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  • Review Article
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Importance of oestrogen receptors to preserve functional β-cell mass in diabetes

Nature Reviews Endocrinology volume 8, pages 342–351 (2012)Cite this article

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Abstract

Protecting the functional mass of insulin-producing β cells of the pancreas is a major therapeutic challenge in patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). The gonadal hormone 17β-oestradiol (E2) is involved in reproductive, bone, cardiovascular and neuronal physiology. In rodent models of T1DM and T2DM, treatment with E2 protects pancreatic β cells against oxidative stress, amyloid polypeptide toxicity, lipotoxicity and apoptosis. Three oestrogen receptors (ERs)—ERα, ERβ and the G protein-coupled ER (GPER)—have been identified in rodent and human β cells. Whereas activation of ERα enhances glucose-stimulated insulin biosynthesis, reduces islet toxic lipid accumulation and promotes β-cell survival from proapoptotic stimuli, activation of ERβ increases glucose-stimulated insulin secretion. However, activation of GPER protects β cells from apoptosis, raises glucose-stimulated insulin secretion and lipid homeostasis without affecting insulin biosynthesis. Oestrogens are also improving islet engraftment in rodent models of pancreatic islet transplantation. This Review describes developments in the role of ERs in islet insulin biosynthesis and secretion, lipid homeostasis and survival. Moreover, we discuss why and how enhancing ER action in β cells without the undesirable effect of general oestrogen therapy is a therapeutic avenue to preserve functional β-cell mass in patients with diabetes mellitus.

Key Points

  • Oestrogen prevents β-cell failure in most common rodent models of β-cell failure

  • Activation of oestrogen receptor (ER) α promotes β-cell survival, insulin biosynthesis and lipid homeostasis

  • Activation of ERβ enhances glucose-stimulated insulin secretion

  • Activation of G protein-coupled receptor ER (GPER) protects β cells from apoptosis, enhances glucose-stimulated insulin secretion and lipid homeostasis

  • The action of ERs in β cells is mediated via extranuclear ERs

  • Enhancing ER action in β cells without the undesirable effect of general oestrogen therapy is a therapeutic avenue to preserve functional β-cell mass in patients with diabetes mellitus

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Figure 1: Crosstalk between pancreatic β cells and other organs in the regulation of glucose homeostasis.
Figure 2: Overview of ER signalling.
Figure 3: Integration of ERs with other β-cell receptors influencing β-cell mass and/or function.

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Acknowledgements

The authors' work was supported by grants from the NIH (RO1 DK074970, P50 HD044405), the Juvenile Diabetes Research Foundation (1-2006-837), the March of Dimes (6-FY7-312) and the American Heart Association (11IRG5570010). J. P. Tiano was supported in part by NIH Training Grant T32 DK007169.

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  1. Division of Endocrinology, Feinberg School of Medicine, Metabolism and Molecular Medicine and Comprehensive Center on Obesity, Northwestern University, 303 East Chicago Avenue, Tarry 15-761, Chicago, 60611, IL, USA

    Joseph P. Tiano & Franck Mauvais-Jarvis

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Both authors contributed equally to all aspects of the article.

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Correspondence to Franck Mauvais-Jarvis.

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J. P. Tiano declares no competing interests. F. Mauvais-Jarvis declares an association with the following company: Pfizer (grant/research support).

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Tiano, J., Mauvais-Jarvis, F. Importance of oestrogen receptors to preserve functional β-cell mass in diabetes. Nat Rev Endocrinol 8, 342–351 (2012). https://doi.org/10.1038/nrendo.2011.242

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