Circulating mesencephalic astrocyte-derived neurotrophic factor is increased in newly diagnosed prediabetic and diabetic patients, and is associated with insulin resistance

Wu, Tong; Fang, Zhang; Yang, Qin; Zhang, Yuwei; Liu, Qinhui; Jiang, Wei; Cao, Hongyan; Li, Daigang; Xie, Shouqi; Tong, Nanwei; He, Jinhan

doi:10.1507/endocrj.ej16-0472

Cited by 37 publications

(38 citation statements)

References 36 publications

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“…sulin resistance by interacting with phosphatidylinositol 5-phosphate 4-kinase type-2 beta (PIP4k2β) [9], yet systemic MANF overexpression improved glucose tolerance [10]. In contrast to our findings, Wu et al found a positive correlation between circulating MANF with insulin resistance in patients with prediabetes, whereas circulating MANF was not related to insulin resistance in T2DM patients even they had severer insulin resistance than prediabetic patients [11]. Their populations had obviously glucose dysmetabolism and pancreatic β-cell failure, while our participants were mainly characterized by hyperinsulinemia and hyperandrogenism.…”

Section: Discussioncontrasting

confidence: 99%

“…Previous data suggest an association between MANF and insulin resistance [9][10][11]. However, human data have not been consistent, and they did not use the EHC, the golden standard for evaluating insulin resistance [15,16].…”

Section: Discussionmentioning

confidence: 99%

“…Studies in mice revealed that MANF overexpression in hypothalamus caused insulin resistance [9], while systemic overexpression of MANF markedly improved glucose and insulin tolerance [10]. In humans, circulating MANF was found to be positively correlated with insulin resistance in patients with prediabetes, but was unrelated to insulin resistance in patients with T2DM [11]. PCOS is a good model of insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

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Decreased Circulating MANF in Women with PCOS is Elevated by Metformin Therapy and is Inversely Correlated with Insulin Resistance and Hyperandrogenism

et al. 2020

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Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel neurotrophic factor. Although recent studies have suggested that MANF appeared to be associated with insulin resistance, the results have been inconsistent. The aim of our study was to determine the serum MANF levels in women with PCOS and controls, to investigate their relationship to insulin resistance, and to evaluate circulating MANF changes with metformin intervention in PCOS women. We conducted a series of cross-sectional and interventional studies in 90 newly diagnosed patients with PCOS and 60 age- and gender-matched controls. Oral glucose tolerance test and euglycemic-hyperinsulinemic clamps were performed to assess the glucose tolerance and insulin sensitivity. Forty-three women with PCOS were randomly assigned to six months of oral metformin therapy. Serum MANF levels were significantly lower in women with PCOS than in controls. Serum MANF levels were positively correlated with M-value and negatively correlated with body mass index (BMI), body fat percentage (FAT), homeostatic model assessment of insulin resistance (HOMA-IR), and free androgen index (FAI). Multivariate stepwise regression demonstrated that serum MANF levels were independently associated with M-value and FAI. After six months of metformin treatment, there was a significant increase in serum MANF levels in PCOS women. Serum MANF levels are decreased in women with PCOS, and are reversely related to insulin resistance and hyperandrogenism. Metformin treatment elevates serum MANF levels and alleviates insulin resistance and hyperandrogenism in PCOS women.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Decreased Circulating MANF in Women with PCOS is Elevated by Metformin Therapy and is Inversely Correlated with Insulin Resistance and Hyperandrogenism

et al. 2020

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“…Although MANF was not completely deleted from all pancreatic b-cells in MIP-1Cre ERT ::Manf fl/fl (TMX) mice, we demonstrate that lack of MANF in the adult b-cells results in reduced expression of b-cell-specific genes and poor b-cell survival and proliferation, leading to hyperglycemia and diabetes. The above results strongly argue against a systemic effect of circulating MANF in rescuing b-cells and clearly demonstrates that local expression of MANF is required to maintain the b-cell phenotype in mice (56,57). Furthermore, MANF expression in pancreatic exocrine acinar cells did not protect MANF-deficient adult b-cells.…”

Section: Discussionmentioning

confidence: 90%

MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

Danilova

Belevich

et al. 2018

Diabetes

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Global lack of mesencephalic astrocyte-derived neurotropic factor (MANF) leads to progressive postnatal loss of b-cell mass and insulin-dependent diabetes in mice. Similar to Manf 2/2 mice, embryonic ablation of MANF specifically from the pancreas results in diabetes. In this study, we assessed the importance of MANF for the postnatal expansion of pancreatic b-cell mass and for adult b-cell maintenance in mice. Detailed analysis of Pdx-1Cre +/2 ::Manf fl/fl mice revealed mosaic MANF expression in postnatal pancreata and a significant correlation between the number of MANF-positive b-cells and b-cell mass in individual mice. In vitro, recombinant MANF induced b-cell proliferation in islets from aged mice and protected from hyperglycemia-induced endoplasmic reticulum (ER) stress. Consequently, excision of MANF from b-cells of adult MIP-1Cre ERT ::Manf fl/fl mice resulted in reduced b-cell mass and diabetes caused largely by b-cell ER stress and apoptosis, possibly accompanied by b-cell dedifferentiation and reduced rates of b-cell proliferation. Thus, MANF expression in adult mouse b-cells is needed for their maintenance in vivo. We also revealed a mechanistic link between ER stress and inflammatory signaling pathways leading to b-cell death in the absence of MANF. Hence, MANF might be a potential target for regenerative therapy in diabetes.

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“…26,27 Studies indicated that activation of the central nerve system GLP-1 receptor improves T2DM via glucose metabolism dependent inhibition of central nerve system AMPK. 28 AMPK activation accelerate fatty acid oxidation and glucose uptake, suppresses triglycerides production in skeletal muscle，which is necessary for the body to maintain the balance of blood glucose. 29 In this study, AMPK and p-AMPK were examined to understand whether Ex-4 improves glucose metabolism by increasing phosphorylation of AMPK.…”

Section: Discussionmentioning

confidence: 99%

Exendin-4 improves glucose metabolism in insulin-resistant cells by upregulating the phosphorylative AMPK

Li¹,

Gong²,

Qu³

et al. 2019

JAH

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Glucagon-like peptide-1 (GLP-1) is a peptide with multiple functions in regulating blood glucose with the mechnism still not throughly understand. AMP-activated protein kinase (AMPK) plays an important role in glucose and energy homeostasis, especially in type 2 diabetes mellitus (T2DM) pathophysiology. This study explores GLP-1 analogue exendin-4 (Ex-4) regulating glucose balance by activating AMPK and regulation gluconeogenesis in insulin-resistant cell model (IR/ HepG2). IR/HepG2 cells were treated with Ex-4, AMPK activator or Ex-4 pretreated with AMPK inhibitor Compound C. The change of cell morphology, glucose consumption and lipid content in IR/HepG2 cells were examined. The expression of AMPK and p-AMPK in IR/HepG2 treated by Ex-4 were determined by Western blot and immunochemisthistology (IHC) assay. Key enzymes of glucose metabolism, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) in IR/HepG2 cells treated by Ex-4 were detected by Western blot, immunohistochemistry and qRT-PCR. The results showed that Ex-4 treatment increased the expression of p-AMPK and reduced the expression of G-6-Pase and PEPCK in IR/HepG2 cells. Pretreatment with AMPK inhibitor Compound C counteracts the effect of Ex-4. These findings suggest that Ex-4 fulfilled it glucose regulation effect by phosphorylation of AMPK and decreased the expression of enzymes involving gluconeogenesis.

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Circulating mesencephalic astrocyte-derived neurotrophic factor is increased in newly diagnosed prediabetic and diabetic patients, and is associated with insulin resistance

Cited by 37 publications

References 36 publications

Decreased Circulating MANF in Women with PCOS is Elevated by Metformin Therapy and is Inversely Correlated with Insulin Resistance and Hyperandrogenism

Decreased Circulating MANF in Women with PCOS is Elevated by Metformin Therapy and is Inversely Correlated with Insulin Resistance and Hyperandrogenism

MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

Exendin-4 improves glucose metabolism in insulin-resistant cells by upregulating the phosphorylative AMPK

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