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Yi Lin and Zhongjie Sun

Conventional therapies for diabetic patients, such as strict glycemic control, do not completely stop the progression of diabetic nephropathy. Serum-free tri-iodothyronine (T3) levels were lower in patients with type II diabetes. The purpose of this study was to test a hypothesis that treatment with T3 would improve diabetic nephropathy in db/db mice, a model of type II diabetes. Male db/db mice (16 weeks) were treated with T3 for 4 weeks. Urinary excretions of albumin and blood glucose levels were measured. Kidneys were collected for histological examination and molecular assays of transforming growth factor-β1 (TGF-β1) expression and phosphatidylinositol 3-kinase (PI3K). T3 attenuated albuminuria in db/db mice, suggesting an improved kidney function. T3 significantly decreased accumulation of collagenous components in cortical interstitium (interstitial fibrosis) and expansion of mesangial matrix in glomeruli (glomerulosclerosis) and prevented the loss of glomeruli in db/db mice. Therefore, T3 improved the renal structural damage seen in diabetic mice. Notably, diabetic nephropathy was accompanied by a significant decrease in PI3K activity and an increase in TGF-β1 expression in kidneys. T3 restored renal PI3K activity, attenuated hyperglycemia, and decreased renal TGF-β1 expression in db/db mice. These effects of T3 were abolished by simultaneous treatment with PI3K inhibitor (LY294002). These data suggest that T3 prevented progressive kidney damage and remodeling in db/db mice by improving insulin signaling (e.g. PI3K activity).

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Yi Lin and Zhongjie Sun

Type 2 diabetes mellitus (T2DM) affects a large population worldwide. T2DM is a complex heterogeneous group of metabolic disorders including hyperglycemia and impaired insulin action and/or insulin secretion. T2DM causes dysfunctions in multiple organs or tissues. Current theories of T2DM include a defect in insulin-mediated glucose uptake in muscle, a dysfunction of the pancreatic β-cells, a disruption of secretory function of adipocytes, and an impaired insulin action in liver. The etiology of human T2DM is multifactorial, with genetic background and physical inactivity as two critical components. The pathogenesis of T2DM is not fully understood. Animal models of T2DM have been proved to be useful to study the pathogenesis of, and to find a new therapy for, the disease. Although different animal models share similar characteristics, each mimics a specific aspect of genetic, endocrine, metabolic, and morphologic changes that occur in human T2DM. The purpose of this review is to provide the recent progress and current theories in T2DM and to summarize animal models for studying the pathogenesis of the disease.

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Jie Wei, Xia Sun, Yajie Chen, Yuanyuan Li, Liqiong Song, Zhao Zhou, Bing Xu, Yi Lin and Shunqing Xu

Bisphenol A (BPA) is one of the environmental endocrine disrupting chemicals, which is present ubiquitously in daily life. Accumulating evidence indicates that exposure to BPA contributes to metabolic syndrome. In this study, we examined whether perinatal exposure to BPA predisposed offspring to fatty liver disease: the hepatic manifestation of metabolic syndrome. Wistar rats were exposed to 50 μg/kg per day BPA or corn oil throughout gestation and lactation by oral gavage. Offspring were fed a standard chow diet (SD) or a high-fat diet (HFD) after weaning. Effects of BPA were assessed by examination of hepatic morphology, biochemical analysis, and the hepatic expression of genes and/or proteins involved in lipogenesis, fatty acid oxidation, gluconeogenesis, insulin signaling, inflammation, and fibrosis. On a SD, the offspring of rats exposed to BPA exhibited moderate hepatic steatosis and altered expression of insulin signaling elements in the liver, but with normal liver function. On a HFD, the offspring of rats exposed to BPA showed a nonalcoholic steatohepatitis-like phenotype, characterized by extensive accumulation of lipids, large lipid droplets, profound ballooning degeneration, impaired liver function, increased inflammation, and even mild fibrosis in the liver. Perinatal exposure to BPA worsened the hepatic damage caused by the HFD in the rat offspring. The additive effects of BPA correlated with higher levels of hepatic oxidative stress. Collectively, exposure to BPA may be a new risk factor for the development of fatty liver disease and further studies should assess whether this finding is also relevant to the human population.

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Andrew W Norris, Katie Larson Ode, Lina Merjaneh, Srinath Sanda, Yaling Yi, Xingshen Sun, John F Engelhardt and Rebecca L Hull

In cystic fibrosis (CF), ductal plugging and acinar loss result in rapid decline of exocrine pancreatic function. This destructive process results in remodeled islets, with only a modest reduction in insulin-producing β cells. However, β-cell function is profoundly impaired, with decreased insulin release and abnormal glucose tolerance being present even in infants with CF. Ultimately, roughly half the CF subjects develop diabetes (termed CF-related diabetes (CFRD)). Importantly, CFRD increases CF morbidity and mortality via worsening catabolism and pulmonary disease. Current accepted treatment options for CFRD are aimed at insulin replacement, thereby improving glycemia as well as preventing nutritional losses and lung decline. CFRD is a unique form of diabetes with a distinct pathophysiology that is as yet incompletely understood. Recent studies highlight emerging areas of interest. First, islet inflammation and lymphocyte infiltration are common even in young children with CF and may contribute to β-cell failure. Second, controversy exists in the literature regarding the presence/importance of β-cell intrinsic functions of CFTR and its direct role in modulating insulin release. Third, loss of the CF transmembrane conductance regulator (CFTR) from pancreatic ductal epithelium, the predominant site of its synthesis, results in paracrine effects that impair insulin release. Finally, the degree of β-cell loss in CFRD does not appear sufficient to explain the deficit in insulin release. Thus, it may be possible to enhance the function of the remaining β-cells using strategies such as targeting islet inflammation or ductal CFTR deficiency to effectively treat or even prevent CFRD.

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Hong Ma, Jin Yuan, Jinyu Ma, Jie Ding, Weiwei Lin, Xinlei Wang, Mingliang Zhang, Yi Sun, Runze Wu, Chun Liu, Cheng Sun and Yunjuan Gu

Bone morphogenetic protein 7 (BMP7), a member of the transforming growth factor-β (TGF-β) family, plays pivotal roles in energy expenditure. However, whether and how BMP7 regulates hepatic insulin sensitivity is still poorly understood. Here, we show that hepatic BMP7 expression is reduced in high-fat diet (HFD)-induced diabetic mice and palmitate (PA)-induced insulin-resistant HepG2 and AML12 cells. BMP7 improves insulin signaling pathway in insulin resistant hepatocytes. On the contrary, knockdown of BMP7 further impairs insulin signal transduction in PA-treated cells. Increased expression of BMP7 by adenovirus expressing BMP7 improves hyperglycemia, insulin sensitivity and insulin signal transduction. Furthermore, BMP7 inhibits mitogen-activated protein kinases (MAPKs) in both the liver of obese mice and PA-treated cells. In addition, inhibition of MAPKs recapitulates the effects of BMP7 on insulin signal transduction in cultured hepatocytes treated with PA. Activation of p38 MAPK abolishes the BMP7-mediated upregulation of insulin signal transduction both in vitro and in vivo. Together, our results show that hepatic BMP7 has a novel function in regulating insulin sensitivity through inhibition of MAPKs, thus providing new insights into treating insulin resistance-related disorders such as type 2 diabetes.

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Kyung-Ah Kim, Sun-O Ka, Woo Sung Moon, Ho-Keun Yi, Young-Hoon Lee, Kang-Beom Kwon, Jin-Woo Park and Byung-Hyun Park

Dermcidin (DCD), an antimicrobial peptide that is secreted by sweat glands, is reportedly a human homolog of mouse proteolysis-inducing factor. This study was conducted to investigate the effect of DCD on body fat mobilization. The expression level of DCD in the livers of Ad-DCD-injected mice was higher than in those of Ad-β-galactosidase (Ad-β-gal)-injected mice 7 days after injection. In addition, injection with the Ad-DCD virus led to decreased body weight and epididymal fat mass when compared with controls. The plasma triglyceride level was decreased, whereas the free fatty acid and glycerol levels were increased in the Ad-DCD-injected group. Epididymal adipose tissues obtained from Ad-DCD-injected mice consisted of smaller adipocytes than tissues obtained from Ad-β-gal-injected mice. The gene expression profiles revealed an upregulation of hormone-sensitive lipase and adipose fatty acid-binding protein, both of which are involved in adipocyte lipolysis, in Ad-DCD-injected mice, and this lipolytic effect of DCD paralleled the increase of circulating tumor necrosis factor-α (TNF-α) level that was observed. The perilipin levels in adipose tissue were decreased in Ad-DCD-injected mice when compared with those of the control mice. Taken together, these results suggest that DCD-mediated body fat reduction might occur as a result of TNF-α-induced downregulation of perilipin in adipose tissue.

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Junhong Chen, Jing Sun, Michelle E Doscas, Jin Ye, Ashley J Williamson, Yanchun Li, Yi Li, Richard A Prinz and Xiulong Xu

p70 S6 kinase (S6K1) is a serine/threonine kinase that phosphorylates the insulin receptor substrate-1 (IRS-1) at serine 1101 and desensitizes insulin receptor signaling. S6K1 hyperactivation due to overnutrition leads to hyperglycemia and type 2 diabetes. Our recent study showed that A77 1726, the active metabolite of the anti-rheumatoid arthritis (RA) drug leflunomide, is an inhibitor of S6K1. Whether leflunomide can control hyperglycemia and sensitize the insulin receptor has not been tested. Here we report that A77 1726 increased AKTS473/T308 and S6K1T389 phosphorylation but decreased S6S235/236 and IRS-1S1101 phosphorylation in 3T3-L1 adipocytes, C2C12 and L6 myotubes. A77 1726 increased insulin receptor tyrosine phosphorylation and binding of the p85 subunit of the PI-3 kinase to IRS-1. A77 1726 enhanced insulin-stimulated glucose uptake in L6 myotubes and 3T3-L1 adipocytes, and enhanced insulin-stimulated glucose transporter type 4 (GLUT4) translocation to the plasma membrane of L6 cells. Finally, we investigated the anti-hyperglycemic effect of leflunomide on ob/ob and high-fat diet (HFD)-induced diabetes mouse models. Leflunomide treatment normalized blood glucose levels and overcame insulin resistance in glucose and insulin tolerance tests in ob/ob and HFD-fed mice but had no effect on mice fed a normal chow diet (NCD). Leflunomide treatment increased AKTS473/T308 phosphorylation in the fat and muscle of ob/ob mice but not in normal mice. Our results suggest that leflunomide sensitizes the insulin receptor by inhibiting S6K1 activity in vitro, and that leflunomide could be potentially useful for treating patients with both RA and diabetes.

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Dae Ryong Cha, Young Sun Kang, Sang Youb Han, Yi Hwa Jee, Kum Hyun Han, Jee Young Han, Young Sik Kim and Nan Hee Kim

Vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of diabetic nephropathy. We investigated serial changes of VEGF in the kidney and assessed whether glomerular and urinary VEGF levels are related to the severity of diabetic nephropathy. Furthermore, we examined the relationship between urinary VEGF levels and the urinary albumin excretion (UAE) rate in Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats. Glomerular VEGF mRNA expression and protein synthesis were evaluated by the reverse transcription-polymerase chain reaction, immunohistochemical staining and in situ hybridization. Urinary levels of VEGF were determined by enzyme-linked immunosorbent assay. UAE was significantly higher in OLETF rats than in control Long-Evans-Tokushima-Fatty (LETO) rats throughout the study period. Urinary VEGF levels were significantly higher from 25 to 37 weeks, and then gradually reduced until 55 weeks, although the levels were still higher than those in control rats. Urinary VEGF levels also showed a significant positive correlation with UAE (r=0.262, P=0.045) and serum creatinine (r=0.398, P=0.044), and were found to be independently correlated with UAE by Spearman’s rank correlation. By immunohistochemical staining and in situ hybridization, VEGF was mainly detected in the podocytes in the glomeruli. Interestingly, a significant increase in VEGF mRNA expression was observed in the early period of diabetic nephropathy, and this was associated with increased urinary VEGF excretion. Thus, the overproduction of VEGF in the diabetic kidney may participate in the pathogenesis of early-stage diabetic nephropathy.

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Hong-Hui Wang, Qian Cui, Teng Zhang, Lei Guo, Ming-Zhe Dong, Yi Hou, Zhen-Bo Wang, Wei Shen, Jun-Yu Ma and Qing-Yuan Sun

As a fat storage organ, adipose tissue is distributed widely all over the body and is important for energy supply, body temperature maintenance, organ protection, immune regulation and so on. In humans, both underweight and overweight women find it hard to become pregnant, which suggests that appropriate fat storage can guarantee the female reproductive capacity. In fact, a large mass of adipose tissue distributes around the reproductive system both in the male and female. However, the functions of ovary fat pad (the nearest adipose tissue to ovary) are not known. In our study, we found that the ovary fat pad-removed female mice showed decreased fertility and less ovulated mature eggs. We further identified that only a small proportion of follicles developed to antral follicle, and many follicles were blocked at the secondary follicle stage. The overall secretion levels of estrogen and FSH were lower in the whole estrus cycle (especially at proestrus); however, the LH level was higher in ovary fat pad-removed mice than that in control groups. Moreover, the estrus cycle of ovary fat pad-removed mice showed significant disorder. Besides, the expression of FSH receptor decreased, but the LH receptor increased in ovary fat pad-removed mice. These results suggest that ovary fat pad is important for mouse reproduction.

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Qiongge Zhang, Chaoqun Wang, Yehua Tang, Qiangqiang Zhu, Yongcheng Li, Haiyan Chen, Yi Bao, Song Xue, Liangliang Sun, Wei Tang, Xiangfang Chen, Yongquan Shi, Lefeng Qu, Bin Lu and Jiaoyang Zheng

Hyperglycemia plays a major role in the development of diabetic macrovascular complications, including atherosclerosis and restenosis, which are responsible for the most of disability and mortality in diabetic patients. Osteopontin (OPN) is an important factor involved in atherogenesis, and hyperglycemia enhances the transcriptional activity of FoxO1 which is closely association with insulin resistance and diabetes. Here, we showed that plasma OPN levels were significantly elevated in type 2 diabetic patients and positively correlated with glycated albumin (GA). The more atherosclerotic lesions were observed in the aorta of diabetic ApoE−/− mice analyzed by Sudan IV staining. High glucose increased both the mRNA and protein expression levels of OPN and inhibited the phosphorylation of FoxO1 in RAW 264.7 cells. Overexpression of WT or constitutively active mutant FoxO1 promoted the expression levels of OPN, while the dominant-negative mutant FoxO1 decreased slightly the expression of OPN. Conversely, knockdown of FoxO1 reduced the expression of OPN. Luciferase reporter assay revealed that high glucose and overexpression of FoxO1 enhanced the activities of the OPN promoter region nt −1918 ~ −713. Furthermore, the interactions between FoxO1 and the OPN promoter were confirmed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). Our results suggest that high glucose upregulates OPN expression via FoxO1 activation, which would play a critical role in the development of diabetic atherogenesis.