations during sleep in young adults with type 1 diabetes mellitus (T1DM). METHODS 27 participants, age 18-30, wore a continuous glucose monitoring system (CGMS) and underwent in-laboratory overnight polysomnography (PSG). Quantitative electroencephalogram (qEEG) metrics were determined from the PSG and included Delta, Theta, Alpha, Sigma, Beta and Gamma Band power at 5-min intervals. Wavelet Coherence Analysis was employed to determine the time varying and frequency specific coupling between glucose and EEG Band power. ANOVA was used to compare differences across fluctuation speeds and EEG bands. RESULTS There was a high degree of time varying and frequency specific coupling between glucose variations and EEG power in all EEG Bands during sleep. The average number of intervals of statistically significant coherence was highest for fluctuations periods between 10 and 30min in all Bands (p<0.0001 for each). Mean significant coherence was negatively correlated with hemoglobin A1c, a marker of glycemic control. CONCLUSIONS The relationship between glucose and EEG power during sleep is time varying and frequency dependent in young adults with T1DM. SIGNIFICANCE Understanding the time varying mutual relationship between glucose changes and brain activity during sleep may have implications for disease management in T1DM.

Routine daily physical activity and glucose variations are strongly coupled in adults with T1DM

Type 1 Diabetes (T1DM) is characterized by altered glucose homeostasis resulting in wide glucose variations throughout a 24‐h period. The relationship between routine daily physical activity and glucose variations has not been systematically investigated in adults with T1DM. The objectives of this study were to characterize and quantify the relationship between routine daily activity and glucose variations in a small group of adults with T1DM. Adults with T1DM treated with an insulin pump were recruited for the study. Over a 3‐day period, glucose variations were monitored with a continuous glucose monitoring system (CGMS) and routine daily physical activity was assessed using an accelerometer‐based physical activity‐monitoring band. Simultaneous glucose and physical activity data for one 24‐h period were used for analysis. Cross‐correlation function and wavelet coherence analyses were employed to quantify the coupling between physical activity and glucose. Twelve subjects were included in the analysis. Cross‐correlation function analysis revealed strong coupling between activity and glucose. Wavelet Coherence demonstrated that slower oscillations (120–340 min) of glucose and physical activity exhibited significantly greater coherence (F = 12.6, P < 0.0001) than faster oscillations (10 and 120 min). Physical activity and glucose demonstrate strong time and frequency‐dependent coupling throughout a 24‐h time period in adults with T1DM.