1921–2021: From insulin discovery to islet transplantation in type 1 diabetes
TL;DR: In this paper, an intraportal islet transplant from a pancreatic donor is indicated in patients with type 1 diabetes complicated with lability or hypoglycemia unawareness, or in case of a functioning kidney graft; islet auto-transplantation may be indicated after pancreatic surgery.
Abstract: One century after the discovery of insulin, the French Health regulations have just authorized the reimbursement for islet transplantation. Intraportal islet allotransplantation from a pancreatic donor is indicated in patients with type 1 diabetes (T1D) complicated with lability or hypoglycemia unawareness, or in case of a functioning kidney graft; islet auto-transplantation may be indicated after pancreatic surgery.Compared with insulin even administered in closed-loop pumps, the specificity of islet allotransplantation is the restoration of C-peptide secretion. Long-term insulin-independence is observed when the engrafted islet mass is sufficient, at the cost of immunosuppression. Fewer low-glucose events and less glucose variability, are observed even with minimal functional islet graft, after islet transplantation as at onset of T1D, when a residual C-peptide secretion is maintained, an objective currently approached with less aggressive immuno-modulating therapies than in the past. Therefore, restoration or preservation of endogen insulin secretion is an important goal, allowing to maintain a long-term glucose balance with more than 70% of time in range 3.9-10 mmol/L and less than 3% of time
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TL;DR: In this article , the authors detect lipohypertrophy (LH) in patients with type 1 diabetes mellitus (T1DM) on multiple daily insulin injections (MDII) or continuous subcutaneous insulin infusion (CSII) and reveal the factors associated with the development and severity of LH.
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TL;DR: Improvement in Clarke score is possible in patients with long-standing T1D, underscoring the need for additional study, and diabetes duration, gender, and eGFR were independent predictors of HU.
Abstract: To analyse predictors of hypoglycemia unawareness (HU) and improvement in Clarke score in clinical practice.
TL;DR: Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with Type 1 diabetes (T1D) by transplanting pancreatic beta cells as discussed by the authors .
Abstract: Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes (T1D) by transplanting pancreatic beta cells. Overall, pancreatic islet transplantation has improved to a great extent, and cellular replacement will likely become the mainstay treatment. We review pancreatic islet transplantation as a treatment for T1D and the immunological challenges faced. Published data demonstrated that the time for islet cell transfusion varied between 2 and 10 h. Approximately 54% of the patients gained insulin independence at the end of the first year, while only 20% remained insulin-free at the end of the second year. Eventually, most transplanted patients return to using some form of exogenous insulin within a few years after the transplantation, which imposed the need to improve immunological factors before transplantation. We also discuss the immunosuppressive regimens, apoptotic donor lymphocytes, anti-TIM-1 antibodies, mixed chimerism-based tolerance induction, induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes, pretransplant infusions of donor apoptotic cells, B cell depletion, preconditioning of isolated islets, inducing local immunotolerance, cell encapsulation and immunoisolation, using of biomaterials, immunomodulatory cells, etc.
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Ljubljana University Medical Centre1, King's College London2, Vita-Salute San Raffaele University3, Stanford University4, American Diabetes Association5, University of Padua6, Harvard University7, University of Amsterdam8, University of Sydney9, University of Colorado Denver10, University of Sheffield11, University of Washington12, University of Cambridge13, Shanghai Jiao Tong University14, University of Virginia15, JDRF16, Katholieke Universiteit Leuven17, University of East Anglia18, San Antonio River Authority19, Steno Diabetes Center20, University of Montpellier21, University of Florida22, Nihon University23, Yale University24, Tel Aviv University25
TL;DR: This article summarizes the ATTD consensus recommendations for relevant aspects of CGM data utilization and reporting among the various diabetes populations.
Abstract: Improvements in sensor accuracy, greater convenience and ease of use, and expanding reimbursement have led to growing adoption of continuous glucose monitoring (CGM). However, successful utilization of CGM technology in routine clinical practice remains relatively low. This may be due in part to the lack of clear and agreed-upon glycemic targets that both diabetes teams and people with diabetes can work toward. Although unified recommendations for use of key CGM metrics have been established in three separate peer-reviewed articles, formal adoption by diabetes professional organizations and guidance in the practical application of these metrics in clinical practice have been lacking. In February 2019, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address this issue. This article summarizes the ATTD consensus recommendations for relevant aspects of CGM data utilization and reporting among the various diabetes populations.
1,776 citations
TL;DR: The effectiveness of day-and-night hybrid closed-loop insulin delivery compared with sensor-augmented pump therapy in people with suboptimally controlled type 1 diabetes aged 6 years and older was assessed.
232 citations
TL;DR: The Diabetes Control and Complications Trial established that a stimulated C-peptide concentration ≥0.2 nmol/L at study entry among subjects with up to a 5-year diabetes duration is associated with favorable metabolic and clinical outcomes over the subsequent 7 years of follow-up, and this work further examines the association of both fasting and stimulating C- peptide numerical values with outcomes.
Abstract: The Diabetes Control and Complications Trial established that a stimulated C-peptide concentration ≥0.2 nmol/L at study entry among subjects with up to a 5-year diabetes duration is associated with favorable metabolic and clinical outcomes over the subsequent 7 years of follow-up. Herein we further examine the association of both fasting and stimulated C-peptide numerical values with outcomes. In the intensive treatment group, for a 50% higher stimulated C-peptide on entry, such as from 0.10 to 0.15 nmol/L, HbA 1c decreased by 0.07% (0.8 mmol/mol; P = 0.0003), insulin dose decreased by 0.0276 units/kg/day ( P P P = 0.0010), all in unadjusted analyses. Other than HbA 1c , these effects remained significant after adjusting for the HbA 1c on entry. While C-peptide was not significantly associated with the incidence of nephropathy, it was strongly associated with the albumin excretion rate. The fasting C-peptide had weaker associations with outcomes. As C-peptide decreased to nonmeasurable concentrations, the outcomes changed in a nearly linear manner, with no threshold or breakpoint. While preservation of stimulated C-peptide at ≥0.2 nmol/L has clinically beneficial outcomes, so also does an increase in the concentration of C-peptide across the range of values.
198 citations
TL;DR: This algorithm provides an evidence-informed approach to resolving problematic hypoglycemia and should be used as a guide, with individual patient circumstances directing suitability and acceptability to ensure the prudent use of technology and scarce transplant resources.
Abstract: Problematic hypoglycemia, defined as two or more episodes per year of severe hypoglycemia or as one episode associated with impaired awareness of hypoglycemia, extreme glycemic lability, or major fear and maladaptive behavior, is a challenge, especially for patients with long-standing type 1 diabetes. Individualized therapy for such patients should include a composite target: optimal glucose control without problematic hypoglycemia. Therefore, we propose a tiered, four-stage algorithm based on evidence of efficacy given the limitations of educational, technological, and transplant interventions. All patients with problematic hypoglycemia should undergo structured or hypoglycemia-specific education programs (stage 1). Glycemic and hypoglycemia treatment targets should be individualized and reassessed every 3-6 months. If targets are not met, one diabetes technology-continuous subcutaneous insulin infusion or continuous glucose monitoring-should be added (stage 2). For patients with continued problematic hypoglycemia despite education (stage 1) and one diabetes technology (stage 2), sensor-augmented insulin pumps preferably with an automated low-glucose suspend feature and/or very frequent contact with a specialized hypoglycemia service can reduce hypoglycemia (stage 3). For patients whose problematic hypoglycemia persists, islet or pancreas transplant should be considered (stage 4). This algorithm provides an evidence-informed approach to resolving problematic hypoglycemia; it should be used as a guide, with individual patient circumstances directing suitability and acceptability to ensure the prudent use of technology and scarce transplant resources. Standardized reporting of hypoglycemia outcomes and inclusion of patients with problematic hypoglycemia in studies of new interventions may help to guide future therapeutic strategies.
166 citations
01 May 2019
TL;DR: The DBLG1 system improves glucose control compared with sensor-assisted insulin pumps and supports the use of closed-loop technology combined with appropriate health care organisation in adults with type 1 diabetes.
Abstract: Summary Background Closed-loop insulin delivery systems are expected to become a standard treatment for patients with type 1 diabetes. We aimed to assess whether the Diabeloop Generation 1 (DBLG1) hybrid closed-loop artificial pancreas system improved glucose control compared with sensor-assisted pump therapy. Methods In this multicentre, open-label, randomised, crossover trial, we recruited adults (aged ≥18 years) with at least a 2 year history of type 1 diabetes, who had been treated with external insulin pump therapy for at least 6 months, had glycated haemoglobin (HbA1c) of 10% or less (86 mmol/mol), and preserved hypoglycaemia awareness. After a 2-week run-in period, patients were randomly assigned (1:1) with a web-based system in randomly permuted blocks of two, to receive insulin via the hybrid closed-loop system (DBLG1; using a machine-learning-based algorithm) or sensor-assisted pump therapy over 12 weeks of free living, followed by an 8-week washout period and then the other intervention for 12 weeks. The primary outcome was the proportion of time that the sensor glucose concentration was within the target range (3·9–10·0 mmol/L) during the 12 week study period. Efficacy analyses were done in the modified intention-to-treat population, which included all randomly assigned patients who completed both 12 week treatment periods. Safety analyses were done in all patients who were exposed to either of the two treatments at least once during the study. This trial is registered with ClinicalTrials.gov, number NCT02987556. Findings Between March 3, 2017, and June 19, 2017, 71 patients were screened, and 68 eligible patients were randomly assigned to the DBLG1 group (n=33) or the sensor-assisted pump therapy group (n=35), of whom five dropped out in the washout period (n=1 pregnancy; n=4 withdrew consent). 63 patients completed both 12 week treatment periods and were included in the modified intention-to-treat analysis. The proportion of time that the glucose concentration was within the target range was significantly higher in the DBLG1 group (68·5% [SD 9·4] than the sensor-assisted pump group (59·4% [10·2]; mean difference 9·2% [95% CI 6·4 to 11·9]; p Interpretation The DBLG1 system improves glucose control compared with sensor-assisted insulin pumps. This finding supports the use of closed-loop technology combined with appropriate health care organisation in adults with type 1 diabetes. Funding French Innovation Fund, Diabeloop.
120 citations