Faculty Bibliography

ABSTRACT: BACKGROUND: To ascertain whether the associations between obesity, inflammation, and insulin resistance established in human adult studies are found among adolescents. METHODS: We contrasted 36 obese and 24 lean youth on fasting glucose, insulin levels, lipid profile, hemoglobin A1C, markers of hepatic function, white blood cell count, C-reactive protein (CRP) and fibrinogen levels. The cytokines IL-6, TNF-alpha, IFN-gamma, IL-10 and IL-4 and the adipokines leptin, resistin, and adiponectin were also compared between the two groups. The fasting glucose and insulin values were used to estimate the degree of insulin resistance with the homeostatic model assessment of insulin resistance (HOMA-IR). T-tests and correlations were run to examine group differences and associations between groups. In addition, regression analyses were used to ascertain whether the markers of inflammation were predictive of the degree of insulin resistance. RESULTS: Although obese adolescents had clear evidence of insulin resistance, only CRP, fibrinogen and leptin were elevated; there were no group differences in pro- or anti-inflammatory cytokines nor adiponectin and resistin. Anthropometric measures of obesity and level of insulin resistance were highly correlated to the acute phase reactants CRP and fibrinogen; however, the degree of insulin resistance was not predicted by the pro- or anti-inflammatory cytokine markers. Obese adolescents had higher white blood cell counts. In addition they had higher circulating alanine aminotransferase concentrations and lower circulating albumin and total protein than lean adolescents, possibly as a result of hepatocyte damage from fatty liver. CONCLUSION: Unlike rodent or adult studies, we found that wide-spread systemic inflammation is not necessarily associated with insulin resistance among adolescents. This finding does not support the current paradigm that the associations between obesity and insulin resistance are, to a significant degree, mediated by low grade systemic inflammation. These data support the need for further adolescent studies to explore these associations.

Type 2 diabetes (T2DM) and cardiovascular disease (CVD) are rising dramatically in adolescents in parallel with excess weight. The Banishing Obesity and Diabetes in Youth (BODY) Project, is a school-based intervention that medically screens overweight and obese high school students, provides personalized feedback, and connects to appropriate healthcare. Body mass index (BMI) was determined for 1,526 students in one New York City public high school with a school-based health center (SBHC). Overweight and obese students (n = 640) were invited to complete a medical evaluation that included a survey, blood pressure and blood tests. 328/640 (51%) eligible students returned signed parental consent and participated. All participants received a personalized report detailing their results along with specific recommendations on how to improve their health. Parents of participants with results outside healthy ranges (82%; 270/328) were called and mailed referral letters to connect with healthcare services. Project staff reached by telephone 74% (199/270) of those families and 29% (58/199) stated that the report led them to make arrangements to see a healthcare provider. Most students (83%; 273/328) were registered at the SBHC, and we shared their medical results with them so they could follow-up with the students. The BODY Project is a feasible program for urban schools with a SBHC. This may allow effective prevention of T2DM, and CVD from dyslipidemia and hypertension.

Hypothalamic-pituitary-adrenal (HPA) axis control may be impaired in type 2 diabetes (T2DM). Glucocorticoids increase consumption of low quality foods high in calories, sugar, and fat. We explored the relationship between cortisol levels, poor blood glucose control, and food quality choice in T2DM. Twenty-seven healthy controls were age-, gender- and education-matched to 27 T2DM participants. Standard clinical blood tests and cortisol values were measured from fasting blood samples. Participants recorded all consumed food and drink items in a consecutive 3-day food diary. Diaries were analyzed for 'high quality' and 'low quality' foods using a standardized method with high reliability (0.97 and 0.86, respectively). Controlling for education, body mass index (BMI) and hemoglobin A1C (HbA1C), log-transformed cortisol (LogC) predicted the percent of low quality foods (R (2) = 0.092, beta = 0.360, P < 0.05), but not the percent of high quality foods chosen. Controlling for education, BMI, and LogC, HbA1C significantly predicted both the percent of low quality foods (DeltaR (2) = 0.079, beta = 0.348, P = 0.024) and high quality foods chosen (DeltaR (2) = 0.085, beta = -0.362, P = 0.022). The relationship between HbA1C and low quality food choice may be mediated by cortisol, controlling for BMI and education (P < 0.01). HbA1C displayed both an indirect (cortisol-mediated) effect (P < 0.05) and direct effect on low quality food choice (P < 0.05). The relationship between HbA1C and low quality food choice may be partially mediated by cortisol. Poor blood glucose control may cause HPA axis disruption, increased consumption of low quality foods

BACKGROUND: Type 2 diabetes mellitus (T2DM) has been shown to result in medical complications on several organ systems including the kidneys, eyes, cardiovascular system, and most recently described the brain, including the hippocampus. There is also evidence that females are disproportionately affected by these medical complications. Brain volume reductions have also been associated with chronic low-grade inflammation and dyslipidaemia. This study investigated the relationships among T2DM, gender, inflammation, dyslipidaemia, and hippocampal volumes. METHOD: Participant groups consisted of 40 obese adults with T2DM and 47 lean adults, group-matched on age, gender, race, and education. Each participant underwent medical examination including a standard panel of blood tests, a magnetic resonance imaging, and cognitive evaluation. RESULTS: We show that there is a gender difference in the association of T2DM and hippocampal volumes: diabetic women are most affected despite having better glucose control than their male counterparts. Although females with T2DM had disproportionately lower high density lipoprotein as well as better haemoglobin A1c, neither of these results explained why females with T2DM had the smallest hippocampal volumes. CONCLUSIONS: These important findings indicate that in addition to the higher rate of traditional medical complication, females with T2DM are likely to suffer more brain complications than males. These observations, if supported by larger studies, suggest that in the future gender could be considered when customizing diabetes treatment.

OBJECTIVE: The aim of this study was to describe the minimum number of anthropometric measures that will optimally predict insulin resistance (IR) and to characterize the utility of these measures among obese and nonobese adolescents. RESEARCH DESIGN AND METHODS: SIX ANTHROPOMETRIC MEASURES (SELECTED FROM THREE CATEGORIES: central adiposity, weight, and body composition) were measured from 1298 adolescents attending two New York City public high schools. Body composition was determined by bioelectric impedance analysis (BIA). The homeostatic model assessment of IR (HOMA-IR), based on fasting glucose and insulin concentrations, was used to estimate IR. Stepwise linear regression analyses were performed to predict HOMA-IR based on the six selected measures, while controlling for age. RESULTS: The stepwise regression retained both waist circumference (WC) and percentage of body fat (BF%). Notably, BMI was not retained. WC was a stronger predictor of HOMA-IR than BMI was. A regression model using solely WC performed best among the obese II group, while a model using solely BF% performed best among the lean group. Receiver operator characteristic curves showed the WC and BF% model to be more sensitive in detecting IR than BMI, but with less specificity. CONCLUSION: WC combined with BF% was the best predictor of HOMA-IR. This finding can be attributed partly to the ability of BF% to model HOMA-IR among leaner participants and to the ability of WC to model HOMA-IR among participants who are more obese. BMI was comparatively weak in predicting IR, suggesting that assessments that are more comprehensive and include body composition analysis could increase detection of IR during adolescence, especially among those who are lean, yet insulin-resistant.

The brain is the most cholesterol-rich organ in the body. Although most of the cholesterol in the brain is produced endogenously, some studies suggest that systemic cholesterol may be able to enter the brain. We investigated whether abnormal cholesterol profiles correlated with diffusion-tensor-imaging-based estimates of white matter microstructural integrity of lean and overweight/obese (o/o) adults. Twenty-two lean and 39 obese adults underwent magnetic resonance imaging, kept a three-day food diary, and had a standardized assessment of fasting blood lipids. The lean group ate less cholesterol-rich food than o/o although both groups ate equivalent servings of food per day. Voxelwise correlational analyses controlling for age, diabetes, and white matter hyperintensities, resulted in two significant clusters of negative associations between abnormal cholesterol profile and fractional anisotropy, located in the left and right prefrontal lobes. When the groups were split, the lean subjects showed no associations, whereas the o/o group expanded the association to three significant clusters, still in the frontal lobes. These findings suggest that cholesterol profile abnormalities may explain some of the reductions in white matter microstructural integrity that are reported in obesity.

BACKGROUND AND PURPOSE: Emerging evidence suggests that obese adolescents show changes in brain structure compared with lean adolescents. In addition, obesity impacts body development during adolescence. We tested a hypothesis that T1, a marker of brain maturation, can show brain differences associated with obesity. MATERIALS AND METHODS: Adolescents similar in sex, family income, and school grade were recruited by using strict entry criteria. We measured brain T1 in 48 obese and 31 lean adolescents by quantitative MR imaging at 1.5T. We combined MPRAGE and inversion-recovery sequences with normalization to standard space and automated skull stripping to obtain T1 maps with a symmetric voxel volume of 1 mm(3). RESULTS: Sex, income, triglycerides, total cholesterol, and fasting glucose did not differ between groups, but obese adolescents had significantly lower HDL, higher LDL, and higher fasting insulin levels than lean adolescents. Intracranial vault volume did not differ between groups, but obese adolescents had smaller intracranial vault-adjusted brain parenchymal volumes. Obese adolescents had 4 clusters (>100 contiguous voxels) of T1 relaxation that were significantly different (P < .005) from those in lean adolescents. Three of these clusters had longer T1s in obese adolescents (in the orbitofrontal and parietal regions), and 1 cluster had shorter T1s, compared with lean adolescents. CONCLUSIONS: Our results suggest that obesity may have a significant impact on brain development, especially in the frontal and parietal lobes. It is unclear if these changes persist into adulthood or whether they indicate that obese subjects follow a different developmental trajectory during adolescence

The brain is the most cholesterol-rich organ in the body. Although most of the cholesterol in the brain is produced endogenously, some studies suggest that systemic cholesterol may be able to enter the brain. We investigated whether abnormal cholesterol profiles correlated with diffusion-tensor-imaging-based estimates of white matter microstructural integrity of lean and overweight/obese (o/o) adults. Twenty-two lean and 39 obese adults underwent magnetic resonance imaging, kept a 3-day food diary, and had a standardized assessment of fasting blood lipids. The lean group ate less cholesterol rich food than o/o although both groups ate equivalent servings of food per day. Voxelwise correlational analyses controlling for age, diabetes, and white matter hyperintensities, resulted in two significant clusters of negative associations between abnormal cholesterol profile and fractional anisotropy, located in the left and right prefrontal lobes. When the groups were split, the lean subjects showed no associations, whereas the o/o group expanded the association to three significant clusters, still in the frontal lobes. These findings suggest that cholesterol profile abnormalities may explain some of the reductions in white matter microstructural integrity that are reported in obesity.

In adults, obesity has been associated with disinhibited eating, decreased cortical gray matter (GM) volume, and lower performance on cognitive assessments. Much less is known about these relationships in adolescence and there are no studies assessing behavioral, cognitive, and neurostructural measures in the same group of study participants. This study examined the relationship between obesity, executive function, disinhibition, and brain volumes in relatively healthy youth. Participants included 54 obese and 37 lean adolescents. Participants received a cognitive battery, questionnaires of eating behaviors, and magnetic resonance imaging (MRI). Neuropsychological assessments included tasks targeting frontal lobe function. Eating behaviors were determined using the Three Factor Eating Questionnaire (TFEQ), and structural MRIs were performed on a 1.5 T Siemens Avanto MRI System (Siemens, Erlangen, Germany) to determine brain GM volumes. Lean and obese adolescents were matched on age, years of education, gender, and socioeconomic status. Relative to lean adolescents, obese participants had significantly higher ratings of disinhibition on the TFEQ, lower performance on the cognitive tests, and lower orbitofrontal cortex (OFC) volume. Disinhibition significantly correlated with BMI, Stroop color-word score, and OFC volume. This is the first report of these associations in adolescents and point to the importance of better understanding the associations between neurostructural deficits and obesity

The rates of type 2 diabetes (T2DM) continue to parallel the rising rates of obesity in the United States, increasingly affecting adolescents as well as adults. Hippocampal and frontal lobe reductions have been found in older adults with type 2 diabetes, and we sought to ascertain if these brain alterations were also present in obese adolescents with T2DM. In a cross-sectional study we compared MRI-based regional brain volumes of 18 obese adolescents with T2DM and 18 obese controls without evidence of marked insulin resistance. Groups were matched on age, sex, school grade, ethnicity, socioeconomic status, body mass index, and waist circumference. Relative to obese controls, adolescents with T2DM had significantly reduced hippocampal and prefrontal volumes, and higher rates of global cerebral atrophy. Hemoglobin A1c, an index of long-term glycemic control, was inversely associated with prefrontal volume and positively associated with global cerebral atrophy (both p < 0.05). Brain integrity is negatively impacted by T2DM already during adolescence, long before the onset of overt macrovascular disease. Paralleling the findings of greater vascular and renal complications among obese adolescents with severe insulin resistance and T2DM relative to their age-matched peers with type 1 diabetes, we find clear evidence of possible brain complications. Our findings call for aggressive and early intervention to limit the negative impact of obesity-associated insulin resistance leading to T2DM on the developing brains of adolescents.