C1q/TNF‐related proteins (CTRP1‐15) constitute a conserved group of secreted proteins of the C1q family with diverse functions. In vitro studies have shown that CTRP11/C1QL4 can inhibit adipogenesis, antagonize myoblast fusion, and promote testosterone synthesis and secretion. Whether CTRP11 is required for these processes in vivo remains unknown. Here, we show that knockout (KO) mice lacking CTRP11 have normal skeletal muscle mass and function, and testosterone level, suggesting that CTRP11 is dispensable for skeletal muscle development and testosterone production. We focused our analysis on whether this nutrient‐responsive secreted protein plays a role in controlling sugar and fat metabolism. At baseline when mice are fed a standard chow, CTRP11 deficiency affects metabolic parameters in a sexually dimorphic manner. Only Ctrp11‐KO female mice have significantly higher fasting serum ketones and reduced physical activity. In the refeeding phase following food withdrawal, Ctrp11‐KO female mice have reduced food intake and increased metabolic rate and energy expenditure, highlighting CTRP11’s role in fasting–refeeding response. When challenged with a high‐fat diet to induce obesity and metabolic dysfunction, CTRP11 deficiency modestly exacerbates obesity‐induced glucose intolerance, with more pronounced effects seen in Ctrp11‐KO male mice. Switching to a low‐fat diet after obesity induction results in greater fat loss in wild type relative to KO male mice, suggesting impaired response to obesity reversal and reduced metabolic flexibility in the absence of CTRP11. Collectively, our data provide genetic evidence for novel sex‐dependent metabolic regulation by CTRP11, but note the overall modest contribution of CTRP11 to systemic energy homeostasis.

Introduction: Pediatric obesity and diabetes has increased over the last several decades. While the role of common adipokines on metabolic parameters has been well studied in adults, the relationship of novel adipokines and hepatokines in pediatric type 1 and type 2 diabetes is not well understood. This study assessed novel adipokines C1q/TNF-related proteins (CTRP1 and CTRP9), and hepatokine fibroblast growth factor 21 (FGF21) in youth with type 1 (T1D) and type 2 (T2D) diabetes. Methods: Participants (n=80) with T1D(n=40) enrolled in the Pediatric Diabetes Consortium (PDC) T1D NeOn registry, and T2D(n=40) from the PDC T2D registry. Cross-sectional analysis compared adipokines (CTRP1, CTRP9, FGF21) between T1D and T2D, and regression models assessed adipokine relationship with clinical characteristics. Results: The mean age was 14.9 ± 2 years, 50% were female. T2D participants had a shorter diabetes duration (p=0.0009), higher weight(p<0.0001) and BMI(p<0.0001) than T1D participants. CTRP9 levels were higher in T1D (13903.6 vs. 3608.5pg/mL, p=0.03) than T2D, FGF21 levels were higher in T2D (70.6 vs. 113.1 pg/mL) than T1D, with no differences in CTRP1. In regression analysis of T1D, CTRP9 was positively associated with C-peptide(p=0.006), and FGF21 was positively associated with hemoglobin A1c(p=0.04). In T2D, CTRP1 was positively associated with HbA1c(p<0.001) and glucose(p=0.004), even after controlling for age, sex, and BMI. Conclusions: CTRP9 levels are higher in youth with T1D compared to T2D, and FGF21 levels are higher in youth with T2D than T1D. Novel adipokines are related to metabolic homeostasis in the inflammatory milieu of pediatric diabetes.

IntroductionThe COVID-19 pandemic has disproportionately affected minority and lower socioeconomic populations, who also have higher rates of type 2 diabetes (T2D). The impact of virtual school, decreased activity level, and worsening food insecurity on pediatric T2D is unknown. The goal of this study was to evaluate weight trends and glycemic control in youth with existing T2D during the COVID-19 pandemic.MethodsA retrospective study of youth &lt;21 years of age diagnosed with T2D prior to March 11, 2020 was conducted at an academic pediatric diabetes center to compare glycemic control, weight, and BMI in the year prior to the COVID-19 pandemic (March 2019-2020) to during COVID-19 (March 2020-2021). Paired t-tests and linear mixed effects models were used to analyze changes during this period.ResultsA total of 63 youth with T2D were included (median age 15.0 (IQR 14-16) years, 59% female, 74.6% black, 14.3% Hispanic, 77.8% with Medicaid insurance). Median duration of diabetes was 0.8 (IQR 0.2-2.0) years. There was no difference in weight or BMI from the pre-COVID-19 period compared to during COVID-19 (Weight: 101.5 v 102.9 kg, p=0.18; BMI: 36.0 v 36.1 kg/m2, p=0.72). Hemoglobin A1c significantly increased during COVID-19 (7.6% vs 8.6%, p=0.0002)ConclusionWhile hemoglobin A1c increased significantly in youth with T2D during the COVID-19 pandemic, there was no significant change in weight or BMI possibly due to glucosuria associated with hyperglycemia. Youth with T2D are at high risk for diabetes complications, and the worsening glycemic control in this population highlights the need to prioritize close follow-up and disease management to prevent further metabolic decompensation.