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

Abstract

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.

Key words

mesencephalic astrocyte-derived neurotrophic factor - polycystic ovary syndrome - insulin resistance - hyperandrogenism - metformin

^* Jie Wei and Cong Wang should be considered as joint first authors.

• References

• 1 March WA, Moore VM, Willson KJ. et al. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010; 25: 544-551
• 2 Rotterdam EA-SPcwg Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41-47
• 3 Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: An update on mechanisms and implications. Endocr Rev 2012; 33: 981-1030
• 4 Kocer D, Bayram F, Diri H. The effects of metformin on endothelial dysfunction, lipid metabolism and oxidative stress in women with polycystic ovary syndrome. Gynecol Endocrinol 2014; 30: 367-371
• 5 Sam S, Ehrmann DA. Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome. Diabetologia 2017; 60: 1656-1661
• 6 Petrova P, Raibekas A, Pevsner J. et al. MANF: A new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. J Mol Neurosci 2003; 20: 173-188
• 7 Lindholm P, Peranen J, Andressoo JO. et al. MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain. Mol Cell Neurosci 2008; 39: 356-371
• 8 Lindahl M, Saarma M, Lindholm P. Unconventional neurotrophic factors CDNF and MANF: Structure, physiological functions and therapeutic potential. Neurobiol Dis 2017; 97: 90-102
• 9 Yang S, Yang H, Chang R. et al. MANF regulates hypothalamic control of food intake and body weight. Nat Commun 2017; 8: 579
• 10 Sousa-Victor P, Neves J, Cedron-Craft W. et al. MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage. Nature Metabol 2019; 1: 276-290
• 11 Wu T, Zhang F, Yang Q. et al. Circulating mesencephalic astrocyte-derived neurotrophic factor is increased in newly diagnosed prediabetic and diabetic patients, and is associated with insulin resistance. Endocr J 2017; 64: 403-410
• 12 Bray GA, Heisel WE, Afshin A. et al. The science of obesity management: An Endocrine Society Scientific Statement. Endocr Rev 2018; 39: 79-132
• 13 Ibanez L, Ong KK, Lopez-Bermejo A. et al. Hyperinsulinaemic androgen excess in adolescent girls. Nat Rev Endocrinol 2014; 10: 499-508
• 14 American Diabetes Association Classification and diagnosis of diabetes. Sec. 2. In Standards of medical care in diabetes – 2019. Diabetes Care 42: 13-28
• 15 DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237: E214-E223
• 16 Zhao W, Yuan T, Sun Q. et al. Establishment of hyperinsulinemic euglycemic clamp technique and the reference value of insulin sensitivity index in Chinese. Chin J Clin Nutri. 2009; 17: 17-20
• 17 Özcan U, Cao Q, Yilmaz E. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306: 457-461
• 18 Banuls C, Rovira-Llopis S, Martinez de Maranon A. et al. Metabolic syndrome enhances endoplasmic reticulum, oxidative stress and leukocyte-endothelium interactions in PCOS. Metabolism 2017; 71: 153-162
• 19 Apostolou A, Shen Y, Liang Y. et al. Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Exp Cell Res 2008; 314: 2454-2467
• 20 Cunha DA, Cito M, Grieco FA. et al. Pancreatic beta-cell protection from inflammatory stress by the endoplasmic reticulum proteins thrombospondin 1 and mesencephalic astrocyte-derived neutrotrophic factor (MANF). J Biol Chem 2017; 292: 14977-14988
• 21 Dooley J, Tian L, Schonefeldt S. et al. Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes. Nat Genet 2016; 48: 519-527
• 22 Galli E, Harkonen T, Sainio MT. et al. Increased circulating concentrations of mesencephalic astrocyte-derived neurotrophic factor in children with type 1 diabetes. Sci Rep 2016; 6: 29058
• 23 Danilova T, Belevich I, Li H. et al. MANF is required for the postnatal expansion and maintenance of pancreatic beta-cell mass in mice. Diabetes 2019; 68: 66-80
• 24 Lindahl M, Danilova T, Palm E. et al. MANF is indispensable for the proliferation and survival of pancreatic beta cells. Cell Rep 2014; 7: 366-375
• 25 Yavarna T, Al-Dewik N, Al-Mureikhi M. et al. High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders. Hum Genet 2015; 134: 967-980
• 26 Cen J, Sargsyan E, Forslund A. et al. Mechanisms of beneficial effects of metformin on fatty acid-treated human islets. J Mol Endocrinol 2018; 61: 91-99