Nature Reviews Endocrinology

Obesity and impaired metabolic health are established risk factors for the non-communicable diseases (NCDs) type 2 diabetes mellitus, cardiovascular disease, neurodegenerative diseases, cancer and nonalcoholic fatty liver disease, otherwise known as metabolic associated fatty liver disease (MAFLD). With the worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), obesity and impaired metabolic health also emerged as important determinants of severe coronavirus disease 2019 (COVID-19). Furthermore, novel findings indicate that specifically visceral obesity and characteristics of impaired metabolic health such as hyperglycaemia, hypertension and subclinical inflammation are associated with a high risk of severe COVID-19. In this Review, we highlight how obesity and impaired metabolic health increase complications and mortality in COVID-19. We also summarize the consequences of SARS-CoV-2 infection for organ function and risk of NCDs. In addition, we discuss data indicating that the COVID-19 pandemic could have serious consequences for the obesity epidemic. As obesity and impaired metabolic health are both accelerators and consequences of severe COVID-19, and might adversely influence the efficacy of COVID-19 vaccines, we propose strategies for the prevention and treatment of obesity and impaired metabolic health on a clinical and population level, particularly while the COVID-19 pandemic is present.

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Type 1 diabetes mellitus as a disease of the ?-cell (do not blame the immune system?)

Bart O. Roep, Sofia Thomaidou, René van Tienhoven & Arnaud Zaldumbide

doi : 10.1038/s41574-020-00443-4

Nature Reviews Endocrinology volume 17, pages150–161 (2021)

Type 1 diabetes mellitus is believed to result from destruction of the insulin-producing ?-cells in pancreatic islets that is mediated by autoimmune mechanisms. The classic view is that autoreactive T cells mistakenly destroy healthy (‘innocent’) ?-cells. We propose an alternative view in which the ?-cell is the key contributor to the disease. By their nature and function, ?-cells are prone to biosynthetic stress with limited measures for self-defence. ?-Cell stress provokes an immune attack that has considerable negative effects on the source of a vital hormone. This view would explain why immunotherapy at best delays progression of type 1 diabetes mellitus and points to opportunities to use therapies that revitalize ?-cells, in combination with immune intervention strategies, to reverse the disease. We present the case that dysfunction occurs in both the immune system and ?-cells, which provokes further dysfunction, and present the evidence leading to the consensus that islet autoimmunity is an essential component in the pathogenesis of type 1 diabetes mellitus. Next, we build the case for the ?-cell as the trigger of an autoimmune response, supported by analogies in cancer and antitumour immunity. Finally, we synthesize a model (‘connecting the dots’) in which both ?-cell stress and islet autoimmunity can be harnessed as targets for intervention strategies.

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Targeting lipid GPCRs to treat type 2 diabetes mellitus — progress and challenges

Julien Ghislain & Vincent Poitout

doi : 10.1038/s41574-020-00459-w

Nature Reviews Endocrinology volume 17, pages162–175 (2021)

Therapeutic approaches to the treatment of type 2 diabetes mellitus that are designed to increase insulin secretion either directly target ?-cells or indirectly target gastrointestinal enteroendocrine cells (EECs), which release hormones that modulate insulin secretion (for example, incretins). Given that ?-cells and EECs both express a large array of G protein-coupled receptors (GPCRs) that modulate insulin secretion, considerable research and development efforts have been undertaken to design therapeutic drugs targeting these GPCRs. Among them are GPCRs specific for free fatty acid ligands (lipid GPCRs), including free fatty acid receptor 1 (FFA1, otherwise known as GPR40), FFA2 (GPR43), FFA3 (GPR41) and FFA4 (GPR120), as well as the lipid metabolite binding glucose-dependent insulinotropic receptor (GPR119). These lipid GPCRs have demonstrated important roles in the control of islet and gut hormone secretion. Advances in lipid GPCR pharmacology have led to the identification of a number of synthetic agonists that exert beneficial effects on glucose homeostasis in preclinical studies. Yet, translation of these promising results to the clinic has so far been disappointing. In this Review, we present the physiological roles, pharmacology and clinical studies of these lipid receptors and discuss the challenges associated with their clinical development for the treatment of type 2 diabetes mellitus.

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Current practice in patients with differentiated thyroid cancer

Martin Schlumberger & Sophie Leboulleux

doi : 10.1038/s41574-020-00448-z

Nature Reviews Endocrinology volume 17, pages176–188 (2021)

Considerable changes have occurred in the management of differentiated thyroid cancer (DTC) during the past four decades, based on improved knowledge of the biology of DTC and on advances in therapy, including surgery, the use of radioactive iodine (radioiodine), thyroid hormone treatment and availability of recombinant human TSH. Improved diagnostic tools are available, including determining serum levels of thyroglobulin, neck ultrasonography, imaging (CT, MRI, SPECT–CT and PET–CT), and prognostic classifications have been improved. Patients with low-risk DTC, in whom the risk of thyroid cancer death is <1% and most recurrences can be cured, currently represent the majority of patients. By contrast, patients with high-risk DTC represent 5–10% of all patients. Most thyroid cancer-related deaths occur in this group of patients and recurrences are frequent. Patients with high-risk DTC require more aggressive treatment and follow-up than patients with low-risk DTC. Finally, the strategy for treating patients with intermediate-risk DTC is frequently defined on a case-by-case basis. Prospective trials are needed in well-selected patients with DTC to demonstrate the extent to which treatment and follow-up can be limited without increasing the risk of recurrence and thyroid cancer-related death.

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Autonomic dyshomeostasis in patients with diabetes mellitus during COVID-19

Virginia Boccardi

doi : 10.1038/s41574-021-00466-5

Nature Reviews Endocrinology volume 17, page189 (2021)

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Reply to: Autonomic dyshomeostasis in patients with diabetes mellitus during COVID-19

Soo Lim, Jae Hyun Bae, Hyuk-Sang Kwon & Michael A. Nauck

doi : 10.1038/s41574-021-00467-4

Nature Reviews Endocrinology volume 17, pages189–190 (2021)

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