PurposeC1q/TNF-related protein-3 (CTRP3) is a novel adipokine that lowers blood glucose levels, reduces liver triglyceride synthesis, and is protective against hepatic steatosis in diet-induced obese mouse models. We hypothesized that higher circulating serum levels of CTRP3 would be associated with a lean body mass index (BMI) and a more favorable metabolic profile in humans. The aim of this study was to investigate CTRP3 levels in lean individuals compared to obese individuals.MethodsThis was a cross-sectional study of obese (n=44) and lean control patients (n=60). Fasting metabolic parameters were measured in all patients and serum CTRP3 levels were measured by ELISA.ResultsBMI of the lean group was 21.9 ± 0.2 kg/m2 and obese group was 45.2 ± 1.1 kg/m2. We found significantly lower circulating levels of CTRP3 in obese individuals (405 ± 8.3 vs. 436± 6.7ng/mL, p=0.004) compared to the lean group. Serum CTRP3 levels were inversely correlated with BMI (p=0.001), and triglycerides (p<0.001), and significantly associated with gender (p<0.01), ethnicity (p=0.05), HDL-cholesterol (p<0.01), and adiponectin (p<0.01). We found BMI (p<0.01), gender (p<0.01), and ethnicity (p<0.05) to be significant predictors of CTRP3 levels when controlling for age in multiple regression analysis.ConclusionsCTRP3 is a beneficial adipokine whose circulating levels are significantly lower in obese individuals. Obesity causes dysregulation in adipokine production, including the down-regulation of CTRP3. Lower CTRP3 levels may contribute to the pathophysiology of metabolic disorders associated with obesity. Optimizing CTRP3 levels through novel therapies may improve obesity and its comorbidities.

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In obesity, copper and cuproproteins are elevated in circulation, adipose tissue, and liver.

IMPORTANCE Diabetic retinopathy (DR) is a leading cause of vision loss worldwide. As the incidence of both type 1 and type 2 diabetes among youths continues to increase around the world, understanding the factors associated with the development of DR in this age group is important.

ouths and adults with diabetes are at risk for diabetic retinopathy (DR), which can lead to vision loss. 1 The prevalence of DR among youths with type 1 diabetes (T1D) and type 2 diabetes (T2D) ranges from 4% to 13%. [2][3][4] Despite recommendations from the American Diabetes Association and American Academy of Ophthalmology for yearly screening, adherence remains low. 5 Although the prevalence is low among youths, the risk of developing DR is high. Diabetic retinopathy is present in up to 50% of patients with T1D 28 years or more after diagnosis 6,7 and already present at the time of diagnosis in 12% to 19% of patients with T2D. 4 Digital teleophthalmology systems that use nonmydriatic cameras have been implemented to improve DR screen-ing rates 8,9 and are cost-effective. 10 Digital fundus photography can be efficiently and safely performed without pupil dilation, including in the pediatric setting. 3,[11][12][13][14] Recently, the US Food and Drug Administration (FDA) approved the first autonomous artificial intelligence (AI) diagnostic system to detect DR in adults. With this system, a minimally trained operator guided by an image-quality AI takes retinal images with a nonmydriatic fundus camera, and these images are subsequently assessed in real time at the point of care (POC) for the presence or absence of DR. 15 In 2020, this form of FDA-validated autonomous AI became part of the American Diabetes Association standard of care for DR screening. 16 IMPORTANCE Screening for diabetic retinopathy is recommended for children with type 1 diabetes (T1D) and type 2 diabetes (T2D), yet screening rates remain low. Point-of-care diabetic retinopathy screening using autonomous artificial intelligence (AI) has become available, providing immediate results in the clinic setting, but the cost-effectiveness of this strategy compared with standard examination is unknown.OBJECTIVE To assess the cost-effectiveness of detecting and treating diabetic retinopathy and its sequelae among children with T1D and T2D using AI diabetic retinopathy screening vs standard screening by an eye care professional (ECP). DESIGN, SETTING, AND PARTICIPANTSIn this economic evaluation, parameter estimates were obtained from the literature from 1994 to 2019 and assessed from March 2019 to January 2020. Parameters included out-of-pocket cost for autonomous AI screening, ophthalmology visits, and treating diabetic retinopathy; probability of undergoing standard retinal examination; relative odds of undergoing screening; and sensitivity, specificity, and diagnosability of the ECP screening examination and autonomous AI screening. MAIN OUTCOMES AND MEASURESCosts or savings to the patient based on mean patient payment for diabetic retinopathy screening examination and cost-effectiveness based on costs or savings associated with the number of true-positive results identified by diabetic retinopathy screening. RESULTSIn this study, the expected true-positive proportions for standard ophthalmologic screening by an ECP were 0.006 for T1D and 0.01 for...

Wolf RM, Lei X, Yang Z, Nyandjo M, Tan SY, Wong GW. CTRP3 deficiency reduces liver size and alters IL-6 and TGF␤ levels in obese mice. Am J Physiol Endocrinol Metab 310: E332-E345, 2016. First published December 15, 2015; doi:10.1152/ajpendo.00248.2015.-C1q/TNF-related protein 3 (CTRP3) is a secreted metabolic regulator whose circulating levels are reduced in human and rodent models of obesity and diabetes. Previously, we showed that CTRP3 infusion lowers blood glucose by suppressing gluconeogenesis and that transgenic overexpression of CTRP3 protects mice against diet-induced hepatic steatosis. Here, we used a genetic loss-of-function mouse model to further address whether CTRP3 is indeed required for metabolic homeostasis under normal and obese states. Both male and female mice lacking CTRP3 had similar weight gain when fed a control low-fat (LFD) or high-fat diet (HFD). Regardless of diet, no differences were observed in adiposity, food intake, metabolic rate, energy expenditure, or physical activity levels between wild-type (WT) and Ctrp3-knockout (KO) animals of either sex. Contrary to expectations, loss of CTRP3 in LFD-or HFD-fed male and female mice also had minimal or no impact on whole body glucose metabolism, insulin sensitivity, and fasting-induced hepatic gluconeogenesis. Unexpectedly, the liver sizes of HFD-fed Ctrp3-KO male mice were markedly reduced despite a modest increase in triglyceride content. Furthermore, liver expression of fat oxidation genes was upregulated in the Ctrp3-KO mice. Whereas the liver and adipose expression of profibrotic TGF␤1, as well as its serum levels, was suppressed in HFD-fed KO mice, circulating proinflammatory IL-6 levels were markedly increased; these changes, however, were insufficient to affect systemic metabolic outcome. We conclude that, although it is dispensable for physiological control of energy balance, CTRP3 plays a previously unsuspected role in modulating liver size and circulating cytokine levels in response to obesity. adipokine; C1q/tumor necrosis factor-related protein; C1q/tumor necrosis factor; fatty liver; obesity; diabetes THE C1Q/TNF-RELATED PROTEIN (CTRP) family comprises 15 secreted plasma proteins of the C1q family, the first seven of which were identified initially on the basis of sequence homology to the globular C1q domain of adiponectin (66); additional members were subsequently described (6, 43, 49, 59 -61, 64, 65). Recent functional studies demonstrated important and distinct roles for CTRPs in regulating glucose and/or lipid metabolism in the peripheral tissues (38 -42, 57-60) as well as having a central role in modulating food intake (6, 7) and adipocyte differentiation in culture (61). Unlike adiponectin, whose expression is restricted to adipocytes (47), CTRP family members are much more widely expressed (65, 66); all are conserved throughout vertebrate evolution (50).Multiple in vitro and in vivo approaches have been used to elucidate the biological function of one member, CTRP3, a secreted plasma protein whose circulating levels ...

Diabetic retinopathy (DR) is a leading cause of vision loss worldwide. Screening for DR is recommended in children and adolescents, but adherence is poor. Recently, autonomous artificial intelligence (AI) systems have been developed for early detection of DR and have been included in the American Diabetes Association's guidelines for screening in adults. We sought to determine the diagnostic efficacy of autonomous AI for the diabetic eye exam in youth with diabetes. RESEARCH DESIGN AND METHODSIn this prospective study, point-of-care diabetic eye exam was implemented using a nonmydriatic fundus camera with an autonomous AI system for detection of DR in a multidisciplinary pediatric diabetes center. Sensitivity, specificity, and diagnosability of AI was compared with consensus grading by retinal specialists, who were masked to AI output. Adherence to screening guidelines was measured before and after AI implementation. RESULTSThree hundred ten youth with diabetes aged 5-21 years were included, of whom 4.2% had DR. Diagnosability of AI was 97.5% (302 of 310). The sensitivity and specificity of AI to detect more-than-mild DR was 85.7% (95% CI 42.1-99.6%) and 79.3% (74.3-83.8%), respectively, compared with the reference standard as defined by retina specialists. Adherence improved from 49% to 95% after AI implementation. CONCLUSIONSUse of a nonmydriatic fundus camera with autonomous AI was safe and effective for the diabetic eye exam in youth in our study. Adherence to screening guidelines improved with AI implementation. As the prevalence of diabetes increases in youth and adherence to screening guidelines remains suboptimal, effective strategies for diabetic eye exams in this population are needed.Diabetes is a significant public health problem worldwide, and in the U.S., it affects almost 30 million people (1). In youth, diabetes is one of the most common chronic childhood diseases, with an incidence that has been increasing over the past decade for both type 1 diabetes (T1D) and type 2 diabetes (T2D) (2). Children with diabetes are at risk for diabetes-related complications, including diabetic retinopathy (DR), which

C1q/TNF‐related protein 3 (CTRP3) is a secreted hormone that modulates hepatic glucose and lipid metabolism. Its circulating levels are reduced in human and rodent models of obesity, a metabolic state accompanied by chronic low‐grade inflammation. Recent studies have demonstrated an anti‐inflammatory role for recombinant CTRP3 in attenuating LPS‐induced systemic inflammation, and its deficiency markedly exacerbates inflammation in a mouse model of rheumatoid arthritis. We used genetic mouse models to explore the immunomodulatory function of CTRP3 in response to acute (LPS challenge) and chronic (high‐fat diet) inflammatory stimuli. In a sublethal dose of LPS challenge, neither CTRP3 deficiency nor its overexpression in transgenic mice had an impact on IL‐1β, IL‐6, TNF‐α, or MIP‐2 induction at the serum protein or mRNA levels, contrary to previous findings based on recombinant CTRP3 administration. In a metabolic context, we measured 71 serum cytokine levels in wild‐type and CTRP3 transgenic mice fed a high‐fat diet or a matched control low‐fat diet. On a low‐fat diet, CTRP3 transgenic mice had elevated circulating levels of multiple chemokines (CCL11, CXCL9, CXCL10, CCL17, CX3CL1, CCL22 and sCD30). However, when obesity was induced with a high‐fat diet, CTRP3 transgenic mice had lower circulating levels of IL‐5, TNF‐α, sVEGF2, and sVEGFR3, and a higher level of soluble gp130. Contingent upon the metabolic state, CTRP3 overexpression altered chemokine levels in lean mice, and attenuated systemic inflammation in the setting of obesity and insulin resistance. These results highlight a context‐dependent immunomodulatory role for CTRP3.