Hepatic Phospholipid Remodeling Modulates Insulin Sensitivity and Systemic Metabolism.

The liver plays a central role in regulating glucose and lipid metabolism. Aberrant insulin action in the liver is a major driver of selective insulin resistance, in which insulin fails to suppress glucose production but continues to activate lipogenesis in the liver, resulting in hyperglycemia and hypertriglyceridemia. The underlying mechanisms of selective insulin resistance are not fully understood. Here It is shown that hepatic membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) regulates insulin signaling and systemic glucose and lipid metabolism. Hyperinsulinemia induced by high-fat diet (HFD) feeding augments hepatic Lpcat3 expression and membrane unsaturation. Loss of Lpcat3 in the liver improves insulin resistance and blunts lipogenesis in both HFD-fed and genetic ob/ob mouse models. Mechanistically, Lpcat3 deficiency directly facilitates insulin receptor endocytosis, signal transduction, and hepatic glucose production suppression and indirectly enhances fibroblast growth factor 21 (FGF21) secretion, energy expenditure, and glucose uptake in adipose tissue. These findings identify hepatic LPCAT3 and membrane phospholipid composition as a novel regulator of insulin sensitivity and provide insights into the pathogenesis of selective insulin resistance.

Trilobatin, a Natural Food Additive, Exerts Anti-Type 2 Diabetes Effect Mediated by Nrf2/ARE and IRS-1/GLUT2 Signaling Pathways.

Oxidative stress and aberrant insulin signaling transduction play vital roles in type 2 diabetes mellitus (T2DM). Our previous research has demonstrated that trilobatin (TLB), derived from the leaves of Lithocarpus Polystachyus (Wall.), exhibits a potent antioxidative profile. In the current study, we investigated the anti-T2DM effect of TLB on KK-Ay diabetic mice and further explored the potential mechanisms. Our results showed that TLB significantly reduced the high fasting blood glucose level and insulin resistance and promoted the tolerances to exogenous glucose and insulin in KK-Ay mice. Moreover, TLB reduced the content of reactive oxygen species; enhanced antioxidant enzymes activities, including serum catalase, glutathione peroxidase, and superoxide dismutase; and regulated the abnormal parameters of lipid metabolism, including triglyceride, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and free fatty acid, as evidenced by enzyme-linked immunosorbent assay. Additionally, TLB markedly ameliorated the pancreatic islet morphology near normal and increased the insulin expression of the islet. Whereafter, TLB promoted Nrf2 that was translocated from cytoplasm to nucleus. Moreover, it increased the protein expressions of HO-1, NQO-1, and GLUT-2, and phosphorylation levels of Akt and GSK-3ß Ser 9 and decreased the protein expressions of keap1 and phosphorylation levels of IRS-1Ser 307 and GSK-3ß Tyr 216. Taken together, our findings reveal that TLB exhibits an anti-T2DM effect in KK-Ay mice by activating the Nrf2/ARE signaling pathway and regulating insulin signaling transduction pathway, and TLB is promising to be developed into a novel candidate for the treatment of T2DM in clinic due to its favorable druggability.

Exercise ameliorates insulin resistance and improves SIRT6-mediated insulin signaling transduction in liver of obese rats.

Physical exercise is essential for the amelioration of insulin resistance (IR). The mechanisms in charge of improved IR, regulated by exercise, are insufficiently studied. Previous research revealed that Sirtuin 6 (SIRT6) - mediated insulin signaling acts a crucial element in hepatic IR. The objective of our research was to determine the effects of exercise on SIRT6-mediated insulin signaling in liver of IR rats. Forty male Sprague Dawley rats were randomly assigned to four groups (n = 10 rats each): control rats fed with standard chow (Lean group); sedentary rats fed with a high-fat diet (HFD-SED); rats fed with HFD and submitted to 8 week chronic swimming exercise training (HFD-CE); and rats fed HFD and submitted to one acute swimming exercise training (HFD-AE). HFD feeding lead to increased body weight, accumulation of hepatic triglyceride and serum free fatty acids, and enhanced gluconeogenesis. Besides, HFD feeding decreased body insulin sensitivity. Hepatic USP10 and SIRT6 protein levels decreased under obese status. Both chronic and acute exercise intervention alleviated physiological and metabolic status, increased hepatic USP10 and SIRT6 levels, improved insulin signaling transduction, and inhibited gluconeogenesis. These results showed that exercise intervention regulated SIRT6-mediated insulin signaling, which contributes to our understanding of the molecular mechanisms behind IR, in that a regular exercise can mitigate the effects of IR.

Bone morphogenetic protein 7 regulates insulin signal transduction in mice / 中华内分泌代谢杂志

Objective To analyze the effects of bone morphogenetic protein 7 (BMP 7) on insulin signaling pathway in mice and its involved molecular mechanisms. Methods To increase BMP7 expression in liver, adenovirus bearing BMP7 was injected into mice via tail vein. The impact of BMP7 overexpression on glucose metabolism was assayed by glucose tolerance test and insulin tolerance test. The levels of proteins involved in insulin signaling pathway and c-Jun N-terminal kinase ( JNK) signaling pathway were analyzed by Western blot. Results The blood glucose level was increased by BMP7 overexpression (P>0. 05), while the glucose tolerance and insulin tolerance were decreased by BMP7. The p-Akt and p-GSK3βin liver and epididymal white adipose tissue (WAT) were reduced in the BMP7-overexpressed mice (P>0. 01), indicating insulin signal transduction was inhibited. In gastrocnemius muscle, the insulin signal transduction was not altered by BMP7. Mechanistically, the JNK pathway was activated by BMP7 in liver and epididymal WAT (P>0. 01), while the JNK pathway in skeletal muscle was not changed. Conclusions In mice, BMP7 elevated blood sugar and decreased glucose and insulin tolerance. BMP7 inhibited the insulin signaling pathway in liver and WAT. These inhibitory effects on insulin signaling pathway was likely to be achieved by an activating JNK signaling pathway.

Polysaccharides from Liriopes Radix ameliorates hyperglycemia via various potential mechanisms in diabetic rats.

BACKGROUND: Liriopes Radix, which is regarded as both drug and healthy diet, is drunk as tea and used in traditional Chinese medicine to treat diabetes. Based on our previous studies, investigated the hypoglycemic effects and explored the mechanisms of total polysaccharides from Liriope spicata var. prolifera (Liriopes Radix) in a diabetic rat model. RESULTS: TLSP reduced hyperglycemia in diabetic rats. The oral glucose tolerance test showed that TLSP could improve the glucose tolerance of diabetic rats. Damage to liver and pancreas tissue was inhibited after treatment with TLSP. Moreover, TLSP increased glycogen content, glucokinase (GK) and glycogen synthetase (GS) activities, and suppressed the elevation of glucose-6-phosphatase (G6Pase) and glycogen phosphorylase (GP) activities in liver. Compared with the diabetic control group, GK and GS mRNA expression were significantly elevated, while G6Pase and GP mRNA expression were decreased in TLSP groups. In addition, TLSP could inhibit glycogen synthase kinase-3ß expression and increase insulin receptor, insulin receptor substrate-1, phosphoinositide 3-kinase, protein kinase B and glucose transport protein-4 expression in liver. CONCLUSION: TLSP showed hypoglycemic function. Improvement of glucose metabolism and insulin-signaling transduction were possible mechanisms.