β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes.

Case Presentation: E.C. is a 53-year-old postmenopausal female, referred for treatment of hypertension, with a family history of type 2 diabetes, hypertension, and coronary heart disease (CHD). Until learning that her blood pressure was “too high” during a routine physical examination, she felt well, and her postmenopausal symptoms had responded to hormone replacement therapy. She was not overweight (her body mass index [BMI] was 23.7 kg/m2), and the only abnormality on physical examination was a blood pressure of 145/95 RAR. Laboratory results revealed a normal blood count and urinalysis, with the following fasting plasma concentrations of relevant metabolic variables (in mg/dL): glucose 102, triglycerides (TG) 238, low-density lipoprotein cholesterol (LDL-C) 147, and high-density lipoprotein cholesterol (HDL-C) 52. E.C. is hypertensive and hypertriglyceridemic and at increased risk for CHD. Less obvious is that these metabolic abnormalities are highly likely to be the manifestations of a more fundamental defect—resistance to insulin-mediated glucose disposal and compensatory hyperinsulinemia, changes that greatly increase CHD risk.1,2⇓ The importance of insulin resistance as a CHD risk factor was first explicated in 1998, and the cluster of abnormalities likely to appear as manifestations of the defect in insulin action designated as syndrome X.1 Support for this notion has grown almost as fast as the names used to describe the phenomenon. The Adult Treatment Panel III (ATP III) has recently3 recognized the importance as CHD risk factors of a “constellation of lipid and nonlipid risk factors of metabolic origin,” designated this cluster of abnormalities as “the metabolic syndrome,” and indicated that “this syndrome is closely linked to insulin resistance.” Table 1 lists the criteria the ATP III stipulated be used to diagnose the metabolic syndrome, and a recent report4 has applied these criteria to the database of the Third National Health and Nutrition …

Metabolic Syndrome (MetS) is a condition characterized by the cooccurrence of several cardiovascular risk factors, including insulin resistance, obesity, dyslipidemia, and hypertension. The development of MetS is closely linked to visceral adiposity, which refers to fat accumulation around critical vital organs in the abdominal cavity. Visceral fat is metabolically active and produces adipokines, proteins that regulate energy balance and play a role in inflammation and atherosclerosis. Some adipokines, such as leptin and adiponectin, have beneficial effects on glucose homeostasis and are considered protective against MetS. However, other adipokines, such as visfatin and resistin, contribute to glucose intolerance and have pro-atherogenic properties. Visceral obesity also contributes to the development of MetS through its effects on blood pressure. It activates the sympathetic nervous system, the reninangiotensin-aldosterone system, and insulin resistance, leading to elevated blood pressure. Another critical factor in the development of MetS is the activation of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). LOX-1 is a protein that acts as a receptor for oxidized LDL on the cell surface. Its activation leads to the production of reactive oxygen species, a decrease in nitric oxide, and increased expression of molecules contributing to hypertension and vascular damage. LOX-1 is also involved in the development of other complications associated with MetS, such as nephropathy and left ventricular hypertrophy.The renin-angiotensin-aldosterone system (RAAS) regulates blood volume, electrolyte balance, and vascular resistance. In patients with MetS, the activation of RAAS leads to increased levels of angiotensin II (Ang II) and aldosterone, which have various effects on blood pressure and sodium and water retention. Ang II also contributes to oxidative stress and inflammation in the vasculature. Insulin resistance, a key feature of MetS, disrupts the insulin signaling process in adipose tissue, leading to increased lipolysis and elevated levels of circulating free fatty acids. These fatty acids further worsen insulin resistance and contribute to impaired glucose metabolism.Oxidative stress, characterized by an imbalance between the production of reactive oxygen species and the body's antioxidant defenses, is closely associated with the development of MetS. Hyperlipidemia and hyperglycemia, standard features of MetS, are linked to increased oxidative stress and ROS production. Oxidative stress and the activation of RAAS and LOX-1 contribute to the progression of dyslipidemia, type 2 diabetes, hypertension, and cardiovascular diseases. The oral-gut-liver axis is an emerging concept that suggests a relationship between oral infections, such as periodontitis, and metabolic dysfunction, including MetS and liver diseases. Periodontitis has been associated with chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD) and liver cirrhosis. The translocation of oral bacteria from the mouth to the gut may contribute to gut dysbiosis, increased intestinal permeability, and systemic inflammation, which can worsen liver functions. Overall, the development of MetS involves the interplay of various factors, including visceral obesity, adipokines, LOX-1 activation, insulin resistance, oxidative stress, and the oral-gut-liver axis. Understanding these mechanisms is crucial for preventing and managing MetS and its associated complications. Further research is needed to fully elucidate the roles of individual factors and develop targeted interventions for MetS.

Historic and emerging studies provide evidence for the deterioration of pancreatic α cell function and identity in diabetes mellitus. Increased access to human tissue and the availability of more sophisticated molecular technologies have identified key insights into how α cell function and identity are preserved in healthy conditions and how they become dysfunctional in response to stress. These studies have revealed evidence of impaired glucagon secretion, shifts in α cell electrophysiology, changes in α cell mass, dysregulation of α cell transcription, and α-to-β cell conversion prior to and during diabetes. In this review, we outline the current state of research on α cell identity in health and disease. Evidence in model organisms and humans suggests that in addition to β cell dysfunction, diabetes is associated with a fundamental dysregulation of α cell identity. Importantly, epigenetic studies have revealed that α cells retain more poised and open chromatin at key cell-specific and diabetes-dysregulated genes, supporting the model that the inherent epigenetic plasticity of α cells makes them susceptible to the transcriptional changes that potentiate the loss of identity and function seen in diabetes. Thus, additional research into the maintenance of α cell identity and function is critical to fully understanding diabetes. Furthermore, these studies suggest α cells could represent an alternative source of new β cells for diabetes treatment.

The metabolic syndrome, a combination of interrelated metabolic risk factors, is associated with insulin resistance and promotes the development of cardiovascular diseases and type 2 diabetes mellitus. There is a close link between inflammation and metabolic disease, but the responsible mechanisms remain elusive. The aim of this study was to identify differentially expressed genes in insulin-resistant skeletal muscle tissue of women with the metabolic syndrome compared with healthy control women. Women with the metabolic syndrome (n = 19) and healthy control women (n = 20) were extensively phenotyped, insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp, and a skeletal muscle biopsy was obtained. Gene expression levels were compared between the two groups by microarrays. The upregulated genes in skeletal muscle of the women with the metabolic syndrome were primarily enriched for inflammatory response-associated genes. The three most significantly upregulated of this group, interleukin 6 receptor (IL6R), histone deacetylase 9 (HDAC9) and CD97 molecule (CD97), were significantly correlated with insulin resistance. Taken together, these findings suggest an important role for a number of inflammatory-related genes in the development of skeletal muscle insulin resistance.

Cluster of differentiation molecules in the metabolic syndrome

BackgroundOur aim was to investigate sex differences in the associations between socioeconomic position (SEP) and metabolic syndrome (MetS) development, and to what extent these associations are mediated by health literacy and self-management skills. MethodsA subsample (n = 88,384, 59.5% female) of the adult Lifelines Cohort Study was used. MetS development according to NCEP-ATPIII criteria was assessed on average 3.8 years after baseline. SEP-MetS associations were assessed for moderation by sex, and sex-stratified accordingly. Associations between SEP measures (education, income and occupational prestige), health literacy and self-management skills, and MetS development were investigated using logistic regression analyses. The mediating effects of health literacy and self-management skills on the SEP-MetS associations were investigated using the Karlson-Holm-Breen method. ResultsAmong males and females, respectively 9.4% and 7.1% developed MetS. For males, education was inversely associated with MetS development; health literacy (7.1%) and self-management skills (1.9%) mediated a proportion of these educational differences. For females, education, income and occupational prestige were inversely associated with MetS development; health literacy (respectively 5.9% and 6.4%) and self-management skills (respectively 4.1% and 3.7%) mediated a proportion of the educational and occupational differences in MetS development. Neither health literacy nor self-management skills mediated female income differences in MetS development. ConclusionsSocioeconomic differences in MetS development differ between males and females. Both for males and females, health literacy and self-management skills mediated a small proportion of socioeconomic differences in MetS development.

β cell dysfunction and failure are driving forces of type 2 diabetes mellitus (T2DM) pathogenesis. Investigating the underlying mechanisms of β cell dysfunction may provide novel targets for the development of next generation therapy for T2DM. Epigenetics is the study of gene expression changes that do not involve DNA sequence changes, including DNA methylation, histone modification, and non-coding RNAs. Specific epigenetic signatures at all levels, including DNA methylation, chromatin accessibility, histone modification, and non-coding RNA, define β cell identity during embryonic development, postnatal maturation, and maintain β cell function at homeostatic states. During progression of T2DM, overnutrition, inflammation, and other types of stress collaboratively disrupt the homeostatic epigenetic signatures in β cells. Dysregulated epigenetic signatures, and the associating transcriptional outputs, lead to the dysfunction and eventual loss of β cells. In this review, we will summarize recent discoveries of the establishment and disruption of β cell-specific epigenetic signatures, and discuss the potential implication in therapeutic development.

Cardiovascular cells that contribute directly to atherosclerosis and cardiac dysfunction are known to exhibit metabolic flexibility, characterized by the ability to switch from generating ATP primarily through oxidative phosphorylation to using glycolysis as the predominate energy source, and to shift from one fuel source to another. This flexibility occurs in endothelial cells (ECs), myeloid cells, and cardiomyocytes during normal development and physiology, and is thought to have evolved to protect cells with heightened energy demand from the increased oxidative stress that can be a result of oxidative phosphorylation,1 to shunt glucose to side branches of glycolysis,2 to provide energy more rapidly,1 or to use the most abundant fuel available.3 With the growing problem of systemic nutrient overload and associated insulin resistance, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, metabolic flexibility and dysfunction in cells involved in cardiovascular disease have received increased attention as possible contributors to systemic inflammation and cardiovascular risk associated with these states. Systemic insulin resistance is thought to be due primarily to nutrient overload in skeletal muscle and liver as a consequence of an inability of adipose tissue to store excess nutrients in the form of triacylglycerol-rich lipid droplets, and a subsequent increase in detrimental lipid species in liver and skeletal muscle, which are inadequately equipped to store large amounts of lipid. Accumulation of noxious lipids leads to dysfunction in liver and skeletal muscle cells characterized by insulin resistance, increased activation of the unfolded protein response, and increased production of inflammatory mediators.4–6 The lipid mediators most likely responsible are diacylglycerols and ceramides, which are associated with insulin resistance in these tissues.5 Insulin resistance is well known to be associated with increased cardiovascular risk. Furthermore, accumulation of hepatic lipids in subjects with nonalcoholic fatty liver disease is associated …

Objective: Metabolic syndrome (METS) is described as cluster of risk factors including central obesity, hyperten-sion, low high-density lipoprotein (HDL), hypertriglyceridemia and hyperglycemia. The prevalence of METs has been associated with increased symptom severity and antidepressants utilization in many psychopathologies among adult population. We aimed to evaluate the effect of psychopathologies and antipsychotics in METs devel- opment, additionally to determine METs characteristics in children and adolescents diagnosed with bipolar and psychotic disorders. Methods: Thirty children and adolescents aged between 13-20 years old of whom were diag-nosed with bipolar mood disorders, schizophrenia, schizoaffective disorder and schizophreniform according to Diag-nostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR) criteria were compared with a 30 healthy children and adolescents in present study. The anthropometric measurements including body weight, height, body mass index (BMI), waist circumference (WC) as well as blood pressure measurements were documented. In addition, total cholesterol, triglyceride (TG), HDL, low-density lipoprotein (LDL) and fasting blood glucose (FBG) levels were measured and METs assessed according to the IDF (International Diabetes Foundation) criteria in participants. Results: Overall the prevalence of METs was 20% (n=12) in our study. Among the METs patients, nine were (27%) in the case group, three were (10%) were in control group. The mean BMI, body weight, WC, serum TG and FBG values of the METs group were found to be statistically higher than the healthy control group. Moreover it was also found that utilization of mood-stabilizing drugs has a statistically significant effect on the development of METs. Conclusion: Psychopathologies and antipsychotic utilization have associated with an increased risk for the development of metabolic disorders and METs in the children and adolescents population. In this respect our findings may provide a new approach with the management of treatment strategies particularly in children and adolescents with high risk of METs.

Low testosterone (T) has been associated with incident metabolic syndrome (MetS), but it remains unclear if this association is independent of sex hormone binding globulin (SHBG). Estradiol (E2) may also be associated with MetS, but few studies have investigated this. To study the association between baseline sex steroids and the development of incident MetS and to investigate the influence of SHBG, body mass index (BMI) and insulin resistance on this risk. Three thousand three hundred sixty nine community-dwelling men aged 40-79 years were recruited for participation in EMAS. MetS was defined by the updated NCEP ATP III criteria. Testosterone and E2 levels were measured by liquid and gas chromatography/mass spectrometry, respectively. Logistic regression was used to assess the association between sex steroids and incident MetS. One thousand six hundred fifty one men without MetS at baseline were identified. During follow-up, 289 men developed incident MetS, while 1362 men did not develop MetS. Men with lower baseline total T levels were at higher risk for developing MetS [odds ratio (OR) = 1.72, P < .001), even after adjustment for SHBG (OR = 1.43, P = .001), BMI (OR = 1.44, P < .001) or homeostasis model assessment of insulin resistance (HOMA-IR) (OR = 1.64, P < .001). E2 was not associated with development of MetS (OR = 1.04; P = .56). However, a lower E2/T ratio was associated with a lower risk of incident MetS (OR = 0.38; P < .001), even after adjustment for SHBG (OR = 0.48; P < .001), BMI (OR = 0.60; P = .001) or HOMA-IR (OR = 0.41; P < .001). In men, lower T levels, but not E2, are linked with an increased risk of developing MetS, independent of SHBG, BMI or insulin resistance. A lower E2/T ratio may be protective against developing MetS.

Plasma apoCIII Levels in Relation to Inflammatory Traits and Metabolic Syndrome in Patients not Treated with Lipid-lowering Drugs Undergoing Coronary Angiography

BackgroundMetabolic syndrome (MetS) development strongly varies based on individuals’ socioeconomic position (SEP), but to date, no studies have assessed the mediating role of perceived stress from long-term difficulties (chronic stress) in this association. The aim of this study is to examine the mediating role of chronic stress in the associations of the SEP measures education, occupational prestige and income, with MetS development, and whether associations between chronic stress and MetS are moderated by sex.MethodsWe used an adult subsample (n = 53,216) from the Lifelines Cohort Study without MetS at baseline. MetS development was measured 3.9 years after baseline (follow-up), and defined according to National Cholesterol Education Program’s Adult Treatment Panel III (NCEP-ATPIII) criteria. Direct associations between SEP, chronic stress and MetS development were estimated using multivariable logistic and linear regression analyses, and were adjusted for age, sex, the other SEP measures, and time between baseline and follow-up. The mediating percentages of chronic stress explaining the associations between SEP and MetS development were estimated using the Karlson-Holm-Breen method.ResultsUpon follow-up, 7.4% of the participants had developed MetS. Years of education and occupational prestige were inversely associated with MetS development. Chronic stress suppressed the association between education and MetS development (5.6%), as well as the association between occupational prestige and MetS development (6.2%). No effect modification of sex on the chronic stress-MetS pathway was observed.ConclusionsChronic stress does not explain educational and occupational differences in developing MetS. In fact, individuals with more years of education or higher occupational prestige perceive more chronic stress than their lower SEP counterparts. Further, no difference between males and females was observed regarding the relationship between chronic stress and MetS development.

Our friend and colleague Wayne Fenton asked to write this article for the Journal because of his desire to educate other psychiatrists about the treatment of schizophrenia, including what he recognized to be a growing problem with the metabolic syndrome. This lifelong passion, which he pursued from his psychiatry residency at Yale, through his directorship of Chestnut Lodge, to his position at NIMH as Director of the Division of Adult Translational Research and Associate Director for Clinical Affairs, ended tragically with his killing during an evaluation of a psychotic young man. Wayne had worked tirelessly to secure support for new drug discovery in the NIMH programs that he directed. The Journal will be initiating in 2007 a series of articles on the discovery of new mental illness treatments. We will dedicate this series to Wayne's memory and include with it a memorial of his life and contributions to the treatment of mental illness.

Insulin signaling is a conserved pathway that orchestrates glucose and lipid metabolism, energy balance, and inflammation, and its dysregulation compromises the homeostasis of multiple systems. Insulin resistance is a shared hallmark of several metabolic diseases, including obesity, metabolic syndrome, and type 2 diabetes, and has been associated with cognitive decline during aging and dementia. Numerous mechanisms promoting the development of peripheral and central insulin resistance have been described, although most of them were not completely clarified. In the last decades, several studies have highlighted that biliverdin reductase-A (BVR-A), over its canonical role in the degradation of heme, acts as a regulator of insulin signaling. Evidence from human and animal studies show that BVR-A alterations are associated with the aberrant activation of insulin signaling, metabolic syndrome, liver steatosis, and visceral adipose tissue inflammation in obese and diabetic individuals. In addition, recent findings demonstrated that reduced BVR-A levels or impaired BVR-A activation contribute to the development of brain insulin resistance and metabolic alterations in Alzheimer’s disease. In this narrative review, we will provide an overview on the literature by focusing on the role of BVR-A in the regulation of insulin signaling and how BVR-A alterations impact on cell dysfunctions in both metabolic and neurodegenerative disorders.

To examine whether shift work accelerates metabolic syndrome (MetS) development among early middle-aged males with elevated alanine aminotransferase (e-ALT). A retrospective, observational follow-up study on MetS development at a 5-year interval was conducted using health examination data. Nine hundred and ninety six male employees not fulfilling MetS criteria at screening were enrolled. Age, MetS-components, liver enzymes, serological markers for viral hepatitis, abdominal ultrasound, insulin resistance status, lifestyles, and workplace factors were analyzed. The prevalence of elevated serum ALT (> 40 U/L, e-ALT) at baseline was 19.1%. There were 381 (38.3%) workers with long-term exposures to day-night rotating shift work (RSW). 14.2% of subjects developed MetS during follow-up. After 5 years, the workers with e-ALT had significantly unfavorable changes in MetS-components, and higher rates of MetS development, vs subjects with normal baseline ALT levels. Workers with both baseline e-ALT and 5-year persistent RSW (pRSW) exposure had the highest rate of MetS development. Also, e-ALT-plus-pRSW workers had a significant increase in MetS-components at follow-up, compared with the other subgroups. After controlling for potential confounders, e-ALT-plus-pRSW workers posed a significant risk for MetS development (odds ratio, 2.7; 95% confidence interval, 1.4-5.3, vs workers without baseline e-ALT nor pRSW). We suggest that all early middle-aged male employees with e-ALT should be evaluated and managed for MetS. Particularly in terms of job arrangements, impacts of long-term RSW on MetS development should be assessed for all male employees having baseline e-ALT.