3-Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγSer273 phosphorylation in type 2 diabetic mice

3-Hydroxybutyrate(3HB)is a small ketone body molecule produced endogenously by the body in the liver.Previous studies have shown that 3HB can reduce blood glucose level in type 2 diabetic(T2D)patients.However,there is no systematic study and clear mechanism to evaluate and explain the hypoglycemic effect of 3HB.Here we demonstrate that 3HB reduces fasting blood glucose level,improves glucose tolerance,and ameliorates insulin resistance in type 2 diabetic mice through hydroxycarboxylic acid receptor 2(HCAR2).Mechanistically,3HB increases intracellular calcium ion(Ca^(2+))levels by activating HCAR2,thereby stimulating adenylate cyclase(AC)to increase cyclic adenosine monophosphate(cAMP)concentration,and then activating protein kinase A(PKA).Activated PKA inhibits Raf1 proto-oncogene serine/threonine-protein kinase(Raf1)activity,resulting in a decrease in extracellular signal-regulated kinases 1/2(ERK1/2)activity and ultimately inhibiting peroxisome proliferator-activated receptorγ(PPARγ)Ser273 phosphorylation in adipocytes.Inhibition of PPARγSer273 phosphorylation by 3HB altered the expression of PPARγregulated genes and reduced insulin resistance.Collectively,3HB ameliorates insulin resistance in type 2 diabetic mice through a pathway of HCAR2/Ca^(2+)/cAMP/PKA/Raf1/ERK1/2/PPARγ.

Development and validation of an individualized nomogram for early prediction of the duration of SARS-CoV-2 shedding in COVID-19 patients with non-severe disease

With the number of cases of coronavirus disease-2019(COVID-19)increasing rapidly,the World Health Organization(WHO)has recommended that patients with mild or moderate symptoms could be released from quarantine without nucleic acid retesting,and self-isolate in the community.This may pose a potential virus transmission risk.We aimed to develop a nomogram to predict the duration of viral shedding for individual COVID-19 patients.This retrospective multicentric study enrolled 135 patients as a training cohort and 102 patients as a validation cohort.Significant factors associated with the duration of viral shedding were identified by multivariate Cox modeling in the training cohort and combined to develop a nomogram to predict the probability of viral shedding at 9,13,17,and 21 d after admission.The nomogram was validated in the validation cohort and evaluated by concordance index(C-index),area under the curve(AUC),and calibration curve.A higher absolute lymphocyte count(P=0.001)and lymphocyte-to-monocyte ratio(P=0.013)were correlated with a shorter duration of viral shedding,while a longer activated partial thromboplastin time(P=0.007)prolonged the viral shedding duration.The C-indices of the nomogram were 0.732(95%confidence interval(CI):0.685-0.777)in the training cohort and 0.703(95%CI:0.642-0.764)in the validation cohort.The AUC showed a good discriminative ability(training cohort:0.879,0.762,0.738,and 0.715 for 9,13,17,and 21 d;validation cohort:0.855,0.758,0.728,and 0.706 for 9,13,17,and 21 d),and calibration curves were consistent between outcomes and predictions in both cohorts.A predictive nomogram for viral shedding duration based on three easily accessible factors was developed to help estimate appropriate self-isolation time for patients with mild or moderate symptoms,and to control virus transmission.