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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- Abstract: Diabetes x
- Abstract: Islets x
- Abstract: Insulin x
- Abstract: BetaCells x
- Abstract: Pancreas x
- Abstract: Obesity x
- Abstract: Glucose x
- Abstract: Hyperglycemia x
- Abstract: Hypoglycemia x
- Abstract: Insulinoma x
- Abstract: IGF* x
- Abstract: Type 1 x
- Abstract: Type 2 x
Junhong Chen, Jing Sun, Michelle E Doscas, Jin Ye, Ashley J Williamson, Yanchun Li, Yi Li, Richard A Prinz and Xiulong Xu
Hongbin Liu, Anthony E Dear, Lotte B Knudsen and Richard W Simpson
Glucagon-like peptide-1 (GLP-1) administration attenuates endothelial cell dysfunction in diabetic patients and inhibits tumour necrosis factor α (TNF)-mediated plasminogen activator inhibitor type-1 (PAI-1) induction in human vascular endothelial cells. The short half-life of GLP-1 mediated via degradation by the enzyme dipeptidyl peptidase 4 mandates the clinical use of long-acting GLP-1 analogues. The effects of a long-acting GLP-1 analogue on PAI-1 and vascular adhesion molecule expression in vascular endothelial cells are unknown. In this report, we demonstrate for the first time that the treatment with liraglutide, a long-acting GLP-1 analogue, inhibited TNF or hyperglycaemia-mediated induction of PAI-1, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 mRNA and protein expression in a human vascular endothelial cell line. In addition, treatment attenuated TNF- or hyperglycaemia-mediated induction of the orphan nuclear receptor Nur77 mRNA expression. Taken together, these observations indicate that liraglutide inhibits TNF- or glucose-mediated induction of PAI-1 and vascular adhesion molecule expression, and this effect may involve the modulation of NUR77. These effects suggest that liraglutide may potentially improve the endothelial cell dysfunction associated with premature atherosclerosis identified in type 2 diabetic patients.
E Zoidis, C Ghirlanda-Keller, M Gosteli-Peter, J Zapf and C Schmid
In osteoblasts only the type III Na(+)-dependent phosphate (NaPi) transporter isoforms Pit-1 and Pit-2 have been identified. We tested the effects of extracellular Pi, Ca(2+) and IGF-I on Na(d)Pi transport and Pit-1 or Pit-2 mRNA expression in rat osteoblastic (PyMS) cells. The v(max) of Na(d)Pi transport was higher in cells kept in Pi-free, serum-free medium for 24 h than in controls at 1 mM Pi (2.47+/-0.20 vs 1.83+/-0.17 nmol/mg protein x 10 min). The apparent affinity constant (K(M)) for Pi remained unchanged. Pi withdrawal for 24 h did not impair cell viability whereas increasing the extracellular Pi to 5 mM resulted in cell death. Pit-1 (but not Pit-2) mRNA was upregulated following Pi deprivation, Ca(2+) treatment or after treatment with 1 nM IGF-I, known to stimulate Na(d)Pi transport and cell proliferation. IGF-I also stimulated Na(d)Pi transport and Pit-1 mRNA in primary rat calvarial osteoblasts. Expression of Pit-1 mRNA in vivo and the coordinate regulation of Pit-1 mRNA and Pi transport in osteoblastic cells suggest that Pit-1 is a candidate transporter of physiological relevance in bone.
Qinkai Li, Weidong Yin, Manbo Cai, Yi Liu, Hongjie Hou, Qingyun Shen, Chi Zhang, Junxia Xiao, Xiaobo Hu, Qishisan Wu, Makoto Funaki and Yutaka Nakaya
Insulin resistance and dyslipidemia are both considered to be risk factors for metabolic syndrome. Low levels of IGF1 are associated with insulin resistance. Elevation of low-density lipoprotein cholesterol (LDL-C) concomitant with depression of high-density lipoprotein cholesterol (HDL-C) increase the risk of obesity and type 2 diabetes mellitus (T2DM). Liver secretes IGF1 and catabolizes cholesterol regulated by the rate-limiting enzyme of bile acid synthesis from cholesterol 7α-hydroxylase (CYP7A1). NO-1886, a chemically synthesized lipoprotein lipase activator, suppresses diet-induced insulin resistance with the improvement of HDL-C. The goal of the present study is to evaluate whether NO-1886 upregulates IGF1 and CYP7A1 to benefit glucose and cholesterol metabolism. By using human hepatoma cell lines (HepG2 cells) as an in vitro model, we found that NO-1886 promoted IGF1 secretion and CYP7A1 expression through the activation of signal transducer and activator of transcription 5 (STAT5). Pretreatment of cells with AG 490, the inhibitor of STAT pathway, completely abolished NO-1886-induced IGF1 secretion and CYP7A1 expression. Studies performed in Chinese Bama minipigs pointed out an augmentation of plasma IGF1 elicited by a single dose administration of NO-1886. Long-term supplementation with NO-1886 recovered hyperinsulinemia and low plasma levels of IGF1 suppressed LDL-C and facilitated reverse cholesterol transport by decreasing hepatic cholesterol accumulation through increasing CYP7A1 expression in high-fat/high-sucrose/high-cholesterol diet minipigs. These findings indicate that NO-1886 upregulates IGF1 secretion and CYP7A1 expression to improve insulin resistance and hepatic cholesterol accumulation, which may represent an alternative therapeutic avenue of NO-1886 for T2DM and metabolic syndrome.
The CCN family comprises cysteine-rich 61 (CYR61/CCN1), connective tIssue growth factor (CTGF/CCN2), nephroblastoma overexpressed (NOV/CCN3), and Wnt-induced secreted proteins-1 (WISP-1/CCN4), -2 (WISP-2/CCN5) and -3 (WISP-3/CCN6). These proteins stimulate mitosis, adhesion, apoptosis, extracellular matrix production, growth arrest and migration of multiple cell types. Many of these activities probably occur through the ability of CCN proteins to bind and activate cell surface integrins. Accumulating evidence supports a role for these factors in endocrine pathways and endocrine-related processes. To illustrate the broad role played by the CCN family in basic and clinical endocrinology, this Article highlights the relationship between CCN proteins and hormone action, skeletal growth, placental angiogenesis, IGF-binding proteins and diabetes-induced fibrosis.
Wang-Yang Xu, Yan Shen, Houbao Zhu, Junhui Gao, Chen Zhang, Lingyun Tang, Shun-Yuan Lu, Chun-Ling Shen, Hong-Xin Zhang, Ziwei Li, Peng Meng, Ying-Han Wan, Jian Fei and Zhu-Gang Wang
Obesity and type 2 diabetes (T2D) are both complicated endocrine disorders resulting from an interaction between multiple predisposing genes and environmental triggers, while diet and exercise have key influence on metabolic disorders. Previous reports demonstrated that 2-aminoadipic acid (2-AAA), an intermediate metabolite of lysine metabolism, could modulate insulin secretion and predict T2D, suggesting the role of 2-AAA in glycolipid metabolism. Here, we showed that treatment of diet-induced obesity (DIO) mice with 2-AAA significantly reduced body weight, decreased fat accumulation and lowered fasting glucose. Furthermore, Dhtkd1−/− mice, in which the substrate of DHTKD1 2-AAA increased to a significant high level, were resistant to DIO and obesity-related insulin resistance. Further study showed that 2-AAA induced higher energy expenditure due to increased adipocyte thermogenesis via upregulating PGC1α and UCP1 mediated by β3AR activation, and stimulated lipolysis depending on enhanced expression of hormone-sensitive lipase (HSL) through activating β3AR signaling. Moreover, 2-AAA could alleviate the diabetic symptoms of db/db mice. Our data showed that 2-AAA played an important role in regulating glycolipid metabolism independent of diet and exercise, implying that improving the level of 2-AAA in vivo could be developed as a strategy in the treatment of obesity or diabetes.
Ruben Rodriguez, Jacqueline N Minas, Jose Pablo Vazquez-Medina, Daisuke Nakano, David G Parkes, Akira Nishiyama and Rudy M Ortiz
Obesity is associated with the inappropriate activation of the renin-angiotensin system (RAS), which increases arterial pressure, impairs insulin secretion and decreases peripheral tissue insulin sensitivity. RAS blockade reverses these detriments; however, it is not clear whether the disease state of the organism and treatment duration determine the beneficial effects of RAS inhibition on insulin secretion and insulin sensitivity. Therefore, the objective of this study was to compare the benefits of acute vs chronic angiotensin receptor type 1 (AT1) blockade started after the onset of obesity, hyperglycemia and hypertension on pancreatic function and peripheral insulin resistance. We assessed adipocyte morphology, glucose intolerance, pancreatic redox balance and insulin secretion after 2 and 11 weeks of AT1 blockade in the following groups of rats: (1) untreated Long-Evans Tokushima Otsuka (lean control; n = 10), (2) untreated Otsuka Long-Evans Tokushima Fatty (OLETF; n = 12) and (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day by oral gavage; n = 12). Regardless of treatment duration, AT1 blockade decreased systolic blood pressure and fasting plasma triglycerides, whereas chronic AT1 blockade decreased fasting plasma glucose, glucose intolerance and the relative abundance of large adipocytes by 22, 36 and 70%, respectively. AT1 blockade, however, did not improve pancreatic oxidative stress or reverse impaired insulin secretion. Collectively, these data show that AT1 blockade after the onset of obesity, hyperglycemia and hypertension improves peripheral tissue insulin sensitivity, but cannot completely reverse the metabolic derangement characterized by impaired insulin secretion once it has been compromised.
Jun-ichi Eiki, Kaori Saeki, Norihiro Nagano, Tomoharu Iino, Mari Yonemoto, Yoko Takayenoki-Iino, Satoru Ito, Teruyuki Nishimura, Yoshiyuki Sato, Makoto Bamba, Hitomi Watanabe, Kaori Sasaki, Sumika Ohyama, Akio Kanatani, Toshio Nagase and Toshihiko Yada
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates insulin secretion in a glucose-dependent manner. Selective GLP-1 secretagogue would be one of the potential therapeutic targets for type 2 diabetes. Here, we describe a newly identified small molecule compound (compound A) that stimulates secretion of GLP-1 in murine enteroendocrine cell lines, STC-1 and GLUTag cells, and in primary cultured fetal rat intestinal cells (FRIC). The underlying mechanism by which compound A stimulated GLP-1 secretion was also examined. Compound A stimulated GLP-1 secretion from STC-1 cells in a concentration-dependent manner, and also from GLUTag cells and FRIC. The action of compound A was selective against other tested endocrine functions such as secretion of insulin from rat islets, growth hormone from rat pituitary gland cells, and norepinephrine from rat PC-12 cells. In STC-1 cells, the compound A-stimulated GLP-1 secretion was neither due to cyclic AMP production nor to Ca2+ release from intracellular stores, but to extracellular Ca2+ influx. The response was inhibited by the presence of either L-type Ca2+ channel blockers or K+ ionophore. Perforated-patch clamp study revealed that compound A induces membrane depolarization. These results suggest that neither Gαs- nor Gαq-coupled signaling account for the mechanism of action, but depolarization-coupled Ca2+ influx from extracellular space is the primary cause for the GLP-1 secretion stimulated by compound A. Identifying a specific target molecule for compound A will reveal a selective regulatory pathway that leads to depolarization-mediated GLP-1 secretion.
M. Tepel, S. Bauer, S. Husseini, A. Raffelsiefer and W. Zidek
Cytosolic free sodium concentrations ([Na+]i) in intact platelets from 32 type 2 (non-insulin-dependent) diabetic patients and from 27 age- and sex-matched non-diabetic control subjects were measured with the novel sodium-sensitive fluorescent dye sodium-binding-benzofuran-isophthalate. [Na+]i was significantly higher in platelets from type 2 diabetic patients compared with control subjects (40·6 ± 2·4 vs 32·0 ± 2·0 mmol/l, means ± s.e.m., P<0·03). Both systolic and diastolic blood pressure were significantly elevated in diabetic patients compared with control subjects. Analysis of diabetic patients showed a significant association between [Na+]i and diastolic blood pressure (P =0·026). Stimulation of Na/H exchange by thrombin increased [Na+]i in both groups. After inhibition of Na/K/ATPase by ouabain (1 mmol/l), [Na+]i was significantly increased both in diabetic patients and non-diabetic subjects in a similar way (by 40·2 ± 7·3 and 31·7 ± 5·3 mmol/l respectively). It is concluded that increased [Na+]i in cells from type 2 diabetic patients may be related to hypertension.
Journal of Endocrinology (1993) 138, 565–572
Weixia Han, Chen Wang, Zhifen Yang, Lin Mu, Ming Wu, Nan Chen, Chunyang Du, Huijun Duan and Yonghong Shi
Renal fibrosis is the major pathological characteristic of diabetic nephropathy (DN). Reportedly, increased SIRT1 expression played a renal protective role in animal models of DN. This study was designed to elucidate the molecular mechanisms underlying the protective effects of SRT1720, an SIRT1 activator, against diabetes-induced renal fibrosis. Type 2 diabetic mice (db/db) were treated with SRT1720 (50 mg/kg/day) by gavage for 10 weeks. Renal proximal tubular epithelial cells (HK-2 cells) were treated with high glucose (HG, 30 mM) in the presence or absence of SRT1720 (2.5 µM) for 48 h. We observed that impaired SIRT1 expression and activity were restored by SRT1720 administration in db/db mice as well as in HG-treated HK-2 cells. Moreover, SRT1720 administration improved the renal function, attenuated glomerular hypertrophy, mesangial expansion, glomerulosclerosis and interstitial fibrosis and inhibited TGFB1 and CTGF expressions and nuclear factor κB (NF-KB) activation in db/db mice. Similarly, HG-induced epithelial-to-mesenchymal transformation (EMT) and collagen IV and fibronectin expressions were inhibited in SRT1720-treated HK-2 cells. Mechanistic studies demonstrated that SRT1720 suppressed HIF1A, GLUT1 and SNAIL expressions both in vivo and in vitro. Furthermore, HIF1A or GLUT1 knockdown effectively abrogated HG-induced EMT and collagen IV and fibronectin expressions in HK-2 cells. These findings suggest that SRT1720 prevented diabetes-induced renal fibrosis via the SIRT1/HIF1A/GLUT1/SNAIL pathway.