Sirimon Reutrakul

Interactions between sleep, circadian function, and glucose metabolism: implications for risk and severity of diabetes

Sleep disturbances, including sleep insufficiency and sleep fragmentation, have been linked to abnormal glucose metabolism and increased diabetes risk. Well‐controlled laboratory studies have provided insights regarding the underlying mechanisms. Several large prospective studies suggest that these sleep disturbances are associated with an increased risk of incident diabetes. Obstructive sleep apnea, which combines sleep fragmentation and hypoxemia, is a major risk factor for insulin resistance and possibly diabetes. Whether glycemic control in type 2 diabetes patients can be improved by treating sleep apnea remains controversial. Recently, sleep disturbances during pregnancy and their relationship to gestational diabetes and hyperglycemia have received considerable attention owing to potential adverse effects on maternal and fetal health. Additionally, evidence from animal models has identified disruption of the circadian system as a putative risk factor for adverse metabolic outcomes. The purpose of this review is to provide an update on the current state of knowledge linking sleep disturbances, circadian dysfunction, and glucose metabolism. Experimental, prospective, and interventional studies are discussed.

Chronotype Is Independently Associated With Glycemic Control in Type 2 Diabetes

OBJECTIVE To examine whether chronotype and daily caloric distribution are associated with glycemic control in patients with type 2 diabetes independently of sleep disturbances. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes had a structured interview and completed questionnaires to collect information on diabetes history and habitual sleep duration, quality, and timing. Shift workers were excluded. A recently validated construct derived from mid-sleep time on weekends was used as an indicator of chronotype. One-day food recall was used to compute the temporal distribution of caloric intake. Hierarchical linear regression analyses controlling for demographic and sleep variables were computed to determine whether chronotype was associated with HbA1c values and whether this association was mediated by a higher proportion of caloric intake at dinner. RESULTS We analyzed 194 completed questionnaires. Multiple regression analyses adjusting for age, sex, race, BMI, insulin use, depressed mood, diabetes complications, and perceived sleep debt found that chronotype was significantly associated with glycemic control (P = 0.001). This association was partially mediated by a greater percentage of total daily calories consumed at dinner. CONCLUSIONS Later chronotype and larger dinner were associated with poorer glycemic control in patients with type 2 diabetes independently of sleep disturbances. These results suggest that chronotype may be predictive of disease outcomes and lend further support to the role of the circadian system in metabolic regulation.

Sleep Disturbances and Their Relationship to Glucose Tolerance in Pregnancy

OBJECTIVE To explore relationships among sleep disturbances, glucose tolerance, and pregnancy outcomes. RESEARCH DESIGN AND METHODS Four validated sleep questionnaires were administered to 169 pregnant women at the time of 50-g oral glucose tolerance testing (OGTT) during the second trimester. Pregnancy outcomes were analyzed in 108 women with normal glucose tolerance (NGT). RESULTS Of the participants, 41% had excessive daytime sleepiness (Epworth Sleepiness Scale [ESS] >8); 64% had poor sleep quality; 25% snored frequently; 29% had increased risk of sleep-disordered breathing (SDB); 52% experienced short sleep (SS); 19% had both increased SDB risk and SS (SDB/SS); and 14% had daytime dysfunction. Reported sleep duration inversely correlated with glucose values from 50-g OGTT (r = −0.21, P < 0.01). Each hour of reduced sleep time was associated with a 4% increase in glucose levels. Increased likelihood of gestational diabetes mellitus (GDM) was found in subjects with increased SDB risk (odds ratio 3.0 [95% CI 1.2–7.4]), SS (2.4 [1.0–5.9]), SDB/SS (3.4 [1.3–8.7]), and frequent snoring (3.4 [1.3–8.8], after adjustment for BMI). Among NGT subjects, preterm delivery was more frequent in those with increased ESS (P = 0.02), poor sleep quality (P = 0.02), and SS (P = 0.03). Neonatal intensive care unit admissions were associated with increased ESS (P = 0.03), SDB/SS (P = 0.03), and daytime dysfunction (P < 0.01) in mothers. CONCLUSIONS Pregnant women experience significant sleep disturbances that are associated with increased risk of GDM and unfavorable pregnancy outcomes. Pregnant women with increased SDB risk, frequent snoring, and sleep duration of <7 h/night have increased risk of developing GDM.

Clinical Use of U-500 Regular Insulin: Review and Meta-Analysis

The use of U-500 regular insulin (U-500R) to treat diabetic patients with severe insulin resistance has increased. In this review, we performed a meta-analysis of PubMed studies reporting the use of U-500R to evaluate the effects of U-500R on hemoglobin A1c (HbA1c), body weight, and total daily insulin dose (TDD). These studies included 310 patients using U-500R as multiple daily injections (MDI) and 55 patients using U-500R via continuous subcutaneous insulin infusion (CSII). Overall, the use of U-500R as MDI resulted in a significant HbA1c reduction of 1.59%, a significant weight gain of 4.38 kg, and a significant increase in TDD by 51.9 units. The use of U-500R via CSII resulted in a similarly significant HbA1c reduction of 1.64% but a nonsignificant weight gain and a nonsignificant change in TDD. The use of U-500 regular insulin both as MDI and via CSII was not reported to be associated with severe hypoglycemia but was associated with an increase in patient satisfaction as well as in cost savings. Suggestions in initiating U-500R in the outpatient setting using U-500R in hospitalized patients are reviewed. In addition, precautions for avoiding prescription and patient errors are discussed.

The Relationship Between Breakfast Skipping, Chronotype, and Glycemic Control in Type 2 Diabetes

Breakfast skipping is associated with obesity and an increased risk of type 2 diabetes. Later chronotypes, individuals who have a preference for later bed and wake times, often skip breakfast. The aim of the study was to explore the relationships among breakfast skipping, chronotype, and glycemic control in type 2 diabetes patients. We collected sleep timing and 24-h dietary recall from 194 non-shift-working type 2 diabetes patients who were being followed in outpatient clinics. Mid-sleep time on free days (MSF) was used as an indicator of chronotype. Hemoglobin A1C (HbA1C) values were obtained from medical records. Hierarchical linear regression analyses controlling for demographic, sleep, and dietary variables were computed to determine whether breakfast skipping was associated with HbA1C. Additional regression analyses were performed to test if this association was mediated by chronotype. There were 22 participants (11.3%) who self-reported missing breakfast. Breakfast skippers had significantly higher HbA1C levels, higher body mass indices (BMI), and later MSF than breakfast eaters. Breakfast skipping was significantly associated with higher HbA1C values (B = 0.108, p = 0.01), even after adjusting for age, sex, race, BMI, number of diabetes complications, insulin use, depressive symptoms, perceived sleep debt, and percentage of daily caloric intake at dinner. The relationship between breakfast skipping and HbA1C was partially mediated by chronotype. In summary, breakfast skipping is associated with a later chronotype. Later chronotype and breakfast skipping both contribute to poorer glycemic control, as indicated by higher HbA1C levels. Future studies are needed to confirm these findings and determine whether behavioral interventions targeting breakfast eating or sleep timing may improve glycemic control in patients with type 2 diabetes.

Interactions Between Pregnancy, Obstructive Sleep Apnea, and Gestational Diabetes Mellitus

CONTEXT Questionnaire studies linked symptoms of obstructive sleep apnea (OSA) to the risk of gestational diabetes mellitus (GDM). Whether this association is present when OSA is assessed objectively by polysomnography is not known. OBJECTIVE The objective of the study was to assess the relationship between pregnancy, OSA, and GDM. DESIGN, SETTING, AND PARTICIPANTS We conducted observational case-control studies using polysomnography in 15 nonpregnant, nondiabetic women (NP-NGT), 15 pregnant women with normal glucose tolerance (P-NGT), and 15 pregnant women with GDM (P-GDM). The groups were frequency matched for age and race/ethnicity. Pregnant women were studied during the late second to early third trimester. MAIN OUTCOME MEASURES Comparisons of OSA diagnosis and sleep parameters between NP-NGT and P-NGT to assess the impact of pregnancy and between P-NGT and P-GDM to explore the association between GDM and OSA were measured. RESULTS Compared with NP-NGT, P-NGT women had a higher apnea hypopnea index (AHI) (median 2.0 vs 0.5, P = .03) and more disrupted sleep as reflected by a higher wake time after sleep onset (median 66 vs 21 min, P < .01) and a higher microarousal index (median 16.4 vs 10.6, P = .01). Among the pregnant women, P-GDM had markedly lower total sleep time (median 397 vs 464 min, P = .02) and a higher AHI (median 8.2 vs 2.0, P = .05) than P-NGT women. OSA was more prevalent in P-GDM than in P-NGT women (73% vs 27%, P = .01). After adjustment for prepregnancy body mass index, the diagnosis of GDM was associated with a diagnosis of OSA [odds ratio 6.60 (95% confidence interval 1.15-37.96)]. In pregnancy, after adjusting for prepregnancy body mass index, higher microarousal index significantly associated with higher hemoglobin A1c and fasting glucose levels. Higher oxygen desaturation index was associated with higher fasting glucose levels. CONCLUSION Pregnancy is associated with sleep disturbances. Sleep is more disturbed in GDM than in P-NGT women. There is a strong association between GDM and OSA.

Consequences of Circadian Disruption on Cardiometabolic Health

Cardiovascular disease, diabetes and obesity are highly prevalent diseases associated with reduced quality of life and life expectancy. We discuss a novel risk factor for these cardiometabolic diseases: circadian disruption. Circadian disruption occurs when the internal circadian (∼24-hour) rhythms are not in synchrony with the environment or each other. This paper reviews (1) cardiometabolic health of shift work, which often leads to circadian disruption, (2) effects of experimentally disrupted circadian rhythms on cardiometabolic function, (3) observational studies of sleep timing and behavioral chronotype, and (4) potential mediators linking chronotype and shift work to circadian disruption and cardiometabolic health.

Sleep characteristics in type 1 diabetes and associations with glycemic control: systematic review and meta-analysis

OBJECTIVES The association between inadequate sleep and type 2 diabetes has garnered much attention, but little is known about sleep and type 1 diabetes (T1D). Our objectives were to conduct a systematic review and meta-analysis comparing sleep in persons with and without T1D, and to explore relationships between sleep and glycemic control in T1D. METHODS Studies were identified from Medline and Scopus. Studies reporting measures of sleep in T1D patients and controls, and/or associations between sleep and glycemic control, were selected. RESULTS A total of 22 studies were eligible for the meta-analysis. Children with T1D had shorter sleep duration (mean difference [MD] = -26.4 minutes; 95% confidence interval [CI] = -35.4, -17.7) than controls. Adults with T1D reported poorer sleep quality (MD in standardized sleep quality score = 0.51; 95% CI = 0.33, 0.70), with higher scores reflecting worse sleep quality) than controls, but there was no difference in self-reported sleep duration. Adults with TID who reported sleeping >6 hours had lower hemoglobin A1c (HbA1c) levels than those sleeping ≤6 hours (MD = -0.24%; 95% CI = -0.47, -0.02), and participants reporting good sleep quality had lower HbA1c than those with poor sleep quality (MD = -0.19%; 95% CI = -0.30, -0.08). The estimated prevalence of obstructive sleep apnea (OSA) in adults with TID was 51.9% (95% CI = 31.2, 72.6). Patients with moderate-to-severe OSA had a trend toward higher HbA1c (MD = 0.39%, 95% CI = -0.08, 0.87). CONCLUSION T1D was associated with poorer sleep and high prevalence of OSA. Poor sleep quality, shorter sleep duration, and OSA were associated with suboptimal glycemic control in T1D patients.

Hypoglycemia in the treatment of hyperkalemia with insulin in patients with end-stage renal disease

Background Hypoglycemia is common in patients with end-stage renal disease (ESRD). We identified the incidence and timing of hypoglycemia and its risk factors in hospitalized patients with ESRD after the treatment of hyperkalemia with insulin. Methods We conducted a retrospective study of all hospitalized adult patients treated with hemodialysis who received intravenous insulin to treat hyperkalemia between 1 January 2011 and 31 December 2011. We identified patients who became hypoglycemic [blood glucose <3.3 mmol/L (60 mg/dL)] after insulin administration. Results Two hundred and twenty-one episodes of hyperkalemia were treated with insulin, resulting in 29 episodes of hypoglycemia (13%). Factors associated with a higher risk of hypoglycemia included no prior diagnosis of diabetes [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.0–5.1, P = 0.05], no use of diabetes medication prior to admission [OR 3.6, 95% CI 1.2–10.7, P = 0.02] and a lower pretreatment glucose level [mean 5.8 ± 0.7 mmol/L (104 ± 12 mg/dL) versus 9.0 ± 0.6 mmol/L (162 ± 11 mg/dL), P = 0.04]. Hypoglycemia occurred at a median of 2 h after insulin administration and persisted for a median of 2 h. Conclusions The treatment of hyperkalemia with insulin in hospitalized patients with ESRD may be complicated by hypoglycemia. Patients with a history of diabetes are less susceptible to this complication. Our study supports the use of a protocol to provide dextrose support and blood glucose monitoring for at least 3 h after insulin treatment of hyperkalemia.

Night eating in patients with type 2 diabetes. Associations with glycemic control, eating patterns, sleep, and mood

Night eating is a complex behavior associated with disruptions in eating, sleep, and mood regulation. While night eating has been associated with alterations in neuroendocrine functioning, night eating and Night Eating Syndrome (NES) are not well understood in patients with prevalent metabolic conditions, such as diabetes. In this study, 194 adults with Type 2 diabetes completed questionnaires assessing night eating symptoms as well as eating, sleep, and depressive symptoms. Glycemic control data, as measured by hemoglobin A1c (HbA1c), were gathered from patient medical charts. Results indicated that 7% of participants met criteria for NES. Increased symptoms of night eating were associated with poorer glycemic control and disruptions in eating, sleep, and mood, including significantly increased likelihood of having HbA1c levels >7% and endorsing clinical levels of depressive symptoms. Increasing understanding of the relationship between night eating and metabolic and psychosocial functioning in patients with diabetes may provide new avenues for treatment of these patients.