The Circadian Syndrome: is the Metabolic Syndrome and much more!

The Metabolic Syndrome is a cluster of cardio-metabolic risk factors and comorbidities conveying high risk of both cardiovascular disease and type 2 diabetes. It is responsible for huge socio-economic costs with its resulting morbidity and mortality in most countries. The underlying aetiology of this clustering has been the subject of much debate. More recently, significant interest has focussed on the involvement of the circadian system, a major regulator of almost every aspect of human health and metabolism. The Circadian Syndrome has now been implicated in several chronic diseases including type 2 diabetes and cardiovascular disease. There is now increasing evidence connecting disturbances in circadian rhythm with not only the key components of the Metabolic Syndrome but also its main comorbidities including sleep disturbances, depression, steatohepatitis and cognitive dysfunction. Based on this, we now propose that circadian disruption may be an important underlying aetiological factor for the Metabolic Syndrome and we suggest that it be renamed the 'Circadian Syndrome'. With the increased recognition of the 'Circadian Syndrome', circadian medicine, through the timing of exercise, light exposure, food consumption, dispensing of medications and sleep, is likely to play a much greater role in the maintenance of both individual and population health in the future.

Barriers to the delivery of diabetes care in the Middle East and South Africa: a survey of 1,082 practising physicians in five countries.

AIMS: Developing countries face a high and growing burden of type 2 diabetes. We surveyed physicians in a diverse range of countries in the Middle East and Africa (Egypt, Kingdom of Saudi Arabia, United Arab Emirates, South Africa and Lebanon) with regard to their perceptions of barriers to type 2 diabetes care identified as potentially important in the literature and by the authors. METHODS: One thousand and eighty-two physicians completed a questionnaire developed by the authors. RESULTS: Most physicians enrolled in the study employed guideline-driven care; 80-100% of physicians prescribed metformin (with lifestyle intervention, where there are no contraindications) for newly diagnosed type 2 diabetes, with lifestyle intervention alone used where metformin was not prescribed. Sulfonylureas were prescribed widely, consistent with the poor economic status of many patients. About one quarter of physicians were not undertaking any form of continuing medical education, and relatively low proportions of practices had their own diabetes educators, dieticians or diabetic foot specialists. Physicians identified the deficiencies of their patients (unhealthy lifestyles, lack of education and poor diet) as the most important barriers to optimal diabetes care. Low-treatment compliance was not ranked highly. Access to physicians did not appear to be a problem, as most patients were seen multiple times per year. CONCLUSIONS: Physicians in the Middle East and South Africa identified limitations relating to their patients as the main barrier to delivering care for diabetes, without giving high priority to issues relating to processes of care delivery. Further study would be needed to ascertain whether these findings reflect an unduly physician-centred view of their practice. More effective provision of services relating to the prevention of complications and improved lifestyles may be needed.

The publication of Diabetes UK position statements and care recommendations; a virtual issue.

Diabetes UK is the charity that cares for, connects with and campaigns on behalf of all people affected by and at risk of diabetes. Founded in 1934 by the novelist H. G. Wells and Dr R. D. Lawrence, the charity has always combined the expertise of lay and professional members to achieve its mission to improve the lives of people with diabetes and to work towards a future without diabetes.

The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation.

This article presents the conclusions of a WHO Expert Consultation that evaluated the utility of the 'metabolic syndrome' concept in relation to four key areas: pathophysiology, epidemiology, clinical work and public health. The metabolic syndrome is a concept that focuses attention on complex multifactorial health problems. While it may be considered useful as an educational concept, it has limited practical utility as a diagnostic or management tool. Further efforts to redefine it are inappropriate in the light of current knowledge and understanding, and there is limited utility in epidemiological studies in which different definitions of the metabolic syndrome are compared. Metabolic syndrome is a pre-morbid condition rather than a clinical diagnosis, and should thus exclude individuals with established diabetes or known cardiovascular disease (CVD). Future research should focus on: (1) further elucidation of common metabolic pathways underlying the development of diabetes and CVD, including those clustering within the metabolic syndrome; (2) early-life determinants of metabolic risk; (3) developing and evaluating context-specific strategies for identifying and reducing CVD and diabetes risk, based on available resources; and (4) developing and evaluating population-based prevention strategies.

Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.

A cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which occur together more often than by chance alone, have become known as the metabolic syndrome. The risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high-density lipoprotein cholesterol), raised fasting glucose, and central obesity. Various diagnostic criteria have been proposed by different organizations over the past decade. Most recently, these have come from the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute. The main difference concerns the measure for central obesity, with this being an obligatory component in the International Diabetes Federation definition, lower than in the American Heart Association/National Heart, Lung, and Blood Institute criteria, and ethnic specific. The present article represents the outcome of a meeting between several major organizations in an attempt to unify criteria. It was agreed that there should not be an obligatory component, but that waist measurement would continue to be a useful preliminary screening tool. Three abnormal findings out of 5 would qualify a person for the metabolic syndrome. A single set of cut points would be used for all components except waist circumference, for which further work is required. In the interim, national or regional cut points for waist circumference can be used.

Higher leptin levels in Asian Indians than Creoles and Europids: a potential explanation for increased metabolic risk.

BACKGROUND AND PURPOSE: Leptin predicts cardiovascular diseases and type 2 diabetes, diseases to which Asian Indians are highly susceptible. As a risk marker, leptin's intra-individual and seasonal stability is unstudied and only small studies have compared leptin levels in Asian Indians with other populations. The aim of this study was to explore ethnicity related differences in leptin levels and its intra-individual and seasonal stability. METHODS: Leptin and anthropometric data from the northern Sweden MONICA (3513 Europids) and the Mauritius Non-communicable Disease (2480 Asian Indians and Creoles) studies were used. In both studies men and women, 25- to 74-year old, participated in both an initial population survey and a follow-up after 5-13 years. For the analysis of seasonal leptin variation, a subset of 1780 participants, 30- to 60-year old, in the Västerbotten Intervention Project was used. RESULTS: Asian Indian men and women had higher levels of leptin, leptin per body mass index (BMI) unit (leptin/BMI) or per cm in waist circumference (WC; leptin/waist) than Creoles and Europids when adjusted for BMI (all P<0.0005) or WC (all P<0.005). In men, Creoles had higher leptin, leptin/BMI and leptin/waist than Europids when adjusted for BMI or WC (all P<0.0005). In women, Creoles had higher leptin/BMI and leptin/waist than Europids only when adjusted for WC (P<0.0005). Asian Indian ethnicity in both sexes, and Creole ethnicity in men, was independently associated with high leptin levels. The intra-class correlation for leptin was similar (0.6-0.7), independently of sex, ethnicity or follow-up time. No seasonal variation in leptin levels was seen. CONCLUSION: Asian Indians have higher levels of leptin, leptin/BMI and leptin/waist than Creoles and Europids. Leptin has a high intra-individual stability and seasonal leptin variation does not appear to explain the ethnic differences observed here.

Optimising the medical management of hyperglycaemia in type 2 diabetes in the Middle East: pivotal role of metformin.

AIMS: Increases in the prevalence of type 2 diabetes will likely be greater in the Middle East and other developing countries than in most other regions during the coming two decades, placing a heavy burden on regional healthcare resources. METHODOLOGY: Medline search, examination of data from major epidemiological studies in the Middle Eastern countries. RESULTS: The aetiology and pathophysiology of diabetes appears comparable in Middle Eastern and other populations. Lifestyle intervention is key to the management of diabetes in all type 2 diabetes patients, who should be encouraged strongly to diet and exercise. The options for pharmacologic therapy in the management of diabetes have increased recently, particularly the number of potential antidiabetic combinations. Metformin appears to be used less frequently to initiate antidiabetic therapy in the Middle East than in other countries. Available clinical evidence, supported by current guidelines, strongly favours the initiation of antidiabetic therapy with metformin in Middle Eastern type 2 diabetes patients, where no contraindications exist. This is due to its equivalent or greater efficacy relative to other oral antidiabetic treatments, its proven tolerability and safety profiles, its weight neutrality, the lack of clinically significant hypoglycaemia, the demonstration of cardiovascular protection for metformin relative to diet in the UK Prospective Diabetes Study and in observational studies, and its low cost. Additional treatments should be added to metformin and lifestyle intervention as diabetes progresses, until patients are receiving an intensive insulin regimen with or without additional oral agents. CONCLUSIONS: The current evidence base strongly favours the initiation of antidiabetic therapy with metformin, where no contraindications exist. However, metformin may be under-prescribed in the Middle East.

Experience of point-of-care HbA1c testing in the English National Health Service Diabetes Prevention Programme: an observational study.

INTRODUCTION: To report the observations of point-of-care (POC) glycated hemoglobin (HbA1c) testing in people with non-diabetic hyperglycemia (NDH; HbA1c 42-47 mmol/mol (6.0%-6.4%)), applied in community settings, within the English National Health Service Diabetes Prevention Programme (NHS DPP). RESEARCH DESIGN AND METHODS: A service evaluation assessing prospectively collected national service-level data from the NHS DPP, using data from the first referral received in June 2016-October 2018. Individuals were referred to the NHS DPP with a laboratory-measured HbA1c in the NDH range and had a repeat HbA1c measured at first attendance of the program using one of three POC devices: DCA Vantage, Afinion or A1C Now+. Differences between the referral and POC HbA1c and the SD of the POC HbA1c were calculated. The factors associated with the difference in HbA1c and the association between POC HbA1c result and subsequent attendance of the NHS DPP were also evaluated. RESULTS: Data from 73 703 participants demonstrated a significant mean difference between the referral and POC HbA1c of -2.48 mmol/mol (-0.23%) (t=157, p<0.001) with significant differences in the mean difference between devices (F(2, 73 700)=738, p<0.001). The SD of POC HbA1c was 4.46 mmol/mol (0.41%) with significant differences in SDs between devices (F(2, 73 700)=1542, p<0.001). Participants who were older, from more deprived areas and from Asian, black and mixed ethnic groups were associated with smaller HbA1c differences. Normoglycemic POC HbA1c versus NDH POC HbA1c values were associated with lower subsequent attendance at behavioral interventions (58% vs 67%, p<0.001). CONCLUSION: POC HbA1c testing in community settings was associated with significantly lower HbA1c values when compared with laboratory-measured referrals. Acknowledging effects of regression to the mean, we found that these differences were also associated with POC method, location, individual patient factors and time between measurements. Compared with POC HbA1c values in the NDH range, normoglycemic POC HbA1c values were associated with lower subsequent intervention attendance.

The metabolic syndrome: in need of a global mission statement.

AIMS: The value of clinical definitions of the metabolic syndrome has been questioned, with confusion surrounding their intended use and purpose. Our aim was to construct a mission statement that outlines the value of the metabolic syndrome in clinical and public health settings. METHODS: Case studies have been used to demonstrate three key points. RESULTS: We argue here for recognition of obesity as being a crucial element within the metabolic syndrome but perhaps even more important before its development. We also contend that the concept does indeed have a role as a risk prediction tool, and that it could provide a useful metric for the scale and progress of the looming global epidemic of diabetes and cardiovascular disease. CONCLUSIONS: Through appreciation of its purpose, and recognition of both its limitations and those attributes that make it unique and valuable, we believe we have demonstrated here that the metabolic syndrome deserves its place in the global toolbox of diabetes and CVD prevention.

Partnering with governments and other institutions: driving change in diabetes care.

The human and material cost of type 2 diabetes is a cause of increasing concern for health professionals, representative organisations and governments worldwide. The scale of morbidity and mortality has led the United Nations to issue a resolution on diabetes, calling for national policies for prevention, treatment and care. There is clearly an urgent need for a concerted response from all interested parties at the community, national and international level to work towards the goals of the resolution and create effective, sustainable treatment models, care systems and prevention strategies. Action requires both a 'bottom-up' approach of public awareness campaigns and pressure from healthcare professionals, coupled with a 'top-down' drive for change, via partnerships with governments, third sector (non-governmental) organisations and other institutions. In this review, we examine how existing collaborative initiatives serve as examples for those seeking to implement change in health policy and practice in the quest to alleviate the health and economic burden of diabetes. Efforts are underway to provide continuous and comprehensive care models for those who already have type 2 diabetes; in some cases, national plans extend to prevention strategies in attempts to improve overall public health. In the spirit of partnership, collaborations with governments that incorporate sustainability, long-term goals and a holistic approach continue to be a driving force for change. It is now critical to maintain this momentum and use the growing body of compelling evidence to educate, inform and deliver a long-term, lasting impact on patient and public health worldwide.

Core verbal autopsy procedures with comparative validation results from two countries.

BACKGROUND: Cause-specific mortality statistics remain scarce for the majority of low-income countries, where the highest disease burdens are experienced. Neither facility-based information systems nor vital registration provide adequate or representative data. The expansion of sample vital registration with verbal autopsy procedures represents the most promising interim solution for this problem. The development and validation of core verbal autopsy forms and suitable coding and tabulation procedures are an essential first step to extending the benefits of this method. METHODS AND FINDINGS: Core forms for peri- and neonatal, child, and adult deaths were developed and revised over 12 y through a project of the Tanzanian Ministry of Health and were applied to over 50,000 deaths. The contents of the core forms draw upon and are generally comparable with previously proposed verbal autopsy procedures. The core forms and coding procedures based on the International Statistical Classification of Diseases (ICD) were further adapted for use in China. These forms, the ICD tabulation list, the summary validation protocol, and the summary validation results from Tanzania and China are presented here. CONCLUSIONS: The procedures are capable of providing reasonable mortality estimates as adjudged against stated performance criteria for several common causes of death in two countries with radically different cause structures of mortality. However, the specific causes for which the procedures perform well varied between the two settings because of differences in the underlying prevalence of the main causes of death. These differences serve to emphasize the need to undertake validation studies of verbal autopsy procedures when they are applied in new epidemiological settings.

Randomised controlled trial evaluating lifestyle interventions in people with impaired glucose tolerance.

AIM: To evaluate the effectiveness of lifestyle interventions in people with impaired glucose tolerance (IGT). METHODS: Participants with IGT (n=78), diagnosed on two consecutive oral glucose tolerance tests (OGTTs), were randomly assigned to a 2-year lifestyle intervention or to a control group. Main outcome measures were changes from baseline in: nutrient intake; physical activity; anthropometry, glucose tolerance and insulin sensitivity. Measurements were repeated at 6, 12 and 24 months follow-up. RESULTS: After 24 months follow-up, there was a significant fall in total fat consumption (difference in change between groups (Delta intervention-Delta control)= -17.9, 95% confidence interval (CI) -33.6 to -2.1g/day) as a result of the intervention. Body mass was significantly lower in the intervention group compared with controls after 6 months (-1.6, 95% CI -2.9 to -0.4 kg) and 24 months (-3.3, 95% CI -5.7 to -0.89 kg). Whole body insulin sensitivity, assessed by the short insulin tolerance test (ITT), improved after 12 months in the intervention group (0.52, 95% CI 0.15-0.89%/min). CONCLUSIONS: These findings complement the findings of the Finnish Diabetes Prevention Study and the American Diabetes Prevention Study, both of which tested intensive interventions, by showing that pragmatic lifestyle interventions result in improvements in obesity and whole body insulin sensitivity in individuals with IGT, without change in other cardiovascular risk factors.

Six year incidence and progression of diabetic retinopathy: results from the Mauritius diabetes complication study.

AIMS: To determine the incidence, progression and risk factors for diabetic retinopathy in the multiethnic population of Mauritius. METHOD: A longitudinal, population-based study was conducted in Mauritius, during 1987, 1992 and 1998. Participants identified through the study as having diabetes (both known and newly diagnosed, by self-report and oral glucose tolerance test) and one in four participants with impaired glucose tolerance (IGT) underwent complications screening in 1992 and 1998. Retinal photographs were taken using a TRC-50VT retinal camera in three fields of the right eye (centred on the optic disc; macula (temporal to the optic disc); and nasal to disc). Photographs were graded according to a simplified version of the Wisconsin grading system. RESULTS: The 6-year incidence of diabetic retinopathy was 23.8% (sight-threatening in 0.4%). Among those with known diabetes mellitus (KDM) and free of retinopathy at baseline the incidence of non-proliferative diabetic retinopathy (NPDR) was 29.2% and proliferative diabetic retinopathy (PDR) was 1.0%. Among those with newly diagnosed diabetes mellitus (NDM) at baseline the incidence of NPDR was 19.1% (no incident cases of PDR were found). Independent risk factors for retinopathy using the baseline population characteristics were duration of diabetes and fasting plasma glucose. CONCLUSIONS: This is one of the few recent population-based studies of diabetic retinopathy undertaken in a developing nation. The incidence of retinopathy in Mauritius was high among those with NDM at baseline, with one in five developing retinopathy over 6 years. These results support the concept that screening for diabetes is important.

Low prevalence of the N363S polymorphism of the glucocorticoid receptor in South Asians living in the United Kingdom.

Similarities between clinical states of glucocorticoid excess and obesity have raised suspicion of a link between the two conditions. An Asn363Ser (N363S) polymorphism in exon 2 of the glucocorticoid receptor has been associated with glucocorticoid sensitivity and excess adiposity in people of European origin. Compared with Europid populations, South Asians have a higher prevalence of cardiovascular risk factors, including type 2 diabetes and central obesity. The aim of this study was to determine the prevalence of the 363S allele in people of South Asian origin living in northeast England in relation to obesity and other cardiovascular risk factors. DNA from 142 males and 153 females was characterized for 363S allele status. Two N363S heterozygotes were identified; both subjects had raised body mass index and central obesity. Despite a higher prevalence of overweight (body mass index >/==" BORDER="0"> 25 kg/m(2)) people in the South Asian group compared with the Europid population in the same geographical area (66 vs. 56%, respectively), the 363S allele frequency was significantly lower in the South Asian group (0.3 vs. 3%, respectively). Therefore, the N363S polymorphism is unlikely to be an important factor in obesity and/or dysmetabolic traits in people of South Asian origin living in the United Kingdom.

Alcohol consumption and the incidence of type II diabetes.

BACKGROUND: This study examines the relation between alcohol and type II diabetes and the possible mediating effects of HDL-cholesterol and serum insulin. METHODS: Prospective study of 5221 men aged 40-59 years with no history of coronary heart disease, diabetes, or stroke drawn from general practices in 18 British towns. RESULTS: During the mean follow up of 16.8 years there were 198 incident cases of type II diabetes. Occasional drinkers were the reference group. A non-linear relation was seen between alcohol intake and age adjusted risk of diabetes, with risk lowest in light and moderate drinkers and highest in heavy drinkers (quadratic trend p=0.03). Further adjustment for body mass index decreased risk in heavy drinkers. After additional adjustment for physical activity, smoking, and (undiagnosed) pre-existing coronary heart disease, only moderate drinkers showed significantly lower risk than occasional drinkers (RR=0.66 95% CI 0.44 to 0.99). Alcohol intake was inversely associated with serum insulin and positively associated with HDL-cholesterol. Adjustment for these factors reduced the "protective" effect in moderate drinkers (adjusted RR=0.73 95% CI 0.48 to 1.10) but the quadratic trend remained significant (p=0.02). CONCLUSION: There is a non-linear relation between alcohol intake and the risk of type II diabetes. Serum insulin and HDL-cholesterol explained a small amount (20%) of the reduction in risk of type II diabetes associated with moderate drinking. The adverse effect of heavy drinking seemed to be partially mediated through its effect on body weight.

Biochemical measures in a population-based study: effect of fasting duration and time of day.

BACKGROUND: Epidemiological studies generally aim to make simple but unbiased measurements of individuals. For this reason measurements of metabolic variables (including blood lipids, glucose and insulin) are usually carried out after a period of fasting. Few studies have examined the extent to which the use of a defined protocol for fasting in epidemiological studies abolishes the influence of fasting duration and time of day on biochemical measurements. METHODS: Cross-sectional survey of British Regional Heart Study participants (4,252 men aged 60-79 years), in which men without diabetes were asked to provide a blood sample after fasting for at least 6 h. Serum total, HDL and LDL cholesterol, triglyceride and insulin, and plasma glucose concentrations were measured between 08:00 h and 18:00 h. RESULTS: Non-fasting men had lower mean LDL cholesterol and higher glucose, insulin and triglyceride levels than fasting men; these differences were more marked among diabetics. Among fasting men without diabetes, insulin and glucose levels were strongly related to time of day, falling gradually throughout the morning and remaining stable in the afternoon. Because of these relationships and the dependence of fasting duration on time of day, insulin and glucose displayed a periodic relation with fasting duration above 6 h. These associations were largely abolished by adjustment for time of day; associations with time of day were unaffected by adjustment for fasting duration. Triglyceride concentrations fell with increasing fasting duration. This relationship was also mediated through a gradual increase in triglyceride levels throughout the day. Adjustments to compensate for these variations are described. DISCUSSION: Even after fasting, biochemical measurements may still differ in relation to fasting duration and time of day. In epidemiological studies, it is important to standardize both the period of fasting and the time of day as much as possible, and make adjustments where necessary.

Associations of infant nutrition with insulin resistance measures in early adulthood: evidence from the Barry-Caerphilly Growth (BCG) study.

BACKGROUND: Previous studies suggest that over-nutrition in early infancy may programme long-term susceptibility to insulin resistance. OBJECTIVE: To assess the association of breast milk and quantity of infant formula and cows' milk intake during infancy with insulin resistance measures in early adulthood. DESIGN: Long-term follow-up of the Barry Caerphilly Growth cohort, into which mothers and their offspring had originally been randomly assigned, between 1972-1974, to receive milk supplementation or not. Participants were the offspring, aged 23-27 years at follow-up (n = 679). Breastfeeding and formula/cows' milk intake was recorded prospectively by nurses. The main outcomes were insulin sensitivity (ISI(0)) and insulin secretion (CIR(30)). RESULTS: 573 (84%) individuals had valid glucose and insulin results and complete covariate information. There was little evidence of associations of breastfeeding versus any formula/cows' milk feeding or of increasing quartiles of formula/cows' milk consumption during infancy (<3 months) with any outcome measure in young adulthood. In fully adjusted models, the differences in outcomes between breastfeeding versus formula/cows' milk feeding at 3 months were: fasting glucose (-0.07 mmol/l; 95% CI: -0.19, 0.05); fasting insulin (8.0%; -8.7, 27.6); ISI(0) (-6.1%; -11.3, 12.1) and CIR(30) (3.8%; -19.0, 32.8). There was also little evidence that increasing intakes of formula/cows' milk at 3 months were associated with fasting glucose (increase per quartile of formula/cows' milk intake = 0.00 mmol/l; -0.03, 0.03); fasting insulin (0.8%; -3.2, 5.1); ISI (0) (-0.9%; -5.1, 3.5) and CIR(30) (-2.6%; -8.4, 3.6). CONCLUSIONS: We found no evidence that increasing consumption of formula/cows' milk in early infancy was associated with insulin resistance in young adulthood.