Real-world use of glucagon-like peptide-1 receptor agonists in youth with type 2 diabetes is associated with short-term improvements in HbA1c.

AIM: To assess the short-term, real-world use and effectiveness of glucagon-like peptide-1 receptor agonist (GLP-1RA) medications in the management of type 2 diabetes (T2D) in a diverse cohort of youth. METHODS: This multicentre retrospective study analysed youth prescribed a GLP-1RA for the management of T2D at two academic paediatric diabetes centres prior to June 2022. Change in HbA1c and insulin use from baseline to first (median 91 days) and second (median 190 days) follow-up were evaluated for those taking a GLP-1RA. Multivariable linear mixed effects models adjusting for baseline sex, age, race/ethnicity, insurance, insulin regimen, metformin regimen, GLP-1RA dosing frequency and the body mass index Z-score (BMI-Z) examined the change in HbA1c for participants for up to 6 months after baseline. RESULTS: A total of 136 patients with T2D (median age 16.1 [interquartile range 13.9-18.0] years, 54% female, 56% non-Hispanic Black, 24% Hispanic, 77% with public insurance) were prescribed GLP-1RAs and taking them at first or second follow-up. Median HbA1c decreased from 7.9% to 7.6% (P < .001) at a median follow-up of 91 days (n = 109) and, among those with HbA1c available at baseline and second follow-up (n = 83), from 8.4% to 7.4%. The proportion of patients prescribed insulin decreased from baseline to the first follow-up visit (basal 69% to 60% [P = .008], prandial 46% to 38% [P = .03]). In multivariable analysis, there was a mean decrease in HbA1c by 0.09 percentage points per month (P = .005, 95% confidence interval -0.15, -0.03). CONCLUSIONS: Real-world use of GLP-1RAs in youth with T2D is associated with decreased HbA1c levels, despite challenges with access and adherence. GLP-1RA treatment may reduce insulin doses for youth with T2D.

The P300 acetyltransferase inhibitor C646 promotes membrane translocation of insulin receptor protein substrate and interaction with the insulin receptor.

Inhibition of P300 acetyltransferase activity by specific inhibitor C646 has been shown to improve insulin signaling. However, the underlying molecular mechanism of this improvement remains unclear. In this study, we analyzed P300 levels of obese patients and found that they were significantly increased in liver hepatocytes. In addition, large amounts of P300 appeared in the cytoplasm. Inhibition of P300 acetyltransferase activity by C646 drastically increased tyrosine phosphorylation of the insulin receptor protein substrates (IRS1/2) without affecting the tyrosine phosphorylation of the beta subunit of the insulin receptor (IRß) in hepatocytes in the absence of insulin. Since IRS1/2 requires membrane translocation and binding to inositol compounds for normal functions, we also examined the role of acetylation on binding to phosphatidylinositol(4,5)P2 and found that IRS1/2 acetylation by P300 reduced this binding. In contrast, we show that inhibition of IRS1/2 acetylation by C646 facilitates IRS1/2 membrane translocation. Intriguingly, we demonstrate that C646 activates IRß's tyrosine kinase activity and directly promotes IRß interaction with IRS1/2, leading to the tyrosine phosphorylation of IRS1/2 and subsequent activation of insulin signaling even in the absence of insulin. In conclusion, these data reveal the unique effects of C646 in activating insulin signaling in patients with obesity and diabetes.

Psychosocial Impact of the COVID-19 Pandemic in Racially/Ethnically Diverse Youth With Diabetes.

OBJECTIVE: This study examined caregiver perceived impact of the Coronavirus Disease 2019 (COVID-19) pandemic on a diverse sample of U.S. youth with diabetes and their families. METHODS: Caregivers of youth with diabetes completed an electronic survey in English or Spanish at two sites. Participants provided demographic and disease characteristics and completed the COVID-19 Exposure and Family Impact Scales (CEFIS). Glycemic health was assessed via Hemoglobin A1c (HbA1c) from medical chart review. Analysis of variance and analyses of covariance were utilized to examine racial/ethnic differences in glycemic health and in COVID-19 Exposure, Impact, and Distress scales. Hierarchical linear regression was conducted to predict HbA1c. Thematic analysis was conducted on open-ended responses regarding the effects of COVID-19 on youth and families' overall and diabetes-related well-being. RESULTS: Caregivers (n = 114) of youth with diabetes (M = 12.6 ± 3.5 years) completed study measures. Mean HbA1c for Non-Hispanic White youth was lowest and significantly different from Hispanic and Non-Hispanic Black youth. Exposure to COVID-19 stressors differed by race/ethnicity (p < .05) with Hispanic caregivers reporting greatest exposure. CEFIS scales did not predict HbA1c after controlling for demographic/disease variables. Caregivers described child/family changes during COVID (e.g., more time together, health-related hypervigilance), as well as differences in diabetes management during COVID-19. CONCLUSIONS: Findings indicate differences in COVID-19 exposure but did not demonstrate other racial/ethnic disparities in COVID-19 impact or distress. Household income was the most important predictor of glycemic health. Addressing structural inequalities experienced by youth with diabetes and their families is critical. Recommendations to support families with diabetes are made.

Perioperative maintenance of hybrid closed loop insulin pump systems in youth with type 1 diabetes mellitus: A case series.

Current guidelines support the use of continuous glucose monitoring devices and insulin pumps in minor surgical procedures for pediatric patients with type 1 diabetes mellitus. However, there are few reported cases of using hybrid closed loop technology in the perioperative period. This retrospective case series presents seven pediatric patients with type 1 diabetes who underwent eight surgical procedures with maintenance of hybrid closed loop systems. This paper also provides considerations for future use of hybrid closed loop systems perioperatively.

A Brief Nutrition Questionnaire for Children With Newly Diagnosed Type 1 Diabetes.

Carbohydrate counting is an important component of type 1 diabetes management that is taught at the time of diagnosis. We implemented and validated a nutrition quiz to assess fundamental carbohydrate counting and nutrition knowledge in newly diagnosed patients. An interactive standard assessment for newly diagnosed type 1 diabetes patients was feasible and reliable to implement for patients and caregivers, but participants with public insurance scored lower overall. This assessment may help to identify nutrition knowledge gaps and provide opportunities for timely education, and providers should place additional focus on nutrition education for patients with public insurance.

Brief Pictorial Quizzes to Assess Carbohydrate Counting and Nutrition Knowledge in Youth With Type 1 Diabetes.

Available assessments of patient nutrition knowledge and carbohydrate counting ability are lengthy. This article reports on a study to implement and validate a series of brief nutrition quizzes of varying difficulty for use in pediatric type 1 diabetes. Among 129 youth with type 1 diabetes, participants completed an average of 2.4 ± 1 of the six quizzes, with a median score of 4.7 of 5. Higher quiz scores were associated with lower A1C (P <0.001), higher parental education (P = 0.02), and higher income (P = 0.01). Such quizzes can help to identify knowledge gaps and provide opportunities for education, which may improve glycemic outcomes in youth with type 1 diabetes.

The Coronavirus Disease 2019 Pandemic is Associated with a Substantial Rise in Frequency and Severity of Presentation of Youth-Onset Type 2 Diabetes.

OBJECTIVES: To evaluate the frequency and severity of new cases of youth-onset type 2 diabetes in the US during the first year of the pandemic compared with the mean of the previous 2 years. STUDY DESIGN: Multicenter (n = 24 centers), hospital-based, retrospective chart review. Youth aged ≤21 years with newly diagnosed type 2 diabetes between March 2018 and February 2021, body mass index ≥85th percentile, and negative pancreatic autoantibodies were included. Demographic and clinical data, including case numbers and frequency of metabolic decompensation, were compared between groups. RESULTS: A total of 3113 youth (mean [SD] 14.4 [2.4] years, 50.5% female, 40.4% Hispanic, 32.7% Black, 14.5% non-Hispanic White) were assessed. New cases of type 2 diabetes increased by 77.2% in the year during the pandemic (n = 1463) compared with the mean of the previous 2 years, 2019 (n = 886) and 2018 (n = 765). The likelihood of presenting with metabolic decompensation and severe diabetic ketoacidosis also increased significantly during the pandemic. CONCLUSIONS: The burden of newly diagnosed youth-onset type 2 diabetes increased significantly during the coronavirus disease 2019 pandemic, resulting in enormous strain on pediatric diabetes health care providers, patients, and families. Whether the increase was caused by coronavirus disease 2019 infection, or just associated with environmental changes and stressors during the pandemic is unclear. Further studies are needed to determine whether this rise is limited to the US and whether it will persist over time.

Foundational Considerations for Artificial Intelligence Using Ophthalmic Images.

IMPORTANCE: The development of artificial intelligence (AI) and other machine diagnostic systems, also known as software as a medical device, and its recent introduction into clinical practice requires a deeply rooted foundation in bioethics for consideration by regulatory agencies and other stakeholders around the globe. OBJECTIVES: To initiate a dialogue on the issues to consider when developing a bioethically sound foundation for AI in medicine, based on images of eye structures, for discussion with all stakeholders. EVIDENCE REVIEW: The scope of the issues and summaries of the discussions under consideration by the Foundational Principles of Ophthalmic Imaging and Algorithmic Interpretation Working Group, as first presented during the Collaborative Community on Ophthalmic Imaging inaugural meeting on September 7, 2020, and afterward in the working group. FINDINGS: Artificial intelligence has the potential to improve health care access and patient outcome fundamentally while decreasing disparities, lowering cost, and enhancing the care team. Nevertheless, substantial concerns exist. Bioethicists, AI algorithm experts, as well as the Food and Drug Administration and other regulatory agencies, industry, patient advocacy groups, clinicians and their professional societies, other provider groups, and payors (i.e., stakeholders) working together in collaborative communities to resolve the fundamental ethical issues of nonmaleficence, autonomy, and equity are essential to attain this potential. Resolution impacts all levels of the design, validation, and implementation of AI in medicine. Design, validation, and implementation of AI warrant meticulous attention. CONCLUSIONS AND RELEVANCE: The development of a bioethically sound foundation may be possible if it is based in the fundamental ethical principles of nonmaleficence, autonomy, and equity for considerations for the design, validation, and implementation for AI systems. Achieving such a foundation will be helpful for continuing successful introduction into medicine before consideration by regulatory agencies. Important improvements in accessibility and quality of health care, decrease in health disparities, and lower cost thereby can be achieved. These considerations should be discussed with all stakeholders and expanded on as a useful initiation of this dialogue.

Youth with type 2 diabetes have a high rate of treatment failure after discontinuation of insulin: A Pediatric Diabetes Consortium study.

Insulin is commonly used to reverse gluco-toxicity in youth with newly diagnosed type 2 diabetes (T2D), but many are subsequently weaned off insulin. We analyzed Pediatric Diabetes Consortium (PDC) data to determine how long glycemic control is maintained after termination of initial insulin treatment. Youth with T2D who had previously been on insulin but were on either an intensive lifestyle intervention alone or metformin alone upon enrollment in the PDC T2D Registry were studied (N = 183). The primary outcome was time to treatment failure, defined by need to restart insulin or metformin or another diabetes medication. Data were analyzed using logistic regression to assess risk factors for treatment failure. Of the 183 participants studied (mean age 15 years, diabetes duration 1.7 years), 54% experienced treatment failure (median follow-up time 1.7 years). In the subgroup on metformin monotherapy (N = 140), 45% subsequently required restart of insulin. Moreover, of participants in the subgroup treated with an intensive lifestyle intervention alone (N = 43), 81% restarted insulin or were treated with metformin or other diabetes medication. In both groups, median time to treatment failure was 1.2 years. Higher HbA1c at enrollment was significantly associated with treatment failure (p < 0.001). Youth with T2D who are initially treated with insulin have a high rate of treatment failure when switched to intensive lifestyle alone or metformin alone. Our data highlight the severe and progressive nature of youth onset T2D, hence patients should be monitored closely for deteriorating glycemic control after being weaned off insulin.

Increase in newly diagnosed type 1 diabetes in youth during the COVID-19 pandemic in the United States: A multi-center analysis.

BACKGROUND: An increase in newly diagnosed type 1 diabetes (T1D) has been posited during the COVID-19 pandemic, but data are conflicting. We aimed to determine trends in newly diagnosed T1D and severity of presentation at diagnosis for pediatric and adolescent patients during COVID-19 (2020) as compared to the previous year (2019) in a multi-center analysis across the United States. METHODS: This retrospective study from seven centers in the T1D Exchange Quality Improvement Collaborative (T1DX-QI) included data on new onset T1D diagnosis and proportion in DKA at diagnosis from January 1 to December 31, 2020, compared to the prior year. Chi-square tests were used to compare differences in patient characteristics during the pandemic period compared to the prior year. RESULTS: Across seven sites, there were 1399 newly diagnosed T1D patients in 2020, compared to 1277 in 2019 (p = 0.007). A greater proportion of newly diagnosed patients presented in DKA in 2020 compared to 2019 (599/1399(42.8%) vs. 493/1277(38.6%), p = 0.02), with a higher proportion presenting with severe DKA (p = 0.01) as characterized by a pH <7.1 and/or bicarbonate of <5 mmol/L. Monthly data trends demonstrated a higher number of new T1D diagnoses over the spring and summer months (March to September) of 2020 compared to 2019 (p < 0.001). CONCLUSIONS: We found an increase in newly diagnosed T1D and a greater proportion presenting in DKA at diagnosis during the COVID-19 pandemic compared to the prior year. Future longitudinal studies are needed to confirm these findings with population level data and determine the long-term impact of COVID-19 on diabetes trends.

Altered adipokines in obese adolescents: a cross-sectional and longitudinal analysis across the spectrum of glycemia.

Obesity and type 2 diabetes are rapidly increasing in the adolescent population. We sought to determine whether adipokines, specifically leptin, C1q/TNF-related proteins 1 (CTRP1) and CTRP9, and the hepatokine fibroblast growth factor 21 (FGF21), are associated with obesity and hyperglycemia in a cohort of lean and obese adolescents, across the spectrum of glycemia. In an observational, longitudinal study of lean and obese adolescents, we measured fasting laboratory tests, oral glucose tolerance tests, and adipokines including leptin, CTRP1, CTRP9, and FGF21. Participants completed baseline and 2-year follow-up study visits and were categorized as lean (LC, lean control; n = 30), obese normoglycemic (ONG; n = 61), and obese hyperglycemic (OHG; n = 31) adolescents at baseline and lean (n = 8), ONG (n = 18), and OHG (n = 4) at follow-up. Groups were compared using ANOVA and regression analysis, and linear mixed effects modeling was used to test for differences in adipokine levels across baseline and follow-up visits. Results showed that at baseline, leptin was higher in all obese groups (P < 0.001) compared with LC. FGF21 was higher in OHG participants compared with LC (P < 0.001) and ONG (P < 0.001) and positively associated with fasting glucose (P < 0.001), fasting insulin (P < 0.001), Homeostasis Model Assessment-Insulin Resistance Index (HOMA-IR; P < 0.001), and hemoglobin A1c (HbA1c; P = 0.01). CTRP1 was higher in OHG compared with ONG (P = 0.03). CTRP9 was not associated with obesity or hyperglycemia in this pediatric cohort. At 2 years, leptin decreased in ONG (P = 0.003) and FGF21 increased in OHG (P = 0.02), relative to lean controls. Altered adipokine levels are associated with the inflammatory milieu in obese youth with and without hyperglycemia. In adolescence, the novel adipokine CTRP1 was elevated with hyperglycemia, whereas CTRP9 was unchanged in this cohort.NEW & NOTEWORTHY Leptin is higher in obese adolescents and FGF21 is higher in obese hyperglycemic adolescents. The novel adipokine CTRP1 is higher in obese hyperglycemic adolescents, whereas CTRP9 was unchanged in this adolescent cohort.

Pediatric Diabetic Retinopathy: Updates in Prevalence, Risk Factors, Screening, and Management.

PURPOSE OF REVIEW: Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus and a major cause of vision loss worldwide. The purpose of this review is to provide an update on the prevalence of diabetic retinopathy in youth, discuss risk factors, and review recent advances in diabetic retinopathy screening. RECENT FINDINGS: While DR has long been considered a microvascular complication, recent data suggests that retinal neurodegeneration may precede the vascular changes associated with DR. The prevalence of DR has decreased in type 1 diabetes (T1D) patients following the results of the Diabetes Control and Complications Trial and implementation of intensive insulin therapy, with prevalence ranging from 14-20% before the year 2000 to 3.7-6% after 2000. In contrast, the prevalence of diabetic retinopathy in pediatric type 2 diabetes (T2D) is higher, ranging from 9.1-50%. Risk factors for diabetic retinopathy are well established and include glycemic control, diabetes duration, hypertension, and hyperlipidemia, whereas diabetes technology use including insulin pumps and continuous glucose monitors has been shown to have protective effects. Screening for DR is recommended for youth with T1D once they are aged ≥ 11 years or puberty has started and diabetes duration of 3-5 years. Pediatric T2D patients are advised to undergo screening at or soon after diagnosis, and annually thereafter, due to the insidious nature of T2D. Recent advances in DR screening methods including point of care and artificial intelligence technology have increased access to DR screening, while being cost-saving to patients and cost-effective to healthcare systems. While the prevalence of diabetic retinopathy in youth with T1D has been declining over the last few decades, there has been a significant increase in the prevalence of DR in youth with T2D. Improving access to diabetic retinopathy screening using novel screening methods may help improve detection and early treatment of diabetic retinopathy.

Diabetes and cardiometabolic risk in South Asian youth: A review.

South Asians are at increased risk for developing type 2 diabetes and cardiovascular disease at lower body mass index compared to other ancestral groups. Many factors contribute to this increased risk, including genetics, maternal-fetal factors, diet, fitness, body composition, and unique pathophysiology. Increased cardiometabolic risk is also seen at younger ages in South Asian individuals as compared to their White counterparts. This risk persists in migrant communities outside of South Asia. With the growing prevalence of obesity, diabetes, and cardiovascular disease in the South Asian population, it is imperative that we had better understand the mechanisms underlying this increased risk and implement strategies to address this growing public health problem during childhood and adolescence.

Prevalence of diabetic retinopathy in children and adolescents at an urban tertiary eye care center.

BACKGROUND: Diabetic retinopathy (DR) is a serious complication that can progress to sight-threatening disease. The prevalence of DR in youth with diabetes has been reported to be 3.8% to 20%. OBJECTIVE: We aimed to evaluate the prevalence of DR among youth with diabetes at a large ophthalmologic referral center. Secondary goals were to determine the risk factors for DR and severity of disease. METHODS: Retrospective chart review of 343 patients with diabetes, <21 years of age, seen at a tertiary referral eye care center from 2013 to 2018. RESULTS: The study included 343 patients, of which 293 had type 1 diabetes (T1D) and 50 had type 2 diabetes (T2D). Thirteen of 343 patients had DR, with an overall incidence of 3.8% (3.4% in T1D and 6% T2D). DR severity included nine with mild non-proliferative, three moderate non-proliferative, and one with proliferative DR. Patients with hemoglobin A1c (HbA1c) > 8% had a higher risk of DR (P = .049). In this cohort, none of the patients with an HbA1c <8% had DR. In the multivariate analysis, a higher systolic blood pressure was marginally associated with risk for DR (P = .07). CONCLUSIONS: We found lower prevalence of DR in youth with diabetes than previously reported. The incidence of DR was higher among patients with T2D and occurred with a shorter duration of disease, as compared with T1D. While the incidence of DR in youth with T1D is low, with the increasing incidence of T2D in adolescents and early risk for DR, early screening must be emphasized.

Discrepancies in Assessing Symptoms of Depression in Adolescents With Diabetes Using the Patient Health Questionnaire and Semi-Structured Interviews.

Adolescents with diabetes have a higher prevalence of depression compared with their peers. The American Diabetes Association recommends routine mental health screening for youth with diabetes. This screening is often conducted through accessible and free depression screeners, such as the nine-item Patient Health Questionnaire (PHQ-9). Although the PHQ-9 has been validated for use in adolescents and with other medical conditions, it has yet to be validated for use in pediatric diabetes. This study evaluated adolescents' depression symptom endorsement through retrospective review of PHQ-9 screening and semi-structured interviews with a mental health provider in a multidisciplinary diabetes clinic (patients with type 1 or type 2 diabetes). Adolescent participants (n = 96) screened during one to three separate visits (n = 148) endorsed some depressive symptoms in 56% of visits (n = 84) and moderate to severe symptoms in 6% of visits on the PHQ-9. Approximately 95% of study participants did not meet the clinic cutoff for further evaluation, but greater rates of depression were endorsed in youth with type 1 diabetes. Low mood was endorsed at a higher rate during a semi-structured interview with embedded mental health providers than on the PHQ-9. Symptoms specific to low mood, including anhedonia, sleep disturbance, concentration disturbance, motor disturbance, and thoughts of death/self-harm, were more frequently endorsed on the PHQ-9 than during the interview. Although the PHQ-9 is a good screening tool, the availability of mental health providers in diabetes clinics is important to address specific endorsed symptoms and place them in perspective based on specialized training. Until more definitive research is available on the sensitivity and specificity of this measure in this population and setting, a two-part screening approach that includes both the screening questionnaire and a brief semi-structured interview is warranted.

Use of continuous subcutaneous insulin infusion (CSII) therapy in pediatric diabetes patients in the perioperative period.

Diabetes mellitus is one of the most common endocrinopathies encountered in the perioperative period, and the pediatric population is increasingly using continuous subcutaneous insulin infusions for diabetes management. As these patients present for procedures or surgery requiring anesthesia, the anesthesia provider is charged with the task of managing these pumps perioperatively. Here, we review our experience from a large tertiary care academic medical center and propose recommendations for the perioperative management of children and adolescents with diabetes who use insulin pumps.

CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress.

Chronic low-grade inflammation and cellular stress are important contributors to obesity-linked metabolic dysfunction. Here, we uncover an immune-metabolic role for C1q/TNF-related protein 7 (CTRP7), a secretory protein of the C1q family with previously unknown function. In obese humans, circulating CTRP7 levels were markedly elevated and positively correlated with body mass index, glucose, insulin, insulin resistance index, hemoglobin A1c, and triglyceride levels. Expression of CTRP7 in liver was also significantly upregulated in obese humans and positively correlated with gluconeogenic genes. In mice, Ctrp7 expression was differentially modulated in various tissues by fasting and refeeding and by diet-induced obesity. A genetic loss-of-function mouse model was used to determine the requirement of CTRP7 for metabolic homeostasis. When fed a control low-fat diet, male or female mice lacking CTRP7 were indistinguishable from wild-type littermates. In obese male mice consuming a high-fat diet, however, CTRP7 deficiency attenuated insulin resistance and enhanced glucose tolerance, effects that were independent of body weight, metabolic rate, and physical activity level. Improved glucose metabolism in CTRP7-deficient mice was associated with reduced adipose tissue inflammation, as well as decreased liver fibrosis and cellular oxidative and endoplasmic reticulum stress. These results provide a link between elevated CTRP7 levels and impaired glucose metabolism, frequently associated with obesity. Inhibiting CTRP7 action may confer beneficial metabolic outcomes in the setting of obesity and diabetes.

CTRP3 deficiency reduces liver size and alters IL-6 and TGFß levels in obese mice.

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 TGFß1, 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.