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      Serum fibroblast growth factor 19 and endogenous islet beta cell function in type 2 diabetic patients

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          Abstract

          Background

          Fibroblast growth factor 19 (FGF19) takes part in maintaining the balance of glycolipids and may be involved in regulating the secretory activity of islet beta cells in patients with type 2 diabetes. This study aimed to evaluate the relationship between the levels of serum FGF19 and endogenous islet beta cell function in type 2 diabetic patients.

          Methods

          Samples were obtained from 271 subjects: 85 drug-naïve type 2 diabetes participants exclusively on lifestyle intervention (N-DM group), 122 type 2 diabetes subjects previously used medications (DM group) and 64 normal controls (NC group). Serum FGF19 concentrations were measured by ELISA. The insulin sensitivity (MI), insulin secretion (AUC ins/AUC glu) and insulin secretion-sensitivity index-2 (ISSI-2) were also measured in the N-DM and DM.

          Results

          Serum FGF19 levels decreased, in order, from the NC group [median (interquartile range), 245.03 (126.23–317.43) pg/mL] to the N-DM group [170.05 (89.01–244.70) pg/mL] and, finally, to the DM group [142.25 (55.55–187.58) pg/mL] ( p for trend < 0.05). Among subjects in the DM group, there was a positive trend in the serum FGF19 concentration; plasma insulin levels at 60 min, 120 min (INS60, INS120, respectively); and area under the insulin curve (AUC ins) at two points ( r = 0.214, p = 0.025; r = 0.189, p = 0.048; r = 0.188, p = 0.049). However, the differences were no longer observed among the N-DM subjects. Simultaneously, the ISSI-2 was closely related to the serum FGF19 levels ( r = 0.297, p = 0.002) among DM subjects. Furthermore, after adjusting for age, sex, duration, therapy and other clinical factors via multiple logistic regression analysis, ISSI-2 was a key independent factor in the levels of FGF19 ( β =  0.281, t =  2.557, p =  0.013).

          Conclusions

          The serum FGF19 level has a close relation with endogenous beta cell function among DM subjects, as assessed by the ISSI-2. As ISSI-2 is higher in N-DM group, FGF19 may be a main protector in dysfunction of beta cell.

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          Most cited references26

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          Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction

          The farnesoid X receptor (FXR) regulates bile acid, lipid and glucose metabolism. Here we show that treatment of mice with glycine-β-muricholic acid (Gly-MCA) inhibits FXR signalling exclusively in intestine, and improves metabolic parameters in mouse models of obesity. Gly-MCA is a selective high-affinity FXR inhibitor that can be administered orally and prevents, or reverses, high-fat diet-induced and genetic obesity, insulin resistance and hepatic steatosis in mice. The high-affinity FXR agonist GW4064 blocks Gly-MCA action in the gut, and intestine-specific Fxr-null mice are unresponsive to the beneficial effects of Gly-MCA. Mechanistically, the metabolic improvements with Gly-MCA depend on reduced biosynthesis of intestinal-derived ceramides, which directly compromise beige fat thermogenic function. Consequently, ceramide treatment reverses the action of Gly-MCA in high-fat diet-induced obese mice. We further show that FXR signalling in ileum biopsies of humans positively correlates with body mass index. These data suggest that Gly-MCA may be a candidate for the treatment of metabolic disorders.
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            FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis.

            Fibroblast growth factor (FGF) 19 is an enterokine synthesized and released when bile acids are taken up into the ileum. We show that FGF19 stimulates hepatic protein and glycogen synthesis but does not induce lipogenesis. The effects of FGF19 are independent of the activity of either insulin or the protein kinase Akt and, instead, are mediated through a mitogen-activated protein kinase signaling pathway that activates components of the protein translation machinery and stimulates glycogen synthase activity. Mice lacking FGF15 (the mouse FGF19 ortholog) fail to properly maintain blood concentrations of glucose and normal postprandial amounts of liver glycogen. FGF19 treatment restored the loss of glycogen in diabetic animals lacking insulin. Thus, FGF19 activates a physiologically important, insulin-independent endocrine pathway that regulates hepatic protein and glycogen metabolism.
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              Farnesoid X Receptor Deficiency Improves Glucose Homeostasis in Mouse Models of Obesity

              OBJECTIVE Bile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed. RESEARCH DESIGN AND METHODS Here, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity. RESULTS FXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism. CONCLUSIONS Overall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis.
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                Author and article information

                Contributors
                931736923@qq.com
                sjbzjx@163.com
                274306464@qq.com
                wangxueqin108@163.com
                zdm@ntu.edu.cn
                893247905@qq.com
                Journal
                Diabetol Metab Syndr
                Diabetol Metab Syndr
                Diabetology & Metabolic Syndrome
                BioMed Central (London )
                1758-5996
                24 September 2019
                24 September 2019
                2019
                : 11
                : 79
                Affiliations
                [1 ]ISNI 0000 0000 9530 8833, GRID grid.260483.b, Department of Endocrinology, , Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, ; No. 6 North Hai-er-xiang Road, Nantong, 226001 China
                [2 ]ISNI 0000 0000 9530 8833, GRID grid.260483.b, Department of Clinical Laboratory, Clinical Medicine Research Center, , Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, ; No. 6 North Hai-er-xiang Road, Nantong, 226001 China
                [3 ]ISNI 0000 0000 9530 8833, GRID grid.260483.b, Medical College of Nantong University, ; No. 19 Qi-xiu Road, Nantong, 226001 China
                Article
                475
                10.1186/s13098-019-0475-1
                6760053
                648647f0-a9a2-433a-8de9-e1569db9b31f
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 17 May 2019
                : 17 September 2019
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Nutrition & Dietetics
                islet beta cell function,insulin sensitivity,fgf19,type 2 diabetes
                Nutrition & Dietetics
                islet beta cell function, insulin sensitivity, fgf19, type 2 diabetes

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