The Expanding Problem of Regional Adiposity: Revisiting a 1985 Diabetes Classic by Ohlson et al.

Body fat distribution is a predictor of metabolic health in obesity. In this Classics in Diabetes article, we revisit a 1985 Diabetes article by Swedish investigators Ohlson et al. This work was one of the first prospective population-based studies that established a relationship between abdominal adiposity and the risk for developing diabetes. Here, we discuss evolving concepts regarding the link between regional adiposity and diabetes and other chronic disorders. Moreover, we highlight fundamental questions that remain unresolved.

Body composition in early pubescent children with obesity: effects following 1 year of nonintervention.

Little is known about whether body composition changes differently between children with and without obesity following 1 year of nonintervention. Therefore, we investigated body composition in early pubescent children (8-12 yr) with and without obesity before and after a period of 1 year of nonintervention. Early pubescent children (8-12 yr; Tanner stage ≤ 3) with (body mass index, BMI ≥ 95th percentile) and without obesity (15th < BMI < 85th percentile) were recruited. At baseline, 88 children (n = 25 without obesity) completed dual-energy X-ray absorptiometry imaging (DXA) for body composition measurements [%body fat, fat mass, fat-free mass (FFM)]. One year later, 47 participants (n = 15 without obesity) returned for repeat testing. The children without obesity were older (11.0 ± 1.0 vs. 10.0 ± 1.2 yr; means ± SD) (P = 0.013). There was no group difference in height, and both groups increased in height similarly after 1 year (147.7 ± 8.9 to 154.5 ± 9.2 cm without vs. 145.6 ± 5.8 to 152.5 ± 5.9 cm with obesity) (P < 0.001). Weight was greater (P < 0.001) in children with obesity at baseline as was the increase in weight after 1 yr (9.25 vs. 5.82 kg) (interaction, P = 0.005). Fat mass increased by 4.4 kg in children with obesity and by 1.1 kg in children without obesity (interaction, P < 0.001). However, there was no difference in fat-free mass between those with and without obesity at baseline (29.9 ± 5.9 vs. 31.6 ± 4.8 kg) (P = 0.206) with both groups increasing similarly over 1 year (gain of 4.87 vs. 4.85 kg with and without obesity, respectively). Without intervention, the increase in fat mass is four times greater in children with obesity after 1 year as compared with children without obesity.NEW & NOTEWORTHY Little is known about changes in body composition in children with and without obesity following 1 year of nonintervention. We report that without intervention, fat mass gain is significantly greater in children with obesity after 1 year compared with those without obesity. Body mass index (BMI) and %body fat measurements after 1 year yielded no significant increase suggesting that BMI and %fat alone are not suitable measures for tracking changes in adiposity among children.

Internet-based cognitive behavioral therapy intervention for youth with type 1 diabetes and depressive symptoms: a pilot and feasibility study.

Depression is more common in youth with type 1 diabetes (T1D) compared to youth without diabetes. This study aims to assess the efficacy of Competent Adulthood Transition with Cognitive Humanistic and Interpersonal Teaching (CATCH-IT), an internet-based cognitive behavioral therapy (CBT) intervention, in adolescents with T1D and depressive symptoms. Adolescents (13 to 17 years old) with T1D and mild (score 5-9) or moderate (score 10-14) depressive symptoms on Patient Health Questionnaire-Adolescent (PHQ-A) screening assessment were recruited to participate and received online access to the CATCH-IT modules for 6 months (requested to complete in 12 weeks). Statistical analyses included paired t-test for changes in Center for Epidemiologic Studies Depression Scale (CES-D), PHQ-A, Problem Areas in Diabetes-Teen version (PAID-T), and hemoglobin A1c (HbA1c). Nineteen patients were consented, 15 met inclusion criteria and received the intervention. In the seven participants that completed the modules, there was a trend towards improvements in PHQ-A, CES-D and HbA1c. Participants provided robust qualitative feedback on the modules and areas for improvement in subsequent iterations, such as inclusion of diabetes-related content. Given the prevalence of depression in diabetes, feasible, low resource interventions are needed. Internet programs such as CATCH-IT can serve as an effective first line intervention in this high-risk population. A modified version of CATCH-IT tailored for adolescents with T1D may be beneficial in this patient population.

Electronic phenotypes to distinguish clinician attention to high body mass index, hypertension, lipid disorders, fatty liver and diabetes in pediatric primary care: Diagnostic accuracy of electronic phenotypes compared to masked comprehensive chart review.

BACKGROUND/OBJECTIVES: Electronic phenotyping is a method of using electronic-health-record (EHR) data to automate identifying a patient/population with a characteristic of interest. This study determines validity of using EHR data of children with overweight/obesity to electronically phenotype evidence of clinician 'attention' to high body mass index (BMI) and each of four distinct comorbidities. METHODS: We built five electronic phenotypes classifying 2-18-year-old children with overweight/obesity (n = 17,397) by electronic/health-record evidence of distinct attention to high body mass index, hypertension, lipid disorders, fatty liver, and prediabetes/diabetes. We reviewed, selected and cross-checked random charts to define items clinicians select in EHRs to build problem lists, and to order medications, laboratory tests and referrals to electronically classify attention to overweight/obesity and each comorbidity. Operating characteristics of each clinician-attention phenotype were determined by comparing comprehensive chart review by reviewers masked to electronic classification who adjudicated evidence of clinician attention to high BMI and each comorbidity. RESULTS: In a random sample of 817 visit-records reviewed/coded, specificity of each electronic phenotype is 99%-100% (with PPVs ranging from 96.8% for prediabetes/diabetes to 100% for dyslipidemia and hypertension). Sensitivities of the attention classifications range from 69% for hypertension (NPV, 98.9%) to 84.7% for high-BMI attention (NPV, 92.3%). CONCLUSIONS: Electronic phenotypes for clinician attention to overweight/obesity and distinct comorbidities are highly specific, with moderate (BMI) to modest (each comorbidity) sensitivity. The high specificity supports using phenotypes to identify children with prior high-BMI/comorbidity attention.

Longitudinal Outcomes in Adolescents After Referral for Metabolic and Bariatric Surgery.

BACKGROUND: Metabolic and bariatric surgery (MBS) can be a well tolerated and effective treatment option for severe obesity in adolescents. We compared outcomes for adolescents that did and did not proceed to surgery. METHODS: A single-center longitudinal study (2015-2020). Patients were identified as LSG if they completed laparoscopic sleeve gastrectomy within 6 months of initial visit and NoLSG if they did not. Chi-square, Fisher exact, nonparametric Kruskal-Wallis tests, and Linear Mixed Models (LMM) were used to compare outcomes over 2 years. RESULTS: Three hundred fifty-two adolescents were referred with a mean age of 15.6 ±â€Š1.4, 69% girls, 38% Hispanic, and 78% had noncommercial insurance. The median baseline weight was 135 kg and body mass index (BMI) was 48 kg/m2; 42% had a BMI >50. Seventy-nine (22%) underwent LSG whereas 273 (78%) did not complete MBS primarily because of lack of interest. LSG patients had 21% total weight loss and 22% total BMI loss at 24 months whereas NoLSG patients had 4% total weight gain and 3% BMI gain (P < 0.01). Obesity-associated conditions improved in the LSG group (P < 0.01). Follow-up in both groups was poor (≤30% at 24 months). Patients with public insurance and those with BMI from 50 to 59.9 kg/m2 were high performing LSG patients. CONCLUSIONS: A minority (22%) of adolescents referred for MBS proceeded to surgery, despite its demonstrated efficacy and safety in adolescence. Those that did not undergo surgery continued to gain weight. Further research is needed to understand patient preferences or concerns related to MBS utilization during adolescence.

Distribution of comorbidities as primary diagnoses by obesity class among patients in a large US paediatric healthcare system.

There is little documentation of the distribution of specific health conditions across obesity classes (I, II, III), especially for paediatric populations who are seen for routine care in large United States US healthcare systems. The aim of this study was to assess the odds of presenting ≥2 obesity-related comorbidities as well as assess the overall distribution of these co-morbidities in children by class I/II/III obesity status controlling for key sociodemographic characteristics. This retrospective (2015-2019) electronic health record review analysed 49 276 patients from the Children's Health System of Texas diagnosed with obesity-related health conditions by obesity status (no obesity, class I, II, III). Crude and adjusted logistic regression models examined the association between obesity class and the likelihood of ≥2 comorbidities as primary diagnoses. Patients with class I obesity were 22% more likely (OR 1.22, 95% CI, 1.16, 1.27), patients with class II obesity were almost 50% more likely (OR 1.44, 95% CI, 1.35, 1.53) and those with class III obesity twice as likely (OR 2.04, 95% CI 1.91, 2.18) to be diagnosed with ≥2 comorbidities as primary diagnoses, compared with patients classified with no obesity. Children with obesity, particularly severe obesity, should be monitored closely by paediatricians for possible diagnoses of risk factors that could lead to adult chronic disease.

Perivascular mesenchymal cells control adipose-tissue macrophage accrual in obesity.

Chronic low-grade white adipose tissue (WAT) inflammation is a hallmark of metabolic syndrome in obesity. Here, we demonstrate that a subpopulation of mouse WAT perivascular (PDGFRß+) cells, termed fibro-inflammatory progenitors (FIPs), activate proinflammatory signalling cascades shortly after the onset of high-fat diet feeding and regulate proinflammatory macrophage accumulation in WAT in a TLR4-dependent manner. FIPs activation in obesity is mediated by the downregulation of zinc-finger protein 423 (ZFP423), identified here as a transcriptional corepressor of NF-κB. ZFP423 suppresses the DNA-binding capacity of the p65 subunit of NF-κB by inducing a p300-to-NuRD coregulator switch. Doxycycline-inducible expression of Zfp423 in PDGFRß+ cells suppresses inflammatory signalling in FIPs and attenuates metabolic inflammation of visceral WAT in obesity. Inducible inactivation of Zfp423 in PDGFRß+ cells increases FIP activity, exacerbates adipose macrophage accrual and promotes WAT dysfunction. These studies implicate perivascular mesenchymal cells as important regulators of chronic adipose-tissue inflammation in obesity and identify ZFP423 as a transcriptional break on NF-κB signalling.

Impact of insulin reduction on glycemic control in children attending a residential diabetes camp.

BACKGROUND/OBJECTIVES: Children attending diabetes camp are more active, increasing the risk of hypoglycemia. Decreasing initial insulin doses may reduce this risk. The objectives of our study were to compare glycemic control between campers receiving multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII), and analyze the impact of decreasing basal insulin by 10%. METHODS: We analyzed 849 camp sessions (599 children, 5-19 years old) from Camp Sweeney's 2016/2017 summers. Campers were separated into groups by year and insulin route (MDI_2016, MDI_2017, CSII_2016, and CSII_2017). The MDI_2016 group had initial basal insulin decreased 10%, while CSII_2016, MDI_2017, and CSII_2017 did not. Time spent in blood glucose ranges and area under the curve (AUC) were compared by year and insulin route using ANOVA. We also performed repeated measures ANOVA using campers who attended both years. RESULTS: No significant differences in time spent in any glucose range could be attributed to the initial 10% basal decrease, including on paired analysis. MDI_2017 had more decreases to basal insulin than the other groups. CSII campers had higher AUC and more hyperglycemia than MDI campers. CONCLUSIONS: Campers on MDI may benefit from decreasing basal insulin, either at the beginning of camp or during the first week. Future research is needed to optimize glycemic control in the camp setting.

A Pilot Study Evaluating a Binge-Eating Screener in Children: Development of the Children's Brief Binge-Eating Questionnaire in a Pediatric Obesity Clinic.

Children referred to pediatric obesity programs are at high risk of binge-eating disorder (BED) symptoms. Our goal was to develop and evaluate the Children's Brief Binge-Eating Questionnaire (CBBEQ) as a rapid screen of BED symptomatology. Seventy patients between the ages of 7 and 18 years (57% females) completed the CBBEQ and underwent the Eating Disorder Assessment for DSM-5 (EDA). Reliability and validity were assessed by examining results of the CBBEQ compared with the EDA, as well as measures of sleep, depression, and anxiety. Twenty-four of seventy (34%) children met full diagnostic interview criteria for BED and 12 (17%) met subclinical criteria. The CBBEQ demonstrated 100% specificity, 93% sensitivity, and a 100% negative predictive value for BED at a cutoff total score of 9. If confirmed in larger sample, this questionnaire could be a quick and accurate clinical tool for non-mental health providers to identify children at risk for BED.

Improving medication adherence in the pediatric population using integrated care of companion animals.

Medication non-adherence occurs in more than half of children with chronic conditions. Unfortunately, most strategies for improving adherence have had limited success in the pediatric population highlighting the need for novel interventions that establish healthy self-management habits for children and adolescents. In this paper we discuss innovative strategies to improve adherence by embedding a medical regimen within a pet care routine, thereby capitalizing on the benefits of a structured habit while providing opportunities for development of autonomy in children and fostering collaborative parent interactions.

Camp-based multi-component intervention for families of young children with type 1 diabetes: A pilot and feasibility study.

BACKGROUND: Managing type 1 diabetes mellitus (T1DM) in preschool-aged children has unique challenges that can negatively impact glycemic control and parental coping. OBJECTIVE: To evaluate the impact of a camp-based multi-component intervention on glycated hemoglobin A1c (HbA1c) in young children with T1DM and psychosocial measures for their parents. SUBJECTS AND METHODS: Two separate cohorts of 18 children (ages 3-5 years) and their families participated in a camp-based intervention that included didactic and interactive parent education, child-centered education and family-based recreational activities. In Camp 1.0, measures of HbA1c, parental fear of hypoglycemia, mealtime behaviors and quality of life (QOL) were compared before and after an initial session (I) and follow-up booster session (II) 6 months later. Based on these results, the intervention was consolidated into 1 session (Camp 2.0) and repeated with additional measures of parental stress and parental self-efficacy with diabetes management tasks. RESULTS: Participants in Camp 2.0 exhibited a significant decrease in mean HbA1c level (-0.5%, P = .002) before and after camp. Mothers exhibited a significant improvement in diabetes-specific QOL (Camp 1.0/Session I and Camp 2.0) and reduction in stress as measured on the Pediatric Inventory for Parent (PIP) assessment (Camp 2.0). The booster session in Camp 1.0 showed no added benefit. CONCLUSIONS: A family centered, camp-based multi-component intervention in young children with T1DM improved HbA1c and perceived QOL and stress in their mothers.

Joint analysis of left ventricular expression and circulating plasma levels of Omentin after myocardial ischemia.

BACKGROUND: Omentin-1, also known as Intelectin-1 (ITLN1), is an adipokine with plasma levels associated with diabetes, obesity, and coronary artery disease. Recent studies suggest that ITLN1 can mitigate myocardial ischemic injury but the expression of ITLN1 in the heart itself has not been well characterized. The purpose of this study is to discern the relationship between the expression pattern of ITLN1 RNA in the human heart and the level of circulating ITLN1 protein in plasma from the same patients following myocardial ischemia. METHODS: A large cohort of patients (n = 140) undergoing elective cardiac surgery for aortic valve replacement were enrolled in this study. Plasma and left ventricular biopsy samples were taken at the beginning of cardiopulmonary bypass and after an average of 82 min of ischemic cross clamp time. The localization of ITLN1 in epicardial adipose tissue (EAT) was also further characterized with immunoassays and cell fate transition studies. RESULTS: mRNA expression of ITLN1 decreases in left ventricular tissue after acute ischemia in human patients (mean difference 280.48, p = 0.001) whereas plasma protein levels of ITLN1 increase (mean difference 5.24, p < 0.001). Immunohistochemistry localized ITLN1 to the mesothelium or visceral pericardium of EAT. Epithelial to mesenchymal transition in mesothelial cells leads to a downregulation of ITLN1 expression. CONCLUSIONS: Myocardial injury leads to a decrease in ITLN1 expression in the heart and a corresponding increase in plasma levels. These changes may in part be due to an epithelial to mesenchymal transition of the cells that express ITLN1 following ischemia. Trial Registration Clinicaltrials.gov ID: NCT00985049.

Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance.

OBJECTIVE: Adipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that promotes hepatic lipid storage, but its role in the adipocyte had not been investigated. Here we tested the hypothesis that Hig2 localization to LDs in adipocytes promotes adipose tissue lipid deposition and systemic glucose homeostasis. METHOD: White and brown adipocyte-deficient (Hig2fl/fl × Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl × Ucp1 cre+) mice were generated to investigate the role of Hig2 in adipose depots. Additionally, we used multiple housing temperatures to investigate the role of active brown/beige adipocytes in this process. RESULTS: Hig2 localized to LDs in SGBS cells, a human adipocyte cell strain. Mice with adipocyte-specific Hig2 deficiency in all adipose depots demonstrated reduced visceral adipose tissue weight and increased glucose tolerance. This metabolic effect could be attributed to brown/beige adipocyte-specific Hig2 deficiency since Hig2fl/fl × Ucp1 cre+ mice displayed the same phenotype. Furthermore, when adipocyte-deficient Hig2 mice were moved to thermoneutral conditions in which non-shivering thermogenesis is deactivated, these improvements were abrogated and glucose intolerance ensued. Adipocyte-specific Hig2 deficient animals displayed no detectable changes in adipocyte lipolysis or energy expenditure, suggesting that Hig2 may not mediate these metabolic effects by restraining lipolysis in adipocytes. CONCLUSIONS: We conclude that Hig2 localizes to LDs in adipocytes, promoting adipose tissue lipid deposition and that its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 °C. Reversal of this phenotype at thermoneutrality in the absence of detectable changes in energy expenditure, adipose mass, or liver triglyceride suggests that Hig2 deficiency triggers a deleterious endocrine or neuroendocrine pathway emanating from brown/beige fat cells.

Connexin 43 Mediates White Adipose Tissue Beiging by Facilitating the Propagation of Sympathetic Neuronal Signals.

"Beige" adipocytes reside in white adipose tissue (WAT) and dissipate energy as heat. Several studies have shown that cold temperature can activate pro-opiomelanocortin-expressing (POMC) neurons and increase sympathetic neuronal tone to regulate WAT beiging. WAT, however, is traditionally known to be sparsely innervated. Details regarding the neuronal innervation and, more importantly, the propagation of the signal within the population of "beige" adipocytes are sparse. Here, we demonstrate that beige adipocytes display an increased cell-to-cell coupling via connexin 43 (Cx43) gap junction channels. Blocking of Cx43 channels by 18α-glycyrrhetinic acid decreases POMC-activation-induced adipose tissue beiging. Adipocyte-specific deletion of Cx43 reduces WAT beiging to a level similar to that observed in denervated fat pads. In contrast, overexpression of Cx43 is sufficient to promote beiging even with mild cold stimuli. These data reveal the importance of cell-to-cell communication, effective in cold-induced WAT beiging, for the propagation of limited neuronal inputs in adipose tissue.

Association between Responsible Pet Ownership and Glycemic Control in Youths with Type 1 Diabetes.

Type 1 diabetes mellitus (T1DM) a chronic characterized by an absolute insulin deficiency requires conscientious patient self-management to maintain glucose control within a normal range. Family cohesion and adaptability, positive coping strategies, social support and adequate self-regulatory behavior are found to favorably influence glycemic control. Our hypothesis was that the responsible care of a companion animal is associated with these positive attributes and correlated with the successful management of a chronic illness such as type 1 diabetes. We recruited 223 youths between 9 and 19 years of age from the Pediatric Diabetes clinic at the University of Massachusetts Medical School, reviewed the status of their glycemic control (using three consecutive A1c values) and asked them questions about the presence of a pet at home, and their level of involvement with its care. Multivariate analyses show that children who care actively for one or more pets at home are 2.5 times more likely to have control over their glycemic levels than children who do not care for a pet, adjusting for duration of disease, socio-economic status, age and self-management [1.1 to 5.8], pWald = 0.032. A separate model involving the care of a petdog only yielded comparable results (ORa = 2.6 [1.1 to 5.9], pWald = 0.023).

Visceral Adipose Tissue Mesothelial Cells: Living on the Edge or Just Taking Up Space?

Visceral adiposity and pathological adipose tissue remodeling, a result of overnutrition, are strong predictors of metabolic health in obesity. Factors intrinsic to visceral adipose depots are likely to play a causal role in eliciting the detrimental effects of this tissue on systemic nutrient homeostasis. The visceral adipose-associated mesothelium, a monolayer of epithelial cells of mesodermal origin that line the visceral serosa, has recently attracted attention for its role in metabolic dysfunction. Here we highlight and consolidate literature from various fields of study that points to the visceral adipose-associated mesothelium as a potential contributor to adipose development and remodeling. We propose a hypothesis in which adipose mesothelial cells represent a visceral depot-specific determinant of adipose tissue health in obesity.

Activated Kupffer cells inhibit insulin sensitivity in obese mice.

Obesity promotes insulin resistance associated with liver inflammation, elevated glucose production, and type 2 diabetes. Although insulin resistance is attenuated in genetic mouse models that suppress systemic inflammation, it is not clear whether local resident macrophages in liver, denoted Kupffer cells (KCs), directly contribute to this syndrome. We addressed this question by selectively silencing the expression of the master regulator of inflammation, NF-κB, in KCs in obese mice. We used glucan-encapsulated small interfering RNA particles (GeRPs) that selectively silence gene expression in macrophages in vivo. Following intravenous injections, GeRPs containing siRNA against p65 of the NF-κB complex caused loss of NF-κB p65 expression in KCs without disrupting NF-κB in hepatocytes or macrophages in other tissues. Silencing of NF-κB expression in KCs in obese mice decreased cytokine secretion and improved insulin sensitivity and glucose tolerance without affecting hepatic lipid accumulation. Importantly, GeRPs had no detectable toxic effect. Thus, KCs are key contributors to hepatic insulin resistance in obesity and a potential therapeutic target for metabolic disease.