Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes.

BACKGROUND: Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. METHODS: In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed. RESULTS: A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P<0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, -0.1 to 0.04; P<0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P = 0.39). No episodes of diabetic ketoacidosis occurred in either group. CONCLUSIONS: In this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.).

Practical Aspects and Exercise Safety Benefits of Automated Insulin Delivery Systems in Type 1 Diabetes.

Regular exercise is essential to overall cardiovascular health and well-being in people with type 1 diabetes, but exercise can also lead to increased glycemic disturbances. Automated insulin delivery (AID) technology has been shown to modestly improve glycemic time in range (TIR) in adults with type 1 diabetes and significantly improve TIR in youth with type 1 diabetes. Available AID systems still require some user-initiated changes to the settings and, in some cases, significant pre-planning for exercise. Many exercise recommendations for type 1 diabetes were developed initially for people using multiple daily insulin injections or insulin pump therapy. This article highlights recommendations and practical strategies for using AID around exercise in type 1 diabetes.

Using Peer Power to Reduce Health Disparities: Implementation of a Diabetes Support Coach Program in Federally Qualified Health Centers.

Community health workers (CHWs) provide vital support to underserved communities in the promotion of health equity by addressing barriers related to the social determinants of health that often prevent people living with diabetes from achieving optimal health outcomes. Peer support programs in diabetes can also offer people living with diabetes invaluable support through a shared understanding of the disease and by offsetting diabetes-related stigma. As part of a Project Extension for Community Healthcare Outcomes (ECHO) Diabetes program, participating federally qualified healthcare centers were provided diabetes support coaches (DSCs) to facilitate patient engagement. DSCs hold invaluable expert knowledge, as they live with diabetes themselves and reside in areas they serve, thus combining the CHW role with peer support models. The use of DSCs and CHWs during the coronavirus disease 2019 pandemic and beyond is highly effective at reaching underserved communities with diabetes and promoting health equity.

Automated insulin dosing systems: Advances after a century of insulin.

The daily complexities of insulin therapy and glucose variability in type 1 diabetes still pose significant challenges, despite advancements in modern insulin analogues. Minimising hypoglycaemia and optimising time spent within target glucose range are recommended to reduce the risk of diabetes-related complications and distress. Access to structured education and adjuvant diabetes technologies, such as insulin pumps and glucose sensors, are recommended by National Institute for Health and Care Excellence (NICE) to enable people with type 1 diabetes achieve their glycaemic goals. One hundred years after the discovery of insulin, automated insulin dosing (AID, a.k.a. closed loop or artificial pancreas) systems are a reality with a number of systems available and being used in usual clinical practice. Evidence from randomised clinical trials and real-world prospective studies support efficacy, effectiveness and safety of AID systems. Qualitative evaluations reveal treatment satisfaction and positive effects on quality of life. Current insulin-only AID systems still require carbohydrate and activity announcement (hybrid closed loop) due to the inherent pharmacokinetic limitations of rapid-acting insulin analogies. Ultra-rapid acting insulin and adjunctive use of other therapies (e.g. glucagon, pramlitide) are being evaluated to achieve full closed loop. Open-source AID (OS-AID) systems have been developed by the diabetes community, driven by a desire for safety and to accelerate technological advancement. In addition to effectiveness and safety, real-world prospective studies suggest that OS-AID systems fulfil unmet needs of commercially approved systems. The development, ongoing challenges and expectations of AID are outlined in this review.

Longevity of the novel ConvaTec infusion set with Lantern technology.

Current insulin infusion sets are approved for only 2-3 days. The novel ConvaTec infusion set with Lantern technology is designed to extend infusion set wear time. The goal of this pilot study was to evaluate the duration of wear for this set. This was a pilot safety study in adults with type 1 diabetes using tethered insulin pumps. Participants inserted the set and wore it for 10 days or until failure. Among 24 participants, two were excluded. Forty-five per cent of the sets lasted 10 days. Median wear time was 9.1 (7.1, 10.0) days. Among 12 premature failures, six (50%) involved adhesive failures, four (33%) hyperglycaemia unresponsive to correction, one (8%) hyperglycaemia with ketones and one (8%) infection. Average CGM glucose per day of infusion set wear showed a statistically significant increase over time, while total daily insulin over the same period did not change. In this pilot study, the duration of wear for the novel infusion set exceeded previously reported commercial sets (P < .001). This extended wear technology may eventually allow for a combined glucose sensor and infusion set.

THE GUIDED TRANSFER OF CARE IMPROVES ADULT CLINIC SHOW RATE.

Objective: Every year, 500,000 youths in the U.S. with chronic disease turn 18 years of age and eventually require transfer to adult subspecialty care. Evidence-based interventions on the organization of transfer of care are limited, although engagement and retention in adult clinic are considered appropriate outcomes. Sustained continuity of care improves patient satisfaction and reduces hospitalization. Methods: We conducted a prospective, nonrandomized cohort study of patients with pediatric endocrine conditions, age 16 to 26 years, enrolled upon referral to the adult endocrine clinic of a physician trained in both adult and pediatric endocrinology (Med+Peds endocrinologist). Patients differed based on whether their referral originated from another pediatric endocrinologist (traditional transfer) or if the Med+Peds endocrinologist previously saw the patient in his pediatric endocrine clinic (guided transfer). Rather than relying on arbitrary age criteria, guided transfer to adult clinic occurred when physician and patient considered it appropriate. The primary outcome was show rate at the first and second adult visits. Results: Of 36 patients, 21 were referred by another pediatric endocrinologist and 15 underwent guided transfer. For traditional transfer, show rate to the first and second visit was 38%, compared to 100% in the guided transfer group (P = .0001). Subgroup analysis of 27 patients with diabetes revealed that both groups had similar initial hemoglobin A1c (P = .38), and the guided transfer group maintained hemoglobin A1c. Conclusion: Most traditional transfers were unsuccessful. Guided transfer was significantly more effective, with every patient successfully transferring, and could be implemented with adult endocrinologists willing to see patients in the pediatric clinic. Abbreviations: DKA = diabetic ketoacidosis; HbA1c = hemoglobin A1c; Med+Peds = Internal Medicine and Pediatrics.

Primary Care Providers in California and Florida Report Low Confidence in Providing Type 1 Diabetes Care.

People with type 1 diabetes may receive a significant portion of their care from primary care providers (PCPs). To understand the involvement of PCPs in delivering type 1 diabetes care, we performed surveys in California and Florida, two of the most populous and diverse states in the United States. PCPs fill insulin prescriptions but report low confidence in providing type 1 diabetes care and difficulty accessing specialty referrals to endocrinologists.

Long-Acting Growth Hormone Preparations in the Treatment of Children.

Human growth hormone (hGH), which had been in use since 1958, was supplanted by recombinant human growth hormone (rhGH) in 1985 for those with growth hormone deficiency (GHD). Adherence to daily subcutaneous growth hormone is challenging for patients. Thus, several companies have pursued the creation of long acting rhGH. These agents can be divided broadly into depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding GH and GH fusion proteins. Nutropin Depot is the only long acting rhGH ever approved by the U.S. Food and Drug Administration, and it was removed from the market in 2004. Of the approximately seventeen candidate drugs, only a handful remain under active clinical investigation or are commercially available.

Development of a Real-time Force-based Algorithm for Infusion Failure Detection.

BACKGROUND: Continuous subcutaneous insulin infusion (CSII) is a common treatment option for people with diabetes (PWD), but insulin infusion failures pose a significant challenge, leading to hyperglycemia, diabetes burnout, and increased hospitalizations. Current CSII pumps' occlusion alarm systems are limited in detecting infusion failures; therefore, a more effective detection method is needed. METHODS: We conducted five preclinical animal studies to collect data on infusion failures, utilizing both insulin and non-insulin boluses. Data were captured using in-line pressure and flow rate sensors, with additional force data from CSII pumps' onboard sensors in one study. A novel classifier model was developed using this dataset, aimed at detecting different types of infusion failures through direct utilization of force sensor data. Performance was compared against various occlusion alarm thresholds from commercially available CSII pumps. RESULTS: The testing dataset included 251 boluses. The Bagging classifier model showed the highest performance metrics among the models tested, exhibiting high accuracy (96%), sensitivity (94%), and specificity (98%), with lower false-positive and false-negative rate compared with traditional occlusion alarm pressure thresholds. CONCLUSIONS: Our study developed a novel non-threshold classifier that outperforms current occlusion alarm systems in CSII pumps in detecting infusion failures. This advancement has the potential to reduce the risk of hyperglycemia and hospitalizations due to undetected infusion failures, offering a more reliable and effective CSII therapy for PWD. Further studies involving human participants are recommended to validate these findings and assess the classifier's performance in a real-world setting.

Use of the Community-Derived Open-Source Automated Insulin Delivery Loop System in Type 2 Diabetes.

Background: No published data are available on the use of the community-derived open-source Loop hybrid closed-loop controller ("Loop") by individuals with type 2 diabetes (T2D). Methods: Through social media postings, we invited individuals with T2D currently using the Loop system to join an observational study. Thirteen responded of whom seven were eligible for the study, were using the Loop algorithm, and provided data. Results: Mean (±standard deviation) age was 61 ± 13 years, and mean body mass index was 31 ± 5 kg/m2. All but one participant were using noninsulin glucose-lowering medications. Self-reported mean hemoglobin A1c decreased from 7.3% ± 1.1% before starting Loop to 6.0% ± 0.5% on Loop. Time in range 70-180 mg/dL increased from 84% to 93%. The amount of time in hypoglycemia was extremely low before and with Loop (time <54 mg/dL was 0.04% ± 0.06% vs. 0.09% ± 0.07%, respectively). No severe hypoglycemia or diabetic ketoacidosis events were reported while using Loop. Conclusion: These data, though limited, suggest that the Loop system is likely to be effective when used by individuals with T2D and should be evaluated in large-scale studies. Clinical Trial Registration numbers: NCT05951569.

Enhancing Therapeutic Insulin Transport from Macroencapsulated Islets Using Sub-Minute Pressure at Physiological Levels.

Cadaveric islet and stem cell-derived transplantations hold promise as treatments for type 1 diabetes. To tackle the issue of immunocompatibility, numerous cellular macroencapsulation techniques have been developed that utilize diffusion to transport insulin across an immunoisolating barrier. However, despite several devices progressing to human clinical trials, none have successfully managed to attain physiologic glucose control or insulin independence. Based on empirical evidence, macroencapsulation methods with multilayered, high islet surface density are incompatible with homeostatic, on-demand insulin delivery and physiologic glucose regulation, when reliant solely on diffusion. An additional driving force is essential to overcome the distance limit of diffusion. In this study, we present both theoretical proof and experimental validation that applying pressure at levels comparable to physiological diastolic blood pressure significantly enhances insulin flux across immunoisolation membranes-increasing it by nearly three orders of magnitude. This significant enhancement in transport rate allows for precise, sub-minute regulation of both bolus and basal insulin delivery. By incorporating this technique with a pump-based extravascular system, we demonstrate the ability to rapidly reduce glucose levels in diabetic rodent models, effectively replicating the timescale and therapeutic effect of subcutaneous insulin injection or infusion. This advance provides a potential path towards achieving insulin independence with islet macroencapsulation. One Sentence Summary: Towards improved glucose control, applying sub-minute pressure at physiological levels enhances therapeutic insulin transport from macroencapsulated islets.

A cysteine-specific solubilizing tag strategy enables efficient chemical protein synthesis of difficult targets.

We developed a new cysteine-specific solubilizing tag strategy via a cysteine-conjugated succinimide. This solubilizing tag remains stable under common native chemical ligation conditions and can be efficiently removed with palladium-based catalysts. Utilizing this approach, we synthesized two proteins containing notably difficult peptide segments: interleukin-2 (IL-2) and insulin. This IL-2 chemical synthesis represents the simplest and most efficient approach to date, which is enabled by the cysteine-specific solubilizing tag to synthesize and ligate long peptide segments. Additionally, we synthesized a T8P insulin variant, previously identified in an infant with neonatal diabetes. We show that T8P insulin exhibits reduced bioactivity (a 30-fold decrease compared to standard insulin), potentially contributing to the onset of diabetes in these patients. In summary, our work provides an efficient tool to synthesize challenging proteins and opens new avenues for exploring research directions in understanding their biological functions.

COVID-19 impacts and inequities among underserved communities with diabetes.

Background: People with diabetes have higher COVID-19 morbidity and mortality. These risks are amplified for underserved communities including racial/ethnic minorities and people with lower socioeconomic status. However, limited research has examined COVID-19 outcomes specifically affecting underserved communities with diabetes. Methods: From November 2021 to July 2022, adults with insulin-requiring diabetes at federally qualified health centers in Florida and California (n = 450) completed surveys examining COVID-19 outcomes and demographics. Surveys assessed COVID-19 severity, vaccination uptake, mask-wearing habits, income changes, and healthcare access changes. Surveys also included the full Coronavirus Anxiety Scale (CAS-19). Descriptive statistics were computed for all outcomes. Between-group comparisons for state and race/ethnicity were evaluated via Chi-Squared, Fisher's Exact, Cochran-Mantel-Haenszel, One-Way ANOVA, and t-tests. Logistic regression determined factors associated with COVID-19 vaccination uptake. Data were self-reported and analyzed cross-sectionally. Results: Overall, 29.7 % reported contracting COVID-19; of those, 45.3 % sought care or were hospitalized. Most (81.3 %) received ≥ 1 vaccine. Hispanics had the highest vaccination rate (91.1 %); Non-Hispanic Blacks (NHBs) had the lowest (73.9 %; p =.0281). Hispanics had 4.63x greater vaccination odds than Non-Hispanic Whites ([NHWs]; 95 % CI = [1.81, 11.89]). NHWs least often wore masks (18.8 %; p <.001). Participants reported pandemic-related healthcare changes (62 %) and higher costs of diabetes medications (41 %). Income loss was more frequent in Florida (76 %; p <.001). NHBs most frequently reported "severe" income loss (26.4 %; p =.0124). Loss of health insurance was more common among NHBs (13.3 %; p =.0416) and in Florida (9.7 %; p =.039). COVID-19 anxiety was highest among NHBs and Hispanics (IQR = [0.0, 3.0]; p =.0232) and in Florida (IQR = [0.0, 2.0]; p =.0435). Conclusions: Underserved communities with diabetes had high COVID-19 vaccine uptake but experienced significant COVID-19-related physical, psychosocial, and financial impacts. NHBs and those in Florida had worse outcomes than other racial/ethnic groups and those in California. Further research, interventions, and policy changes are needed to promote health equity for this population.

Multisite Quality Improvement Program Within the Project ECHO Diabetes Remote Network.

BACKGROUND: The telementoring Project ECHO (Extension for Community Healthcare Outcomes) model has been shown to improve disease management in diabetes in many underserved communities. The authors aim to evaluate if ECHO could also be an effective tool for quality improvement (QI) of diabetes care in these communities. METHODS: Thirteen clinics in underserved communities in California and Florida participating in Project ECHO Diabetes were recruited for a 12-month QI program. The program provided weekly tele-education sessions, including a didactic presentation and case-based discussion. In addition, clinics chose their own set of quality measures to improve and met remotely to discuss their efforts, successes, and setbacks every quarter with mentorship from QI experts. RESULTS: Of the 31 QI initiatives attempted by different clinics, all had either made improvements (25 initiatives, 80.6%) or were in the process of making improvements (6 initiatives, 19.4%) in structural, process, and outcome measures. Examples of these measures include whether clinics have protocols to identify high-risk patients (structure), numbers of continuous glucose monitor prescriptions submitted by the clinics (process), and percentage of patients with diabetes whose most recent HbA1c are > 9% (outcome). For one measure, 40.0% of the clinics had achieved a higher percentage of cumulative HbA1c measurement in the third quarter of the year, compared to the fourth quarter in the previous year. The cost of QI implementation varied widely due to different number of personnel involved across sites. CONCLUSION: A QI program delivered via Project ECHO Diabetes can facilitate quality improvements in underserved communities.

The First Regulatory Clearance of an Open-Source Automated Insulin Delivery Algorithm.

Open-source Automated Insulin Dosing (OS-AID) algorithms are made publicly accessible so that every facet of their operation can be understood. Currently, commercial AID algorithms are kept proprietary trade secrets, despite the role they take in making life and death decisions for people living with type 1 diabetes. Loop was the second OS-AID algorithm, developed initially by Nate Racklyeft and Pete Schwamb. In 2018, the nonprofit organization Tidepool (Palo Alto, CA) announced the launch of the "Tidepool Loop" initiative with the aim to generate real-world evidence and obtain regulatory clearance. By the end of 2020, the U.S. Food and Drug Administration received Tidepool's application for an interoperable automated glycemic controller based on Loop. After 2 years, the FDA approved the Tidepool Loop on January 23, 2023.

Psychosocial Effects of the Loop Open-Source Automated Insulin Delivery System.

AIMS: This study examined the psychosocial impact of Loop, an open-source automated insulin dosing system that has emerged from the diabetes technology "Do-It-Yourself" (DIY) movement. METHODS: Subsamples of 239 adults, 115 children, and 243 parents completed data collection at the time of Loop initiation and 3 and 6 months later. Surveys collected demographic and clinical information, percent time-in-range, HbA1c, and validated psychosocial measures. Analyses included paired t tests and McNemar's tests to compare psychosocial functioning at 3 and 6 months and regression models to assess baseline predictors of psychosocial outcomes at 6 months. RESULTS: Adults reported significant improvements in diabetes distress (t = -7.20 P < .001; t = -8.01, P < .001), sleep quality (t = 6.81, P < .001; t = 2.98, P = .003), fear of hypoglycemia (t = -4.42, P < .001; t = -4.97, P < .001), and hypoglycemia confidence (t = 8.68, P < .001; t = 7.96 P < .001) from baseline to 3 months and 6 months, respectively. Significant improvements in parents' and children's sleep quality and parents' fear of hypoglycemia were also observed. Several baseline characteristics were associated with psychosocial outcomes at 6 months. CONCLUSIONS: The current findings support the broad and sustained benefits of Loop across multiple aspects of psychosocial well-being. Advancement and dissemination of such technologies has the potential to improve mental and physiological health among people living with type 1 diabetes.

Spectro-spatial features in distributed human intracranial activity proactively encode peripheral metabolic activity.

Mounting evidence demonstrates that the central nervous system (CNS) orchestrates glucose homeostasis by sensing glucose and modulating peripheral metabolism. Glucose responsive neuronal populations have been identified in the hypothalamus and several corticolimbic regions. However, how these CNS gluco-regulatory regions modulate peripheral glucose levels is not well understood. To better understand this process, we simultaneously measured interstitial glucose concentrations and local field potentials in 3 human subjects from cortical and subcortical regions, including the hypothalamus in one subject. Correlations between high frequency activity (HFA, 70-170 Hz) and peripheral glucose levels are found across multiple brain regions, notably in the hypothalamus, with correlation magnitude modulated by sleep-wake cycles, circadian coupling, and hypothalamic connectivity. Correlations are further present between non-circadian (ultradian) HFA and glucose levels which are higher during awake periods. Spectro-spatial features of neural activity enable decoding of peripheral glucose levels both in the present and up to hours in the future. Our findings demonstrate proactive encoding of homeostatic glucose dynamics by the CNS.