MANF and Diabetes

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a secreted protein that can rescue brain neurons and heart muscle cells from cell death in animal models for Parkinson´s disease, but also in brain and heart ischemia [1]. It is upregulated in cells that actively secrete proteins, and in various situations where protein aggregates accumulate in the endoplasmic reticulum (ER), causing ER stress. The exact mechanism of MANF action is still unknown.

We developed MANF knockout mice, which lack the gene that encodes the MANF protein in all cells. These mice develop severe insulin-deficient diabetes due to progressive postnatal reduction of the β-cell mass, caused by decreased β-cell proliferation and increased β-cell death [2]. Importantly, MANF is needed for the survival of adult mouse β-cells, as induced removal of MANF from this cell population in mice leads to β-cell loss and diabetes [3]. ER stress and sustained activation of the UPR was found to be one of the mechanisms underpinning the destruction of MANF-deficient β-cells in this model. In a separate mouse model of type 1 diabetes, we found that over-expression of MANF in the pancreas enhances β-cell proliferation and prevents β-cell death. Furthermore, recombinant MANF protein stimulates mouse and human islet β-cell proliferation and protection in culture [2-6]. Importantly, collaborative efforts revealed that lack of MANF in humans result in diabetes, with impaired insulin processing and b-cell failure due to increased b-cell ER stress, similarly to MANF knockout mice [7]. Thus, our results demonstrate that MANF constitutes a novel promising therapeutic candidate for β-cell protection and regeneration in diabetes.

When we examined newly diagnosed type 1 diabetic patients, MANF levels were increased in sera [8] suggesting that MANF can potentially serve as a diagnostic biomarker for young children diagnosed for type 1 diabetes.

Given these clear advances in understanding the role that MANF plays in β cells and diabetes, our group is continuing to pursue studies into the mechanisms of MANF action in β cells, as well as other metabolic tissues using transgenic, knockout, and diabetic mouse models.

References:

  1. Lindahl, M., Saarma, M., Lindholm, P. Unconventional neurotrophic factors CDNF and MANF: Structure, physiological functions and therapeutic potential. Neurobiol. Dis., 97 (Pt B): 90-102 (2017). 10.1016/j.nbd.2016.07.009
  2. Lindahl, M., Danilova, T., Palm, E., Lindholm, P., Võikar, V., Hakonen, E., Ustinov, J., Andressoo, J.-O., Harvey, B. K., Otonkoski, T., Rossi, J. and Saarma, M. MANF is indispensable for the proliferation and survival of pancreatic b-cells. Cell Rep, 7 (2), 366-75 (2014). 10.1016/j.celrep.2014.03.023
  3. Danilova, T., Belevich, I., Li, H., Palm, E., Jokitalo, E., Otonkoski, T., Lindahl, M. MANF is required for the postnatal expansion and maintenance of the pancreatic b-cell mass in mice. Diabetes, 2018 Oct 10. 10.2337/db17-1149
  4. Danilova, T. and Lindahl, M., Emerging roles for mesencephalic astrocyte-derived neurotrophic factor (MANF) in pancreatic beta cells and diabetes. Front. Physiol. 2018, 9: 1457. 10.3389/fphys.2018.01457
  5. Cunha, D.A., Cito, M., Grieco, F.A., Cosentino, C., Danilova, T., Ladrière, L., Lindahl, M., Domanskyi, A., Bugliani, M., Marchetti, P., Eizirik, D.L., Cnop, M. Pancreatic β-cell protection from inflammatory stress by the endoplasmic reticulum proteins thrombospondin 1 and mesencephalic astrocyte-derived neutrotrophic factor (MANF). J Biol Chem 2017 Sep 8;292(36):14977-14988. 10.1074/jbc.M116.769877
  6. Hakonen, E, Chandra, V, Fogarty, C.L., Yu, N.Y., Ustinov, J., Katayama, S., Galli, E., Danilova, T., Lindholm, P., Vartiainen, A., Einarsdottir, E., Krjutškov, K., Kere, J., Saarma, M., Lindahl, M., Otonkoski, T. MANF protects human pancreatic beta cells against stress-induced cell death. Diabetologia, 2018, 61(19):2202-2214. 10.1007/s00125-018-4687-y
  7. Montaser, H., Patel, KA., Balboa, D., Ibrahim, H., Lithovius, V., Näätänen, A., Chandra, V., Demir, K., Acar, S., Ben-Omran, T., Colclough, K., Locke, JM., Wakeling, M., Lindahl, M., Hattersley, A., Saarimäki-Vire, J., Otonkoski, T. Loss of MANF causes childhood-onset syndromic diabetes due to increased endoplasmic reticulum stress. Diabetes, Jan 2021. 10.2337/db20-1174
  8. Galli, E., Härkönen, T., Sainio, M.T., Ustav, M., Toots, U., Urtti, A., Yliperttula, M., Lindahl, M., Knip, M., Saarma, M., Lindholm, P. Increased circulating concentrations of mesencephalic astrocyte-derived neurotrophic factor in children with type 1 diabetes. Sci Rep, June 30, 6: 29058 (2016). 10.1038/srep29058