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Insulin-producing cells could not mimic the physiological regulation of insulin secretion performed by pancreatic beta cells
Qiping Shi , Simin Luo , Haiying Jia, Lie Feng, Xiaohua Lu, Lixin Zhou and Jiye Cai
Nanoscale Research Letters , 2013, DOI: 10.1186/1556-276X-8-90
Abstract: Our results firstly revealed that the cellular ultrastructure of IPCs was closer to that of normal human pancreatic beta cells, but they still could not mimic the physiological regulation of insulin secretion performed by pancreatic beta cells.
Insulin-Mimetic Action of Rhoifolin and Cosmosiin Isolated from Citrus grandis (L.) Osbeck Leaves: Enhanced Adiponectin Secretion and Insulin Receptor Phosphorylation in 3T3-L1 Cells
Yerra Koteswara Rao,Meng-Jen Lee,Keru Chen,Yi-Ching Lee,Wen-Shi Wu,Yew-Min Tzeng
Evidence-Based Complementary and Alternative Medicine , 2011, DOI: 10.1093/ecam/nep204
Abstract: Citrus grandis (L.) Osbeck (red wendun) leaves have been used in traditional Chinese medicine to treat several illnesses including diabetes. However, there is no scientific evidence supporting these actions and its active compounds. Two flavone glycosides, rhoifolin and cosmosiin were isolated for the first time from red wendun leaves and, identified these leaves are rich source for rhoifolin (1.1%, w/w). In differentiated 3T3-L1 adipocytes, rhoifolin and cosmosiin showed dose-dependent response in concentration range of o.oo1–5 μM and 1–20 μM, respectively, in biological studies beneficial to diabetes. Particularly, rhoifolin and cosmosiin at 0.5 and 20 μM, respectively showed nearly similar response to that 10 nM of insulin, on adiponectin secretion level. Furthermore, 5 μM of rhoifolin and 20 μM of cosmosiin showed equal potential with 10 nM of insulin to increase the phosphorylation of insulin receptor-β, in addition to their positive effect on GLUT4 translocation. These findings indicate that rhoifolin and cosmosiin from red wendun leaves may be beneficial for diabetic complications through their enhanced adiponectin secretion, tyrosine phosphorylation of insulin receptor-β and GLUT4 translocation.
Geniposide Regulates Glucose-Stimulated Insulin Secretion Possibly through Controlling Glucose Metabolism in INS-1 Cells  [PDF]
Jianhui Liu, Lixia Guo, Fei Yin, Yonglan Zhang, Zixuan Liu, Yanwen Wang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078315
Abstract: Glucose-stimulated insulin secretion (GSIS) is essential to the control of metabolic fuel homeostasis. The impairment of GSIS is a key element of β-cell failure and one of causes of type 2 diabetes mellitus (T2DM). Although the KATP channel-dependent mechanism of GSIS has been broadly accepted for several decades, it does not fully describe the effects of glucose on insulin secretion. Emerging evidence has suggested that other mechanisms are involved. The present study demonstrated that geniposide enhanced GSIS in response to the stimulation of low or moderately high concentrations of glucose, and promoted glucose uptake and intracellular ATP levels in INS-1 cells. However, in the presence of a high concentration of glucose, geniposide exerted a contrary role on both GSIS and glucose uptake and metabolism. Furthermore, geniposide improved the impairment of GSIS in INS-1 cells challenged with a high concentration of glucose. Further experiments showed that geniposide modulated pyruvate carboxylase expression and the production of intermediates of glucose metabolism. The data collectively suggest that geniposide has potential to prevent or improve the impairment of insulin secretion in β-cells challenged with high concentrations of glucose, likely through pyruvate carboxylase mediated glucose metabolism in β-cells.
The Rab11 Effector Protein FIP1 Regulates Adiponectin Trafficking and Secretion  [PDF]
Brian P. Carson, Josep Maria Del Bas, Jose Maria Moreno-Navarrete, Jose Manuel Fernandez-Real, Silvia Mora
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074687
Abstract: Adiponectin is an adipokine secreted by white adipocytes involved in regulating insulin sensitivity in peripheral tissues. Secretion of adiponectin in adipocytes relies on the endosomal system, however, the intracellular machinery involved in mediating adiponectin release is unknown. We have previously reported that intracellular adiponectin partially compartmentalizes with rab 5 and rab11, markers for the early/sorting and recycling compartments respectively. Here we have examined the role of several rab11 downstream effector proteins (rab11 FIPs) in regulating adiponectin trafficking and secretion. Overexpression of wild type rab11 FIP1, FIP3 and FIP5 decreased the amount of secreted adiponectin expressed in HEK293 cells, whereas overexpression of rab11 FIP2 or FIP4 had no effect. Furthermore shRNA-mediated depletion of FIP1 enhanced adiponectin release whereas knock down of FIP5 decreased adiponectin secretion. Knock down of FIP3 had no effect. In 3T3L1 adipocytes, endogenous FIP1 co-distributed intracellularly with endogenous adiponectin and FIP1 depletion enhanced adiponectin release without altering insulin-mediated trafficking of the glucose transporter Glut4. While adiponectin receptors internalized with transferrin receptors, there were no differences in transferrin receptor recycling between wild type and FIP1 depleted adipocytes. Consistent with its inhibitory role, FIP1 expression was decreased during adipocyte differentiation, by treatment with thiazolidinediones, and with increased BMI in humans. In contrast, FIP1 expression increased upon exposure of adipocytes to TNFα. In all, our findings identify FIP1 as a novel protein involved in the regulation of adiponectin trafficking and release.
A Genetic Strategy to Measure Circulating Drosophila Insulin Reveals Genes Regulating Insulin Production and Secretion  [PDF]
Sangbin Park,Ronald W. Alfa,Sydni M. Topper,Grace E. S. Kim,Lutz Kockel,Seung K. Kim
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004555
Abstract: Insulin is a major regulator of metabolism in metazoans, including the fruit fly Drosophila melanogaster. Genome-wide association studies (GWAS) suggest a genetic basis for reductions of both insulin sensitivity and insulin secretion, phenotypes commonly observed in humans with type 2 diabetes mellitus (T2DM). To identify molecular functions of genes linked to T2DM risk, we developed a genetic tool to measure insulin-like peptide 2 (Ilp2) levels in Drosophila, a model organism with superb experimental genetics. Our system permitted sensitive quantification of circulating Ilp2, including measures of Ilp2 dynamics during fasting and re-feeding, and demonstration of adaptive Ilp2 secretion in response to insulin receptor haploinsufficiency. Tissue specific dissection of this reduced insulin signaling phenotype revealed a critical role for insulin signaling in specific peripheral tissues. Knockdown of the Drosophila orthologues of human T2DM risk genes, including GLIS3 and BCL11A, revealed roles of these Drosophila genes in Ilp2 production or secretion. Discovery of Drosophila mechanisms and regulators controlling in vivo insulin dynamics should accelerate functional dissection of diabetes genetics.
A paradox: Insulin inhibits expression and secretion of resistin which induces insulin resistance  [cached]
Feng Liu, Hong-Qi Fan, Jie Qiu, Bin Wang, Min Zhang, Nan Gu, Chun-Mei Zhang, Li Fei, Xiao-Qing Pan, Mei Guo, Rong-Hua Chen, Xi-Rong Guo
World Journal of Gastroenterology , 2008,
Abstract: AIM: To confirm whether insulin regulates resistin expression and secretion during differentiation of 3T3-L1 preadipocytes and the relationship of resistin with insulin resistance both in vivo and in vitro.METHODS: Supernatant resistin was measured during differentiation of 3T3-L1 preadipocytes. L6 rat myoblasts and hepatoma cell line H4IIE were used to confirm the cellular function of resistin. Diet-induced obese rats were used as an insulin resistance model to study the relationship of resistin with insulin resistance.RESULTS: Resistin expression and secretion were enhanced during differentiation 3T3-L1 preadipocytes. This cellular differentiation stimulated resistin expression and secretion, but was suppressed by insulin. Resistin also induced insulin resistance in H4IIE hepatocytes and L6 myoblasts. In diet-induced obese rats, serum resistin levels were negatively correlated with insulin sensitivity, but not with serum insulin.CONCLUSION: Insulin can inhibit resistin expression and secretion in vitro, but insulin is not a major regulator of resistin in vivo. Fat tissue mass affects insulin sensitivity by altering the expression and secretion of resistin.
Mifepristone Promotes Adiponectin Production and Improves Insulin Sensitivity in a Mouse Model of Diet-Induced-Obesity  [PDF]
Takeshi Hashimoto, Junsuke Igarashi, Arif U. Hasan, Koji Ohmori, Masakazu Kohno, Yukiko Nagai, Tetsuo Yamashita, Hiroaki Kosaka
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079724
Abstract: The steroid receptor antagonist mifepristone is used as an anti-cancer agent, eliciting both cytostatic and cytotoxic effects on malignant cells. However, the metabolic effects of long-term treatment with mifepristone have remained unclear. The effects of mifepristone on insulin sensitivity and adiponectin secretion were evaluated both in in vivo and in vitro. First, we explored the effects of mifepristone, on metabolic functions in obese mice receiving a high-fat diet. When these mice were fed mifepristone, they exhibited a marked improvement in insulin sensitivity, attenuated hepatic injury, and decreased adipocyte size, compared with mice that received only the high-fat diet. Intriguingly, mifepristone-treated mice showed significantly elevated plasma adiponectin levels. Second, we tested the effects of mifepristone on differentiated 3T3-L1 adipocytes in vitro. When differentiated adipocytes were treated with mifepristone for 48 h, adiponectin was upregulated at both mRNA and protein levels. Collectively, these results reveal novel actions of mifepristone on metabolic functions, in vivo and in vitro, in which the drug exerts antidiabetic effects associated with an upregulation in adiponectin-secretion.
Leucine supplementation improves adiponectin and total cholesterol concentrations despite the lack of changes in adiposity or glucose homeostasis in rats previously exposed to a high-fat diet
Francisco L Torres-Leal, Miriam H Fonseca-Alaniz, Gabriela FR Teodoro, Mariana D de Capitani, Daiana Vianna, Lucas C Pantale?o, Emidio M Matos-Neto, Marcelo M Rogero, Jose Donato, Julio Tirapegui
Nutrition & Metabolism , 2011, DOI: 10.1186/1743-7075-8-62
Abstract: Forty-seven rats were randomly divided into two groups. Animals were fed a control diet-low fat (n = 10) or HFD (n = 37). After 15 weeks on HFD, all rats received the control diet-low fat and were randomly divided according to treatment: reference (REF), LS, ET, and LS+ET (n = 7-8 rats per group). After 6 weeks of treatment, the animals were sacrificed and body composition, fat cell volume, and serum concentrations of total cholesterol, HDL-cholesterol, triacylglycerol, glucose, adiponectin, leptin and tumor necrosis factor-alpha (TNF-α) were analyzed.At the end of the sixth week of treatment, there was no significant difference in body weight between the REF, LS, ET and LS+ET groups. However, ET increased lean body mass in rats (P = 0.019). In addition, ET was more effective than LS in reducing adiposity (P = 0.019), serum insulin (P = 0.022) and TNF-α (P = 0.044). Conversely, LS increased serum adiponectin (P = 0.021) levels and reduced serum total cholesterol concentration (P = 0.042).The results showed that LS had no beneficial effects on insulin sensitivity or adiposity in previously obese rats. On the other hand, LS was effective in increasing adiponectin levels and in reducing total cholesterol concentration.Obesity is associated with a number of health problems that are often summarized as the metabolic syndrome, and its etiology may be associated with the consumption of high energy-dense foods [1]. Excessive intake of dietary fat promotes adipocyte hypertrophy, altering their normal endocrine function to an inflammatory pathologic condition that increases the secretion of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), among other proinflammatory cytokines, and concomitantly reducing adiponectin secretion [2,3].Previous studies have demonstrated that dietary leucine regulates body weight and glucose homeostasis [4-10]. Within this context, several studies support the hypothesis that leucine plays an important role in the regulation of metaboli
Liraglutide Increases FGF-21 Activity and Insulin Sensitivity in High Fat Diet and Adiponectin Knockdown Induced Insulin Resistance  [PDF]
Mengliu Yang, Lili Zhang, Chong Wang, Hua Liu, Guenther Boden, Gangyi Yang, Ling Li
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048392
Abstract: Background Liraglutide is a glucagon-like peptide-1 analogue that stimulates insulin secretion and improves β-cell function. However, it is not clear whether liraglutide achieves its glucose lowering effect only by its known effects or whether other as yet unknown mechanisms are involved. The aim of this study was to examine the effects of liraglutide on Fibroblast growth factor-21 (FGF-21) activity in High-fat diet (HFD) fed ApoE?/? mice with adiponectin (Acrp30) knockdown. Method HFD-fed ApoE?/? mice were treated with adenovirus vectors expressing shAcrp30 to produce insulin resistance. Hyperinsulinemic-euglycemic clamp studies were performed to evaluate insulin sensitivity of the mouse model. QRT-PCR and Western blot were used to measure the mRNA and protein expression of the target genes. Results The combination of HFD, ApoE deficiency, and hypoadiponectinemia resulted in an additive effect on insulin resistance. FGF-21 mRNA expressions in both liver and adipose tissues were significantly increased while FGF-21 receptor 1 (FGFR-1) and β-Klotho mRNA levels in adipose tissue, as well as FGFR-1-3 and β-Klotho mRNA levels in liver were significantly decreased in this model. Liraglutide treatment markedly improved insulin resistance and increased FGF-21 expression in liver and FGFR-3 in adipose tissue, restored β-Klotho mRNA expression in adipose tissue as well as FGFR-1-3, β-Klotho levels and phosphorylation of FGFR1 up to the levels observed in control mice in liver. Liraglutide treatment also further increased FGF-21 proteins in liver and plasma. In addition, as shown by hyperinsulinemic-euglycemic clamp, liraglutide treatment also markedly improved glucose metabolism and insulin sensitivity in these animals. Conclusion These findings demonstrate an additive effect of HFD, ApoE deficiency, and adiponectin knockdown on insulin resistance and unveil that the regulation of glucose metabolism and insulin sensitivity by liraglutide may be partly mediated via increased FGF-21 and its receptors action.
Intracellular Serotonin Modulates Insulin Secretion from Pancreatic β-Cells by Protein Serotonylation  [PDF]
Nils Paulmann,Maik Grohmann,J?rg-Peter Voigt,Bettina Bert,Jakob Vowinckel,Michael Bader,Ma?a Skelin,Marko Jev?ek,Heidrun Fink,Marjan Rupnik,Diego J. Walther
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000229
Abstract: While serotonin (5-HT) co-localization with insulin in granules of pancreatic β-cells was demonstrated more than three decades ago, its physiological role in the etiology of diabetes is still unclear. We combined biochemical and electrophysiological analyses of mice selectively deficient in peripheral tryptophan hydroxylase (Tph1?/?) and 5-HT to show that intracellular 5-HT regulates insulin secretion. We found that these mice are diabetic and have an impaired insulin secretion due to the lack of 5-HT in the pancreas. The pharmacological restoration of peripheral 5-HT levels rescued the impaired insulin secretion in vivo. These findings were further evidenced by patch clamp experiments with isolated Tph1?/? β-cells, which clearly showed that the secretory defect is downstream of Ca2+-signaling and can be rescued by direct intracellular application of 5-HT via the clamp pipette. In elucidating the underlying mechanism further, we demonstrate the covalent coupling of 5-HT by transglutaminases during insulin exocytosis to two key players in insulin secretion, the small GTPases Rab3a and Rab27a. This renders them constitutively active in a receptor-independent signaling mechanism we have recently termed serotonylation. Concordantly, an inhibition of such activating serotonylation in β-cells abates insulin secretion. We also observed inactivation of serotonylated Rab3a by enhanced proteasomal degradation, which is in line with the inactivation of other serotonylated GTPases. Our results demonstrate that 5-HT regulates insulin secretion by serotonylation of GTPases within pancreatic β-cells and suggest that intracellular 5-HT functions in various microenvironments via this mechanism in concert with the known receptor-mediated signaling.
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