Mimi Z Chen

The Impact of Sleep Debt on Excess Adiposity and Insulin Sensitivity in Patients with Early Type 2 Diabetes Mellitus

STUDY OBJECTIVES We examined cross-sectional and prospective associations between sleep debt and adiposity measures, as well as homeostatic model assessment-insulin resistance (HOMA-IR) in early type 2 diabetes. METHODS Prospective data analysis from participants of a randomized controlled trial based on an intensive lifestyle intervention (usual care, diet, or diet and physical activity). Data were collected at baseline, 6 months, and 12 months post-intervention. The study was performed across five secondary care centers in the United Kingdom. Patients (n = 593) with a recent diagnosis of type 2 diabetes were recruited. Objective height and weight were ascertained for obesity status (body mass index [BMI]; ≥ 30 kg/m(2)), waist circumference (cm) for central adiposity, and fasting blood samples drawn to examine insulin resistance (IR). Seven-day sleep diaries were used to calculate weekday sleep debt at baseline, calculated as average weekend sleep duration minus average weekday sleep duration. RESULTS At baseline, compared to those without weekday sleep debt, those with weekday sleep debt were 72% more likely to be obese (OR = 1.72 [95% CI:1.03-2.88]). At six months, weekday sleep debt was significantly associated with obesity and IR after adjustment, OR = 1.90 (95% CI:1.10-3.30), OR = 2.07 (95% CI:1.02-4.22), respectively. A further increase at 12 months was observed for sleep debt with obesity and IR: OR = 2.10 (95% CI:1.14-3.87), OR = 3.16 (95% CI:1.38-7.24), respectively. For every 30 minutes of weekday sleep debt, the risk of obesity and IR at 12 months increased by 18% and 41%, respectively. CONCLUSIONS Sleep debt resulted in long-term metabolic disruption, which may promote the progression of type 2 diabetes in newly diagnosed patients. Sleep hygiene/education could be an important factor for future interventions to target early diabetes.

An investigation of the associations among sleep duration and quality, body mass index and insulin resistance in newly diagnosed type 2 diabetes mellitus patients:

Objectives: To examine direct and indirect associations of sleep duration and quality with insulin resistance, considering body mass index (BMI) as a potential mediator in newly diagnosed type 2 diabetes mellitus patients. Methods: Cross-sectional data from patients enrolled in the Early Activity in Diabetes study. We studied 522 newly diagnosed type 2 diabetes mellitus patients, 65.9% male, mean age 63.5 ± 10.1 years. Of the total sample 53% had a BMI of ⩾30 kg/m2. Participants completed a 7-day sleep diary and sleep questionnaire. Average sleep duration (minutes), average nap duration (minutes) and average number of night awakenings were derived. Objective measures of height and body weight were obtained for the BMI calculation (kg/m2). Insulin resistance was obtained using the homeostatic model assessment – insulin resistance (HOMA2-IR) standardized technique. Results: Average number of night awakenings was positively correlated with BMI (r= 0.22, p < 0.001) and negatively associated with logged HOMA2-IR (r= -0.16, p = 0.04). Path analysis demonstrated night awakenings were directly associated with BMI and indirectly associated with insulin resistance, whilst considering BMI as a potential mediator (p < 0.05). Sleep duration was not associated with BMI or insulin resistance (p > 0.05). Conclusions: Sleep quality, not sleep duration, plays an important role in insulin resistance in newly diagnosed type 2 diabetes mellitus patients. BMI may mediate the relationship between indicators of sleep quality and insulin resistance. There is a need to examine the impact of improving sleep quality on obesity and insulin resistance in patients with type 2 diabetes mellitus.

Bariatric surgery in morbidly obese insulin resistant humans normalises insulin signalling but not insulin-stimulated glucose disposal

Aims Weight-loss after bariatric surgery improves insulin sensitivity, but the underlying molecular mechanism is not clear. To ascertain the effect of bariatric surgery on insulin signalling, we examined glucose disposal and Akt activation in morbidly obese volunteers before and after Roux-en-Y gastric bypass surgery (RYGB), and compared this to lean volunteers. Materials and Methods The hyperinsulinaemic euglycaemic clamp, at five infusion rates, was used to determine glucose disposal rates (GDR) in eight morbidly obese (body mass index, BMI=47.3±2.2 kg/m2) patients, before and after RYGB, and in eight lean volunteers (BMI=20.7±0.7 kg/m2). Biopsies of brachioradialis muscle, taken at fasting and insulin concentrations that induced half-maximal (GDR50) and maximal (GDR100) GDR in each subject, were used to examine the phosphorylation of Akt-Thr308, Akt-473, and pras40, in vivo biomarkers for Akt activity. Results Pre-operatively, insulin-stimulated GDR was lower in the obese compared to the lean individuals (P<0.001). Weight-loss of 29.9±4 kg after surgery significantly improved GDR50 (P=0.004) but not GDR100 (P=0.3). These subjects still remained significantly more insulin resistant than the lean individuals (p<0.001). Weight loss increased insulin-stimulated skeletal muscle Akt-Thr308 and Akt-Ser473 phosphorylation, P=0.02 and P=0.03 respectively (MANCOVA), and Akt activity towards the substrate PRAS40 (P=0.003, MANCOVA), and in contrast to GDR, were fully normalised after the surgery (obese vs lean, P=0.6, P=0.35, P=0.46, respectively). Conclusions Our data show that although Akt activity substantially improved after surgery, it did not lead to a full restoration of insulin-stimulated glucose disposal. This suggests that a major defect downstream of, or parallel to, Akt signalling remains after significant weight-loss.

Bariatric surgery for type 2 diabetes always produces a good outcome

Weight is very important in type 2 diabetes (T2DM); 1 kg of weight gained annually over 10 years is associated with a 49% increase in risk of developing T2DM in the subsequent 10 years. In patients with T2DM a weight loss of 5–10% results in a 0.5% reduction in HbA1c, a 5mmHg decrease in systolic blood pressure and diastolic blood pressure, a 0.13mmol/L increase in HDL cholesterol, and a 0.45mmol/L decrease in triglycerides.1 For these reasons the ADA and EASD recommend that weight loss should be strived for in all patients who have T2DM. In spite of this recommendation, few patients with T2DM are offered comprehensive weight loss programmes; instead treatment focuses on using medication to control glucose, blood pressure and lipids, with many of these medications causing weight gain. In the past, excuses for not targeting weight loss have been that it is hard to maintain weight loss in the long-term without high levels of contact or continuation of weight loss drugs. Bariatric surgery, however, does not suffer from the above problems. The mean 20 years’ weight reduction in the Swedish Obese Subjects study, a very large prospective study, was 15–25% dependent on the type of surgery performed, and contact levels required post surgery were low.2 This and other studies have led NICE to state that bariatric surgery should be offered to patients with a BMI of 35–40kg/m2 who have obesity-related conditions such as diabetes mellitus or obstructive sleep apnoea, or in those with a BMI of 40kg/m2 or greater regardless of weightrelated comorbidities. Updated NICE guidance due in the New Year is likely to suggest that the BMI cut-off for surgery in patients with T2DM should be lowered to 30kg/m2. In spite of these NICE recommendations, many physicians are reluctant to refer patients for bariatric surgery. The common reasons stated for this are: there are no long-term data that bariatric surgery improves diabetes control; there are no outcome data on macroand microvasular diabetes complications; there are no data that bariatric surgery is better than medical therapy; bariatric surgery is very risky; complication rates are high and can be very serious; there are no cost-effective data; and most of our patients do not want surgery. The following takes each of these statements in turn.