Islets-on-Chip: A Tool for Real-Time Assessment of Islet Function Prior to Transplantation.

Islet transplantation improves metabolic control in patients with unstable type 1 diabetes. Clinical outcomes have been improving over the last decade, and the widely used beta-score allows the evaluation of transplantation results. However, predictive pre-transplantation criteria of islet quality for clinical outcomes are lacking. In this proof-of-concept study, we examined whether characterization of the electrical activity of donor islets could provide a criterion. Aliquots of 8 human donor islets from the STABILOT study, sampled from islet preparations before transplantation, were characterized for purity and split for glucose-induced insulin secretion and electrical activity using multi-electrode-arrays. The latter tests glucose concentration dependencies, biphasic activity, hormones, and drug effects (adrenalin, GLP-1, glibenclamide) and provides a ranking of CHIP-scores from 1 to 6 (best) based on electrical islet activity. The analysis was performed online in real time using a dedicated board or offline. Grouping of beta-scores and CHIP-scores with high, intermediate, and low values was observed. Further analysis indicated correlation between CHIP-score and beta-score, although significance was not attained (R = 0.51, p = 0.1). This novel approach is easily implantable in islet isolation units and might provide means for the prediction of clinical outcomes. We acknowledge the small cohort size as the limitation of this pilot study.

[Place of the insulin pump for the treatment of type 2 diabetic patients]. / Place de la pompe à insuline pour le traitement des patients avec un diabète de type 2.

Continuous subcutaneous insulin infusion devices, commonly called insulin pumps, have been used for the treatment of patients with type 1 diabetes for several years. The benefits on glycemic control and on the quality of life of these patients are clear and well documented in the literature. On the other hand, their use in insulin-requiring patients with type 2 diabetes is less widespread. However, studies have shown that this therapeutic option is safe and effective for this population as well. In all cases, individualized assessment and follow-up by a specialized multidisciplinary care team is necessary to support patients with type 2 diabetes for whom an insulin pump is considered. We propose to describe here the current state of this clinical practice.

Les dispositifs de perfusion sous-cutanée continue d'insuline, communément appelés pompes à insuline, sont utilisés pour le traitement des patients avec un diabète de type 1 (PDT1) depuis plusieurs années. Les bénéfices sur le contrôle glycémique et sur la qualité de vie de ces patients sont clairs et bien documentés dans la littérature. En revanche, leur utilisation chez les patients avec un diabète de type 2 (PDT2) insulino-requérants est moins répandue. Pourtant, des études ont démontré que cette thérapie est également sûre et efficace pour cette population. Dans tous les cas, une évaluation et un suivi individualisé par une équipe de soins multidisciplinaire spécialisée est nécessaire pour accompagner les PDT2 chez qui on considère une pompe à insuline. Dans cet article, nous ferons le point sur l'état actuel de cette pratique clinique.

Direct reprogramming of human fibroblasts into insulin-producing cells using transcription factors.

Direct lineage reprogramming of one somatic cell into another without transitioning through a progenitor stage has emerged as a strategy to generate clinically relevant cell types. One cell type of interest is the pancreatic insulin-producing ß cell whose loss and/or dysfunction leads to diabetes. To date it has been possible to create ß-like cells from related endodermal cell types by forcing the expression of developmental transcription factors, but not from more distant cell lineages like fibroblasts. In light of the therapeutic benefits of choosing an accessible cell type as the cell of origin, in this study we set out to analyze the feasibility of transforming human skin fibroblasts into ß-like cells. We describe how the timed-introduction of five developmental transcription factors (Neurog3, Pdx1, MafA, Pax4, and Nkx2-2) promotes conversion of fibroblasts toward a ß-cell fate. Reprogrammed cells exhibit ß-cell features including ß-cell gene expression and glucose-responsive intracellular calcium mobilization. Moreover, reprogrammed cells display glucose-induced insulin secretion in vitro and in vivo. This work provides proof-of-concept of the capacity to make insulin-producing cells from human fibroblasts via transcription factor-mediated direct reprogramming.

Prolonged culture of human pancreatic islets under glucotoxic conditions changes their acute beta cell calcium and insulin secretion glucose response curves from sigmoid to bell-shaped.

AIMS/HYPOTHESIS: The rapid remission of type 2 diabetes by a diet very low in energy correlates with a marked improvement in glucose-stimulated insulin secretion (GSIS), emphasising the role of beta cell dysfunction in the early stages of the disease. In search of novel mechanisms of beta cell dysfunction after long-term exposure to mild to severe glucotoxic conditions, we extensively characterised the alterations in insulin secretion and upstream coupling events in human islets cultured for 1-3 weeks at ~5, 8, 10 or 20 mmol/l glucose and subsequently stimulated by an acute stepwise increase in glucose concentration. METHODS: Human islets from 49 non-diabetic donors (ND-islets) and six type 2 diabetic donors (T2D-islets) were obtained from five isolation centres. After shipment, the islets were precultured for 3-7 days in RPMI medium containing ~5 mmol/l glucose and 10% (vol/vol) heat-inactivated FBS with selective islet picking at each medium renewal. Islets were then cultured for 1-3 weeks in RPMI containing ~5, 8, 10 or 20 mmol/l glucose before measurement of insulin secretion during culture, islet insulin and DNA content, beta cell apoptosis and cytosolic and mitochondrial glutathione redox state, and assessment of dynamic insulin secretion and upstream coupling events during acute stepwise stimulation with glucose [NAD(P)H autofluorescence, ATP/(ATP+ADP) ratio, electrical activity, cytosolic Ca2+ concentration ([Ca2+]c)]. RESULTS: Culture of ND-islets for 1-3 weeks at 8, 10 or 20 vs 5 mmol/l glucose did not significantly increase beta cell apoptosis or oxidative stress but decreased insulin content in a concentration-dependent manner and increased beta cell sensitivity to subsequent acute stimulation with glucose. Islet glucose responsiveness was higher after culture at 8 or 10 vs 5 mmol/l glucose and markedly reduced after culture at 20 vs 5 mmol/l glucose. In addition, the [Ca2+]c and insulin secretion responses to acute stepwise stimulation with glucose were no longer sigmoid but bell-shaped, with maximal stimulation at 5 or 10 mmol/l glucose and rapid sustained inhibition above that concentration. Such paradoxical inhibition was, however, no longer observed when islets were acutely depolarised by 30 mmol/l extracellular K+. The glucotoxic alterations of beta cell function were fully reversible after culture at 5 mmol/l glucose and were mimicked by pharmacological activation of glucokinase during culture at 5 mmol/l glucose. Similar results to those seen in ND-islets were obtained in T2D-islets, except that their rate of insulin secretion during culture at 8 and 20 mmol/l glucose was lower, their cytosolic glutathione oxidation increased after culture at 8 and 20 mmol/l glucose, and the alterations in GSIS and upstream coupling events were greater after culture at 8 mmol/l glucose. CONCLUSIONS/INTERPRETATION: Prolonged culture of human islets under moderate to severe glucotoxic conditions markedly increased their glucose sensitivity and revealed a bell-shaped acute glucose response curve for changes in [Ca2+]c and insulin secretion, with maximal stimulation at 5 or 10 mmol/l glucose and rapid inhibition above that concentration. This novel glucotoxic alteration may contribute to beta cell dysfunction in type 2 diabetes independently from a detectable increase in beta cell apoptosis.

[Treatment of congestive heart failure in older persons and SGLT2 inhibitors - Having your patient's best interests at heart]. / Traitement de l'insuffisance cardiaque chez la personne âgée et inhibiteurs du SGLT2 - En avoir le cœur net.

The treatment and management of heart failure (HF) are constantly evolving. The latest guidelines recommend the use of SGLT2 inhibitors (SGLT2i) as an integral part to treating HF with reduced ejection fraction (< 40%). However, given that the patients included in these trials do not reflect the heterogeneity of the health of many elderly patients, we recommend basing the therapeutic decision on the patient's state of frailty. If a SGLT2i treatment at a standard dose (10 mg 1x/day) is recommended for robust patients, we suggest initiating treatment at 5 mg 1x/day for vulnerable patients, and then after 1 month increasing the dose to 10 mg 1x/day. Finally, for dependent patients, we recommend therapeutic abstention in the absence of sufficient scientific evidence.

La prise en charge de l'insuffisance cardiaque (IC) est en constante évolution. Les dernières recommandations préconisent l'utilisation des inhibiteurs du SGLT2 (iSGLT2) pour le traitement de l'IC à fraction d'éjection réduite (< 40%). Cependant, les populations des études ne reflètent pas l'hétérogénéité de la population âgée en termes de santé et nous proposons de baser la décision thérapeutique selon la Clinical Frailty Scale : si, pour les patients robustes, un traitement par iSGLT2 à dose standard (10 mg 1 x/jour) est préconisé, nous proposons, pour les patients vulnérables, d'initier le traitement à 5 mg 1 x/jour, puis d'augmenter à 10 mg 1 x/jour après 1 mois. Finalement, pour les patients dépendants, nous recommandons une abstention thérapeutique en l'absence d'évidences scientifiques suffisantes.

Canakinumab in patients with COVID-19 and type 2 diabetes - A multicentre, randomised, double-blind, placebo-controlled trial.

Background: Patients with type 2 diabetes and obesity have chronic activation of the innate immune system possibly contributing to the higher risk of hyperinflammatory response to SARS-CoV2 and severe COVID-19 observed in this population. We tested whether interleukin-1ß (IL-1ß) blockade using canakinumab improves clinical outcome. Methods: CanCovDia was a multicenter, randomised, double-blind, placebo-controlled trial to assess the efficacy of canakinumab plus standard-of-care compared with placebo plus standard-of-care in patients with type 2 diabetes and a BMI > 25 kg/m2 hospitalised with SARS-CoV2 infection in seven tertiary-hospitals in Switzerland. Patients were randomly assigned 1:1 to a single intravenous dose of canakinumab (body weight adapted dose of 450-750 mg) or placebo. Canakinumab and placebo were compared based on an unmatched win-ratio approach based on length of survival, ventilation, ICU stay and hospitalization at day 29. This study is registered with ClinicalTrials.gov, NCT04510493. Findings: Between October 17, 2020, and May 12, 2021, 116 patients were randomly assigned with 58 in each group. One participant dropped out in each group for the primary analysis. At the time of randomization, 85 patients (74·6 %) were treated with dexamethasone. The win-ratio of canakinumab vs placebo was 1·08 (95 % CI 0·69-1·69; p = 0·72). During four weeks, in the canakinumab vs placebo group 4 (7·0%) vs 7 (12·3%) participants died, 11 (20·0 %) vs 16 (28·1%) patients were on ICU, 12 (23·5 %) vs 11 (21·6%) were hospitalised for more than 3 weeks, respectively. Median ventilation time at four weeks in the canakinumab vs placebo group was 10 [IQR 6.0, 16.5] and 16 days [IQR 14.0, 23.0], respectively. There was no statistically significant difference in HbA1c after four weeks despite a lower number of anti-diabetes drug administered in patients treated with canakinumab. Finally, high-sensitive CRP and IL-6 was lowered by canakinumab. Serious adverse events were reported in 13 patients (11·4%) in each group. Interpretation: In patients with type 2 diabetes who were hospitalised with COVID-19, treatment with canakinumab in addition to standard-of-care did not result in a statistically significant improvement of the primary composite outcome. Patients treated with canakinumab required significantly less anti-diabetes drugs to achieve similar glycaemic control. Canakinumab was associated with a prolonged reduction of systemic inflammation. Funding: Swiss National Science Foundation grant #198415 and University of Basel. Novartis supplied study medication.

[Rapid and ultrarapid insulins: when and how?] / Insulines rapides et ultrarapides : quelles indications et utilités ?

Treatment combining long-acting and short-acting insulins is essential for people with type 1 diabetes, but may become also compulsory in other forms of diabetes in case of insulinopenia. The purpose of short-acting insulins is to mimic physiological insulin secretion in response to carbohydrate intake at meals. There is a delay between the injection and its action, sometimes limiting their use and effectiveness. Ultra-rapid insulins have been developed to more closely approximate the expected insulin response to a meal, through faster absorption. They do not improve diabetes control but allow more flexibility with mealtime injections. These new analogues are also an attractive alternative for use in insulin pumps.

Un traitement combinant insulines lente et rapide est essentiel pour les personnes avec un diabète de type 1, mais peut le devenir dans d'autres formes de diabète en cas d'insulinopénie. Le but des insulines rapides est de mimer la sécrétion physiologique d'insuline en réponse à la prise de glucides aux repas. Il y a un délai entre l'injection et son action, limitant parfois leur usage et leur efficacité. Des insulines ultrarapides ont été développées pour se rapprocher davantage de la réponse insulinique attendue à un repas, grâce à une absorption plus rapide. Elles n'améliorent pas le contrôle du diabète mais permettent plus de flexibilité avec les injections aux repas. Ces nouveaux analogues sont également une alternative intéressante pour une utilisation dans les pompes à insuline.

[Continuous glucose monitoring Respective roles of healthcare professionals and quick interpretation guide]. / Mesure continue du glucose - Rôles respectifs des personnels de santé et guide d'interprétation rapide.

The use of continuous interstitial glucose measurement systems (CGM) has revolutionized the management of patients with diabetes for 15 years. This is true both for professional use (diagnostic CGM) and personal use for patients (therapeutic CGM). The role of health professionals - general practitioners, diabetologists, nurses, dieticians - is important to coordinate, with a specific role for each. The clinical situations are all different and the systematic analysis of the data has ideally to be carried out with the participation of the patient. These devices allow significant improvements in glycemic control, making this technology one of the most important advances in diabetes for many years.

L'utilisation des systèmes de mesure continue du glucose interstitiel (CGM) révolutionne la prise en charge des patients avec diabète depuis 15 ans, cela aussi bien pour l'usage professionnel (CGM diagnostique) que personnel pour le patient avec diabète de type 1 ou 2 (CGM thérapeutique). Le rôle des différents professionnels de la santé ­ médecins, infirmier-ère-s, diététicien-nes ­ est important à coordonner, avec un rôle possiblement spécifique de chacun. Les situations cliniques sont diverses et l'analyse systématique des données doit s'effectuer idéalement avec la participation du patient. Ces dispositifs permettent des améliorations importantes de l'équilibre glycémique faisant de cette technologie l'une des avancées les plus importantes en diabétologie depuis de très nombreuses années.

Real world hypoglycaemia related to glucose variability and Flash glucose scan frequency assessed from global FreeStyle Libre data.

AIM: Flash glucose monitoring provides a range of glucose metrics. In the current study, we aim to identify those that indicate that glycaemic targets can be consistently met and contrast the total (t-CV) and within-day coefficient of variation (wd-CV) to guide the assessment of glucose variability and hypoglycaemia exposure. METHODS: De-identified data from Flash readers were collected. The readers were sorted into 10 equally sized groups of scan frequency followed by quartiles of estimated A1c (eA1c). A similar grouping was performed for the total coefficient of variation (t-CV) and within-day coefficient of variation (wd-CV). In addition, analysis of the association of time below 54 mg/dl and glucose variability measured by t-CV and wd-CV was performed. RESULTS: The dataset included 1 002 946 readers. Readers sorted by 10 equal groups of scan rate and quartiles by eA1c, t-CV and wd-CV represented 25 074 readers per group. The association of lower eA1c with higher time in range and reduced time above range was clear. The correlation of eA1c quartiles and time below range was not consistent. An association between glucose variability and hypoglycaemia was found. Both wd-CV and t-CV were associated with time below range. For achieving the consensus target of <1% time below 54 mg/dl, the associated wd-CV and t-CV values were 33.5% and 39.5%, respectively. CONCLUSIONS: The type of CV reported by the different continuous glucose monitoring systems should be acknowledged. CV <36% might not be adequate to ensure low hypoglycaemia exposure. To our knowledge, the majority of continuous glucose monitoring reports the t-CV. Appropriate thresholds should be used to identify patients that would probably meet time below range targets (t-CV <40% or wd-CV <34%).

The nuclear receptor REV-ERBα is implicated in the alteration of ß-cell autophagy and survival under diabetogenic conditions.

Pancreatic ß-cell failure in type 2 diabetes mellitus (T2DM) is associated with impaired regulation of autophagy which controls ß-cell development, function, and survival through clearance of misfolded proteins and damaged organelles. However, the mechanisms responsible for defective autophagy in T2DM ß-cells remain unknown. Since recent studies identified circadian clock transcriptional repressor REV-ERBα as a novel regulator of autophagy in cancer, in this study we set out to test whether REV-ERBα-mediated inhibition of autophagy contributes to the ß-cell failure in T2DM. Our study provides evidence that common diabetogenic stressors (e.g., glucotoxicity and cytokine-mediated inflammation) augment ß-cell REV-ERBα expression and impair ß-cell autophagy and survival. Notably, pharmacological activation of REV-ERBα was shown to phenocopy effects of diabetogenic stressors on the ß-cell through inhibition of autophagic flux, survival, and insulin secretion. In contrast, negative modulation of REV-ERBα was shown to provide partial protection from inflammation and glucotoxicity-induced ß-cell failure. Finally, using bioinformatic approaches, we provide further supporting evidence for augmented REV-ERBα activity in T2DM human islets associated with impaired transcriptional regulation of autophagy and protein degradation pathways. In conclusion, our study reveals a previously unexplored causative relationship between REV-ERBα expression, inhibition of autophagy, and ß-cell failure in T2DM.

LDHA is enriched in human islet alpha cells and upregulated in type 2 diabetes.

The lactate dehydrogenase isoform A (LDHA) is a key metabolic enzyme that preferentially catalyzes the conversion of pyruvate to lactate. Whereas LDHA is highly expressed in many tissues, its expression is turned off in the differentiated adult ß-cell within the pancreatic islets. The repression of LDHA under normal physiological condition and its inappropriate upregulation under a diabetogenic environment is well-documented in rodent islets/ß-cells but little is known about LDHA expression in human islet cells and whether its abundance is altered under diabetic conditions. Analysis of public single-cell RNA-seq (sc-RNA seq) data as well as cell type-specific immunolabeling of human pancreatic islets showed that LDHA was mainly localized in human α-cells while it is expressed at a very low level in ß-cells. Furthermore, LDHA, both at mRNA and protein, as well as lactate production is upregulated in human pancreatic islets exposed to chronic high glucose treatment. Microscopic analysis of stressed human islets and autopsy pancreases from individuals with type 2 diabetes (T2D) showed LDHA upregulation mainly in human α-cells. Pharmacological inhibition of LDHA in isolated human islets enhanced insulin secretion under physiological conditions but did not significantly correct the deregulated secretion of insulin or glucagon under diabetic conditions.

SGLT2 Inhibitors, What the Emergency Physician Needs to Know: A Narrative Review.

Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin belong to a class of antidiabetic treatments referred to as sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors, or SGLT2is). SGLT2is are currently indicated in North America and in Europe in type 2 diabetes mellitus, especially in patients with cardiovascular (CV) disease, high CV risk, heart failure, or renal disease. In Europe, dapagliflozin is also approved as an adjunct to insulin in patients with type 1 diabetes mellitus. New data provide evidence for benefits in heart failure with reduced ejection fraction and chronic kidney disease, including in patients without diabetes. The use of SGLT2is is expected to increase, suggesting that a growing number of patients will present to the emergency departments with these drugs. Most common adverse events are easily treatable, including mild genitourinary infections and conditions related to volume depletion. However, attention must be paid to some potentially serious adverse events, such as hypoglycemia (when combined with insulin or insulin secretagogues), lower limb ischemia, and diabetic ketoacidosis. We provide an up-to-date practical guide highlighting important elements on the adverse effects of SGLT2is and their handling in some frequently encountered clinical situations such as acute heart failure and decompensated diabetes.

[New-onset diabetes and novel targeted therapies against cancer]. / Diabète secondaire aux nouvelles thérapies ciblées contre le cancer.

New systemic cancer therapies are increasingly oriented towards specific signaling pathways involved in carcinogenesis. However, these new treatments may lead to disorders of glycemic homeostasis ranging from glucose intolerance, diabetes or the occurrence of severe acute hyperglycemic syndrome due to blockade of certain pathways common to glucose metabolism. This article discusses the estimated frequency of new-onset diabetes, the pathophysiological mechanisms as well as the diagnostic, therapeutic, monitoring and prognostic management of glycemic dysfunction in patients treated with these novel systemic cancer therapies.

Les nouvelles thérapies du cancer sont de plus en plus orientées contre des voies de signalisation spécifiques à la carcinogenèse. Cependant, ces nouveaux traitements peuvent mener à des troubles de l'homéostasie glucidique, allant d'une intolérance au glucose au diabète insulinorequérant, avec une potentielle décompensation aiguë, en raison du blocage de certaines voies communes à l'homéostasie glucidique. Cet article discute de la fréquence estimée de la survenue du diabète, des mécanismes physiopathologiques ainsi que de la prise en charge diagnostique et thérapeutique, de la surveillance et du pronostic de la dysfonction glycémique chez les patients traités par ces nouvelles thérapies contre le cancer.

[Basal insulin therapy in patients with type 2 diabetes]. / Insulinothérapie basale chez les patients diabétiques de type 2.

Insulin therapy, often initiated after hygiene and dietary measures and non-insulin antidiabetics, is part of the treatment of patients with type 2 diabetes. Fear of injections or hypoglycemia often delays its implementation. However, its introduction is recommended in cases of poorly balanced diabetes despite a well-controlled therapeutic escalation but also in cases of acute imbalance. Introduction of insulin therapy requires patient education and close monitoring by the healthcare team. Type of insulin and its titration reduce the incidence of hypoglycemia in patients at risk. The determination of the fasting glycemic target - relative to HbA1c - for the titration of insulin is important to define for an optimal benefit (prevention of secondary complications)/risk (hypoglycemia, weight gain) balance.

L'insulinothérapie, souvent mise en place après les mesures hygiéno-diététiques et les antidiabétiques non insuliniques, fait partie du traitement des patients diabétiques de type 2. La peur des injections ou des hypoglycémies retarde souvent sa mise en place. Cependant, son introduction est recommandée en cas de diabète mal équilibré malgré une escalade thérapeutique bien conduite mais aussi en cas de déséquilibre aigu. L'insulinothérapie implique un enseignement au patient et un suivi rapproché par l'équipe soignante. Le type d'insuline et sa titration progressive permettent de réduire l'incidence des hypoglycémies chez les patients à risque. La détermination de la cible glycémique pour la titration de l'insuline est importante à définir pour une balance bénéfice (prévention des complications secondaires)/risque (hypoglycémie, prise pondérale) optimale.

Ten-year outcomes of islet transplantation in patients with type 1 diabetes: Data from the Swiss-French GRAGIL network.

To describe the 10-year outcomes of islet transplantation within the Swiss-French GRAGIL Network, in patients with type 1 diabetes experiencing high glucose variability associated with severe hypoglycemia and/or with functional kidney graft. We conducted a retrospective analysis of all subjects transplanted in the GRAGIL-1c and GARGIL-2 islet transplantation trials and analyzed components of metabolic control, graft function and safety outcomes over the 10-year period of follow-up. Forty-four patients were included between September 2003 and April 2010. Thirty-one patients completed a 10-year follow-up. Ten years after islet transplantation, median HbA1c was 7.2% (6.2-8.0) (55 mmol/mol [44-64]) versus 8.0% (7.1-9.1) (64 mmol/mol [54-76]) before transplantation (p < .001). Seventeen of 23 (73.9%) recipients were free of severe hypoglycemia, 1/21 patients (4.8%) was insulin-independent and median C-peptide was 0.6 ng/ml (0.2-1.2). Insulin requirements (UI/kg/day) were 0.3 (0.1-0.5) versus 0.5 (0.4-0.6) before transplantation (p < .001). Median (IQR) ß-score was 1 (0-4) (p < .05 when comparing with pre-transplantation values) and 51.9% recipients had a functional islet graft at 10 years. With a 10-year follow-up in a multicentric network, islet transplantation provided sustained improvement of glycemic control and was efficient to prevent severe hypoglycemia in almost 75% of the recipients.