Nature Reviews Endocrinology

Diabetes mellitus has profound effects on multiple organ systems; however, the loss of vision caused by diabetic retinopathy might be one of the most impactful in a patient’s life. The retina is a highly metabolically active tissue that requires a complex interaction of cells, spanning light sensing photoreceptors to neurons that transfer the electrochemical signal to the brain with support by glia and vascular tissue. Neuronal function depends on a complex inter-dependency of retinal cells that includes the formation of a blood–retinal barrier. This dynamic system is negatively affected by diabetes mellitus, which alters normal cell–cell interactions and leads to profound vascular abnormalities, loss of the blood–retinal barrier and impaired neuronal function. Understanding the normal cell signalling interactions and how they are altered by diabetes mellitus has already led to novel therapies that have improved visual outcomes in many patients. Research highlighted in this Review has led to a new understanding of retinal pathophysiology during diabetes mellitus and has uncovered potential new therapeutic avenues to treat this debilitating disease.

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Clinical aspects of multiple endocrine neoplasia type 1

Abdallah Al-Salameh, Guillaume Cadiot, Alain Calender, Pierre Goudet & Philippe Chanson

doi : 10.1038/s41574-021-00468-3

Nature Reviews Endocrinology volume 17, pages207–224 (2021)

Multiple endocrine neoplasia type 1 (MEN1) is a rare syndrome characterized by the co-occurrence of primary hyperparathyroidism, duodenopancreatic neuroendocrine tumours (NETs) and/or pituitary adenomas. MEN1 can predispose patients to other endocrine and non-endocrine tumours, such as cutaneous tumours, central nervous system tumours and breast cancer. Endocrine tumours in patients with MEN1 differ from sporadic tumours in that they have a younger age at onset, present as multiple tumours in the same organ and have a different clinical course. Therefore, patients with overt MEN1 and those who carry a MEN1 mutation should be offered tailored biochemical and imaging screening to detect tumours and evaluate their progression over time. Fortunately, over the past 10 years, knowledge about the clinical phenotype of these tumours has markedly progressed, thanks to the implementation of national registries, particularly in France and the Netherlands. This Review provides an update on the clinical management of MEN1-related tumours. Epidemiology, the clinical picture, diagnostic work-up and the main lines of treatment for MEN1-related tumours are summarized. Controversial therapeutic aspects and issues that still need to be addressed are also discussed. Moreover, special attention is given to MEN1 manifestations in children and adolescents.

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Multikinase inhibitors in thyroid cancer: timing of targeted therapy

Matti L. Gild, Venessa H. M. Tsang, Roderick J. Clifton-Bligh & Bruce G. Robinson

doi : 10.1038/s41574-020-00465-y

Nature Reviews Endocrinology volume 17, pages225–234 (2021)

In the 9 years since the publication of our 2011 review of targeted treatment of thyroid cancer with multikinase inhibitors, much has changed in the landscape of this heterogeneous disease. New multikinase and selective inhibitor treatments for medullary thyroid cancer, radioiodine-refractory thyroid cancer and anaplastic thyroid cancer have completed trials and improved progression-free survival. Many physicians are concerned by dose-limiting adverse effects of these drugs and are wary to begin treatment in patients who are systemically well but have marked disease burden, which makes the timing of treatment initiation challenging. Published mechanistic data on tyrosine kinase inhibitors (TKIs) have helped guide our understanding of how to dose effectively with these drugs. A major goal in TKI therapy is to optimize inhibition of oncogenic kinase drivers while maintaining patient quality of life. Real-world data have now been published on how TKIs have fared outside the clinical trial environment. In this Review, we provide a summary of published data on the efficacy of TKIs in clinical practice, to provide clinicians with a more realistic view of how their patients will manage and respond to TKI therapy. Furthermore, we review the data on mechanisms of inhibition, outcomes and adverse effects of TKIs and provide an update on targeted treatment of thyroid cancer, focusing on optimizing the timing of treatment initiation.

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Immune dysfunction in developmental programming of type 2 diabetes mellitus

Thea N. Golden & Rebecca A. Simmons

doi : 10.1038/s41574-020-00464-z

Nature Reviews Endocrinology volume 17, pages235–245 (2021)

Intrauterine growth restriction (IUGR) is a common complication of pregnancy and increases the risk of the offspring developing type 2 diabetes mellitus (T2DM) later in life. Alterations in the immune system are implicated in the pathogenesis of IUGR-induced T2DM. The development of the fetal immune system is a delicate balance as it must remain tolerant of maternal antigens whilst also preparing for the post-birth environment. In addition, the fetal immune system is susceptible to an altered intrauterine milieu caused by maternal and placental inflammatory mediators or secondary to nutrient and oxygen deprivation. Pancreatic-resident macrophages populate the pancreas during fetal development, and their phenotype is dynamic through the neonatal period. Furthermore, macrophages in the islets are instrumental in islet development as they influence ?-cell proliferation and islet neogenesis. In addition, cytokines, derived from ?-cells and macrophages, are important to islet homeostasis in the fetus and adult and, when perturbed, can cause islet dysfunction. Several activated immune pathways have been identified in the islets of people who experienced IUGR, with alternations in the levels of IL-1? and IL-4 as well as changes in TGF? signalling. Leptin levels are also altered. Immunomodulation has shown therapeutic benefit in T2DM and might be particularly useful in IUGR-induced T2DM.

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From Wingspread to CLARITY: a personal trajectory

Ana M. Soto, Cheryl M. Schaeberle & Carlos Sonnenschein

doi : 10.1038/s41574-020-00460-3

Nature Reviews Endocrinology volume 17, pages247–256 (2021)

In the three decades since endocrine disruption was conceptualized at the Wingspread Conference, we have witnessed the growth of this multidisciplinary field and the accumulation of evidence showing the deleterious health effects of endocrine-disrupting chemicals. It is only within the past decade that, albeit slowly, some changes regarding regulatory measures have taken place. In this Perspective, we address some historical points regarding the advent of the endocrine disruption field and the conceptual changes that endocrine disruption brought about. We also provide our personal recollection of the events triggered by our serendipitous discovery of oestrogenic activity in plastic, a founder event in the field of endocrine disruption. This recollection ends with the CLARITY study as an example of a discordance between ‘science for its own sake’ and ‘regulatory science’ and leads us to offer a perspective that could be summarized by the motto attributed to Ludwig Boltzmann: “Nothing is more practical than a good theory”.

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