Browsing by Author "Tersey, Sarah"

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    Persistent elevations in circulating INS DNA among subjects with longstanding type 1 diabetes
    (Wiley, 2018) Neyman, Anna; Nelson, Jennifer; Tersey, Sarah; Mirmira, Raghavendra G.; Evans-Molina, Carmella; Sims, Emily K.; Pediatrics, School of Medicine
    Aim To evaluate whether β cells continue to undergo death in the later stages of type 1 diabetes (T1D). Materials and Methods Fasting banked sera from a cross‐section of 90 participants in the T1D Exchange Registry with longstanding T1D (median duration of 9 years) were analysed. Subjects were determined to be C‐peptide (−) or (+) based on mixed‐meal tolerance testing. Results were compared with 54 adult non‐diabetic controls. Stimulated samples were assayed in a subset of subjects. Levels of unmethylated and methylated preproinsulin (INS) DNA were analysed using digital droplet PCR. Results Fasting and stimulated circulating unmethylated INS DNA levels were increased among both C‐peptide (−) and C‐peptide (+) subjects with longstanding T1D compared with non‐diabetic controls (P < 0.01). Consistent with prior reports, unmethylated INS DNA values correlated with methylated INS DNA values, which were also elevated among T1D subjects (P < 0.001). There was wide variation in the effects of mixed‐meal stimulation on DNA levels, with fasting values in the highest quartiles decreasing with stimulation (P < 0.05). Conclusions These results could reflect ongoing β cell death in individuals with longstanding T1D, even in the absence of detectable C‐peptide production, suggesting that therapies targeting β cell survival could be beneficial among individuals with longstanding T1D.
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    ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice
    (Wiley, 2020-01) Wei, Lei; Surma, Michelle; Yang, Yang; Tersey, Sarah; Shi, Jianjian; Pediatrics, School of Medicine
    The RhoA/ROCK-mediated actin cytoskeleton dynamics have been implicated in adipogenesis. The two ROCK isoforms, ROCK1 and ROCK2, are highly homologous. The contribution of ROCK2 to adipogenesis in vivo has not been elucidated. The present study aimed at the in vivo and in vitro roles of ROCK2 in the regulation of adipogenesis and the development of obesity. We performed molecular, histological and metabolic analyses in ROCK2+/− and ROCK2+/KD mouse models, the latter harboring an allele with a kinase-dead (KD) mutation. Both ROCK2+/− and ROCK2+/KD mouse models showed a lean body mass phenotype during aging, associated with increased amounts of beige cells in subcutaneous white adipose tissue (sWAT) and increased thermogenic gene expression in all fat depots. ROCK2+/− mice on a high-fat diet showed increased energy expenditure accompanying by reduced obesity, and improved insulin sensitivity. In vitro differentiated ROCK2+/− stromal-vascular (SV) cells revealed increased beige adipogenesis associated with increased thermogenic gene expressions. Treatment with a selective ROCK2 inhibitor, KD025, to inhibit ROCK2 activity in differentiated SV cells reproduced the pro-beige phenotype of ROCK2+/− SV cells. In conclusion, ROCK2 activity-mediated actin cytoskeleton dynamics contribute to the inhibition of beige adipogenesis in WAT, and also promotes age-related and diet-induced fat mass gain and insulin resistance.