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Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by ill-defined mechanisms. Here we report a large metabolomics study of plasma and cerebrospinal fluid, showing in independent cohorts that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. Immune cells of people with DS overexpress IDO1 , the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, the levels of IFN-inducible cytokines positively correlate with KP dysregulation. Using metabolic tracing assays, we show that overexpression of IFN receptors encoded on chromosome 21 contribute to enhanced IFN stimulation, thereby causing IDO1 overexpression and kynurenine overproduction in cells with T21. Finally, a mouse model of DS carrying triplication of IFN receptors exhibits KP dysregulation. Together, our results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS. Down syndrome (DS) is caused by trisomy 21 (T21), but the underlying etiology of the related immune and neurological dysfunction is unclear. Here, the authors show that T21 activates the kynurenine pathway via increased interferon receptor copy number, which could contribute to DS pathophysiology.

Aims/hypothesis Although insulin resistance often leads to type 2 diabetes mellitus, its early stages are often unrecognised, thus reducing the probability of successful prevention and intervention. Moreover, treatment efficacy is affected by the genetics of the individual. We used gene expression profiles from a cross-sectional study to identify potential candidate genes for the prediction of diabetes risk and intervention response. Methods Using a multivariate regression model, we linked gene expression profiles of human skeletal muscle and intermuscular adipose tissue (IMAT) to fasting glucose levels and glucose infusion rate. Based on the expression patterns of the top predictive genes, we characterised and compared individual gene expression with clinical classifications using k -nearest neighbour clustering. The predictive potential of the candidate genes identified was validated using muscle gene expression data from a longitudinal intervention study. Results We found that genes with a strong association with clinical measures clustered into three distinct expression patterns. Their predictive values for insulin resistance varied substantially between skeletal muscle and IMAT. Moreover, we discovered that individual gene expression-based classifications may differ from classifications based predominantly on clinical variables, indicating that participant stratification may be imprecise if only clinical variables are used for classification. Of the 15 top candidate genes, ST3GAL2 , AASS , ARF1 and the transcription factor SIN3A are novel candidates for predicting a refined diabetes risk and intervention response. Conclusion/interpretation Our results confirm that disease progression and successful intervention depend on individual gene expression states. We anticipate that our findings may lead to a better understanding and prediction of individual diabetes risk and may help to develop individualised intervention strategies. Graphical abstract

Obesity-associated changes in adipose tissue composition and function contribute to the development of metabolic diseases such as type 2 diabetes and cardiovascular disease. Our appreciation of the role of adipose tissue in metabolic health is unrefuted, however, our understanding of the dynamic, malleable, and networking nature of adipose tissue continues to develop. Endocrine signaling has emerged as an important functional attribute of adipose tissue, secreting bioactive mediators that regulate insulin sensitivity and glucose homeostasis. In addition to the systemic impact of adipose tissue secretions, direct, local, paracrine interactions between adipose tissue and neighboring metabolic tissues/organs are of particular relevance to metabolic disease, however studies focused on understanding these interactions are limited. The work in this dissertation is directed at investigating the secretomes of distinct adipose depots from different anatomical locations, in an attempt to gain insight into the direct paracrine impact on adjacent metabolic tissues. In particular, focused studies on the secretory capabilities of intermuscular adipose tissue (IMAT), which neighbors skeletal muscle within the fascial compartment, are performed to better understand the negative association between IMAT and metabolic disease. Multi-omics approaches are taken to describe the adipose tissue secretome composition, and in vitro models of insulin sensitivity are used to assess the functional response to adipose tissue secretome exposure. Additionally, specific IMAT-derived mediators which are identified as being related to insulin resistance measured in vivo are interrogated for their individual ability to regulate skeletal muscle insulin sensitivity in vitro. Major themes emerging from these combined studies are that meaningful distinctions between heterogeneous adipose depots from different anatomical locations center on their secretion of mediators involved in immune/inflammatory processes, as well as extracellular matrix (ECM) organization. Increased inflammation and fibrosis are associated with adipose tissue accumulation in individuals with obesity. However, the significance and magnitude of paracrine interactions occurring between adipose-derived cytokine, chemokine, and ECM proteins and local metabolic tissues displayed in this work highlights the need for more studies focused on the impact of local microenvironments in the regulation of metabolic health and disease.

Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by unknown mechanisms. We report here the results of a large metabolomics study showing that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. We found that immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, we found a positive correlation between levels of specific inflammatory cytokines and KP dysregulation. Using metabolic flux assays, we found that IFN stimulation causes IDO1 overexpression and kynurenine overproduction in cells with T21, dependent on overexpression of IFN receptors encoded on chromosome 21. Finally, KP dysregulation is conserved in a mouse model of DS carrying triplication of the IFN receptors. Altogether, these results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.

OBJECTIVE:--We sought to determine whether an oral disposition index (DIO) predicts the development of diabetes over a 10-year period. First, we assessed the validity of the DIO by demonstrating that a hyperbolic relationship exists between oral indexes of insulin sensitivity and β-cell function. RESEARCH DESIGN AND METHODS--A total of 613 Japanese-American subjects (322 men and 291 women) underwent a 75-g oral glucose tolerance test (OGTT) at baseline, 5 years, and 10 years. Insulin sensitivity was estimated as 1/fasting insulin or homeostasis model assessment of insulin sensitivity (HOMA-S). Insulin response was estimated as the change in insulin divided by change in glucose from 0 to 30 min (ΔI₀₋₃₀/ΔG₀₋₃₀). RESULTS:--ΔI₀₋₃₀/ΔG₀₋₃₀ demonstrated a curvilinear relationship with 1/fasting insulin and HOMA-S with a left and downward shift as glucose tolerance deteriorated. The confidence limits for the slope of the loge-transformed estimates included -1 for ΔI₀₋₃₀/ΔG₀₋₃₀ versus 1/fasting insulin for all glucose tolerance groups, consistent with a hyperbolic relationship. When HOMA-S was used as the insulin sensitivity measure, the confidence limits for the slope included -1 only for subjects with normal glucose tolerance (NGT) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) but not diabetes. On the basis of this hyperbolic relationship, the product of ΔI₀₋₃₀/ΔG₀₋₃₀ and 1/fasting insulin was calculated (DIO) and decreased from NGT to IFG/IGT to diabetes (P < 0.001). Among nondiabetic subjects at baseline, baseline DIO predicted cumulative diabetes at 10 years (P < 0.001) independent of age, sex, BMI, family history of diabetes, and baseline fasting and 2-h glucose concentrations. CONCLUSIONS:--The DIO provides a measure of β-cell function adjusted for insulin sensitivity and is predictive of development of diabetes over 10 years.

Intra-Abdominal Fat Is a Major Determinant of the National Cholesterol Education Program Adult Treatment Panel III Criteria for the Metabolic Syndrome Darcy B. Carr 1 , Kristina M. Utzschneider 2 , Rebecca L. Hull 2 , Keiichi Kodama 2 , Barbara M. Retzlaff 2 , John D. Brunzell 2 , Jane B. Shofer 3 , Brian E. Fish 2 , Robert H. Knopp 2 and Steven E. Kahn 2 1 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington 2 Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, Veterans Affairs Puget Sound Health Care System and Harborview Medical Center, University of Washington, Seattle, Washington 3 Department of Rehabilitation Research and Development, University of Washington, Seattle, Washington Address correspondence and reprint requests to Darcy B. Carr, MD, Assistant Professor, Box 356460, Dept. OB/GYN, University of Washington, Seattle, WA 98195-6460. E-mail: darcarr{at}u.washington.edu Abstract The underlying pathophysiology of the metabolic syndrome is the subject of debate, with both insulin resistance and obesity considered as important factors. We evaluated the differential effects of insulin resistance and central body fat distribution in determining the metabolic syndrome as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III. In addition, we determined which NCEP criteria were associated with insulin resistance and central adiposity. The subjects, 218 healthy men ( n = 89) and women ( n = 129) with a broad range of age (26–75 years) and BMI (18.4–46.8 kg/m 2 ), underwent quantification of the insulin sensitivity index ( S i ) and intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas. The metabolic syndrome was present in 34 (15.6%) of subjects who had a lower S i [median: 3.13 vs. 6.09 × 10 −5 min −1 /(pmol/l)] and higher IAF (166.3 vs. 79.1 cm 2 ) and SCF (285.1 vs. 179.8 cm 2 ) areas compared with subjects without the syndrome ( P < 0.001). Multivariate models including S i , IAF, and SCF demonstrated that each parameter was associated with the syndrome. However, IAF was independently associated with all five of the metabolic syndrome criteria. In multivariable models containing the criteria as covariates, waist circumference and triglyceride levels were independently associated with S i and IAF and SCF areas ( P < 0.001). Although insulin resistance and central body fat are both associated with the metabolic syndrome, IAF is independently associated with all of the criteria, suggesting that it may have a pathophysiological role. Of the NCEP criteria, waist circumference and triglycerides may best identify insulin resistance and visceral adiposity in individuals with a fasting plasma glucose <6.4 mmol/l. ATP III, Adult Treatment Panel III BP, blood pressure FPG, fasting plasma glucose GEE, generalized estimating equation IAF, intra-abdominal fat NCEP, National Cholesterol Education Program NHANES III, Third National Health and Nutrition Examination Survey PAI-1, plasminogen activator inhibitor type 1 SCF, subcutaneous fat TG, triglyceride TNF-α, tumor necrosis factor-α WC, waist circumference Footnotes Accepted May 17, 2004. Received February 28, 2004. DIABETES

Gestational Diabetes Mellitus Increases the Risk of Cardiovascular Disease in Women With a Family History of Type 2 Diabetes Darcy B. Carr , MD, MS 1 , Kristina M. Utzschneider , MD 2 , Rebecca L. Hull , PHD 2 , Jenny Tong , MD, MPH 2 , Tara M. Wallace , MD 2 , Keiichi Kodama , MD 2 , Jane B. Shofer , MS 3 , Susan R. Heckbert , MD, PHD 4 5 , Edward J. Boyko , MD, MPH 2 6 , Wilfred Y. Fujimoto , MD 2 , Steven E. Kahn , MB, CHB 2 and the American Diabetes Association GENNID Study Group * 1 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington 2 Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, VA Puget Sound Health Care System and the University of Washington, Seattle, Washington 3 Department of Rehabilitation Research and Development, University of Washington, Seattle, Washington 4 Department of Epidemiology, University of Washington, Seattle, Washington 5 Cardiovascular Health Research Unit, VA Puget Sound Health Care System, Seattle, Washington 6 Epidemiologic Research and Information Center, VA Puget Sound Health Care System, Seattle, Washington Address correspondence and reprint requests to Darcy B. Carr, MD, MS, Box 356460, University of Washington, Seattle, WA 98195-6460. E-mail: darcarr{at}u.washington.edu Abstract OBJECTIVE — We sought to determine whether a history of gestational diabetes mellitus (GDM) further increases the risk of cardiovascular disease (CVD) in parous women with first-degree relatives with type 2 diabetes. RESEARCH DESIGN AND METHODS — Women with ( n = 332) and without ( n = 663) a history of GDM were compared regarding 1 ) the revised National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome criteria, 2 ) the prevalence of type 2 diabetes, and 3 ) self-reported CVD. RESULTS — Women with prior GDM were younger (48.6 ± 0.7 vs. 52.4 ± 0.6 years [means ± SE]; P < 0.001) and less likely to be postmenopausal (48.3 vs. 57.9%; P < 0.005). Although both groups were obese (BMI 34.4 ± 1.2 vs. 33.7 ± 0.6 kg/m 2 ), women with prior GDM were more likely to have metabolic syndrome (86.6 vs. 73.5%; P < 0.001) and type 2 diabetes (93.4 vs. 63.3%; P < 0.001). Moreover, they had a higher prevalence of CVD (15.5 vs. 12.4%; adjusted odds ratio 1.85 [95% CI 1.21–2.82]; P = 0.005) that occurred at a younger age (45.5 ± 2.2 vs. 52.5 ± 1.9 years; P = 0.02) and was independent of metabolic syndrome (1.74 [1.10–2.76]; P = 0.02) and type 2 diabetes (1.56 [1.002–2.43]; P < 0.05). CONCLUSIONS — Among women with a family history of type 2 diabetes, those with prior GDM were even more likely to not only have CVD risk factors, including metabolic syndrome and type 2 diabetes, but also to have experienced CVD events, which occurred at a younger age. Thus, women with both a family history of type 2 diabetes and personal history of GDM may be especially suitable for early interventions aimed at preventing or reducing their risk of CVD and diabetes. CVD, cardiovascular disease GENNID, GENetics of Non-Insulin dependent Diabetes GDM, gestational diabetes mellitus Footnotes * ↵ * *The list of centers that comprise the American Diabetes Association GENNID Study Group can be found in ref. 24 . ↵ A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. ↵ The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 10, 2006. Received December 16, 2005. DIABETES CARE

OBJECTIVE:--The relative roles of insulin resistance and β-cell dysfunction in the pathogenesis of impaired glucose tolerance (IGT) and type 2 diabetes are debated. First-degree relatives of individuals with type 2 diabetes are at increased risk of developing hyperglycemia. RESEARCH DESIGN AND METHODS--We evaluated the evolution of insulin sensitivity, β-cell function, glucose effectiveness, and glucose tolerance over 7 years in 33 nondiabetic, first-degree relatives of type 2 diabetic individuals using frequently sampled tolbutamide-modified intravenous and oral glucose tolerance tests. RESULTS:--Subjects gained weight, and their waist circumference increased (P < 0.05). Insulin sensitivity, the acute insulin response to glucose, and glucose effectiveness did not change significantly. However, when we accounted for the modulating effect of insulin sensitivity on insulin release, β-cell function determined as the disposition index decreased by 22% (P < 0.05). This decrease was associated with declines in intravenous and oral glucose tolerance (P < 0.05 and P < 0.001, respectively). Of the subjects with normal glucose tolerance at the first assessment, we compared those who progressed to IGT with those who did not. The disposition index was 50% lower in the progressors than in the nonprogressors at follow-up (P < 0.05). CONCLUSIONS:--The decline in glucose tolerance over time in first-degree relatives of type 2 diabetic individuals is strongly related to the loss of β-cell function. Thus, early interventions to slow the decline in β-cell function should be considered in high-risk individuals.

Obesity is associated with insulin resistance, particularly when body fat has a central distribution. However, insulin resistance also frequently occurs in apparently lean individuals. It has been proposed that these lean insulin-resistant individuals have greater amounts of body fat than lean insulin-sensitive subjects. Alternatively, their body fat distribution may be different. Obesity is associated with elevated plasma leptin levels, but some studies have suggested that insulin sensitivity is an additional determinant of circulating leptin concentrations. To examine how body fat distribution contributes to insulin sensitivity and how these variables are related to leptin levels, we studied 174 individuals (73 men, 101 women), a priori classified as lean insulin-sensitive (LIS, n = 56), lean insulin-resistant (LIR, n = 61), and obese insulin-resistant (OIR, n = 57) based on their BMI and insulin sensitivity index (S(I)). Whereas the BMI of the two lean groups did not differ, the S(I) of the LIR subjects was less than half that of the LIS group. The subcutaneous and intra-abdominal fat areas, determined by computed tomography, were 45 and 70% greater in the LIR subjects (P < 0.001) and 2.5- and 3-fold greater in the OIR group, as compared with the LIS group. Fasting plasma leptin levels were moderately increased in LIR subjects (10.8 +/- 7.1 vs. 8.1 +/- 6.4 ng/ml in LIS subjects; P < 0.001) and doubled in OIR subjects (21.9 +/- 15.5 ng/ml; P < 0.001). Because of the confounding effect of body fat, we examined the relationships between adiposity, insulin sensitivity, and leptin concentrations by multiple regression analysis. Intra-abdominal fat was the best variable predicting insulin sensitivity in both genders and explained 54% of the variance in S(I). This inverse relationship was nonlinear (r = -0.688). On the other hand, in both genders, fasting leptin levels were strongly associated with subcutaneous fat area (r = 0.760) but not with intra-abdominal fat. In line with these analyses, when LIS and LIR subjects were matched for subcutaneous fat area, age, and gender, they had similar leptin levels, whereas their intra-abdominal fat and insulin sensitivity remained different. Thus, accumulation of intra-abdominal fat correlates with insulin resistance, whereas subcutaneous fat deposition correlates with circulating leptin levels. We conclude that the concurrent increase in these two metabolically distinct fat compartments is a major explanation for the association between insulin resistance and elevated circulating leptin concentrations in lean and obese subjects.

Background Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus. Results Mouse global array data identified serpinA3N as a novel gene highly upregulated by both a HFD and leptin challenge. In situ hybridisation showed serpinA3N expression upregulation by HFD and leptin in all major hypothalamic nuclei in agreement with transcriptomic gene expression data. Immunohistochemistry and studies in the hypothalamic clonal neuronal cell line, mHypoE-N42 (N42), confirmed that alpha 1-antichymotrypsin (α 1 AC), the protein encoded by serpinA3 , is localised to neurons and revealed that it is secreted into the media. SerpinA3N expression in N42 neurons is upregulated by palmitic acid and by leptin, together with IL-6 and TNFα , and all three genes are downregulated by the anti-inflammatory monounsaturated fat, oleic acid. Additionally, palmitate upregulation of serpinA3 in N42 neurons is blocked by the NFκB inhibitor, BAY11, and the upregulation of serpinA3N expression in the hypothalamus by HFD is blunted in IL-1 receptor 1 knockout ( IL-1R1 −/− ) mice. Conclusions These data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammation.