Missed diagnosis-a major barrier to patient access to obesity healthcare in the primary care setting.

OBJECTIVE: To investigate whether individuals with an elevated BMI measurement, for whom a diagnosis of overweight or obesity (OW/OB) is not recorded, are less likely to be offered clinical care for obesity compared to those with a recorded diagnosis. SUBJECTS: A retrospective cohort study using the electronic medical record database of Maccabi Healthcare Services (MHS) in Israel. Included were 200,000 adults with BMI ≥ 25 kg/m2 measurement recorded during a primary care visit between 2014 and 2020, and no prior diagnosis of OW/OB or related co-morbidities. METHODS: The relationships between a recorded diagnosis of OW/OB and two composite outcomes: 1. A composite of referrals to screening tests for metabolic complications; 2. A composite of weight loss intervention and follow up, were analyzed using multivariate logistic regression models. RESULTS: In only 18% of individuals, a diagnosis of OW/OB was recorded. After adjusting for multiple potential confounding factors, individuals who received a recorded diagnosis were 18% more likely to be offered an evaluation for obesity-related metabolic complication, (OR 1.18, 95% CI 1.15-1.21, p < 0.001), and almost twice as likely to be offered intervention and follow up for their excess body weight (OR 1.84, 95% CI 1.76-1.94, p < 0.001) compared to individuals with missed diagnosis. These results persisted after adjusting for inter-physician variability. In addition, male sex, older age, and Arab sector were all associated with lower rates of weight loss intervention and follow up, while young individuals were less likely to be screened for metabolic complications. CONCLUSION: Beyond BMI measurement, a recorded diagnosis of OW/OB is associated with statistically and clinically significant higher rates of performance of obesity care and intervention. Undiagnosed OW/OB presents a significant clinical opportunity, as recording a diagnosis of OW/OB would predict improved patient access to obesity healthcare and improved clinical outcomes.

C1q/TNF-Related Proteins, HIV and HIV-Associated Factors, and Cardiometabolic Phenotypes in Middle-Aged Women.

C1q/tumor necrosis factor (TNF)-related proteins (CTRPs) have been linked to energy homeostasis and vascular health. People with HIV are susceptible to cardiometabolic disease, but the contributions of different CTRPs are unknown. We investigated the associations of HIV and related factors with serum CTRPs, and CTRPs' relationships with cardiometabolic phenotypes. This involved a cross-sectional analysis of participants in the Women's Interagency HIV Study aged ≥35 with (n = 209) and without (n = 92) HIV who underwent carotid ultrasound in 2004-2005 and had stored serum available for measurement of total adiponectin and CTRPs 1, 3, 5, and 9. The Benjamini/Hochberg procedure was used to control the study-wide false-positive rate. HIV-positive women had significantly higher adiponectin than HIV-negative women after adjustment for sociodemographic, behavioral, and clinical variables [beta = 0.29 (95% confidence interval 0.11-0.47)]. Among HIV-positive women, lower CD4 count was associated with higher adiponectin and history of AIDS with higher CTRP9, but these were only nominally significant. There was no relationship between HIV status and CTRP 1, 3, or 5, nor was antiretroviral therapy or viral load associated with any CTRP. In the entire cohort, higher adiponectin was associated with significantly lower fasting glucose and insulin resistance, while higher CTRP5 [beta = -0.02 (-0.033 to -0.007)]-and, at a nominal level, CTRPs 1 and 3-was associated with significantly lower carotid intima-media thickness. In conclusion, in this sample of middle-aged women, HIV serostatus was positively associated with adiponectin, but not CTRPs. In turn, serum adiponectin was inversely associated with glucose dysregulation, whereas CTRP5 was inversely associated with carotid intima-media thickness. Further research is needed to determine CTRPs' role in atherosclerosis.

Lipolysis defect in white adipose tissue and rapid weight regain.

Weight regain after weight loss is a well-described phenomenon in both humans and animal models of obesity. Reduced energy expenditure and increased caloric intake are considered the main drivers of weight regain. We hypothesized that adipose tissue with obesity memory (OM) has a tissue-autonomous lipolytic defect, allowing for increased efficiency of lipid storage. We utilized a mouse model of diet-induced obesity, which was subjected to 60% caloric restriction to achieve lean body weight, followed by a short period of high-fat diet (HFD) rechallenge. Age-matched lean mice fed HFD for the first time were used as the control group. Upon rechallenge with HFD, mice with OM had higher respiratory exchange ratios than lean mice with no OM despite comparable body weight, suggesting higher utilization of glucose over fatty acid oxidation. White adipose tissue explants with OM had comparable lipolytic response after caloric restriction; however, reduced functional lipolytic response to norepinephrine was noted as early as 5 days after rechallenge with HFD and was accompanied by reduction in hormone-sensitive lipase serine phosphorylation. The relative lipolytic defect was associated with increased expression of inflammatory genes and a decrease in adrenergic receptor genes, most notably Adrb3. Taken together, white adipose tissue of lean mice with OM shows increased sensitization to HFD compared with white adipose tissue with no OM, rendering it resistant to catecholamine-induced lipolysis. This relative lipolytic defect is tissue-autonomous and could play a role in the rapid weight regain observed after weight loss.

The fructose-2,6-bisphosphatase TIGAR suppresses NF-κB signaling by directly inhibiting the linear ubiquitin assembly complex LUBAC.

The systems integration of whole-body metabolism and immune signaling are central homeostatic mechanisms necessary for maintenance of normal physiology, and dysregulation of these processes leads to a variety of chronic disorders. However, the intracellular mechanisms responsible for cell-autonomous cross-talk between the inflammatory signaling pathways and metabolic flux have remained enigmatic. In this study, we discovered that the fructose-2,6-bisphosphatase TIGAR (Tp53-induced glycolysis and apoptosis regulator) critically regulates NF-κB activation. We found that TIGAR potently inhibits NF-κB-dependent gene expression by suppressing the upstream activation of IKKß phosphorylation and kinase activation. This inhibition occurred through a direct binding competition between NEMO and TIGAR for association with the linear ubiquitination assembly complex (LUBAC). This competition prevented linear ubiquitination of NEMO, which is required for activation of IKKß and other downstream targets. Furthermore, a TIGAR phosphatase activity-deficient mutant was equally effective as WT TIGAR in inhibiting NEMO linear ubiquitination, IKKß phosphorylation/activation, and NF-κB signaling, indicating that TIGAR's effect on NF-κB signaling is due to its interaction with LUBAC. Physiologically, TIGAR knockout mice displayed enhanced adipose tissue NF-κB signaling, whereas adipocyte-specific overexpression of TIGAR suppressed adipose tissue NF-κB signaling. Together, these results demonstrate that TIGAR has a nonenzymatic molecular function that modulates the NF-κB signaling pathway by directly inhibiting the E3 ligase activity of LUBAC.

Preventing progression from gestational diabetes mellitus to diabetes: A thought-filled review.

Women with a history of gestational diabetes are at high risk for developing type 2 diabetes mellitus. In studies with long periods of follow-up, diabetes incidence of up to 70% has been reported. The appropriate follow-up of women following a pregnancy complicated by gestational diabetes has not been studied. Published guidelines recommend that obstetrician/gynaecologists, who are often the de facto primary care physicians for these otherwise healthy young women, incorporate glucose monitoring in the post-partum period into their annual examinations. In reality, reported rates of screening have been low. There is also no clear evidence for any beneficial interventions to prevent diabetes in patients with prior history of gestational diabetes. Lifestyle intervention programmes for diabetes prevention among these patients yielded disappointing results. Metformin, pioglitazone, liraglutide, and bariatric surgery are possible options but based on inadequate data. There remains a need for randomized, placebo-controlled studies to evaluate various pharmacologic treatments, with and without lifestyle interventions, to prevent type 2 diabetes mellitus in women with a history of gestational diabetes.

BMI at Age 17 Years and Diabetes Mortality in Midlife: A Nationwide Cohort of 2.3 Million Adolescents.

OBJECTIVE: The sequelae of increasing childhood obesity are of major concern. We assessed the association of BMI in late adolescence with diabetes mortality in midlife. RESEARCH DESIGN AND METHODS: The BMI values of 2,294,139 Israeli adolescents (age 17.4 ± 0.3 years), measured between 1967 and 2010, were grouped by U.S. Centers for Disease Control and Prevention age/sex percentiles and by ordinary BMI values. The outcome, obtained by linkage with official national records, was death attributed to diabetes mellitus (DM) as the underlying cause. Cox proportional hazards models were applied. RESULTS: During 42,297,007 person-years of follow-up (median, 18.4 years; range <1-44 years) there were 481 deaths from DM (mean age at death, 50.6 ± 6.6 years). There was a graded increase in DM mortality evident from the 25th to the 49th BMI percentile group onward and from a BMI of 20.0-22.4 kg/m2 onward. Overweight (85th to 94th percentiles) and obesity (the 95th percentile or higher), compared with the 5th to 24th percentiles, were associated with hazard ratios (HRs) of 8.0 (95% CI 5.7-11.3) and 17.2 (11.9-24.8) for DM mortality, respectively, after adjusting for sex, age, birth year, height, and sociodemographic variables. The HR for the 50th through 74th percentiles was 1.6 (95% CI 1.1-2.3). Findings persisted in a series of sensitivity analyses. The estimated population-attributable fraction for DM mortality, 31.2% (95% CI 26.6-36.1%) for the 1967-1977 prevalence of overweight and obesity at age 17, rose to a projected 52.1% (95% CI 46.4-57.4%) for the 2012-2014 prevalence. CONCLUSIONS: Adolescent BMI, including values within the currently accepted "normal" range, strongly predicts DM mortality up to the seventh decade. The increasing prevalence of childhood and adolescent overweight and obesity points to a substantially increased future adult DM burden.

Cognitive Performance at Late Adolescence and the Risk for Impaired Fasting Glucose Among Young Adults.

CONTEXT: Although dysglycemia is a risk factor for cognitive decline, it is unknown whether cognitive performance among young and apparently healthy adults affect the risk for impaired fasting glucose (IFG). OBJECTIVE: This study aimed to characterize the relationship between cognitive function and the risk for IFG among young adults. DESIGN AND SETTING: This was a retrospective cohort study utilizing data collected at pre-military recruitment assessments with information collected at the screening center of Israeli Army Medical Corps. PARTICIPANTS: Normoglycemic adults (n = 17 348) (free of IFG and diabetes; mean age 31.0 ± 5.6 y; 87% men) of the Metabolic Lifestyle and Nutrition Assessment in Young Adults (MELANY) cohort with data regarding their General Intelligence Score (GIS), a comprehensive measure of cognitive function, at age 17 y. INTERVENTIONS: Fasting plasma glucose was assessed every 3-5 y at scheduled visits. Cox proportional hazards models were applied. MAIN OUTCOMES MEASURES: The main outcome of the study was incident IFG (≥ 100 mg/dL and <126 mg/dL) at scheduled visits. RESULTS: During a median followup of 6.6 y, 1478 cases of IFG were recorded (1402 men). After adjustment for age and sex, participants in the lowest GIS category had a 1.9-fold greater risk for incident IFG compared with those in the highest GIS category. In multivariable analysis adjusted for age, sex, body mass index, fasting plasma glucose, family history of diabetes, country of origin, socioeconomic status, education, physical activity, smoking status, alcohol consumption, breakfast consumption, triglyceride level, white blood cell count, the risk for IFG was nearly doubled in the lowest GIS category compared with the highest GIS category (hazard ratio, 1.8; 95% confidence interval, 1.4-2.3; P < .001). These results persisted when GIS was treated as a continuous variable and when the model was adjusted also for body mass index at the end of followup. CONCLUSIONS: This study demonstrates that lower cognitive function at late adolescence is independently associated with an elevated risk IFG in both men and women.

Chemerin concentrations in maternal and fetal compartments: implications for metabolic adaptations to normal human pregnancy.

OBJECTIVES: Chemerin, a novel adipocytokine, has been implicated in major metabolic and inflammatory processes. Study aims were to determine whether circulating maternal chemerin concentration (1) differs between pregnant and non-pregnant women, (2) changes as a function of gestational age, and (3) correlates with maternal insulin resistance. In addition, we investigated which compartment, maternal, fetal or placental, is the source of chemerin in maternal circulation. METHODS: The study included three groups: Non-pregnant (n=18), pregnant women in the first trimester (n=19) and pregnant women in the third trimester (n=33). Chemerin was measured in cord blood and in maternal serum samples taken before and after delivery. Chemerin mRNA expression was evaluated in fetal and human adult tissues. RESULTS: Chemerin serum concentration was significantly higher in pregnant women in the third trimester than in non-pregnant and pregnant women in the first trimester. Chemerin concentration positively correlated with body mass index (BMI) and insulin resistance. Antenatal chemerin concentration was significantly lower than that during the postpartum period. Neonatal chemerin did not correlate with maternal one. Chemerin mRNA expression was abundant in fetal and adult liver and omental fat, but relatively low in placenta. CONCLUSIONS: Chemerin is increased during normal gestation and is associated with maternal BMI and insulin resistance. Maternal tissues, possibly liver and adipose tissue, contribute to the increased maternal chemerin concentration.

Chemerin is present in human cord blood and is positively correlated with birthweight.

OBJECTIVE: Chemerin, a novel adipokine, has been implicated in adipogenesis, inflammation, and metabolism. The aims of this study were to determine the presence of chemerin in cord blood and its association with birthweight. STUDY DESIGN: This cross-sectional study included the following: (1) twins with (n = 24) or without (n = 28) birthweight discordancy; and (2) singletons subclassified into small-for-gestational-age (SGA; n = 18); appropriate for gestational age (AGA; n = 33); and large-for-gestational-age (LGA; n = 8). Cord blood chemerin was determined. Parametric and nonparametric statistics were used for analysis. RESULTS: The results of the study included the following: (1) within the discordant twins group, the median chemerin concentration was significantly lower in the SGA group than in their cotwins; (2) within singletons, the median chemerin concentration was significantly higher in the LGA than the AGA newborns; and (3) the regression model revealed that chemerin was independently associated with birthweight. CONCLUSION: Cord blood chemerin is present in cord blood and its concentrations are positively correlated with birthweight. These novel findings support a role of adipokines in fetal growth.

p38 mitogen-activated protein kinase-dependent transactivation of ErbB receptor family: a novel common mechanism for stress-induced IRS-1 serine phosphorylation and insulin resistance.

OBJECTIVE: Stress stimuli such as tumor necrosis factor (TNF) have been shown to induce insulin receptor substrate (IRS)-1 serine phosphorylation and insulin resistance by transactivation of ErbB receptors. We aimed at elucidating the potential role of p38 mitogen-activated protein kinase (p38MAPK) in mediating stress-induced ErbB receptors activation. RESEARCH DESIGN AND METHODS: p38MAPK effect on ErbBs transactivation and insulin signaling was assessed in Fao or HepG2 cells, exposed to stress stimuli, and on metabolic parameters in ob/ob and C57/BL6 mice. RESULTS: High-fat diet-fed mice and ob/ob mice exhibited elevated hepatic p38MAPK activation associated with glucose intolerance and hyperinsulinemia. Liver expression of dominant-negative (DN)-p38MAPKα in ob/ob mice reduced fasting insulin levels and improved glucose tolerance, whereas C57/BL6 mice overexpressing wild-type p38MAPKα exhibited enhanced IRS-1 serine phosphorylation and reduced insulin-stimulated IRS-1 tyrosine phosphorylation. Fao or HepG2 cells exposed to TNF, anisomycin, or sphingomyelinase demonstrated rapid transactivation of ErbB receptors leading to PI3-kinase/Akt activation and IRS-1 serine phosphorylation. p38MAPK inhibition either by SB203580, by small interfering RNA, or by DN-p38MAPKα decreased ErbB receptors transactivation and IRS-1 serine phosphorylation and partially restored insulin-stimulated IRS-1 tyrosine phosphorylation. When cells were incubated with specific ErbB receptors antagonists or in cells lacking ErbB receptors, anisomycin- and TNF-induced IRS-1 serine phosphorylation was attenuated, despite intact p38MAPK activation. The stress-induced p38MAPK activation leading to ErbB receptors transactivation was associated with intracellular reactive oxygen species generation and was attenuated by treatment with antioxidants. CONCLUSIONS: Hepatic p38MAPK is activated following various stress stimuli. This event is upstream to ErbB receptors transactivation and plays an important role in stress-induced IRS-1 serine phosphorylation and insulin resistance.