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In this new study the Authors demonstrated that the IGFBP3/TMEM219 pathway is a physiological regulator of pancreatic beta cell homeostasis and it is dysregulated in diabetes. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes. Loss of pancreatic beta cells is a central feature of type 1 (T1D) and type 2 (T2D) diabetes, but a therapeutic strategy to preserve beta cell mass remains to be established. Here we show that the death receptor TMEM219 is expressed on pancreatic beta cells and that signaling through its ligand insulin-like growth factor binding protein 3 (IGFBP3) leads to beta cell loss and dysfunction. Increased peripheral IGFBP3 was observed in established and at-risk T1D/T2D patients and was confirmed in T1D/T2D preclinical models, suggesting that dysfunctional IGFBP3/TMEM219 signaling is associated with abnormalities in beta cells homeostasis. In vitro and in vivo short-term IGFBP3/TMEM219 inhibition and TMEM219 genetic ablation preserved beta cells and prevented/delayed diabetes onset, while long-term IGFBP3/TMEM219 blockade allowed for beta cell expansion. Interestingly, in several patients cohorts restoration of appropriate IGFBP3 levels was associated with improved beta cell function. The IGFBP3/TMEM219 pathway is thus shown to be a physiological regulator of beta cell homeostasis and is also demonstrated to be disrupted in T1D/T2D. IGFBP3/TMEM219 targeting may therefore serve as a therapeutic option in diabetes. Funding Agencies|SID Lombardia Grant; EFSD/JDRF/Lilly Programme on Type 1 Diabetes Research; Italian Ministry of HealthMinistry of Health, Italy [RF-2016-02362512]; Universita di Milano; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DK104155]; Juvenile Diabetes Research FoundationJuvenile Diabetes Research Foundation; Enthera S.r.l.

BackgroundType 2 diabetes (T2D) is a common comorbidity in people living with HIV (PLWH). Anti-hyperglycemic treatment in PLWH is still a challenge, and no randomized controlled studies using new glucose-lowering agents are currently available.Case DescriptionA 55-year-old-women was admitted to our Diabetes Unit because of hyperosmolar hyperglycemic state (HHS) and sepsis. The medical history included HIV infection and insulin-treated diabetes. On clinical examination, the lady appeared dehydrated with dry buccal mucosa, tachycardia, altered mental status, genital infection, and fever. On admission, plasma glucose was 54.5 mmol/L, HbA1c 155 mmol/mol, osmolarity 389.4 mOsm/kg, bicarbonate 24.6 mmol/L with no detectable serum ketones. The patient was treated with i.v. fluid and insulin, and antibiotic therapy commenced. Upon HHS and sepsis resolution, a basal-bolus insulin therapy was implemented that was followed by significant improvement of daily glucose profiles and progressive reduction of insulin requirement until complete discontinuation. A low dose of metformin plus linagliptin was started. Since a severe atherosclerotic disease was diagnosed, a GLP-1 receptor agonist, dulaglutide, was added to metformin upon linagliptin withdrawal with maintenance of good glycemic control, treatment adherence and amelioration of quality of life and no side effects.ConclusionThis case suggests that GLP-1 receptor agonist therapy may be effective and safe for treatment of T2D with high cardiovascular risk in PLWH, supporting the need of clinical trials directly assessing the safety and the efficacy of GLP-1 receptor agonist in these individuals.

Additional file 1: Table S1. Demographics and baseline characteristics in the four patient groups. Figure S1. Patient enrollment and disposition

Funding Information: Sponsorship for this study and journal?s Rapid Service Fee were funded by Abbott Diabetes Care. Editorial assistance in the preparation of this manuscript was provided by Dr Robert Brines of Bite Medical Consulting. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. Thomas Danne and Alexander Seibold had the idea for the article, all authors contributed to the literature search and data analysis. Thomas Danne, Catarina Limbert and Alexander Seibold drafted the first version of the manuscript, all authors contributed to subsequent versions and read and approved the final manuscript. Editorial assistance in the preparation of this article was provided by Rob Brines and Wiebke Jessen. Support for this assistance was funded by Abbott Diabetes Care. Thomas Danne reports grants and personal fees from Abbott, AstraZeneca, Boehringer, DexCom, Lilly, Medtronic, Novo Nordisk, Roche, Sanofi outside the submitted work and is a shareholder of DreaMed Ltd. Catarina Limbert reports grants and personal fees from Abbott, Ipsen and Sanofi. Pratik Choudhary reports grants and personal fees from Abbott, Dexcom, Lilly, Novo Nordisk, Sanofi and Insulet. Manuel Puig-Domingo reports grants, consultant and speaker fees from Sanofi, Novo Nordisk, AstraZeneca, Lilly, Recordati, Pfizer, Ipsen and Novartis outside the submitted work. Eric Renard reports personal fees as consultant/advisor for Abbott, Air Liquide, AstraZeneca, Boehringer Ingelheim, Cellnovo, Dexcom, Eli Lilly, Insulet, Johnson & Johnson (Animas, LifeScan), Medirio, Medtronic, Novo Nordisk, Roche Diagnostics, Sanofi-Aventis and Tandem, and research grant/material support from Abbott, Dexcom, Insulet, Roche Diagnostics and Tandem. Stefano Del Prato has served on the scientific board and received honoraria for consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Merck & Co., Novartis Pharmaceuticals, Novo Nordisk, sanofi, servier, Takeda Pharmaceuticals. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Data sharing is not applicable to this article as no new data sets were generated during the current study. Funding Information: Sponsorship for this study and journal’s Rapid Service Fee were funded by Abbott Diabetes Care. Publisher Copyright: © 2021, The Author(s). People with diabetes are at greater risk for negative outcomes from COVID-19. Though this risk is multifactorial, poor glycaemic control before and during admission to hospital for COVID-19 is likely to contribute to the increased risk. The COVID-19 pandemic and restrictions on mobility and interaction can also be expected to impact on daily glucose management of people with diabetes. Telemonitoring of glucose metrics has been widely used during the pandemic in people with diabetes, including adults and children with T1D, allowing an exploration of the impact of COVID-19 inside and outside the hospital setting on glycaemic control. To date, 27 studies including 69,294 individuals with T1D have reported the effect of glycaemic control during the COVID-19 pandemic. Despite restricted access to diabetes clinics, glycaemic control has not deteriorated for 25/27 cohorts and improved in 23/27 study groups. Significantly, time in range (TIR) 70–180 mg/dL (3.9–10 mmol/L) increased across 19/27 cohorts with a median 3.3% (− 6.0% to 11.2%) change. Thirty per cent of the cohorts with TIR data reported an average clinically significant TIR improvement of 5% or more, possibly as a consequence of more accurate glucose monitoring and improved connectivity through telemedicine. Periodic consultations using telemedicine enables care of people with diabetes while limiting the need for in-person attendance at diabetes clinics. Reports that sustained hyperglycaemia and early-stage diabetic ketoacidosis may go untreated because of the lockdown and concerns about potential exposure to the risk of infection argue for wider access to glucose telemonitoring. Therefore, in this paper we have critically reviewed reports concerning use of telemonitoring in the acute hospitalized setting as well as during daily diabetes management. Furthermore, we discuss the indications and implications of adopting telemonitoring and telemedicine in the present challenging time, as well as their potential for the future. publishersversion published