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The nephrological perspective on SGLT-2 inhibitors in type 1 diabetes.
Gillard, P, Schnell, O, Groop, PH
Diabetes research and clinical practice. 2020;:108462
Abstract
Prevalence of type 1 diabetes mellitus (T1DM) is globally continuously increasing. T1DM is accompanied by a high risk of developing cardiovascular and renal comorbidities and is one of the leading causes of end-stage renal disease (ESRD). However, current therapeutic approaches for chronic and/or diabetic kidney disease (CKD/DKD) existed for a long time, and offer room for improvement, particularly in T1DM. In 2019, the European Medicines Agency (EMA) approved a first sodium/glucose co-transporter 2 inhibitor (SGLT-2i) and a first dual SGLT-1/-2i to improve glycaemic control, as an adjunctive treatment to insulin in persons with T1DM and a body mass index ≥27 kg/m2. Of note, SGLT-1/2is and SGLT-2is are not approved by the Food and Drug Administration (FDA) as an adjunct treatment in T1DM, nor approved for the treatment of CKD or DKD by EMA and FDA. SGLT is have shown to mediate different renoprotective effects in type 2 diabetes mellitus in corresponding cardiovascular and renal outcome trials. First efficacy trials offer insights into potential positive effects on renal function and kidney disease of SGLTis in T1DM. This review summarizes and discusses latest available data on SGLT inhibition and provides an update on the nephrological perspective on SGLTis, specifically in T1DM.
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Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity.
Rutter, GA, Georgiadou, E, Martinez-Sanchez, A, Pullen, TJ
Diabetologia. 2020;(10):1990-1998
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Abstract
All forms of diabetes mellitus involve the loss or dysfunction of pancreatic beta cells, with the former predominating in type 1 diabetes and the latter in type 2 diabetes. Deeper understanding of the coupling mechanisms that link glucose metabolism in these cells to the control of insulin secretion is therefore likely to be essential to develop new therapies. Beta cells display a remarkable metabolic specialisation, expressing high levels of metabolic sensing enzymes, including the glucose transporter GLUT2 (encoded by SLC2A2) and glucokinase (encoded by GCK). Genetic evidence flowing from both monogenic forms of diabetes and genome-wide association studies for the more common type 2 diabetes, supports the importance for normal glucose-stimulated insulin secretion of metabolic signalling via altered ATP generation, while also highlighting unsuspected roles for Zn2+ storage, intracellular lipid transfer and other processes. Intriguingly, genes involved in non-oxidative metabolic fates of the sugar, such as those for lactate dehydrogenase (LDHA) and monocarboxylate transporter-1 ([MCT-1] SLC16A1), as well as the acyl-CoA thioesterase (ACOT7) and others, are selectively repressed ('disallowed') in beta cells. Furthermore, mutations in genes critical for mitochondrial oxidative metabolism, such as TRL-CAG1-7 encoding tRNALeu, are linked to maternally inherited forms of diabetes. Correspondingly, impaired Ca2+ uptake into mitochondria, or collapse of a normally interconnected mitochondrial network, are associated with defective insulin secretion. Here, we suggest that altered mitochondrial metabolism may also impair beta cell-beta cell communication. Thus, we argue that defective oxidative glucose metabolism is central to beta cell failure in diabetes, acting both at the level of single beta cells and potentially across the whole islet to impair insulin secretion. Graphical abstract.
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Guidelines on use of interventions to enhance healing of chronic foot ulcers in diabetes (IWGDF 2019 update).
Rayman, G, Vas, P, Dhatariya, K, Driver, V, Hartemann, A, Londahl, M, Piaggesi, A, Apelqvist, J, Attinger, C, Game, F, et al
Diabetes/metabolism research and reviews. 2020;:e3283
Abstract
The International Working Group on the Diabetic Foot (IWGDF) has published evidence-based guidelines on the prevention and management of diabetic foot disease since 1999. In conjunction with advice from internal and external reviewers and expert consultants in the field, this update is based on a systematic review of the literature centred on the following: the Population (P), Intervention (I), Comparator (C) and Outcomes (O) framework; the use of the SIGN guideline/Cochrane review system; and the 21 point scoring system advocated by IWGDF/EWMA. This has resulted in 13 recommendations. The recommendation on sharp debridement and the selection of dressings remain unchanged from the last recommendations published in 2016. The recommendation to consider negative pressure wound therapy in post-surgical wounds and the judicious use of hyperbaric oxygen therapy in certain non-healing ischaemic ulcers also remains unchanged. Recommendations against the use of growth factors, autologous platelet gels, bioengineered skin products, ozone, topical carbon dioxide, nitric oxide or interventions reporting improvement of ulcer healing through an alteration of the physical environment or through other systemic medical or nutritional means also remain. New recommendations include consideration of the use of sucrose-octasulfate impregnated dressings in difficult to heal neuro-ischaemic ulcers and consideration of the use of autologous combined leucocyte, platelet and fibrin patch in ulcers that are difficult to heal, in both cases when used in addition to best standard of care. A further new recommendation is the consideration of topical placental derived products when used in addition to best standard of care.
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Psychological interventions to improve self-management of type 1 and type 2 diabetes: a systematic review.
Winkley, K, Upsher, R, Stahl, D, Pollard, D, Kasera, A, Brennan, A, Heller, S, Ismail, K
Health technology assessment (Winchester, England). 2020;(28):1-232
Abstract
BACKGROUND For people with diabetes mellitus to achieve optimal glycaemic control, motivation to perform self-management is important. The research team wanted to determine whether or not psychological interventions are clinically effective and cost-effective in increasing self-management and improving glycaemic control. OBJECTIVES The first objective was to determine the clinical effectiveness of psychological interventions for people with type 1 diabetes mellitus and people with type 2 diabetes mellitus so that they have improved (1) glycated haemoglobin levels, (2) diabetes self-management and (3) quality of life, and fewer depressive symptoms. The second objective was to determine the cost-effectiveness of psychological interventions. DATA SOURCES The following databases were accessed (searches took place between 2003 and 2016): MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, PsycINFO, EMBASE, Cochrane Controlled Trials Register, Web of Science, and Dissertation Abstracts International. Diabetes conference abstracts, reference lists of included studies and Clinicaltrials.gov trial registry were also searched. REVIEW METHODS Systematic review, aggregate meta-analysis, network meta-analysis, individual patient data meta-analysis and cost-effectiveness modelling were all used. Risk of bias of randomised and non-randomised controlled trials was assessed using the Cochrane Handbook (Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928). DESIGN Systematic review, meta-analysis, cost-effectiveness analysis and patient and public consultation were all used. SETTING Settings in primary or secondary care were included. PARTICIPANTS Adolescents and children with type 1 diabetes mellitus and adults with types 1 and 2 diabetes mellitus were included. INTERVENTIONS The interventions used were psychological treatments, including and not restricted to cognitive-behavioural therapy, counselling, family therapy and psychotherapy. MAIN OUTCOME MEASURES Glycated haemoglobin levels, self-management behaviours, body mass index, blood pressure levels, depressive symptoms and quality of life were all used as outcome measures. RESULTS A total of 96 studies were included in the systematic review (n = 18,659 participants). In random-effects meta-analysis, data on glycated haemoglobin levels were available for seven studies conducted in adults with type 1 diabetes mellitus (n = 851 participants) that demonstrated a pooled mean difference of -0.13 (95% confidence interval -0.33 to 0.07), a non-significant decrease in favour of psychological treatment; 18 studies conducted in adolescents/children with type 1 diabetes mellitus (n = 2583 participants) that demonstrated a pooled mean difference of 0.00 (95% confidence interval -0.18 to 0.18), indicating no change; and 49 studies conducted in adults with type 2 diabetes mellitus (n = 12,009 participants) that demonstrated a pooled mean difference of -0.21 (95% confidence interval -0.31 to -0.10), equivalent to reduction in glycated haemoglobin levels of -0.33% or ≈3.5 mmol/mol. For type 2 diabetes mellitus, there was evidence that psychological interventions improved dietary behaviour and quality of life but not blood pressure, body mass index or depressive symptoms. The results of the network meta-analysis, which considers direct and indirect effects of multiple treatment comparisons, suggest that, for adults with type 1 diabetes mellitus (7 studies; 968 participants), attention control and cognitive-behavioural therapy are clinically effective and cognitive-behavioural therapy is cost-effective. For adults with type 2 diabetes mellitus (49 studies; 12,409 participants), cognitive-behavioural therapy and counselling are effective and cognitive-behavioural therapy is potentially cost-effective. The results of the individual patient data meta-analysis for adolescents/children with type 1 diabetes mellitus (9 studies; 1392 participants) suggest that there were main effects for age and diabetes duration. For adults with type 2 diabetes mellitus (19 studies; 3639 participants), baseline glycated haemoglobin levels moderated treatment outcome. LIMITATIONS Aggregate meta-analysis was limited to glycaemic control for type 1 diabetes mellitus. It was not possible to model cost-effectiveness for adolescents/children with type 1 diabetes mellitus and modelling for type 2 diabetes mellitus involved substantial uncertainty. The individual patient data meta-analysis included only 40-50% of studies. CONCLUSIONS This review suggests that psychological treatments offer minimal clinical benefit in improving glycated haemoglobin levels for adults with type 2 diabetes mellitus. However, there was no evidence of benefit compared with control interventions in improving glycated haemoglobin levels for people with type 1 diabetes mellitus. FUTURE WORK Future work should consider the competency of the interventionists delivering a therapy and psychological approaches that are matched to a person and their life course. STUDY REGISTRATION This study is registered as PROSPERO CRD42016033619. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 28. See the NIHR Journals Library website for further project information.
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Evening and overnight closed-loop control versus 24/7 continuous closed-loop control for type 1 diabetes: a randomised crossover trial.
Kovatchev, BP, Kollar, L, Anderson, SM, Barnett, C, Breton, MD, Carr, K, Gildersleeve, R, Oliveri, MC, Wakeman, CA, Brown, SA
The Lancet. Digital health. 2020;(2):e64-e73
Abstract
BACKGROUND Automated closed-loop control (CLC), known as the "artificial pancreas" is emerging as a treatment option for Type 1 Diabetes (T1D), generally superior to sensor-augmented insulin pump (SAP) treatment. It is postulated that evening-night (E-N) CLC may account for most of the benefits of 24-7 CLC; however, a direct comparison has not been done. METHODS In this trial (NCT02679287), adults with T1D were randomised 1:1 to two groups, which followed different sequences of four 8-week sessions, resulting in two crossover designs comparing SAP vs E-N CLC and E-N CLC vs 24-7 CLC, respectively. Eligibility: T1D for at least 1 year, using an insulin pump for at least six months, ages 18 years or older. Primary hypothesis: E-N CLC compared to SAP will decrease percent time <70mg/dL (3.9mmol/L) measured by continuous glucose monitoring (CGM) without deterioration in HbA1c. Secondary Hypotheses: 24-7 CLC compared to SAP will increase CGM-measured time in target range (TIR, 70-180mg/dL; 3.9-10mmol/L) and will reduce glucose variability during the day. FINDINGS Ninety-three participants were randomised and 80 were included in the analysis, ages 18-69 years; HbA1c levels 5.4-10.6%; 66% female. Compared to SAP, E-N CLC reduced overall time <70mg/dL from 4.0% to 2.2% () resulting in an absolute difference of 1.8% (95%CI: 1.2-2.4%), p<0.0001. This was accompanied by overall reduction in HbA1c from 7.4% at baseline to 7.1% at the end of study, resulting in an absolute difference of 0.3% (95% CI: 0.1-0.4%), p<0.0001. There were 5 severe hypoglycaemia adverse events attributed to user-directed boluses without malfunction of the investigational device, and no diabetic ketoacidosis events. INTERPRETATION In type 1 diabetes, evening-night closed-loop control was superior to sensor-augmented pump therapy, achieving most of the glycaemic benefits of 24-7 closed-loop.
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Immunomodulatory Dual-Sized Microparticle System Conditions Human Antigen Presenting Cells Into a Tolerogenic Phenotype In Vitro and Inhibits Type 1 Diabetes-Specific Autoreactive T Cell Responses.
Brusko, MA, Stewart, JM, Posgai, AL, Wasserfall, CH, Atkinson, MA, Brusko, TM, Keselowsky, BG
Frontiers in immunology. 2020;:574447
Abstract
Current monotherapeutic agents fail to restore tolerance to self-antigens in autoimmune individuals without systemic immunosuppression. We hypothesized that a combinatorial drug formulation delivered by a poly-lactic-co-glycolic acid (PLGA) dual-sized microparticle (dMP) system would facilitate tunable drug delivery to elicit immune tolerance. Specifically, we utilized 30 µm MPs to provide local sustained release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor β1 (TGF-β1) along with 1 µm MPs to facilitate phagocytic uptake of encapsulated antigen and 1α,25(OH)2 Vitamin D3 (VD3) followed by tolerogenic antigen presentation. We previously demonstrated the dMP system ameliorated type 1 diabetes (T1D) and experimental autoimmune encephalomyelitis (EAE) in murine models. Here, we investigated the system's capacity to impact human cell activity in vitro to advance clinical translation. dMP treatment directly reduced T cell proliferation and inflammatory cytokine production. dMP delivery to monocytes and monocyte-derived dendritic cells (DCs) increased their expression of surface and intracellular anti-inflammatory mediators. In co-culture, dMP-treated DCs (dMP-DCs) reduced allogeneic T cell receptor (TCR) signaling and proliferation, while increasing PD-1 expression, IL-10 production, and regulatory T cell (Treg) frequency. To model antigen-specific activation and downstream function, we co-cultured TCR-engineered autoreactive T cell "avatars," with dMP-DCs or control DCs followed by β-cell line (ßlox5) target cells. For G6PC2-specific CD8+ avatars (clone 32), dMP-DC exposure reduced Granzyme B and dampened cytotoxicity. GAD65-reactive CD4+ avatars (clone 4.13) exhibited an anergic/exhausted phenotype with dMP-DC presence. Collectively, these data suggest this dMP formulation conditions human antigen presenting cells toward a tolerogenic phenotype, inducing regulatory and suppressive T cell responses.
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Diabetic Ketoacidosis and Related Events With Sotagliflozin Added to Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of the inTandem 1 and 2 Studies.
Peters, AL, McGuire, DK, Danne, T, Kushner, JA, Rodbard, HW, Dhatariya, K, Sawhney, S, Banks, P, Jiang, W, Davies, MJ, et al
Diabetes care. 2020;(11):2713-2720
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Abstract
OBJECTIVE To evaluate the incidence and risk factors for diabetic ketoacidosis (DKA) and related adverse events (AEs) in adults with type 1 diabetes treated with sotagliflozin adjunctive to insulin. RESEARCH DESIGN AND METHODS Data from two identically designed, 52-week, randomized studies were pooled and analyzed for DKA, changes in β-hydroxybutyrate (BHB), and percentage of patients with BHB >0.6 and >1.5 mmol/L. The patients were administered placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg once daily. RESULTS A total of 191 ketosis-related AEs were reported, and 98 underwent adjudication. Of these, 37 events (36 patients) were adjudicated as DKA, with an exposure-adjusted incidence rate of 0.2, 3.1, and 4.2 events per 100 patient-years for placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively. No patient died of a DKA event. From a baseline BHB of ∼0.13 mmol/L, sotagliflozin treatment led to a small median increase over 52 weeks (≤0.05 mmol/L at all time points). Of sotagliflozin-treated patients, approximately 47% and 7% had ≥1 BHB measurement >0.6 mmol/L and >1.5 mmol/L, respectively (vs. 20% and 2%, respectively, of placebo-treated patients). Subsequent to the implementation of a risk mitigation plan, annualized DKA incidence was lower versus preimplementation in both the sotagliflozin 200 and 400 mg groups. CONCLUSIONS In patients with type 1 diabetes, confirmed DKA incidence increased when sotagliflozin was added to insulin compared with insulin alone. A lower incidence of DKA was observed following the implementation of an enhanced risk mitigation plan, suggesting that this risk can be managed with patient education.
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Automated Insulin Delivery: The Artificial Pancreas Technical Challenges.
Hernando, ME, García-Sáez, G, Gómez, EJ, Pérez-Gandía, C, Rodríguez-Herrero, A
American journal of therapeutics. 2020;(1):e62-e70
Abstract
BACKGROUND The automation of glucose control has been an important goal of diabetes treatment for many decades. The first artificial pancreas experiences were in-hospital, closely supervised, small-scale, and short-term studies that demonstrated their superiority over continuous subcutaneous insulin infusion therapy. At present, long-term outpatient studies are being conducted in free-living scenarios. AREAS OF UNCERTAINTY The integration of multiple devices increases patients' burden and the probability of technical risks. Control algorithms must be robust to manage disturbance variables, such as physical exercise, meal composition, stress, illness, and circadian variations in insulin sensitivity. Extra layers of safety could be achieved through remote supervision. Dual-hormone systems reduce the incidence and duration of hypoglycemia, but the availability of stable pumpable glucagon needs to be solved. Faster insulin analogues are expected to improve all types of artificial pancreas. THERAPEUTIC ADVANCES Artificial pancreas safety and feasibility are being demonstrated in outpatient studies. Artificial pancreas use increases the time of sensor-measured glucose in near-normoglycemia and reduces the risk of hyperglycemia and hypoglycemia. The benefits are observed both in single- and dual-hormone algorithms and in full- or semi-closed loop control. A recent meta-analysis including 41 randomized controlled trials showed that artificial pancreas use achieves a reduction of time in hyperglycemia (2 hours less than control treatment) and in hypoglycemia (20 minutes less); mean levels of continuous glucose sensor fell by 8.6 mg/dL over 24 hours and by 14.6 mg/dL overnight. The OpenAPS community uses Do It Yourself artificial pancreas in the real world since 2013, and a recent retrospective cross-over study (n = 20) compared continuous glucose sensor readings before and after initiation: mean levels of blood glucose fell by 7.4 mg/dL over 24 hours and time in range increased from 75.8% to 82.2% (92 minutes more). CONCLUSIONS The outpatient use of artificial pancreas is safe and improves glucose control in outpatients with type 1 diabetes compared with the use of any type of insulin-based treatment. The availability of open-source solutions and data sharing is needed to foster the development of new artificial pancreas approaches and to promote the wide use of Big Data tools for knowledge discovery, decision support, and personalization.
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Precision Dosing of Rapid-Acting Insulin Matters.
Aanstoot, HJ, Rodriguez, H, Weinzimer, S, Vint, N, Koeneman, L
Diabetes technology & therapeutics. 2020;(5):346-351
Abstract
Despite several molecular and technological advances in insulin therapy and insulin delivery, global evidence highlights inadequate glycemic control in populations with type 1 diabetes (T1D) and type 2 diabetes (T2D). In this review, we discuss the importance of more precise dosing of insulin as one of the approaches to improve glycemic control while reducing hypoglycemic events. This report is based on the expert opinion of authors and literature search of articles relevant to the past and present insulin delivery devices in diabetes management, especially half-unit insulin pens. We describe the various factors that facilitate better glycemic control, focusing on the impact of appropriate insulin delivery device selection on diabetes management. Precision dosing of insulin is a lesser-studied factor that contributes toward better glycemic control. Insulin pens have consistently outperformed syringes as delivery devices due to their greater accuracy and precision of dosing, ease-of-use, and patient preference. These advantages make them better suited to administer insulin in hypoglycemia-prone insulin-sensitive people with T1D, particularly younger children and geriatric patients. Half-unit insulin pens further extend this benefit by delivering half-unit doses of insulin accurately. They may contribute to better management of diabetes by allowing flexible dosing for mealtimes and physical activities even in erratic diet situations or illnesses by offering corrective doses in small increments. They are ideal delivery devices for insulin-sensitive people with T1D who require greater accuracy and precision in insulin delivery to achieve more stringent glycemic control.
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The competitive athlete with type 1 diabetes.
Riddell, MC, Scott, SN, Fournier, PA, Colberg, SR, Gallen, IW, Moser, O, Stettler, C, Yardley, JE, Zaharieva, DP, Adolfsson, P, et al
Diabetologia. 2020;(8):1475-1490
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Regular exercise is important for health, fitness and longevity in people living with type 1 diabetes, and many individuals seek to train and compete while living with the condition. Muscle, liver and glycogen metabolism can be normal in athletes with diabetes with good overall glucose management, and exercise performance can be facilitated by modifications to insulin dose and nutrition. However, maintaining normal glucose levels during training, travel and competition can be a major challenge for athletes living with type 1 diabetes. Some athletes have low-to-moderate levels of carbohydrate intake during training and rest days but tend to benefit, from both a glucose and performance perspective, from high rates of carbohydrate feeding during long-distance events. This review highlights the unique metabolic responses to various types of exercise in athletes living with type 1 diabetes. Graphical abstract.