Dysregulated 24 h melatonin secretion associated with intrinsically photosensitive retinal ganglion cell function in diabetic retinopathy: a cross-sectional study.

AIMS/HYPOTHESIS: The aim of this study was to explore whether diabetic retinopathy is associated with alterations of the circadian system, and to examine the role of reduced intrinsically photosensitive retinal ganglion cell (ipRGC) function. METHODS: Participants with type 2 diabetes, with diabetic retinopathy (n=14) and without diabetic retinopathy (n=9) underwent 24 h blood sampling for melatonin and cortisol under controlled laboratory conditions. ipRGC function was inferred from the post-illumination pupil response (PIPR). Habitual sleep duration, efficiency and variability were assessed by actigraphy. RESULTS: Participants with diabetic retinopathy compared to participants without diabetic retinopathy had smaller PIPR (p=0.007), lower 24 h serum melatonin output (p=0.042) and greater day-to-day sleep variability (p=0.012). By contrast, 24 h cortisol profiles, sleep duration and efficiency were similar in both groups. Six individuals with diabetic retinopathy had no detectable dim-light melatonin onset. PIPR correlated with 24 h mean melatonin levels (r=0.555, p=0.007). CONCLUSIONS/INTERPRETATION: ipRCG dysfunction in diabetic retinopathy is associated with disruptions of the 24 h melatonin rhythm, suggesting circadian dysregulation in diabetic retinopathy.

Greater sleep variability is associated with higher systemic inflammation in type 2 diabetes.

Sleep irregularity and variability have been shown to be detrimental to cardiometabolic health. The present pilot study explored if higher day-to-day sleep irregularity and variability were associated with systemic inflammation, as assessed by high-sensitivity C-reactive protein, in type 2 diabetes. Thirty-five patients with type 2 diabetes (mean age 54.3 years, 54.3% female) who were not shift-workers participated. The presence of diabetic retinopathy was determined. The standard deviation of sleep duration and sleep midpoint across all recorded nights were used to quantify sleep variability and regularity, respectively, assessed by 14-day actigraphy. The presence and severity of sleep apnea were assessed using an overnight home monitor. Low-density lipoprotein, haemoglobin A1C and high-sensitivity C-reactive protein were collected. Multiple regression analysis using natural-log-transformed values was performed to establish an independent association between sleep variability and high-sensitivity C-reactive protein. Twenty-two (62.9%) patients had diabetic retinopathy. The median (interquartile range) of high-sensitivity C-reactive protein was 2.4 (1.4, 4.6) mg L-1 . Higher sleep variability was significantly associated with higher high-sensitivity C-reactive protein (r = 0.342, p = 0.044), as was haemoglobin A1C (r = 0.431, p = 0.010) and low-density lipoprotein (r = 0.379, p = 0.025), but not sleep regularity, sleep apnea severity or diabetic retinopathy. Multiple regression analysis showed that higher sleep variability (B = 0.907, p = 0.038) and higher HbA1c (B = 1.519, p = 0.035), but not low-density lipoprotein, contributed to higher high-sensitivity C-reactive protein. In conclusion, higher sleep variability in patients with type 2 diabetes who were not shift-workers was independently associated with higher systemic inflammation, conferring increased cardiovascular risk. Whether sleep interventions to reduce sleep variability can reduce systemic inflammation and improve cardiometabolic health should be investigated.

Multidimensional sleep health and diabetic retinopathy: Systematic review and meta-analysis.

Diabetic retinopathy (DR) is one of the most prevalent microvascular diabetic complications. Poor sleep health and obstructive sleep apnea (OSA) are risk factors for diabetes and poor glycemic control. Recent studies have suggested associations between poor sleep health/OSA and DR. Furthermore, there have been suggestions of melatonin dysregulation in the context of DR. We conducted a systematic review and meta-analysis exploring the associations between multidimensional sleep health (duration, satisfaction, efficiency, timing/regularity and alertness), OSA and melatonin with DR. Forty-two studies were included. Long, but not short sleep, was significantly associated with DR, OR 1.41 (95%CI 1.21, 1.64). Poor sleep satisfaction was also significantly associated with DR, OR 2.04 (1.41, 2.94). Sleep efficiency and alertness were not associated with DR, while the evidence on timing/regularity was scant. Having OSA was significantly associated with having DR, OR 1.34 (1.07, 1.69). Further, those with DR had significantly lower melatonin/melatonin metabolite levels than those without DR, standardized mean difference -0.94 (-1.44, -0.44). We explored whether treating OSA with continuous positive airway pressure (CPAP) led to improvement in DR (five studies). The results were mixed among studies, but potential benefits were observed in some. This review highlights the association between poor multidimensional sleep health and DR.

Predictors of slow-wave sleep in a clinic-based sample.

Slow-wave sleep has been associated with several physiological phenomena, including glucose metabolism, sympathetic nervous system activity, hormonal secretion and blood pressure regulation. The aim of these analyses was to determine which sociodemographic and medical factors were associated with slow-wave sleep duration in a large clinical sample. We conducted cross-sectional analysis of clinical data from 1019 consecutive adults over a 10-month period who had their first in-laboratory polysomnogram for suspicion of obstructive sleep apnea. Patients either underwent in-laboratory full-night polysomnogram followed by full-night continuous positive airway pressure titration or split-night polysomnogram. Patients also completed questionnaires to assess race, education, marital status and medical co-morbidities. A multiple linear regression model that predicted the natural log of slow-wave sleep in minutes indicated that African Americans had approximately 48% less slow-wave sleep than non-African Americans. Increasing age and male gender were also associated with less slow-wave sleep. Overweight and obese individuals had significantly less slow-wave sleep than those not overweight, even after adjustment for obstructive sleep apnea severity. Finally, those with severe obstructive sleep apnea had significantly less slow-wave sleep than those with less severe obstructive sleep apnea even after adjustment for obesity. Results remained unchanged when patients who had a split-night polysomnogram were excluded. We observed less slow-wave sleep in African Americans, a group at increased risk of diabetes and hypertension compared with Caucasians, and in those who are overweight and obese and those with severe obstructive sleep apnea. Future research needs to explore potential reasons for reduced slow-wave sleep in these individuals.

Pharmacotherapy of obesity in complex diseases.

More than 40% of adults in the United States suffer from obesity. Obesity is inextricably linked to many chronic illnesses like type-2 diabetes mellitus, hypertension, hyperlipidemia, heart disease, sleep apnea, stroke, and cancers. When used in combination with lifestyle modifications, pharmacotherapy has a vital role in treating obesity and improves short-term and long-term outcomes. A growing number of physicians are now interested in obesity medicine, and many of them are seeking guidance on how to treat complex patients with co-morbidities. This review provides a practical guide to the use of anti-obesity medications across various obesity-related comorbidities. It provides a general review of the currently approved anti-obesity medications and effective combinations. It discusses the highlights of the major trials and recent studies assessing the benefits of anti-obesity medications in comorbid conditions such as type-2 diabetes mellitus, psychiatric disorders, cardiovascular diseases, hypertension, renal diseases, and liver diseases. This review briefly examines the aspects of recognizing and addressing iatrogenic weight gain; discusses the precautions and prescribing considerations of anti-obesity medications, including side effects and possible dose adjustments in various comorbid conditions; and provides an expert opinion on an individualized choice of the best anti-obesity medication.

Sleep and obesity.

PURPOSE OF REVIEW: This review summarizes the most recent evidence linking decreased sleep duration and poor sleep quality to obesity, focusing upon studies in adults. RECENT FINDINGS: Published and unpublished health examination surveys and epidemiological studies suggest that the worldwide prevalence of obesity has doubled since 1980. In 2008, 1 in 10 adults was obese, with women more likely to be obese than men. This obesity epidemic has been paralleled by a trend of reduced sleep duration. Poor sleep quality, which leads to overall sleep loss has also become a frequent complaint. Growing evidence from both laboratory and epidemiological studies points to short sleep duration and poor sleep quality as new risk factors for the development of obesity. SUMMARY: Sleep is an important modulator of neuroendocrine function and glucose metabolism and sleep loss has been shown to result in metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, increased evening concentrations of cortisol, increased levels of ghrelin, decreased levels of leptin, and increased hunger and appetite. Recent epidemiological and laboratory evidence confirm previous findings of an association between sleep loss and increased risk of obesity.

Association between Timing of Energy Intake and Insulin Sensitivity: A Cross-Sectional Study.

In addition to the caloric and macronutrient composition of meals, timing of energy consumption may be important for optimal glucose metabolism. Our goal was to examine whether the habitual timing of energy intake was associated with insulin sensitivity in healthy volunteers. Volunteers without diabetes aged 21-50 years completed a 3-day food diary and underwent an oral glucose tolerance test to estimate insulin sensitivity (n = 44). From the food diary, we calculated the proportions of the total energy and macronutrients consumed in the morning and evening, and the clock time at which 25%, 50% and 75% of total energy was consumed. A greater proportion of energy intake in the morning was significantly associated with higher insulin sensitivity estimated by Matsuda Index (B = 2.8 per 10%; 95%CI: 0.3, 5.2). The time at which 25% of energy was consumed was associated with insulin sensitivity estimated by Matsuda Index (B = -1.6 per hour; 95%CI: -3.0, -0.3) and QUICKI (B = -1.4 per hour, 95%CI: -2.8, -0.1). The timing of carbohydrate consumption demonstrated similar associations. Greater energy intake earlier in the day was associated with higher insulin sensitivity in individuals without diabetes.

A Novel Mutation in the TBG Gene Producing Partial Thyroxine-Binding Globulin Deficiency (Glencoe) Identified in 2 Families.

BACKGROUND: Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein in serum. Located on the long arm of the X chromosome, TBG (SERPINA7) gene mutations most commonly produce inherited partial TBG deficiency (TBG-PD). OBJECTIVE: We report a novel TBG variant associated with TBG-PD identified in 2 different families of Ashkenazi origin residing in greater Chicago. METHODS: Family 1: The proband was 12.6 years old when she presented for delayed puberty and was placed on L-T4. Although her serum TSH normalized, her serum T4 remained low. Affected family members had low total T4 and T3, but a normal free T4 index, even when serum TSH concentrations were normal. Family 2: A 71-year-old male presented with a history of a nonfunctioning pituitary adenoma and normal pituitary axes except for low total T4 and T3. His brother had a similar thyroid phenotype. RESULTS: Following direct DNA sequencing, both index patients were found to carry a missense mutation in the TBG gene (c.751T>G) producing p.V215G. The proposita of family 1 was heterozygous and the proband in family 2 was hemizygous for the mutation. Isoelectric focusing showed no alteration in the TBG isoforms and in vitro expression demonstrated a TBG with reduced affinity for T4. CONCLUSIONS: We report a novel mutation in the TBG gene in 2 unrelated families that produces a molecule with reduced affinity for T4 resulting in low serum T4. However, the physical properties of the mutant molecule remained unaltered as determined by isoelectric focusing.

Outcomes of Pancreatic Islet Allotransplantation Using the Edmonton Protocol at the University of Chicago.

OBJECTIVE: The aim of this study was to assess short-term and long-term results of the pancreatic islet transplantation using the Edmonton protocol at the University of Chicago. MATERIALS AND METHODS: Nine patients underwent pancreatic islet cell transplantation using the Edmonton Protocol; they were followed up for 10 years after initial islet transplant with up to 3 separate islet infusions. They were given induction treatment using an IL-2R antibody and their maintenance immunosuppression regimen consisted of sirolimus and tacrolimus. RESULTS: Nine patients received a total of 18 islet infusions. Five patients dropped out in the early phase of the study. Greater than 50% drop-out and noncompliance rate resulted from both poor islet function and recurrent side effects of immunosuppression. The remaining 4 (44%) patients stayed insulin free with intervals for at least over 5 years (cumulative time) after the first transplant. Each of them received 3 infusions, on average 445 000 islet equivalent per transplant. Immunosuppression regimen required multiple adjustments in all patients due to recurrent side effects. In the long-term follow up, kidney function remained stable, and diabetic retinopathy and polyneuropathy did not progress in any of the patients. Patients' panel reactive antibodies remained zero and anti-glutamic acid decarboxylase 65 antibody did not rise after the transplant. Results of metabolic tests including hemoglobin A1c, arginine stimulation, and mixed meal tolerance test were correlated with clinical islet function. CONCLUSIONS: Pancreatic islet transplantation initiated according to Edmonton protocol offered durable long-term insulin-free glycemic control in only highly selected brittle diabetics providing stable control of diabetic neuropathy and retinopathy and without increased sensitization or impaired renal function. Immunosuppression adjustments and close follow-up were critical for patient retention and ultimate success.

Inpatient Glycemic Protocol for Patients with Diabetes Undergoing Bariatric Surgery.

BACKGROUND: Bariatric surgery is a recommended treatment for diabetes in severely obese patients. Their immediate post-operative anti-hyperglycemic requirements differ from other hospitalized diabetics, yet no standardized protocols addressing glycemic control for this group exist. OBJECTIVE: We aimed to create a safe, easily implemented protocol for immediate post-operative glycemic control, which we defined as the first 30 days. METHODS: The protocol was designed by an interdisciplinary workgroup using review of available literature, approved institutional glycemic guidelines, and team members' experience with caring for bariatric surgery patients. RESULTS: Patients are offered post-discharge recommendations using the inpatient glycemic protocol. CONCLUSION: We designed a protocol with low risk of hypoglycemia that addresses the unique glycemic needs of diabetic bariatric population in the immediate post-operative period.

Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity.

OBJECTIVE: To estimate whether metformin use by ovarian cancer patients with type II diabetes was associated with improved survival. METHODS: We reviewed the effect of diabetes and diabetes medications on ovarian cancer treatment and outcomes in a single-institution retrospective cohort. Inclusion criteria were International Federation of Gynecology and Obstetrics stage I-IV epithelial ovarian, fallopian, or peritoneal cancer. Exclusion criteria were noninvasive pathology or nonepithelial malignancies. The primary exposures analyzed were history of type II diabetes and diabetes medications. The primary outcomes were progression-free and overall ovarian cancer survival. RESULTS: Of the 341 ovarian cancer patients included in the study, 297 did not have diabetes, 28 were type II diabetic patients who did not use metformin, and 16 were type II diabetic patients who used metformin. The progression-free survival at 5 years was 51% for diabetic patients who used metformin compared with 23% for the nondiabetic patients and 8% for the diabetic patients who did not use metformin (P=.03). The overall survival at 5 years was 63%, 37%, and 23% for the diabetic patients who used metformin, the nondiabetic patients, and the diabetic patients who did not use metformin, respectively (P=.03). The patients with diabetes received the same treatment for ovarian cancer as the patients without diabetes. The association of metformin use and increased progression-free survival, but not overall survival, remained significant after controlling for standard clinicopathologic parameters. CONCLUSION: In this ovarian cancer cohort, the patients with type II diabetes who used metformin had longer progression-free survival, despite receiving similar treatment for ovarian cancer.

Does lack of sleep cause diabetes?

Several lines of evidence indicate that chronic lack of sleep may contribute to the risk of type 2 diabetes mellitus. Adequate sleep and good sleep hygiene should be included among the goals of a healthy lifestyle, especially for patients with diabetes. We urge clinicians to recommend at least 7 hours of uninterrupted sleep per night as part of a healthy lifestyle.

Bariatric surgery and its impact on sleep architecture, sleep-disordered breathing, and metabolism.

Over the last several decades, the prevalence of obesity has increased significantly worldwide. This has translated into an increased prevalence of obesity-associated morbidities including sleep-disordered breathing and metabolic disorders. While the medical management of obesity is relatively ineffective, bariatric surgery is the most successful method for sustained weight loss and markedly reduces obesity-related morbidity and mortality. The anatomical changes created with different types of procedures lead to variable weight loss and improvement of co-morbidities; however the latter does not appear to be exclusively dependent on the amount of weight loss. Bariatric surgery does not always lead to complete resolution of obstructive sleep apnea and age, gender and severity of the obstructive sleep apnea predict the residual disease after peak weight loss. Metabolic disorders and specifically diabetes often improve dramatically early after the procedure, before any significant weight loss has occurred. The modified gastrointestinal anatomy and physiology may explain this phenomenon.

Impact of sleep and sleep loss on neuroendocrine and metabolic function.

BACKGROUND: Sleep exerts important modulatory effects on neuroendocrine function and glucose regulation. During the past few decades, sleep curtailment has become a very common behavior in industrialized countries. This trend toward shorter sleep times has occurred over the same time period as the dramatic increases in the prevalence of obesity and diabetes. AIMS: This article will review rapidly accumulating laboratory and epidemiologic evidence indicating that chronic partial sleep loss could play a role in the current epidemics of obesity and diabetes. CONCLUSIONS: Laboratory studies in healthy young volunteers have shown that experimental sleep restriction is associated with a dysregulation of the neuroendocrine control of appetite consistent with increased hunger and with alterations in parameters of glucose tolerance suggestive of an increased risk of diabetes. Epidemiologic findings in both children and adults are consistent with the laboratory data.

Identification of a locus for nongoitrous congenital hypothyroidism on chromosome 15q25.3-26.1.

Permanent congenital hypothyroidism is the most prevalent inborn endocrine disorder, and principally due to developmental defects leading to absent, ectopic or hypoplastic thyroid gland. Although commonly regarded as sporadic disease, nonsyndromic thyroid hypoplasia has, in rare cases, been attributed to inherited defects in PAX8 and the TSHR gene. The shared clinical picture caused by these defects is a variable degree of thyrotropin resistance (RTSH [MIM 275200]), accompanied in its severe form by thyroid gland hypoplasia. We recently identified six extended kindreds with autosomal dominant RTSH, only one of which was linked to a mutation in the PAX8 candidate gene. Genome wide scans conducted in two of the remaining five families revealed independently significant linkage to chromosome 15q25.3-26.1, with maximum multipoint LOD scores of 8.51 and 4.31. Linkage to this novel locus was replicated (P<0.01) in each of the three remaining kindreds. Fine mapping of key recombinants in the largest family localized the causative gene within a 3 cM/2.9 Mb interval. Thus, we report the first locus for congenital nongoitrous hypothyroidism identified by a genome wide screening approach.