Sex hormone-binding globulin, but not testosterone, is associated prospectively and independently with incident metabolic syndrome in men: the framingham heart study

OBJECTIVE

The association between total testosterone and metabolic syndrome has prompted speculation that low testosterone contributes to the pathophysiology of metabolic syndrome in men. We determined whether testosterone or sex hormone–binding globulin (SHBG) is independently associated with the risk of metabolic syndrome.

RESEARCH DESIGN AND METHODS

Cross-sectional relationships of hormone levels with metabolic syndrome were assessed in a sample of men in generation 2 of the Framingham Heart Study (FHS) who did not receive testosterone or androgen-deprivation therapy (n = 1,625) and confirmed in a validation sample of men in FHS generation 3 (n = 1,912). Hormone levels in generation 2 examination 7 were related prospectively to incident metabolic syndrome 6.6 years later at examination 8. Testosterone was measured using liquid chromatography–tandem mass spectrometry, SHBG was measured by immunofluorometric assay, and free testosterone was calculated. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria.

RESULTS

Cross-sectionally, testosterone and SHBG were more strongly associated with metabolic syndrome than free testosterone in the training sample. SHBG, but not testosterone or free testosterone, was significantly associated with metabolic syndrome after adjusting for age, smoking, BMI, and insulin sensitivity (homeostasis model assessment of insulin resistance [HOMA-IR]). These findings were confirmed in a validation sample. Longitudinally, SHBG at examination 7, but not testosterone or free testosterone, was associated with incident metabolic syndrome at examination 8 after adjusting for age, smoking, BMI, and HOMA-IR. Multivariable analyses suggested that age, BMI, and insulin sensitivity independently affect SHBG and testosterone levels and the risk of metabolic syndrome and its components.

CONCLUSIONS

SHBG, but not testosterone, is independently associated with the risk of metabolic syndrome. These data do not reveal an independent prospective relationship between testosterone and metabolic syndrome in men.Epidemiological studies have reported that low total testosterone levels are associated with an increased risk of metabolic syndrome in men (1–8). Circulating testosterone levels also have been associated with individual components of metabolic syndrome, such as insulin resistance (9,10), visceral adiposity (10), hypertension (11), and dyslipidemia. These epidemiological observations have led to speculation that testosterone deficiency contributes to the pathophysiology of metabolic syndrome and that diagnostic evaluation for androgen deficiency and testosterone therapy might be indicated in men with metabolic syndrome (12,13).Circulating testosterone is partly bound to sex hormone–binding globulin (SHBG) with high affinity, and testosterone levels are strongly related to SHBG concentrations. SHBG levels also have been associated with the risk of metabolic syndrome in men (1–4,8). However, we do not know whether the observed association between total testosterone and metabolic syndrome reflects an independent influence of testosterone on the risk of metabolic syndrome or primarily an association of SHBG with this disorder. The relationship of free testosterone and metabolic syndrome has been inconsistent or weak (1–8), suggesting that SHBG may be the primary determinant of the apparent relationship between total testosterone and metabolic syndrome.This issue has therapeutic implications; if low testosterone levels are causally related to metabolic syndrome, then testosterone therapy of men with low testosterone levels might be expected to prevent or ameliorate metabolic syndrome, as has been suggested (12–14). If SHBG is the primary determinant of this apparent relationship between total testosterone and metabolic syndrome, as we hypothesize, then efforts should be directed at remediable factors, such as obesity and insulin resistance that regulate SHBG as well as the risk of metabolic syndrome.Here, we investigated the relationship between total and free testosterone as well as SHBG with metabolic syndrome cross-sectionally in community-dwelling men in the Framingham Heart Study (FHS) and confirmed these associations in a validation sample. We also longitudinally evaluated the association of these hormones with incident metabolic syndrome. Previous studies measured testosterone levels using immunoassays (1–7) that lack accuracy in the low range (15). We measured total testosterone by liquid chromatography–tandem mass spectrometry (LC-MS/MS), the method with the highest accuracy and specificity (15). We adjusted the analyses for factors that independently affect metabolic syndrome and testosterone levels, such as age, BMI, smoking, and insulin sensitivity index (homeostasis model assessment of insulin resistance [HOMA-IR]). We also determined whether testosterone levels were associated with metabolic syndrome after adjusting for SHBG. We hypothesized that the apparent relationship between total testosterone and metabolic syndrome is driven mostly by the association of SHBG with metabolic syndrome.     

Plasma 25-Hydroxyvitamin D Concentration and Metabolic Syndrome Among Middle-Aged and Elderly Chinese Individuals

OBJECTIVE

To evaluate the association between 25-hydroxyvitamin D [25(OH)D] and metabolic syndrome in the Chinese population.

RESEARCH DESIGN AND METHODS

Plasma 25(OH)D was measured in a cross-sectional sample of 1,443 men and 1,819 women aged 50–70 years from Beijing and Shanghai. Metabolic syndrome was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans. Fasting plasma glucose, insulin, lipid profile, A1C, and inflammatory markers were measured.

RESULTS

The geometric mean of plasma 25(OH)D was 40.4 nmol/l, and percentages of vitamin D deficiency [25(OH)D <50 nmol/l] and insufficiency [50 ≤ 25(OH)D <75 nmol/l] were 69.2 and 24.4%, respectively. Compared with the highest 25(OH)D quintile (≥57.7 nmol/l), the odds ratio for metabolic syndrome in the lowest quintile (≤28.7 nmol/l) was 1.52 (95% CI 1.17–1.98, P_trend = 0.0002) after multiple adjustment. Significant inverse associations also existed between 25(OH)D and individual metabolic syndrome components plus A1C. Moreover, we observed significant inverse associations of 25(OH)D with fasting insulin and the insulin resistance index (homeostasis model assessment of insulin resistance [HOMA-IR]) in overweight and obese individuals (BMI ≥24 kg/m²) but not in their normal-weight counterparts (test for interaction: P = 0.0363 and 0.0187 for insulin and HOMA-IR, respectively).

CONCLUSIONS

Vitamin D deficiency is common in the middle-aged and elderly Chinese population, and a low 25(OH)D level is significantly associated with an increased risk of having metabolic syndrome and insulin resistance. Prospective studies and randomized clinical trials are warranted to determine the role of 25(OH)D in the development of metabolic syndrome and related metabolic diseases.Vitamin D deficiency is now recognized as a worldwide concern (1). A growing body of evidence suggests that 25-hydroxyvitamin D [25(OH)D], a generally accepted indicator of vitamin D status, is inversely associated with adiposity, glucose homeostasis, lipid profiles, and blood pressure along with its classic role in calcium homeostasis and bone metabolism (1–6). Even though the underlying mechanism has not been well understood, vitamin D appears to exert effects through direct modulation of gene expression via vitamin D receptors (VDRs) (1) and through regulation of extra- and intracellular calcium (1,7).Metabolic syndrome, a constellation of cardiometabolic disease risk factors, has become a global epidemic (8). Several epidemiologic studies (5,6,9,10) have suggested that 25(OH)D status is inversely associated with metabolic syndrome in western populations, although data for morbidly obese individuals are inconsistent (11,12). Nevertheless, evidence from the Asian population is limited. Because of ethnic differences in vitamin D metabolism and its nutritional status indicated by previous studies (3,13), it is not clear whether the findings from western populations could be extrapolated directly to Asian individuals. With rapid nutrition and lifestyle transitions in the last 20 years, metabolic syndrome has become one of the most widespread health problems in Asian countries (8). However, little is known regarding whether vitamin D deficiency plays an important role in the heightened prevalence of metabolic syndrome and other metabolic disorders among Asian individuals. Therefore, the aim of our study was to evaluate the plasma 25(OH)D concentration and its association with metabolic syndrome among Chinese individuals aged 50–70 years.     

The relationship between insulin resistance and incidence and progression of coronary artery calcification: the Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE

We sought to determine whether insulin resistance predicts the incidence and progression of coronary artery calcification (CAC).

RESEARCH DESIGN AND METHODS

We studied 5,464 participants not on hypoglycemic therapy from the Multi-Ethnic Study of Atherosclerosis (MESA). Each had baseline homeostasis model assessment of insulin resistance (HOMA-IR) and baseline and follow-up CAC scores. Incident CAC was defined as newly detectable CAC; progression was defined as advancing CAC volume score at follow-up.

RESULTS

Median HOMA-IR was 1.2 (0.8–2.0). Across all ethnicities, there was a graded increase in CAC incidence and progression with increasing HOMA-IR. When compared with those in the 1st quartile, participants in the 2nd–4th quartiles had 1.2, 1.5, and 1.8 times greater risk of developing CAC. Median annualized CAC score progression was 8, 14, and 17 higher, respectively. However, HOMA-IR was not predictive after adjustment for metabolic syndrome components.

CONCLUSIONS

HOMA-IR predicts CAC incidence and progression, but not independently of metabolic syndrome.Sensitivity to insulin-mediated glucose uptake varies at least sixfold in the general healthy population, with variability attributable to genetic and behavioral factors (1–4). In the clinical setting, insulin resistance is commonly inferred via its adverse consequences, which include dysglycemia, hypertension, low HDL cholesterol (HDL-C), high triglycerides, and subclinical inflammation (collectively, the metabolic syndrome) (5).Insulin resistance and the metabolic syndrome have both been shown to be strongly associated with measures of subclinical atherosclerosis, including coronary artery calcification (CAC) (6,7). Consistent with these observations, prospective studies have demonstrated that insulin resistance and metabolic syndrome are independent predictors of cardiovascular events (8,9). However, the degree to which insulin resistance and metabolic syndrome are mutually independent predictors remains debated, with prior results mixed (7,10). We sought to determine whether insulin resistance prospectively predicts the onset and progression of CAC, independent of metabolic syndrome.     

Impact of Metabolic Syndrome Compared With Impaired Fasting Glucose on the Development of Type 2 Diabetes in a General Japanese Population: The Hisayama study

OBJECTIVE

We examined whether metabolic syndrome predicts incident type 2 diabetes more effectively than impaired fasting glucose (IFG) in a general Japanese population.

RESEARCH DESIGN AND METHODS

A total of 1,935 nondiabetic subjects aged 40–79 years were followed-up prospectively for a mean of 11.8 years.

RESULTS

During the follow-up, 286 subjects developed type 2 diabetes. Compared with those without metabolic syndrome, the multivariate-adjusted hazard ratio (HR) for incident type 2 diabetes was significantly higher in subjects of both sexes with metabolic syndrome, even after adjustment for confounding factors, age, family history of diabetes, total cholesterol, alcohol intake, smoking habits, and regular exercise (men: HR 2.58 [95% CI 1.85–3.59]; women: 3.69 [2.58–5.27]). The multivariate-adjusted HR of metabolic syndrome for type 2 diabetes was slightly lower in men and similar in women compared with that of IFG. The multivariate-adjusted HR for type 2 diabetes rose progressively as the number of metabolic syndrome components increased in both subjects with and without IFG. In stratified analysis, the multivariate-adjusted risk of type 2 diabetes was significantly higher in subjects with metabolic syndrome alone (2.37 [1.45–3.88]) or IFG alone (3.49 [2.57–4.74]) and markedly increased in subjects with both metabolic syndrome and IFG (6.76 [4.75–9.61]) than in subjects with neither metabolic syndrome nor IFG. Furthermore, the multivariate-adjusted risk for type 2 diabetes was also significantly higher in subjects with both metabolic syndrome and IFG than in those with either one alone (both P < 0.001).

CONCLUSIONS

Our findings suggest that metabolic syndrome significantly increases the risk of incident type 2 diabetes, independent of IFG, and is therefore a valuable tool to identify individuals at high risk of type 2 diabetes.Metabolic syndrome consists of a clustering of cardiovascular risk factors, such as central obesity, elevated blood pressure, glucose intolerance, and dyslipidemia, and individuals with this condition have an elevated risk of developing cardiovascular diseases (1–5) and type 2 diabetes in different ethnic populations (1–4,6–11). Thus, the concept of metabolic syndrome could be used to reduce the incidence of these diseases worldwide. However, a number of experts in the field of diabetes have questioned whether the idea of metabolic syndrome is useful and valuable (12–14). Because all of the criteria sets for metabolic syndrome have included the component of impaired fasting glucose (IFG), which is a powerful predictor of type 2 diabetes, detractors have questioned whether the more complex definition of metabolic syndrome is better than a simple measurement of fasting plasma glucose (FPG). However, reported findings concerning this issue are controversial: a cohort study has shown that the ability of metabolic syndrome to predict type 2 diabetes was superior to that of IFG alone (3), whereas in other studies, the value of metabolic syndrome was comparable or inferior to that of IFG alone (2,6,7). Furthermore, most of these epidemiological studies were performed in Western populations, and this subject has not been assessed sufficiently in Asian populations.The purpose of the present study was to investigate the association between metabolic syndrome and the development of type 2 diabetes in a prospective study of a defined Japanese population, taking into account comprehensive risk factors. In addition, we compared which of the two measures, metabolic syndrome or IFG, better predicted incident type 2 diabetes.     

Early Microvascular Recruitment Modulates Subsequent Insulin-Mediated Skeletal Muscle Glucose Metabolism During Lipid Infusion

OBJECTIVE

To test whether early, insulin-mediated microvascular recruitment in skeletal muscle predicts steady-state glucose metabolism in the setting of physiological elevation of free fatty acid concentrations.

RESEARCH DESIGN AND METHODS

We measured insulin’s microvascular and metabolic effects in 14 healthy young adults during a 2-h euglycemic insulin clamp. Plasma free fatty acid concentrations were raised (Intralipid and heparin infusion) for 3 h before the clamp and maintained at postprandial concentrations during the clamp. Microvascular blood volume (MBV) was measured by contrast-enhanced ultrasound (CEU) continuously from baseline through the first 30 min of the insulin clamp. Muscle glucose and insulin uptake were measured by the forearm balance method.

RESULTS

The glucose infusion rate (GIR) necessary to maintain euglycemia during the clamp varied by fivefold across subjects (2.5–12.5 mg/min/kg). The early MBV responses to insulin, as indicated by CEU video intensity, ranged widely, from a 39% decline to a 69% increase. During the clamp, steady state forearm muscle glucose uptake and GIR each correlated significantly with the change in forearm MBV (P < 0.01). To explore the basis for the wide range of vascular and metabolic insulin sensitivity observed, we also measured Vo_2max in a subset of eight subjects. Fitness (Vo_2max) correlated significantly with the GIR, the forearm glucose uptake, and the percentage change in MBV during the insulin clamp (P < 0.05 for each).

CONCLUSIONS

Early microvascular responses to insulin strongly associate with steady state skeletal muscle insulin-mediated glucose uptake. Physical fitness predicts both metabolic and vascular insulin responsiveness.Insulin recruits underperfused capillaries to increase skeletal muscle microvascular blood volume (MBV), as measured by contrast-enhanced ultrasound (CEU), within 20 min in both rats (1) and humans (2,3). This effect occurs with physiological insulin concentrations (2,4) and precedes both changes in total limb blood flow (1,5,6) and insulin’s metabolic action (1). In rodents, microvascular recruitment enhances the rate at which insulin is delivered to muscle interstitium (7), thereby facilitating insulin’s metabolic action, and exercise training has been shown to enhance insulin-induced microvascular recruitment and muscle glucose disposal in rodents (8).Raising plasma concentrations of free fatty acids (FFAs) induces insulin resistance within 2–4 h, can induce inflammation in muscle (9) and in circulating leukocytes (10), and produces endothelial dysfunction (10,11). Clinical studies have shown a marked impairment in insulin’s ability to recruit both muscle and skin microvasculature in chronically insulin-resistant obese subjects (12–14). FFA-induced insulin resistance impairs insulin-mediated microvascular recruitment in skin with elevation of FFA to physiological levels (∼1 mmol/L) (15) and in muscle microvasculature with higher FFA levels ∼3 mmol/L (16).Both acute exercise and training can affect the metabolic response to raising plasma FFA. Raising plasma FFA acutely through lipid and heparin infusion has less effect on insulin sensitivity in individuals who exercised intensively the preceding day (17). Exercise training also prevents FFA-induced hepatic and peripheral insulin resistance (18). It is not known whether training affects insulin-induced microvascular recruitment or the ability of FFA to inhibit recruitment in humans.Recently, we reported that human skeletal muscle insulin uptake (product of forearm blood flow and arteriovenous concentration) could be quantified and that it occurred through a saturable transport process at physiological concentrations of insulin (2). Whether FFA elevation would, by blocking insulin-induced increases in MBV, also limit muscle insulin uptake is not known.In this study, CEU was used to measure muscle microvascular perfusion and paired arterial and venous sampling to measure muscle insulin and glucose uptake in response to a physiologic insulin infusion in 14 healthy volunteers whose plasma FFA levels were maintained in a range encountered in human insulin-resistant states (∼1.0 mmol/L). To examine whether fitness was predictive of these responses, a subset of 8 volunteers underwent maximal exercise testing to quantify the relationship between Vo_2max and muscle metabolic and microvascular insulin sensitivity.     

Metabolic Syndrome, Brain Magnetic Resonance Imaging, and Cognition

OBJECTIVE

We explored cognitive impairment in metabolic syndrome in relation to brain magnetic resonance imaging (MRI) findings.

RESEARCH DESIGN AND METHODS

We studied 819 participants free of clinical stroke and dementia of the population-based Austrian Stroke Prevention Study who had undergone brain MRI, neuropsychological testing, and a risk factor assessment relevant to National Cholesterol Education Program Adult Treatment Panel III criteria–defined metabolic syndrome. High-sensitivity C-reactive protein (hs-CRP) was also determined.

RESULTS

Of 819 subjects, 232 (28.3%) had metabolic syndrome. They performed worse than those without metabolic syndrome on cognitive tests assessing memory and executive functioning after adjustment for possible confounders. Stratification by sex demonstrated that metabolic syndrome was related to cognitive dysfunction in men but not in women. Only in men was an increasing number of metabolic syndrome components associated with worse cognitive performance. MRI showed no significant differences in focal ischemic lesions and brain volume between subjects with and without metabolic syndrome, and MRI abnormalities failed to explain impaired cognition. Cognitive performance was most affected in male subjects with metabolic syndrome who also had high hs-CRP levels.

CONCLUSIONS

Metabolic syndrome exerts detrimental effects on memory and executive functioning in community-dwelling subjects who have not had a clinical stroke or do not have dementia. Men are more affected than women, particularly if they have high inflammatory markers. MRI-detected brain abnormalities do not play a crucial role in these relationships.Metabolic syndrome is a cluster of cardiovascular risk factors, including abdominal obesity, atherogenic dyslipidemia, raised blood pressure, and insulin resistance and glucose intolerance (1). It has been associated with cognitive dysfunction (2,3) and Alzheimer''s disease (4), but data are discordant (5–7). Negative associations were reported with memory, processing speed, and fluid intelligence (3). Impaired cognition was linked to high-level inflammation (2).Although components of the metabolic syndrome have been individually related to cognitive outcomes, the mechanisms affecting cognition in metabolic syndrome are undetermined. Factors related to peripheral hyperinsulinemia are probably highly relevant. Peripheral hyperinsulinemia downregulates blood-brain barrier insulin receptors and subsequently reduces insulin transport to the brain followed by decreased acetylcholine neurotransmission and cerebral blood flow (8). In addition, hyperglycemia itself contributes to neuronal apoptosis via increased generation of free radicals, enhanced glycation end products, and elevated lipid peroxidation (8). Interactive effects between hyperglycemia and components of metabolic syndrome such as arterial hypertension have been reported (9). Another possible mechanism are vascular lesions as a sequela of components of metabolic syndrome including hypertension, impaired glucose tolerance, and dyslipidemia. Previous magnetic resonance imaging (MRI) studies described higher rates of silent brain infarcts (10) and leukoaraiosis (11). A diffusion tensor imaging study found evidence for ultrastructural tissue damage in frontal and temporal lobes (12). These studies did not include cognitive testing and thus cannot imply the higher frequency of brain lesions to be responsible for metabolic syndrome–related cognitive dysfunction.We evaluated both cognitive function and brain MRI-detected lesions in a large cohort of community-dwelling subjects. We hypothesize that individuals with metabolic syndrome have global and domain-specific cognitive dysfunction, a higher frequency of brain abnormalities, and a cognitive status that relates to brain MRI findings.     

Stressful Life Events and the Metabolic Syndrome: The Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia Study

OBJECTIVE

Stress may play a role in the pathogenesis of the metabolic syndrome. However, the scant evidence available is not population-based, restricting the external validity of the findings. Our aim was to test associations between stressful life events, their accumulation, and the metabolic syndrome in a large population-based cohort. We also tested associations between stress and the individual components related to the metabolic syndrome.

RESEARCH DESIGN AND METHODS

This was a population-based, random sample of 3,407 women and men aged 18–78 years residing in Western Finland. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III and International Diabetes Federation criteria. The severity of 15 stressful life events pertaining to finance, work, social relationships, health, and housing was self-rated.

RESULTS

In comparison with subjects not reporting any extremely stressful life events, those reporting work- or finance-related events had an increased odds for having the metabolic syndrome. The risk was further increased according to accumulation of stressful finance-related events and to having at least three stressful life events in any of the life domains assessed. Accumulation of stressful life events was associated with insulin resistance, obesity, and triglycerides. The associations were not confounded by sex, age, lifestyle, or family history of diabetes.

CONCLUSIONS

Life events perceived as stressful, particularly those related to finance and work, may be a signal for poor metabolic health.Metabolic syndrome refers to a cluster of aberrations of metabolic origin that increases the risk for morbidity and mortality from type 2 diabetes (1,2), cardiovascular disease (3), and all-cause mortality (1). Features of the metabolic syndrome include a combination of impaired glucose and lipid metabolism, obesity, and hypertension (4–6). Along with the worldwide increase in the prevalence of the metabolic syndrome (7), there exists a strong need to identify underlying, causative factors that may render an individual susceptible to the metabolic syndrome.The metabolic syndrome is thought to be multifactorial in origin, arising from a combination of genetic and environmental factors (4). Among the plausible environmental factors is psychosocial stress (8). However, research on the importance of stress in the etiology of the metabolic syndrome is scanty. Vogelzangs et al. (9) found in their cross-sectional cohort study of 2,917 elderly men and women that for each experienced negative life event the odds for having the metabolic syndrome increased by 13%. In a small sample of elderly women and men (10), caregiver stress predicted metabolic syndrome at follow-up >15 years later. In the Whitehall II study of >10,000 middle-aged civil servants, chronic work stress predicted higher odds for having the metabolic syndrome at a follow-up 14 years later (11). In the Pittsburgh Healthy Women Study, middle-aged women who experienced life events as extremely stressful had an increased risk for developing the metabolic syndrome over an average 15 years of follow-up (12). In the same study marital dissatisfaction, divorce, and widowhood also predicted an increased risk for developing the metabolic syndrome over an average follow-up of 11.5 years (13).Although important, none of the studies so far have been population-based, restricting the external validity of the findings: the participants have been recruited from health care beneficiaries (9), from Alzheimer''s caregivers (10), from employees of civil service departments (11), and from initially healthy premenopausal women holding a driver''s license (12,13). Accordingly, the first major aim of this study was to test associations between severity of stressful life events arising from various life domains and the metabolic syndrome defined according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and International Diabetes Federation (IDF) clinical criteria in a large population-based sample of women and men residing in Western Finland. The second major aim of our study was to test the significance of stressful life events for the individual components of the metabolic syndrome.     

Metabolic Syndrome Over 10 Years and Cognitive Functioning in Late Midlife: The Whitehall II study

OBJECTIVE

Evidence that the metabolic syndrome is a risk factor for poor cognition is mixed and is focused mainly on the elderly population; rarely is an adjustment made for socioeconomic factors. We examined this association in late midlife, with particular focus on cumulative effects and the role of socioeconomic circumstances.

RESEARCH DESIGN AND METHODS

Analyses were performed for 4,150 white participants from the Whitehall II study. Metabolic syndrome, using the National Cholesterol Education Program Adult Treatment Panel III criteria, was assessed three times over the 10-year follow-up (1991–2001). Cognitive function was assessed using a battery of six tests at the end of the follow-up.

RESULTS

After adjustment for demographic variables, health behaviors, and health status, participants with persistent metabolic syndrome (at least two of the three screenings) over the 10-year follow-up had lower cognitive performance than participants who never had metabolic syndrome. No significant differences in cognitive function were observed between participants with nonpersistent metabolic syndrome (one of the three screenings) and those who never had metabolic syndrome during the follow-up. Adjustment for adult occupational position attenuated this association by between 41 and 86%, depending on the measure of cognitive function. Adjustment for education had little effect.

CONCLUSIONS

Only persistent metabolic syndrome was associated with lower cognitive performance in late midlife. Adult occupational position but not education had a substantial impact on this association; these results highlight the importance of adult socioeconomic circumstances in identifying and targeting risk factors for cognitive aging.Cardiovascular risk factors have increasingly been recognized as important contributors to cognitive outcomes such as dementia (1). The metabolic syndrome comprises five cardiovascular risk factors including abdominal obesity, hypertriglyceridemia, low HDL cholesterol, hypertension, and hyperglycemia (2). Numerous studies have shown several of the individual components of the metabolic syndrome to be linked to the risk of cognitive decline and dementia (3). However, the nature of the association between metabolic syndrome and cognition remains unclear. There are only a few studies on the metabolic syndrome as a whole, and most of them have been limited to elderly or older populations (4–12). Furthermore, the findings are mixed: although some reports suggest that metabolic syndrome predicts cognitive deficit (4), cognitive decline (5,11,12), and dementia (8,10), at least two studies showed metabolic syndrome to be associated with better cognitive performance (6) and decelerated cognitive decline (9). A further study found no significant relationship between metabolic syndrome and dementia (7).Several limitations in previous studies that are possible to overcome may have contributed to inconsistencies in the evidence. First, as subclinical manifestations of dementia are believed to be present many years before the diagnosis, examining the role of risk factors, such as the metabolic syndrome, before old age would provide insight into their impact on cognitive function (13,14). Second, no previous study has examined the effects of persistent metabolic syndrome, assessed repeatedly rather than at a single time point, on cognition. Third, existing research has not taken full account of the potential for confounding by socioeconomic position (SEP).In this field of research, SEP may play a particularly important role as, on the one hand, it contributes to cognitive reserve (15), and, on the other hand, it is associated with vascular and other risk factors for cognitive aging (16). Although studies on the association between metabolic syndrome and cognition usually adjust for education, they do not take into account the effects of later life measures of SEP. Education reflects early SEP but may not capture changes in socioeconomic circumstances in adult life. Other measures, such as household income or occupational position, may better reflect adult socioeconomic circumstances.We use data from a large prospective middle-aged cohort (the Whitehall II study) to examine the association between metabolic syndrome and cognitive function in mid-life. Our focus is on investigating the effect of cumulative exposure to metabolic syndrome over 10 years and the influence of SEP as indicated by education and occupational position.     

Metabolically Healthy Obesity and Risk of Mortality: Does the definition of metabolic health matter?

OBJECTIVE

To assess the association of a “metabolically healthy obese” phenotype with mortality using five definitions of metabolic health.

RESEARCH DESIGN AND METHODS

Adults (n = 5,269; 71.7% men) aged 39–62 years in 1991 through 1993 provided data on BMI and metabolic health, defined using data from the Adult Treatment Panel-III (ATP-III); criteria from two studies; and the Matsuda and homeostasis model assessment (HOMA) indices. Cross-classification of BMI categories and metabolic status (healthy/unhealthy) created six groups. Cox proportional hazards regression models were used to analyze associations with all-cause and cardiovascular disease (CVD) mortality during a median follow-up of 17.7 years.

RESULTS

A total of 638 individuals (12.1% of the cohort) were obese, of whom 9–41% were metabolically healthy, depending on the definition. Regardless of the definition, compared with metabolically healthy, normal-weight individuals, both the metabolically healthy obese (hazard ratios [HRs] ranged from 1.81 [95% CI 1.16–2.84] for ATP-III to 2.30 [1.13–4.70] for the Matsuda index) and the metabolically abnormal obese (HRs ranged from 1.57 [1.08–2.28] for the Matsuda index to 2.05 [1.44–2.92] for criteria defined in a separate study) had an increased risk of mortality. The only exception was the lack of excess risk using the HOMA criterion for the metabolically healthy obese (1.08; 0.67–1.74). Among the obese, the risk of mortality did not vary as a function of metabolic health apart from when using the HOMA criterion (1.93; 1.15–3.22). Similar results were obtained for cardiovascular mortality.

CONCLUSIONS

For most definitions of metabolic health, both metabolically healthy and unhealthy obese patients carry an elevated risk of mortality.Obesity is a major public health problem that has reached epidemic proportions worldwide (1). It is associated with numerous metabolic and cardiovascular disturbances such as insulin resistance, type 2 diabetes, hypertension, and dyslipidemia (2–5). However, these cardiometabolic abnormalities are not found in all obese people (6,7), as evidenced by the occurrence of a subset of apparently healthy obese subjects referred to as metabolically healthy obese (MHO) (8,9). Several studies have confirmed the existence of MHO individuals (10–16), accounting for as much as 40% of the obese population. MHO individuals display a favorable metabolic profile, characterized by high levels of insulin sensitivity, a low prevalence of hypertension, and a favorable lipid and inflammation profile.The long-term health consequences of obesity among those who are metabolically healthy remain unclear. Obesity is known to carry an elevated risk of mortality (17), but few studies have examined associations of the MHO phenotype with mortality, and the evidence from these studies is mixed. In general population samples from Scotland and England, MHO individuals were not at increased risk of all-cause and cardiovascular disease (CVD) mortality compared with healthy nonobese individuals (18), a finding replicated in an Italian study of obesity and insulin sensitivity (19). However, overweight and obese individuals without the metabolic syndrome had an increased risk of mortality compared with normal-weight individuals without the metabolic syndrome in a Swedish cohort of middle-aged men (20). Furthermore, in the U.S. National Health and Nutrition Examination Survey III (21), metabolically healthy and abnormal obese individuals had similar elevations in mortality risk compared with metabolically healthy, normal-weight subjects. Several factors may have contributed to these inconsistencies. The comparison group varies when estimating risk of mortality in the MHO phenotype; risk is compared either with metabolically healthy nonobese (18,19) or metabolically healthy, normal-weight people (20,21). Another difference between the studies is that metabolic health is defined in different ways, with little consensus on how best to define it. Therefore, the objective of the current study is to assess whether there is consistency in the association of the MHO phenotype with all-cause and CVD mortality using different definitions of metabolic health and reference groups.     

Fibroblast Growth Factor 21 Predicts the Metabolic Syndrome and Type 2 Diabetes in Caucasians

OBJECTIVE

The incidence of the metabolic syndrome and type 2 diabetes mellitus (T2DM) is rising worldwide. Liver-derived fibroblast growth factor (FGF)-21 affects glucose and lipid metabolism. The aim of this study was to analyze the predictive value of FGF-21 on the incidence of T2DM and the metabolic syndrome.

RESEARCH DESIGN AND METHODS

The Metabolic Syndrome Berlin Potsdam (MeSyBePo) recall study includes 440 individuals. Glucose metabolism was analyzed using an oral glucose tolerance test, including insulin measurements. FGF-21 was measured using enzyme-linked immunosorbent assay. Primary study outcome was diabetes and the metabolic syndrome incidence and change of glucose subtraits.

RESULTS

During a mean follow-up of 5.30 ± 0.1 years, 54 individuals developed the metabolic syndrome, 35 developed T2DM, and 69 with normal glucose tolerance at baseline progressed to impaired glucose metabolism, defined as impaired fasting glucose, impaired glucose tolerance, or T2DM. FGF-21 predicted incident metabolic syndrome (lnFGF-21 odds ratio [OR] 2.6 [95% CI 1.5 – 4.5]; P = 0.001), T2DM (2.4 [1.2–4.7]; P = 0.01), and progression to impaired glucose metabolism (2.2 [1.3 – 3.6]; P = 0.002) after adjustment for age, sex, BMI, and follow-up time. Additional adjustment for waist-to-hip ratio, systolic blood pressure, HDL cholesterol, triglycerides, and fasting glucose did not substantially modify the predictive value of FGF-21.

CONCLUSIONS

FGF-21 is an independent predictor of the metabolic syndrome and T2DM in apparently healthy Caucasians. These results may indicate FGF-21 resistance precedes the onset of the metabolic syndrome and T2DM.Numerous adipose tissue–derived hormones, the so-called adipokines, have been shown to predict and to be involved in the pathogenesis of type 2 diabetes mellitus (T2DM) (1,2). Recent data revealed increasing evidence that liver-derived hormones might affect glucose and lipid metabolism. Among these “hepatokines,” fibroblast growth factor (FGF)-21 has recently received increasing attention. FGF-21 expression and secretion is induced in the liver during periods of fasting (3,4). Recent studies suggested that fatty acids induce the expression and secretion of FGF-21 in a peroxisome proliferator–activated receptor-α (PPAR-α)–dependent fashion (5,6). FGF-21 signaling requires FGF receptor and the adapter molecule, β-Klotho (7,8), which targets FGF-21 primarily to the liver itself, but also to pancreas and adipose tissue. FGF-21 signaling has been suggested to affect glucose, lipid, cholesterol, and bile acid metabolism (3,9), which has turned FGF-21 into a reasonable candidate directly affecting the pathophysiology of the metabolic syndrome and T2DM. Notably, studies in animal models have found FGF-21 has antidiabetic properties (10), whereas a number of human studies observed increased circulating FGF-21 levels in subjects with existing insulin resistance, impaired glucose tolerance (IGT), and hypertriglyceridemia (11–13). Zhang and coworkers (13) demonstrated that FGF-21 is independently associated with the metabolic syndrome in Asian individuals, and another study in an Asian cohort recently demonstrated that genetic polymorphisms within a 3′-untranslated region of FGF-21 are also associated with the metabolic syndrome (14). Most interestingly an association between FGF-21 and incident diabetes was observed in an Asian cohort (15). However, whether FGF-21 predicts metabolic syndrome and whether the findings in Asian individuals are comparably found in Caucasian individuals is unclear. We therefore investigated whether FGF-21 predicts incident metabolic syndrome and T2DM, both defined by World Health Organization (WHO) criteria, and the progression of healthy controls to impaired glucose metabolism (IGM), defined as incident impaired fasting glucose (IFG), IGT, or incident diabetes, in a cohort of apparently healthy individuals.     

The prevalence of metabolic syndrome and determination of the optimal waist circumference cutoff points in a rural South african community

OBJECTIVE

To determine the prevalence of metabolic syndrome and to define optimal ethnic-specific waist-circumference cutoff points in a rural South African black community.

RESEARCH DESIGN AND METHODS

This was a cross-sectional survey conducted by random-cluster sampling of adults aged >15 years. Participants had demographic, anthropometric, and biochemical measurements taken, including a 75-g oral glucose tolerance test. Metabolic syndrome was defined using the 2009 Joint Interim Statement (JIS) definition.

RESULTS

Of 947 subjects (758 women) studied, the age-adjusted prevalence of metabolic syndrome was 22.1%, with a higher prevalence in women (25.0%) than in men (10.5%). Peak prevalence was in the oldest age-group (≥65 years) in women (44.2%) and in the 45- to 54-year age-group in men (25.0%). The optimal waist circumference cutoff point to predict the presence of at least two other components of the metabolic syndrome was 86 cm for men and 92 cm for women. The crude prevalence of metabolic syndrome was higher with the JIS definition (26.5%) than with the International Diabetes Federation (IDF) (23.3%) or the modified Third Report of the National Cholesterol Education Program Adult Treatment Panel (ATPIII) (18.5%) criteria; there was very good agreement with the IDF definition (κ = 0.90 [95% CI 0.87–0.94]) and good concordance with ATPIII criteria (0.77 [0.72–0.82]).

CONCLUSIONS

There is a high prevalence of metabolic syndrome, especially in women, suggesting that this community, unlike other rural communities in Africa, already has entered the epidemic of metabolic syndrome. Waist circumference cutoff points differ from those currently recommended for Africans.Metabolic syndrome is a cluster of risk factors for type 2 diabetes and cardiovascular disease (CVD), with insulin resistance proposed as a linking factor (1–8). Metabolic syndrome is common and is increasing in prevalence worldwide, largely attributed to increasing obesity and sedentary lifestyles, and now is both a public health and clinical problem (5).Since the first formalized definition (6) of metabolic syndrome, there have been several definitions using different criteria (1–4,7,8), leading to widely differing prevalence estimates (5). The two major sets of criteria that have been used are those of the National Cholesterol Education Program Third Adult Treatment Panel (ATPIII) (2–4) and International Diabetes Federation (IDF) (1). The main difference between the two systems is that central obesity, as measured by waist circumference, is a prerequisite in the IDF definition, with cut points of waist circumference being ethnic specific and lower than in the ATPIII definition.In 2009, an additional definition of metabolic syndrome was proposed as a joint interim statement (JIS) by several organizations in an attempt to harmonize the definition of metabolic syndrome (5). The available information based on ATPIII and IDF criteria suggests that metabolic syndrome is pandemic but that prevalence varies widely depending on the ethnic groups studied and criteria applied (9).Sub-Saharan Africa currently is experiencing one of the most rapid demographic and epidemiological transitions with one of the fastest rates of urbanization, which is thought to be mainly responsible for the rising burden of diabetes and other noncommunicable diseases (10–13).The available information on the prevalence of metabolic syndrome in epidemiology studies in sub-Saharan Africa is limited to reports on West Africans in Cameroon (14), Benin (15), and Nigeria (16) and based on ATPIII (2–4) or IDF definitions (1). The crude prevalence in these studies ranged from an absence or low prevalence (0–4.1%) in rural communities in all three countries as well as in an urban community in Cameroon. In Benin, prevalence was higher in semiurban (6.4%) and urban samples (11.0%). To date, there are no reports on the prevalence of metabolic syndrome from epidemiology studies in South Africa and none (urban or rural) using the JIS definition.A cross-sectional diabetes epidemiology study in rural South Africans of Zulu descent allowed for the determination of the prevalence of metabolic syndrome using the JIS definition and the optimal waist circumference cutoff points to predict the presence of metabolic syndrome in this population.     

Large Pre- and Postexercise Rapid-Acting Insulin Reductions Preserve Glycemia and Prevent Early- but Not Late-Onset Hypoglycemia in Patients With Type 1 Diabetes

OBJECTIVE

To examine the acute and 24-h glycemic responses to reductions in postexercise rapid-acting insulin dose in type 1 diabetic patients.

RESEARCH DESIGN AND METHODS

After preliminary testing, 11 male patients (24 ± 2 years, HbA_1c 7.7 ± 0.3%; 61 ± 3.4 mmol/mol) attended the laboratory on three mornings. Patients consumed a standardized breakfast (1 g carbohydrate ⋅ kg⁻¹ BM; 380 ± 10 kcal) and self-administered a 25% rapid-acting insulin dose 60 min prior to performing 45 min of treadmill running at 72.5 ± 0.9% VO_2peak. At 60 min postexercise, patients ingested a meal (1 g carbohydrate ⋅ kg⁻¹ BM; 660 ± 21 kcal) and administered a Full, 75%, or 50% rapid-acting insulin dose. Blood glucose concentrations were measured for 3 h postmeal. Interstitial glucose was recorded for 20 h after leaving the laboratory using a continuous glucose monitoring system.

RESULTS

All glycemic responses were similar across conditions up to 60 min postexercise. After the postexercise meal, blood glucose was preserved under 50%, but declined under Full and 75%. Thence at 3 h, blood glucose was highest under 50% (50% [10.4 ± 1.2] vs. Full [6.2 ± 0.7] and 75% [7.6 ± 1.2 mmol ⋅ L⁻¹], P = 0.029); throughout this period, all patients were protected against hypoglycemia under 50% (blood glucose ≤3.9; Full, n = 5; 75%, n = 2; 50%, n = 0). Fifty percent continued to protect patients against hypoglycemia for a further 4 h under free-living conditions. However, late-evening and nocturnal glycemia were similar; as a consequence, late-onset hypoglycemia was experienced under all conditions.

CONCLUSIONS

A 25% pre-exercise and 50% postexercise rapid-acting insulin dose preserves glycemia and protects patients against early-onset hypoglycemia (≤8 h). However, this strategy does not protect against late-onset postexercise hypoglycemia.Patients with type 1 diabetes are encouraged to engage in regular exercise as part of a healthy lifestyle (1,2). However, engaging in exercise is not without its difficulties (1). Defective glucose regulation presents a significant challenge in preventing hypoglycemia during, and particularly after, exercise (3,4). Exercise-induced hypoglycemia is both a frequent (5) and dangerous occurrence (6) and remains a major obstacle to patients who wish to engage in exercise (7).Much of the literature has focused on providing strategies to help combat hypoglycemia during, and early after, exercise (8–17), with investigations focusing on altering exercise modality (14,18), carbohydrate consumption (12,16,17), and reductions to pre-exercise, rapid-acting insulin dose (10–12,17,19). Prior to moderate-intensity, continuous, aerobic exercise, it is recommended that patients should reduce their prandial rapid-acting insulin dose by ∼75% to prevent hypoglycemia during exercise (10–12). However, despite best preserving blood glucose, it has been shown that this strategy is not fully protective against postexercise hypoglycemia (11,12). This has, in part, been attributed to iatrogenic causes (11), whereby patients administer their usual doses of rapid-acting insulin in a heightened insulin-sensitive state, potentially leading to unexpected falls in blood glucose and, consequently, hypoglycemia (11).A potential strategy to help minimize the risk of developing hypoglycemia after exercise could be to reduce the dose of rapid-acting insulin administered with the postexercise meal (20). Exercise increases the sensitivity of the body to insulin for many hours after exercise (3) and patients could be faced with a window of particularly high sensitivity around the postexercise meal, whereby greater rates of glucose uptake could occur to supplement the high metabolic priority of replenishing muscle glycogen (21). Thus, the meal consumed after exercise is important. With this in mind, it would be intuitive to reduce the amount of insulin administered with the meal consumed at this time; this may preserve glycemia and prevent postexercise hypoglycemia. Conversely, severe reductions in rapid-acting insulin dose may incur prolonged postexercise hyperglycemia, even more so if the pre-exercise dose is also reduced. However, there is a lack of data to confirm or refute these hypotheses. In addition, it would be prudent to examine the extent to which rapid-acting insulin dose adjustments may help combat late falls in glycemia after exercise, considering type 1 diabetic patients are susceptible to late-onset, postexercise hypoglycemia (3), suggested to be due to a biphasic response in glucose uptake occurring early and also late after exercise (22). Therefore, the aim of this study was to examine the acute and 24-h postexercise glycemic responses to reducing the postexercise rapid-acting insulin dose, when using the recommended pre-exercise insulin reductions, in type 1 diabetic patients.     

Exposure to the chinese famine in early life and the risk of metabolic syndrome in adulthood

OBJECTIVE

To examine whether exposure to the Chinese famine during fetal life and early childhood is associated with the risks of metabolic syndrome and whether this association is modified by later life environment.

RESEARCH DESIGN AND METHODS

We used data of 7,874 adults born between 1954 and 1964 from the 2002 China National Nutrition and Health Survey. Famine exposure groups were defined as nonexposed; fetal exposed; and early childhood, midchildhood, or late childhood exposed. Excess death rate was used to determine the severity of the famine. The ATP III criteria were used for the definition of metabolic syndrome (three or more of the following variables: elevated fasting triglyceride levels, lower HDL cholesterol levels, elevated fasting glucose levels, higher waist circumference, high blood pressure).

RESULTS

In severely affected famine areas, adults who were exposed to the famine during fetal life had a higher risk of metabolic syndrome, as compared with nonexposed subjects (odds ratio 3.13 [95% CI 1.24–7.89, P = 0.016]). Similar associations were observed among adults who were exposed to the famine during early childhood, but not for adults exposed to the famine during mid- or late childhood. Participants who were born in severely affected famine areas and had Western dietary habits in adulthood or were overweight in adulthood had a particularly high risk of metabolic syndrome in later life.

CONCLUSIONS

Exposure to the Chinese famine during fetal life or infancy is associated with an increased risk of metabolic syndrome in adulthood. These associations are stronger among subjects with a Western dietary pattern or who were overweight in adulthood.Famine studies may give direct evidence for the hypotheses that early malnutrition plays a role in the origins of hypertension (1–3), insulin resistance (4,5), central obesity (6), and dyslipidemia (7), which are all components of the metabolic syndrome. Fetal famine exposure has been shown to be associated with the risk of hypertension in later life in subjects exposed to the Dutch Hunger Winter (1944–1945) (1), Leningrad Siege (1941–1944) (2), and Chinese famine (1959–1961) (3). Prenatal exposure to both the Dutch Hunger Winter and Chinese famine was also associated with impaired glucose tolerance among adults (4,5,8). Maternal famine exposure during gestation was also associated with higher BMI and waist circumference in Dutch (6) and Chinese women (9,10) and a more atherogenic lipid profile among Dutch adults (7).The only famine study that examined the associations of fetal famine exposure with metabolic syndrome was conducted in the Dutch Famine Cohort and did not observe significant associations (11). This might be because of the limited period of the Dutch Hunger Winter, which did not last for the whole gestation period, whereas the different metabolic syndrome components have different underlying origins and critical periods (11).The risks of adverse long-term consequences of famine exposure during early life may be further increased in a nutritionally rich environment in later life (12,13). The associations between low birth weight and later risk of hypertension seem to be stronger among subjects who become overweight in later life (13,14). Our previous study indicated that the association of fetal famine exposure with the risk of hyperglycemia appeared to be exacerbated by Western dietary pattern and improved economic status (8). No previous study had examined the joint association of early life famine exposure and later life nutritional rich environments with the risk of metabolic syndrome during adulthood.The purpose of present study was to examine whether exposure to Chinese famine during fetal life and childhood was associated with the risk of metabolic syndrome and whether this association was modified by later life nutritional environment.     

TRAF-interacting Protein (TRIP): A Novel Component of the Tumor Necrosis Factor Receptor (TNFR)- and CD30-TRAF Signaling Complexes That Inhibits TRAF2-mediated NF-κB Activation

Through their interaction with the TNF receptor–associated factor (TRAF) family, members of the tumor necrosis factor receptor (TNFR) superfamily elicit a wide range of biological effects including differentiation, proliferation, activation, or cell death. We have identified and characterized a novel component of the receptor–TRAF signaling complex, designated TRIP (TRAF-interacting protein), which contains a RING finger motif and an extended coiled-coil domain. TRIP associates with the TNFR2 or CD30 signaling complex through its interaction with TRAF proteins. When associated, TRIP inhibits the TRAF2-mediated NF-κB activation that is required for cell activation and also for protection against apoptosis. Thus, TRIP acts as a receptor–proximal regulator that may influence signals responsible for cell activation/proliferation and cell death induced by members of the TNFR superfamily.Members of the TNF receptor (TNFR)¹ superfamily play important roles in the induction of diverse signals leading to cell growth, activation, and apoptosis (1). Whether the signals induced by a given receptor leads to cell activation or death is, however, highly cell-type specific and tightly regulated during differentiation of cells. For example, the TNFRs can exert costimulatory signals for proliferation of naive lymphocytes but also induce death signals required for deletion of activated T lymphocytes (1). The cytoplasmic domains of these receptors lack intrinsic catalytic activity and also exhibit no significant homology to each other or to other known proteins. Exceptions to this include Fas(CD95) and TNFR1 that share a significant homology within an 80–amino acid region of their cytoplasmic tails (called the “death domain”; 2, 3). Therefore, it is suggested that the TNFR family members can initiate different signal transduction pathways by recruiting different types of intracellular signal transducers to the receptor complex (1).Indeed, several types of intracellular signal transducers have been identified that initiate distinct signal transduction pathways when recruited to the members of TNFR superfamily (4–19). Recent biochemical and molecular studies showed that a class of signal-transducing molecules are recruited to Fas(CD95) or TNFR1 via interaction of the death domains (2, 3, 6, 12, 17, 20). For example, Fas(CD95) and TNFR1 recruit FADD(MORT1)/RIP or TRADD/FADD (MORT1)/RIP through the interactions of their respective death domains (2, 3, 6, 12, 17, 20, 21). Clustering of these signal transducers leads to the recruitment of FLICE/ MACH, and subsequently, to cell death (13, 14).The TNFR family members can also recruit a second class of signal transducers called TRAFs (TNFR-associated factor), some of which are responsible for the activation of NF-κB or JNK (9, 20, 22). TRAF proteins were identified by their biochemical ability to interact with TNFR2, CD40, CD30, or LT-βR (4, 5, 10, 11, 15, 23–27). These receptors interact directly with TRAFs via a short stretch of amino acids within their cytoplasmic tails, but do not interact with the death domain containing proteins (4, 5, 15, 24–27). To date, five members of the TRAF family have been identified as signaling components of the TNFR family members. All TRAF members contain a conserved TRAF domain, ∼230 amino acids in length, that is used for either homo- or heterooligomerization among the TRAF family, for interactions with the cytoplasmic regions of the TNFR superfamily, or for interactions with downstream signal transducers (4, 5, 8, 10, 11, 19, 23–25, 28). In addition to the TRAF domain, most of the TRAF family members contain an NH₂-terminal RING finger and several zinc finger structures, which appear to be important for their effector functions (4, 5, 10, 11, 23–25).Several effector functions of TRAFs were revealed by recent experiments based on a transfection system. TRAF2, first identified by its interaction with TNFR2 (4), was subsequently shown to mediate NF-κB activation induced by two TNF receptors, CD40 and CD30 (9, 28–30). TRAF5 was also implicated in NF-κB activation mediated by LTβR (10), whereas TRAF3 (also known as CRAF1, CD40bp, or LAP1; references 5, 11, 24, and 25) was shown to be involved in the regulation of CD40-mediated CD23 upregulation in B cells (5). The role of other TRAF members in the TNFR family–mediated signal transduction is not clear. They may possess some effector functions as yet to be revealed, or work as adapter proteins to recruit different downstream signal transducers to the receptor complex. For example, TRAF1 is required for the recruitment of members of the cellular inhibitor of apoptosis protein (c-IAP) family to the TNFR2-signaling complex (7). In addition to the signal transduction by the TNFR family members, TRAFs may regulate other receptor-mediated signaling pathways. For example, TRAF6 is a component of IL-1 receptor (IL1R)–signaling complex, in which it mediates the activation of NF-κB by IL-1R (31). Since TRAFs form homo- or heterooligomers, it is suggested that the repertoire of TRAF members in a given cell type may differentially affect the intracellular signals triggered by these receptors. This may be accomplished by the selective interaction of TRAFs with a specific set of downstream signal transducers. Although many aspects of TRAF-mediated effector functions leading to cellular activation have been defined, it needs to be determined whether TRAF proteins will also mediate the apoptotic signals induced by the “death-domain-less” members of the TNFR superfamily (1, 27, 32–36).Here we report the isolation and characterization of a novel component of the TNFR superfamily/TRAFs signaling complex, named TRIP (TRAF-interacting protein). TRIP associates with the receptor/TRAF signaling complex, and inhibits the TRAF2-mediated NF-κB activation. Biochemical studies indicate that TRIP associates with the TNFR2 or CD30 receptor complex via its interaction with TRAF proteins, suggesting a model which can explain why the ligation of these receptors can promote different cell fates: proliferation or death.     

Association of Serum Ferritin and the Development of Metabolic Syndrome in Middle-Aged Korean Men: A 5-year follow-up study

OBJECTIVE

Elevated serum ferritin has been known to be associated with the prevalence of metabolic syndrome (MetS). However, there was no research to examine whether serum ferritin levels have been actually associated with the prospective development of MetS. Accordingly, we carried out a prospective study to evaluate the longitudinal effects of baseline serum ferritin levels on the development of MetS.

RESEARCH DESIGN AND METHODS

A MetS-free cohort of 18,022 healthy Korean men, who had participated in a medical health checkup program in 2005, was followed until 2010. MetS was defined according to the joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention. Cox proportional hazards models were performed.

RESULTS

During 45,919.3 person-years of follow-up, 2,127 incident cases of MetS developed between 2006 and 2010. After adjusting for multiple covariates, the hazard ratios (95% CI) for incident MetS comparing the second quintile to the fifth quintile of serum ferritin levels versus the first quintile were 1.19 (0.98–1.45), 1.17 (0.96–1.43), 1.36 (1.12–1.65), and 1.66 (1.38–2.01), respectively (P for trend <0.001). These associations were apparent in the clinically relevant subgroup analyses.

CONCLUSIONS

Elevated serum ferritin levels were independently associated with future development of MetS during the 5-year follow-up period.Iron is a ubiquitous metal of vital importance to the normal physiologic processes of many organisms (1). The serum ferritin concentration reflects iron stores in the body (2).There have been several studies that showed the significant association between elevated serum ferritin levels and metabolic disorders. In a population study of Finnish men, serum ferritin levels were correlated with fasting serum glucose and insulin concentrations (3). In several other studies, elevated serum ferritin concentrations were reported to be associated with cardiovascular disease (4–6), essential hypertension (7), insulin resistance (8,9), diabetes (10,11), gestational diabetes mellitus (12), and central adiposity (13). In addition, recent studies showed that serum ferritin levels are positively associated with the prevalence of metabolic syndrome (MetS) in western countries (14,15). In the Asian population, some studies reported the relationship between serum ferritin concentrations and the prevalence of MetS (16,17). However, most of the studies have been confined to the cross-sectional nature. To the best of our knowledge, no prospective research has been conducted to evaluate the longitudinal association between baseline serum ferritin levels and the development of MetS. Therefore, we performed this study to assess the longitudinal effects of baseline serum ferritin levels on the development of MetS during a 5-year follow-up period in middle-aged Korean men.     

Improved metabolic control in children and adolescents with type 1 diabetes: a trend analysis using prospective multicenter data from Germany and Austria

OBJECTIVE

To investigate the temporal trend of metabolic control and potential predictors in German and Austrian children and adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

This study is based on a large, multicenter database for prospective longitudinal documentation of diabetes care in Germany and Austria. Data from 30,708 patients documented in 305 diabetes centers between 1995 and 2009 were analyzed. Generalized linear mixed regression models were used to adjust trend analysis for relevant confounders.

RESULTS

Unadjusted mean HbA_1c decreased from 8.7 ± 1.8% in 1995 to 8.1 ± 1.5% in 2009. In multiple regression analysis, treatment year, age, sex, diabetes duration, migration background, BMI-SDS, and daily insulin dose were significant predictors of metabolic control (P < 0.001). After multiple adjustment, mean HbA_1c decreased significantly by 0.038% per year (95% CI 0.032–0.043%), average odds ratio (OR) per year for HbA_1c >7.5% (>9.0%) was 0.969 (95% CI 0.961–0.977) (0.948, 95% CI 0.941–0.956). Intensified insulin regimen was associated with lower frequency of poor metabolic control (HbA_1c >9%; P = 0.005) but not with average HbA_1c (P = 0.797). Rate of severe hypoglycemia and hypoglycemic coma decreased significantly (relative risk [RR] per year 0.948, 95% CI 0.918–0.979; RR 0.917, 95% CI 0.885–0.950) over the study period. Diabetic ketoacidosis rate showed no significant variation over time.

CONCLUSIONS

This study showed a significant improvement in metabolic control in children and adolescents with type 1 diabetes during the past decade and a simultaneous decrease in hypoglycemic events. The improvement was not completely explained by changes in the mode of insulin treatment. Other factors such as improved patient education may have accounted for the observed trend.The Diabetes Control and Complications Trial (DCCT) showed that improved metabolic control reduces the risk of long-term complications in both adult and adolescent patients with type 1 diabetes (1,2). The observational follow-up study of the DCCT (the Epidemiology of Diabetes Interventions and Complications [EDIC] study) further proved that good glycemic control had persistent beneficial effects on long-term complications (3). Based on the results of the DCCT/EDIC study, it was recommended to optimize glycemic control as early and close to normal as possible in all patients with type 1 diabetes in order to prevent development and progression of microvascular complications.Diabetes treatment has been intensified in pediatric and adolescent patients during the past 15 years. Insulin therapy has changed from twice-daily injection regimen to intensified therapy with multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII). This has been reported from single-center and multicenter studies (4–10). In the 1990s, mainly an increased use of MDI was observed, whereas since 2000, pump therapy increased considerably, paralleled by a decrease in MDI therapy (11). With the intensification of insulin regimen, the frequency of daily self-monitoring of blood glucose (SMBG) increased continuously (5,10–12), as close glucose monitoring is a precondition for intensified insulin therapy with an appropriate dose adjustment. Likewise, the use of short-acting insulin analogs has continuously increased since the mid-1990s and the use of long-acting analogs since 2000 (4,5,10).Despite these far-ranging changes in diabetes therapy, the anticipated improvement in metabolic control in children and adolescents with type 1 diabetes has not been achieved in all settings. The multicenter Hvidoere studies did not observe any improvement in glycemic control during 1995–2005 (6–8). Other studies, however, reported a significant decrease in average HbA_1c level over the past two decades (4,5,10,11,13). Concordantly, several studies indicated a notable increase in the proportion of children and adolescents with good metabolic control (HbA_1c <7.5 or <8%) over the past years (11,13).In the DCCT study, the tradeoff with intensified insulin therapy was a marked increase in episodes of severe hypoglycemia (2). Several studies reported a higher hypoglycemia risk with lower HbA_1c level (4,6,7,10,14), but others did not (15,16). Results on the trend of severe hypoglycemic events over the past 15 years are also inconsistent (4,5,8,9,11).The aim of this study was to give a current update on the temporal trend of metabolic control in German and Austrian children and adolescents over the past 15 years (1995–2009), to identify potential determinants of metabolic control, and to analyze the simultaneous trend of severe hypoglycemic and diabetic ketoacidotic events.     

Effect of longitudinal changes in visceral fat area and other anthropometric indices to the changes in metabolic risk factors in Japanese men: the Hitachi Health Study

OBJECTIVE

The effects of longitudinal changes in the visceral fat area (VFA), and other anthropometric indices, on the risk factors of metabolic syndrome were not studied. We calculated the changes in metabolic risk factors in relation to changes in certain anthropometric indices in a large-scale study of Japanese men.

RESEARCH DESIGN AND METHODS

The subjects were 1,106 men participating in the Hitachi Health Study who received a computed tomography examination in both 2004 and 2007. VFA, subcutaneous fat area (SFA), and waist circumference were measured using the computed tomography. We examined how longitudinal changes in each anthropometric index over a 3-year period influenced the value of each metabolic risk factor.

RESULTS

Changes (∆) over a 3-year period in body weight, SFA, and waist circumference strongly correlated, while the changes in body weight and VFA were weakly correlated. Changes in the VFA were associated with changes in metabolic risk factors, especially changes in triglyceride and HDL; we found these changes to be independent of the ∆body weight and ∆waist circumference.

CONCLUSIONS

Change in body weight is not a precise surrogate marker of ∆VFA, and repeated VFA measurements over time are useful. Adopting a lifestyle that does not increase the VFA is important in preventing metabolic syndrome.Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality in the world (1). Previous reports have shown that obesity plays a significant role in increasing cardiovascular risk (2). Certain indicators of obesity, such as the visceral fat area (VFA), or visceral adipose tissue, are more strongly associated with the risk of CVD than other indicators of obesity, such as waist circumference, BMI (3), or the subcutaneous fat area (SFA) (2). A large VFA is strongly related to a higher prevalence of impaired fasting glucose levels (4,5), diabetes (4,6,7), insulin resistance (4,8–10), hypertension (11,12), abnormality of lipid metabolism (13–16), and metabolic risk factors (14,17,18). Previous studies have examined the relationship between baseline VFA and metabolic risk factors. In a previous intervention study of 54 postmenopausal women, an increase in VFA strongly correlated with changes in triglyceride and HDL cholesterol levels compared with changes in the blood pressure and fasting blood glucose levels (19). In the current study, we examined the relationships between changes in the VFA, SFA, body weight, and waist circumference and changes in CVD risk factors to determine the relative contributions of the longitudinal changes in these anthropometric indices to the changes in metabolic risk factors over a 3-year period. Determining the relationships between the anthropometric indices and metabolic risk factors would be useful for preventing CVD in clinical settings.     

Effect of Insulin Glargine and n-3FA on Carotid Intima-Media Thickness in People With Dysglycemia at High Risk for Cardiovascular Events: The Glucose Reduction and Atherosclerosis Continuing Evaluation Study (ORIGIN-GRACE)

OBJECTIVE

To evaluate the effects of insulin glargine and n-3 polyunsaturated fatty acid (n-3FA) supplements on carotid intima-media thickness (CIMT).

RESEARCH DESIGN AND METHODS

We enrolled 1,184 people with cardiovascular (CV) disease and/or CV risk factors plus impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes in a randomized multicenter 2 × 2 factorial design trial. Participants received open-label insulin glargine (targeting fasting glucose levels ≤5.3 mmol/L [95 mg/dL]) or standard glycemic care and double-blind therapy with a 1-g capsule of n-3FA or placebo. The primary trial outcome was the annualized rate of change in maximum CIMT for the common carotid, bifurcation, and internal carotid artery segments. Secondary outcomes were the annualized rates of change in maximum CIMT for the common carotid and the common carotid plus bifurcation, respectively. Baseline followed by annual ultrasounds were obtained during a median follow-up of 4.9 years.

RESULTS

Compared with standard care, insulin glargine reduced the primary CIMT outcome, but the difference was not statistically significant (difference = 0.0030 ± 0.0021 mm/year; P = 0.145) and significantly reduced the secondary CIMT outcomes (differences of 0.0033 ± 0.0017 mm/year [P = 0.049] and 0.0045 ± 0.0021 mm/year [P = 0.032], respectively). There were no differences in the primary and secondary outcomes between the n-3FA supplement and placebo groups.

CONCLUSIONS

In people with CV disease and/or CV risk factors and dysglycemia, insulin glargine used to target normoglycemia modestly reduced CIMT progression, whereas daily supplementation with n-3FA had no effect on CIMT progression.Atherosclerosis is the major cause of death and disability in people with type 2 diabetes and lesser degrees of dysglycemia (1,2). Large epidemiological studies show consistent independent associations between glycemia and cardiovascular (CV) risk (1–4), and the metabolic abnormalities associated with dysglycemia promote atherosclerosis (5). Exogenous insulin can provide effective glycemic control, but its effects on atherosclerosis are unknown. Moreover, some studies suggest possible proatherogenic effects (6,7).Essential long-chain n-3 polyunsaturated fatty acids (n-3FA) may have beneficial effects on atherosclerosis (8). Higher intake of fish or n-3FA supplements is associated with lower rates of coronary heart disease and death (9,10) and lower atherosclerotic burden (11,12), and some, but not all, previous trials reported reduced CV events in patients receiving n-3FA supplements (13–16). The effects of these supplements on human atherosclerosis progression were evaluated in a few small studies, which were inconclusive (17–21).Therefore, we evaluated the effects of insulin glargine and n-3FA supplements on carotid intima-media thickness (CIMT) in people with dysglycemia and additional risk factors for atherosclerosis progression in a substudy of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial (22–24).     

White Matter Alteration in Metabolic Syndrome: Diffusion tensor analysis

OBJECTIVE

We explored the regional pattern of white matter alteration in subjects with metabolic syndrome. We also investigated whether white matter alteration was correlated with BMI.

RESEARCH DESIGN AND METHODS

Seven middle-aged men with metabolic syndrome and seven without metabolic syndrome underwent diffusion tensor imaging with a 3T magnetic resonance imaging imager. We analyzed the fractional anisotropy (FA) values by using a tract-based spatial statistics technique (whole-brain analysis). We subsequently focused on measuring the mean FA values of the right inferior fronto-occipital fasciculus (IFOF) of all subjects by tract-specific analysis (regional brain analysis). We used a Pearson correlation coefficient to evaluate the relationship between BMI and mean FA values of the right IFOF.

RESULTS

In the whole-brain analysis, subjects with metabolic syndrome had significantly lower FA values than control subjects in part of the right external capsule (part of the right IFOF), the entire corpus callosum, and part of the deep white matter of the right frontal lobe. In the regional brain analysis, the mean FA value of the right IFOF was 0.41 ± 0.03 for subjects with metabolic syndrome and 0.44 ± 0.05 for control subjects. A significant negative correlation was observed between BMI and FA values in the right IFOF (r = −0.56, P < 0.04).

CONCLUSIONS

Our results show that microstructural white matter changes occur in patients with metabolic syndrome. FA values may be useful indices of white matter alterations in patients with metabolic syndrome.The prevalence of overweight and obesity has been increasing in most developed countries (1,2). Direct associations between obesity and several diseases, including diabetes mellitus, hypertension, and ischemic heart disease, are well recognized (3). The BMI is one of the most commonly used indices of obesity. Although increased BMI itself does not always cause symptoms, a greater-than-normal BMI in midlife is associated with increased risk of dementia (4). Recent epidemiological evidence suggests that metabolic syndrome itself may be a risk factor for cognitive decline and dementia (5,6). Several volumetric assessment studies have revealed greater-than-normal brain atrophy in middle-aged obese adults (7,8) who are potentially at greater risk than normal for future dementia and Alzheimer disease (9). Recent voxel-based approaches have shown that the whole brain volume in obese individuals is less than that in individuals of normal weight, indicating that the relationship between BMI and reduced brain volume is not limited to older adults and is found across the adult life span (10). A magnetic resonance spectroscopic imaging study has found that increased BMI in midlife is associated with neuronal or myelin abnormalities, or both, mainly in the frontal lobe (11). A recent tensor-based morphometry study has shown that higher BMI is associated with lower brain volume in cognitively normal elderly subjects (12). Orsi et al. (13) have demonstrated that the volume of the right amygdala is negatively correlated with BMI in overweight men.As these studies indicate, associations between obesity and brain volume have been demonstrated, especially for gray matter. However, the effects of obesity on the microstructure of white matter remain less well-documented. Although recent studies have found that elderly adults with metabolic syndrome show subtle deficits in cognitive function (14) as well as microstructural changes in white matter (15), whether the microstructure of white matter is altered in middle-aged adults remains unknown.Here, we examined whether the microstructure of white matter is altered in middle-aged individuals with metabolic syndrome. We explored the regional pattern of white matter alteration in middle-aged individuals with metabolic syndrome by using diffusion tensor imaging (DTI), which is sensitive to subtle changes in cerebral white matter (16,17) and thus is a powerful tool for analyzing such changes (16). We also investigated whether the observed white matter alterations were related to BMI.     

Early Diabetic Nephropathy: A complication of reduced insulin sensitivity in type 1 diabetes

OBJECTIVE

Diabetic nephropathy (DN) is a major cause of mortality in type 1 diabetes. Reduced insulin sensitivity is a well-documented component of type 1 diabetes. We hypothesized that baseline insulin sensitivity would predict development of DN over 6 years.

RESEARCH DESIGN AND METHODS

We assessed the relationship between insulin sensitivity at baseline and development of early phenotypes of DN—microalbuminuria (albumin-creatinine ratio [ACR] ≥30 mg/g) and rapid renal function decline (glomerular filtration rate [GFR] loss >3 mL/min/1.73 m² per year)—with three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations over 6 years. Subjects with diabetes (n = 449) and without diabetes (n = 565) in the Coronary Artery Calcification in Type 1 Diabetes study had an estimated insulin sensitivity index (ISI) at baseline and 6-year follow-up.

RESULTS

The ISI was lower in subjects with diabetes than in those without diabetes (P < 0.0001). A higher ISI at baseline predicted a lower odds of developing an ACR ≥30 mg/g (odds ratio 0.65 [95% CI 0.49–0.85], P = 0.003) univariately and after adjusting for HbA_1c (0.69 [0.51–0.93], P = 0.01). A higher ISI at baseline conferred protection from a rapid decline of GFR as assessed by CKD-EPI cystatin C (0.77 [0.64–0.92], P = 0.004) and remained significant after adjusting for HbA_1c and age (0.80 [0.67–0.97], P = 0.02). We found no relation between ISI and rapid GFR decline estimated by CKD-EPI creatinine (P = 0.38) or CKD-EPI combined cystatin C and creatinine (P = 0.50).

CONCLUSIONS

Over 6 years, a higher ISI independently predicts a lower odds of developing microalbuminuria and rapid GFR decline as estimated with cystatin C, suggesting a relationship between insulin sensitivity and early phenotypes of DN.Diabetic nephropathy (DN) is a common and serious complication of diabetes. Its incidence is rising rapidly (1), and it is the most common cause of end-stage renal disease in the U.S. and Europe (2). The 2011 U.S. Renal Data System showed that DN accounted for 44.5% of all cases of end-stage renal disease in 2009 (3). Despite improvements in the outlook of this complication in past decades, it continues to be one of the major causes of morbidity and mortality in type 1 diabetes (4,5). DN is an important risk factor for coronary artery disease (6–8) and overall mortality (6,9). These findings highlight the need for improved methods of identifying persons at high risk for DN (10).The role of insulin sensitivity in the development and progression of macro- (7,11,12) and microvascular complications (12,13) in type 1 diabetes is increasingly recognized. Reduced insulin sensitivity also is a plausible mechanism linking renal disease with excess mortality in type 1 diabetes. Historically, when glycemic control is poor, reduced insulin sensitivity was believed to be directly related to body weight and HbA_1c (14,15), but more recent data suggest that reduced insulin sensitivity cannot simply be explained by weight or poor glycemic control. In fact, reduced insulin sensitivity has been documented in type 1 diabetic subjects with normal BMI and HbA_1c compared with nondiabetic individuals (16). The Coronary Artery Calcification in Type 1 Diabetes (CACTI) longitudinal cohort study of adults with type 1 diabetes investigated the determinants of early and accelerated atherosclerosis and found that insulin sensitivity independently predicted coronary artery calcification (17,18). Reduced insulin sensitivity has also been shown to predict diabetic retinopathy, neuropathy, and nephropathy in subjects with type 1 diabetes (13).Despite advances in the estimation of insulin sensitivity (insulin sensitivity index [ISI]) (19) and glomerular filtration rate (GFR) (20), research in the association of insulin sensitivity with DN has been limited since the Pittsburgh Epidemiology of Diabetes Complications (EDC) cohort showed more than a decade ago that the estimated glucose disposal rate (eGDR) predicts overt nephropathy (13). To readdress this relationship with contemporary data and estimating equations, we hypothesized that higher insulin sensitivity measured by ISI at baseline would be associated with decreased odds of developing two early phenotypes of DN—microalbuminuria (albumin-creatinine ratio [ACR] ≥30 mg/g) and rapid renal function decline (GFR loss >3 mL/min/1.73 m² per year) (21–23)—calculated by the three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations (20) over 6 years in the CACTI study.