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Hope vs hype: where are we in type 1 diabetes?

Jay S. Skyler

Investigators, patients and their families, and the public all wish for research to advance, to enable us to prevent or cure human type 1 diabetes. There has been much progress towards potentially achieving this; yet, there are a number of issues associated with conducting and reporting studies in this area. In this issue, Jay Skyler ( reviews how the reporting of research findings creates hope amongst patients. Sadly, headlines often overstate results and give hype to advances that are but one small step on the road to achievement of a clinically meaningful outcome. It is important to recognise the limitations of studies, such as those conducted in rodent models, and even pilot studies conducted in human beings. The entire scientific enterprise (investigators, funders, journal editors) collectively need to take responsibility for tempered and realistic reporting. Significant progress is being made, however, and with time, will result in clinically useful approaches to preventing and/or curing type 1 diabetes. The figures from this review are available as a downloadable slideset.

Blood pressure targets in type 2 diabetes. Evidence against or in favour of an aggressive approach

Giuseppe Mancia, Guido Grassi

The blood pressure targets to pursue with antihypertensive treatment are the subject of continuing debate. For the general hypertensive population, the current trend is to suggest blood pressure values <130/80 mmHg, based on meta-analyses of available randomised trials. For individuals with type 2 diabetes, however, the data from meta-analyses are less clear and information from trials is inconsistent, with some showing a maximal benefit for a systolic blood pressure (SBP) target of <140 mmHg, while others support an SBP <130 mmHg. In this issue, Mancia and Grassi ( review the evidence for and against these different targets. They conclude that, in type 2 diabetes, evidence is strong for blood pressure targets in the range of 130–140/70–80 mmHg, but that it is less compelling for lower blood pressure values. This is possibly due to vital organ underperfusion, leading to an increased cardiovascular risk (a ‘J curve’ phenomenon) or because lower blood pressure values are more commonly associated with serious side effects, resulting in treatment discontinuation, partially or completely offsetting any potential benefit that may eventually occur when SBP values reach <120 mmHg. However, further evidence is needed to resolve this fundamental issue and, ultimately, to ensure the maximally achievable cardiovascular protection of patients with diabetes and hypertension. The figures from this review are available as a downloadable slideset.

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Considerations and guidelines for mouse metabolic phenotyping in diabetes research

Thierry Alquier, Vincent Poitout

The advent of gene-targeting strategies in mice has enabled scientists to study the biological function and pathological role of genes implicated in metabolic physiology. However, metabolic phenotyping of pharmacological mouse models is not trivial and can be profoundly influenced by numerous methodological and genetic variables. In this issue, Alquier and Poitout ( review the most commonly used experimental tests to assess glucose and energy homeostasis in mice. They also provide some guidelines regarding the design, analysis and interpretation of these tests and identify important caveats and confounding factors that must be taken into account when drawing conclusions from the findings generated. In the context of the current reproducibility debate in biomedical sciences, this review also emphasises the importance of reporting methods accurately and transparently, acknowledging limitations and pitfalls, as well as reproducing the findings using complementary approaches. The figure from this review is available as a downloadable slide.

IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells

Alexandra Coomans de Brachène, Reinaldo S. Dos Santos, Laura Marroqui, Maikel L. Colli, Lorella Marselli, Raghavendra G. Mirmira, Piero Marchetti, Decio L. Eizirik

IFN-α, a cytokine present in islets of individuals with type 1 diabetes, plays a key role in the pathogenesis of diabetes. IFN-α upregulates islet inflammation, endoplasmic reticulum (ER) stress and MHC class I overexpression. Furthermore, it may contribute to presentation of beta cell autoantigens. In this issue, Coomans de Brachène and Dos Santos et al ( report that IFN-α-induced expression of inflammatory and ER stress markers in human beta cells returned to baseline after 24–48 h following removal of the cytokine, while MHC class I overexpression at the cell surface persisted for at least 7 days. Pretreatment with Janus kinase (JAK) inhibitors (mediators of IFN-α signalling) prevented IFN-α-induced MHC class I overexpression but, when added 24 h after IFN-α exposure, JAK inhibitors did not accelerate the return of MHC class I levels to baseline following IFN-α removal. These findings suggest that JAK inhibitors may protect beta cells in type 1 diabetes, but that these agents probably need to be introduced ahead of the clinical onset of disease.

Bioelectronic modulation of carotid sinus nerve activity in the rat: a potential therapeutic approach for type 2 diabetes

Joana F. Sacramento, Daniel J. Chew, Bernardete F. Melo, Matteo Donegá, Wesley Dopson, Maria P. Guarino, Alison Robinson, Jesus Prieto-Lloret, Sonal Patel, Bradley J. Holinski, Nishan Ramnarain, Victor Pikov, Kristoffer Famm, Silvia V. Conde

The carotid body, an organ classically defined as an oxygen sensor, regulates peripheral insulin sensitivity and glucose homeostasis, representing a novel therapeutic target for metabolic diseases. Surgical resection of the carotid body or of its sensitive nerve, the carotid sinus nerve (CSN), has been tested as a therapeutic approach for carotid body-mediated diseases. However, this procedure is prone to cause side effects. In this issue, Sacramento and Chew et al ( report that bioelectronic neuromodulation of the CSN by kilohertz frequency alternating current (KHFAC) restores insulin sensitivity and glucose tolerance in a rat model of type 2 diabetes. Additionally, the authors show that KHFAC neuromodulation of the CSN is reversible. These findings indicate that a bioelectronic medicine approach could bring significant improvements to care for type 2 diabetes, providing long-term glucose control and avoiding systemic effects, with negligible interference with daily activities. Thus, it is suggested that if these findings can be repeated in human studies, there is potential for this therapy to result in high treatment adherence and increased quality of life for individuals with metabolic diseases.

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Up front. Diabetologia 61, 507–508 (2018).

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