No abstract

Pathogenic factors driving obesity to type 2 diabetes (T2D) are not fully understood. Group 1 innate lymphoid cells (ILC1s) are effectors of innate immunity and enriched in inflamed tissues. Here we show that the number of adipose ILC1s increases in obese T2D patients and correlates with glycemic parameters and with the number of ILC1s in the blood; circulating ILC1 numbers decrease as a result of metabolic improvements after bariatric surgery. In vitro co-culture experiments show that human adipose ILC1s promote adipose fibrogenesis and CD11c + macrophage activation. Reconstruction of the adipose ILC1 population in Prkdc −/− IL2rg −/− mice by adoptive transfer drives adipose fibrogenesis through activation of TGFβ1 signaling; however, transfer of Ifng −/− ILC1s has no effect on adipose fibrogenesis. Furthermore, inhibiting adipose accumulation of ILC1s using IL-12 neutralizing antibodies attenuates adipose tissue fibrosis and improves glycemic tolerance. Our data present insights into the mechanisms of local immune disturbances in obesity-related T2D.

Podocyte injury and the appearance of proteinuria are features of minimal-change disease (MCD). Cyclosporin A (CsA) and tacrolimus (FK506) has been reported to reduce proteinuria in patients with nephrotic syndrome, but mechanisms remain unknown. We, therefore, investigated the protective mechanisms of CsA and FK506 on proteinuria in a rat model of MCD induced by puromycin aminonucleoside (PAN) and in vitro cultured mouse podocytes. Our results showed that CsA and FK506 treatment decreased proteinuria via a mechanism associated to a reduction in the foot-process fusion and desmin, and a recovery of synaptopodin and podocin. In PAN-treated mouse podocytes, pre-incubation with CsA and FK506 restored the distribution of the actin cytoskeleton, increased the expression of synaptopodin and podocin, improved podocyte viability, and reduced the migrating activities of podocytes. Treatment with CsA and FK506 also inhibited PAN-induced podocytes apoptosis, which was associated with the induction of Bcl-xL and inhibition of Bax, cleaved caspase 3, and cleaved PARP expression. Further studies revealed that CsA and FK506 inhibited PAN-induced p38 and JNK signaling, thereby protecting podocytes from PAN-induced injury. In conclusion, CsA and FK506 inhibit proteinuria by protecting against PAN-induced podocyte injury, which may be associated with inhibition of the MAPK signaling pathway.

Abstract. Xu W, Bi Y, Sun Z, Li J, Guo L, Yang T, Wu G, Shi L, Feng Z, Qiu L, Li Q, Guo X, Luo Z, Lu J, Shan Z, Yang W, Ji Q, Yan L, Li H, Yu X, Li S, Zhou Z, Lv X, Liang Z, Lin S, Zeng L, Yan J, Ji L, Weng J (The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou; Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing; Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, Nanjing; Objective. Progressive b-cell dysfunction hinders the maintenance of glycaemic control in type 2 diabetes, but comparative data on b-cell-protective therapies are lacking in the early stage of type 2 diabetes. Here we evaluated the comparative glycaemic efficacy and impact on b-cell function of three antihyperglycaemic agents that have a b-cell-protective effect, exenatide, insulin and pioglitazone, in newly diagnosed patients with type 2 diabetes.Design and methods. In this 48-week, multicentre, parallel-group study, 416 patients newly diagnosed with type 2 diabetes were randomly assigned 1 : 1 : 1 to receive exenatide, insulin or pioglitazone. The primary end-point was the change in glycosylated haemoglobin (HbA1c) from baseline. Secondary end-points included effects on weight, blood pressure, lipid profiles and b-cell function assessed by homeostasis model assessment, fasting proinsulin:insulin (PI/I), disposition index (DI) and acute insulin response (AIR).Results. At week 48, mean [95% confidence interval (CI)] HbA 1c changes from baseline were À1.8% (À1.55% to À2.05%) with exenatide, À1.7% (À1.52% to À1.96%) with insulin and À1.5% (À1.23% to À1.71%) with pioglitazone. Treatment differences were À0.20% (95% CI À0.46% to 0.06%) for exenatide versus insulin (P = 0.185), and À0.37% (95% CI À0.63% to À0.12%) for exenatide versus pioglitazone (P = 0.002). Significant improvements from baseline in AIR, PI/I and DI were observed with all treatments, with the greatest improvements in DI, as well as weight, blood pressure and lipid profile, observed with exenatide.Conclusions. All three agents showed efficacy regarding glycaemic control and metabolic benefits; however, exenatide showed the greatest efficacy. b-cell function improved in all treatment groups; hence, early initiation of b-cell-protective therapy may halt the decline in b-cell function in type 2 diabetes.