A CRISPR interference system for engineering biological nitrogen fixation.

A grand challenge for the next century is in facing a changing climate through bioengineering solutions. Biological nitrogen fixation, the globally consequential, nitrogenase-catalyzed reduction of atmospheric nitrogen to bioavailable ammonia, is a vital area of focus. Nitrogen fixation engineering relies upon extensive understanding of underlying genetics in microbial models, including the broadly utilized gammaproteobacterium, Azotobacter vinelandii (A. vinelandii). Here, we report the first CRISPR interference (CRISPRi) system for targeted gene silencing in A. vinelandii that integrates genomically via site-specific transposon insertion. We demonstrate that CRISPRi can repress transcription of an essential nitrogen fixation gene by ~60%. Further, we show that nitrogenase genes are suitably expressed from the transposon insertion site, indicating that CRISPRi and engineered nitrogen fixation genes can be co-integrated for combinatorial studies of gene expression and engineering. Our established CRISPRi system fills an important gap for engineering microbial nitrogen fixation for desired purposes.IMPORTANCEAll life on Earth requires nitrogen to survive. About 78% of the atmosphere alone is nitrogen, yet humans cannot use it directly. Instead, we obtain the nitrogen we need for our survival through the food we eat. For more than 100 years, a substantial portion of agricultural productivity has relied on industrial methods for nitrogen fertilizer synthesis, which consumes significant amounts of nonrenewable energy resources and exacerbates environmental degradation and human-induced climate change. Promising alternatives to these industrial methods rely on engineering the only biological pathway for generating bioaccessible nitrogen: microbial nitrogen fixation. Bioengineering strategies require an extensive understanding of underlying genetics in nitrogen-fixing microbes, but genetic tools for this critical goal remain lacking. The CRISPRi gene silencing system that we report, developed in the broadly utilized nitrogen-fixing bacterial model, Azotobacter vinelandii, is an important step toward elucidating the complexity of nitrogen fixation genetics and enabling their manipulation.

Fitness benefits of a synonymous substitution in an ancient EF-Tu gene depend on the genetic background.

Synonymous mutations are changes to DNA sequence, which occur within translated genes but which do not affect the protein sequence. Although often referred to as silent mutations, evidence suggests that synonymous mutations can affect gene expression, mRNA stability, and even translation efficiency. A collection of both experimental and bioinformatic data has shown that synonymous mutations can impact cell phenotype, yet less is known about the molecular mechanisms and potential of beneficial or adaptive effects of such changes within evolved populations. Here, we report a beneficial synonymous mutation acquired via experimental evolution in an essential gene variant encoding the translation elongation factor protein EF-Tu. We demonstrate that this particular synonymous mutation increases EF-Tu mRNA and protein levels as well as global polysome abundance on RNA transcripts. Although presence of the synonymous mutation is clearly causative of such changes, we also demonstrate that fitness benefits are highly contingent on other potentiating mutations present within the genetic background in which the mutation arose. Our results underscore the importance of beneficial synonymous mutations, especially those that affect levels of proteins that are key for cellular processes.IMPORTANCEThis study explores the degree to which synonymous mutations in essential genes can influence adaptation in bacteria. An experimental system whereby an Escherichia coli strain harboring an engineered translation protein elongation factor-Tu (EF-Tu) was subjected to laboratory evolution. We find that a synonymous mutation acquired on the gene encoding for EF-Tu is conditionally beneficial for bacterial fitness. Our findings provide insight into the importance of the genetic background when a synonymous substitution is favored by natural selection and how such changes have the potential to impact evolution when critical cellular processes are involved.

Randomized Trial of the Insulin-Only iLet Bionic Pancreas for the Treatment of Cystic Fibrosis- Related Diabetes.

OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) affects up to 50% of adults with cystic fibrosis and adds significant morbidity and treatment burden. We evaluated the safety and efficacy of automated insulin delivery with the iLet bionic pancreas (BP) in adults with CFRD in a single-center, open-label, random-order, crossover trial. RESEARCH DESIGN AND METHODS: Twenty participants with CFRD were assigned in random order to 14 days each on the BP or their usual care (UC). No restrictions were placed on diet or activity. The primary outcome was the percent time sensor-measured glucose was in target range 70-180 mg/dL (time in range [TIR]) on days 3-14 of each arm, and key secondary outcomes included mean continuous glucose monitoring (CGM) glucose and the percent time sensor-measured glucose was in hypoglycemic range <54 mg/dL. RESULTS: TIR was significantly higher in the BP arm than the UC arm (75 ± 11% vs. 62 ± 22%, P = 0.001). Mean CGM glucose was lower in the BP arm than in the UC arm (150 ± 19 vs. 171 ± 45 mg/dL, P = 0.007). There was no significant difference in percent time with sensor-measured glucose <54 mg/dL (0.27% vs. 0.36%, P = 1.0), although self-reported symptomatic hypoglycemia episodes were higher during the BP arm than the UC arm (0.7 vs. 0.4 median episodes per day, P = 0.01). No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either arm. CONCLUSIONS: Adults with CFRD had improved glucose control without an increase in CGM-measured hypoglycemia with the BP compared with their UC, suggesting that this may be an important therapeutic option for this patient population.

A beneficial synonymous substitution in EF-Tu is contingent on genetic background.

Synonymous mutations are changes to DNA sequence that occur within translated genes but which do not affect the protein sequence. Although often referred to as silent mutations, evidence suggests that synonymous mutations can affect gene expression, mRNA stability, and even translation efficiency. A collection of both experimental and bioinformatic data has shown that synonymous mutations can impact cell phenotype, yet less is known about the molecular mechanisms and potential of beneficial or adaptive effects of such changes within evolved populations. Here, we report a beneficial synonymous mutation acquired via experimental evolution in an essential gene variant encoding the translation Elongation Factor protein EF-Tu. We demonstrate that this particular synonymous mutation increases EF-Tu mRNA and protein levels, as well as the polysome abundance on global transcripts. Although presence of the synonymous mutation is clearly causative of such changes, we also demonstrate that fitness benefits are highly contingent on other potentiating mutations present within the genetic background in which the mutation arose. Our results underscore the importance of beneficial synonymous mutations, especially those that affect levels of proteins that are key for cellular processes.

Testing the Real-World Accuracy of the Dexcom G6 Pro CGM During the Insulin-Only Bionic Pancreas Pivotal Trial.

Continuous glucose monitors (CGMs) have transformed the way people with type 1 diabetes can self-monitor glucose levels. Past studies have evaluated the accuracy of CGMs in clinic-based studies, but few have analyzed their accuracy in real-world settings. The Insulin-Only Bionic Pancreas Trial provided the opportunity to assess real-world accuracy of the blinded Dexcom G6 Pro sensor over the first 48-60 h of wear using a blood glucose meter (BGM) as a comparator for 1073 CGM-BGM pairs across 53 participants. The mean absolute relative difference (MARD) was 11.0% over a median period of 50 h (range 47-79 h). The MARD was 13.6% in the first 12 h, 10.5% in hours 12-24, and 10.1% after the first 24 h. These results are comparable with accuracy shown previously with laboratory-based measurements and provide real-world evidence of Dexcom G6 Pro accuracy, which improved after the first 12 h and then remained stable thereafter. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

Psychosocial Impact of the Insulin-Only iLet Bionic Pancreas for Adults, Youth, and Caregivers of Youth with Type 1 Diabetes.

Objective: To evaluate the psychosocial impact and user experience for the insulin-only configuration of iLet bionic pancreas (BP) in persons 6-83 years years of age with type 1 diabetes. Research Design and Methods: In this multicenter, randomized controlled, 13-week trial, 275 adults (221 randomly assigned to the BP group and 54 to the standard of care [SC] group) and 165 youth and their caregivers (112 randomly assigned to the BP group and 53 to the SC group) completed psychosocial questionnaires at baseline, mid-study, and the end of the trial. Results: In all age groups, most participants would recommend using the BP, including those with previous experience using automated insulin delivery devices. Similarly, the vast majority of participants reported a high level of perceived benefits and a low number of perceived burdens. Adult participants reported significant decreases in the fear of hypoglycemia and in diabetes-specific emotional distress, as well as improvements in their perceived well-being. Conclusion: Findings demonstrate acceptability, reduced burden, and positive psychosocial outcomes for adults. Children and teenagers also report high acceptability and reduced burden, but less clear improvements in psychosocial outcomes. Clinical Trial Registration Number: NCT04200313.

Utility and Safety of Backup Insulin Regimens Generated by the Bionic Pancreas: A Randomized Study.

The bionic pancreas (BP) is initialized with body weight only and doses insulin autonomously without carbohydrate counting, instead using qualitative meal announcements. In case of device malfunction, the BP generates and continuously updates backup insulin doses for injection or pump users, including long-acting insulin dose, a four-period basal insulin profile, short-acting meal doses, and a glucose correction factor. Following a 13-week trial in type 1 diabetes, participants using the BP (6-83 years) completed 2-4 days, in which they were randomly assigned to their prestudy insulin regimen (N = 147) or to follow BP-provided guidance (N = 148). Glycemic outcomes with BP guidance were similar to those reinstituting their prestudy insulin regimen, with both groups having higher mean glucose and lower time-in-range than while using the BP during the 13-week trial. In conclusion, a backup insulin regimen automatically generated by the BP can be safely implemented if need arises to discontinue use of the BP. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

The Insulin-Only Bionic Pancreas Improves Glycemic Control in Non-Hispanic White and Minority Adults and Children With Type 1 Diabetes.

OBJECTIVE: We evaluated the performance of the iLet bionic pancreas (BP) in non-Hispanic White individuals (here referred to as "Whites") and in Black, Hispanic, and other individuals (here collectively referred to as "Minorities"). RESEARCH DESIGN AND METHODS: A multicenter, randomized controlled trial evaluated glycemic management with the BP versus standard of care (SC) in 161 adult and 165 pediatric participants with type 1 diabetes over 13 weeks. RESULTS: In Whites (n = 240), the mean baseline-adjusted difference in 13-week HbA1c between the BP and SC groups was -0.45% (95% CI -0.61 to -0.29 [-4.9 mmol/mol; -6.6 to -3.1]; P < 0.001), while this difference among Minorities (n = 84) was -0.53% (-0.83 to -0.24 [-6.0 mmol/mol; -9.2 to -2.8]; P < 0.001). In Whites, the mean baseline-adjusted difference in time in range between the BP and SC groups was 10% (95% CI 7-12; P < 0.001) and in Minorities was 14% (10-18; P < 0.001). CONCLUSIONS: The BP improves glycemic control in both Whites and Minorities and offers promise in decreasing health care disparities.

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.).

A Multicenter Randomized Trial Evaluating Fast-Acting Insulin Aspart in the Bionic Pancreas in Adults with Type 1 Diabetes.

Objective: To evaluate the insulin-only configuration of the iLet® bionic pancreas (BP) using fast-acting insulin aspart (Fiasp®) in adults with type 1 diabetes (T1D). Research Design and Methods: In this multicenter, randomized trial, 275 adults with T1D (18-83 years old, baseline HbA1c 5.3%-14.9%) were randomly assigned 2:2:1 to use the BP with fast-acting insulin aspart (BP-F group, N = 114), BP with aspart or lispro (BP-A/L group, N = 107), or a control group using their standard-care insulin delivery (SC group, N = 54) plus real-time continuous glucose monitoring (CGM). The primary outcome was HbA1c at 13 weeks. The BP-F versus SC comparison was considered primary and BP-F versus BP-A/L secondary. Results: Mean ± standard deviation (SD) HbA1c decreased from 7.8% ± 1.2% at baseline to 7.1% ± 0.6% at 13 weeks with BP-F versus 7.6% ± 1.2% to 7.5% ± 0.9% with SC (adjusted difference = -0.5%, 95% CI -0.7 to -0.3, P < 0.001). CGM-measured percent time <54 mg/dL over 13 weeks with BP-F was noninferior to SC (adjusted difference = 0.00%, 95% CI -0.07 to 0.05, P < 0.001 for noninferiority based on a prespecified noninferiority limit of 1%). Over 13 weeks, mean time in range 70-180 mg/dL (TIR) increased by 14% (3.4 h/day) and mean CGM glucose was reduced by 18 mg/dL with BP-F compared with SC (P < 0.001). Analyses of time >180 mg/dL, time >250 mg/dL, and the SD of CGM glucose all favored BP-F compared with SC (P < 0.001). Differences between BP-F and BP-A/L were minimal, with no difference in HbA1c at 13 weeks (adjusted difference = -0.0%, 95% CI -0.2 to 0.1, P = 0.67) or mean glucose (adjusted difference = -2.0 mg/dL, 95% CI -4.3 to 0.4, P = 0.10). Mean TIR was 2% greater with BP-F than BP-A/L (95% CI 1 to 4, P = 0.005), but the percentages of participants improving TIR by ≥5% were not significantly different (P = 0.49) and there were no significant differences comparing BP-F versus BP-A/L across nine patient-reported outcome surveys. The rate of severe hypoglycemia events did not differ among the three groups. Conclusions: In adults with T1D, HbA1c was improved with the BP using fast-acting insulin aspart compared with standard care without increasing CGM-measured hypoglycemia. However, the effect was no better than the reduction observed with the BP using aspart or lispro. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

A Multicenter Randomized Trial Evaluating the Insulin-Only Configuration of the Bionic Pancreas in Adults with Type 1 Diabetes.

Objective: To evaluate the insulin-only configuration of the iLet® bionic pancreas (BP) using insulin aspart or insulin lispro in adults with type 1 diabetes (T1D). Methods: In this multicenter, randomized, controlled trial, 161 adults with T1D (18-79 years old, baseline HbA1c 5.5%-13.1%, 32% using multiple daily injections, 27% using a pump without automation, 5% using a pump with predictive low glucose suspend, and 36% using a hybrid closed loop system before the study) were randomly assigned 2:1 to use the BP (N = 107) with insulin aspart or insulin lispro (BP group) or a standard-of-care (SC) control group (N = 54) using their usual insulin delivery plus continuous glucose monitoring (CGM). The primary outcome was HbA1c at 13 weeks. Results: Mean HbA1c decreased from 7.6% ± 1.2% at baseline to 7.1% ± 0.6% at 13 weeks with BP versus 7.6% ± 1.2% to 7.5% ± 0.9% with SC (adjusted difference = -0.5%, 95% confidence interval -0.6% to -0.3%, P < 0.001). Over 13 weeks, mean time in range 70-180 mg/dL (TIR) increased by 11% (2.6 h/d) and mean CGM glucose was reduced by 16 mg/dL with BP compared with SC (P < 0.001). Improvement in these metrics was seen during the first day of BP use and by the end of the first week reached levels that remained relatively stable through 13 weeks. Analyses of time >180 mg/dL, time >250 mg/dL, and standard deviation of CGM glucose all favored the BP group (P < 0.001). The CGM-measured hypoglycemia was low at baseline (median time <54 mg/dL of 0.21% [3 min/d] for the BP group and 0.11% [1.6 min/d] for the SC group) and not significantly different between groups over the 13 weeks (P = 0.51 for time <70 mg/dL and 0.33 for time <54 mg/dL). There were 7 (6.5% of 107 participants) severe hypoglycemic events in the BP group and 2 events in the SC group (1.9% of 54 participants, P = 0.40). Conclusions: In adults with T1D, use of the BP with insulin aspart or insulin lispro improved HbA1c, TIR, and hyperglycemic metrics without increasing CGM-measured hypoglycemia compared with standard of care. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

The Insulin-Only Bionic Pancreas Pivotal Trial Extension Study: A Multi-Center Single-Arm Evaluation of the Insulin-Only Configuration of the Bionic Pancreas in Adults and Youth with Type 1 Diabetes.

Objective: To evaluate a transition from standard-of-care (SC) management of type 1 diabetes (any insulin delivery method including hybrid closed-loop systems plus real-time continuous glucose monitoring [CGM]) to use of the insulin-only configuration of the iLet® bionic pancreas (BP) in 90 adults and children (age 6-71 years). Research Design and Methods: After the SC group completed the randomized controlled trial (RCT) portion of the Insulin-Only BP Pivotal Trial, 90 of the 107 participants participated in a 13-week study using the BP. The key outcomes were change from baseline in HbA1c and CGM metrics after 13 weeks on the BP. Results: Using the BP, mean HbA1c decreased from 7.7% ± 1.0% (61 ± 10.9 mmol/mol) at baseline to 7.1% ± 0.6% (54 ± 6.6 mmol/mol) at 13 weeks (mean change -0.55% ± 0.72% [-6 ± 7.9 mmol/mol], P < 0.001), time in range 70-180 mg/dL increased by 12.0% ± 12.5% (from 53% ± 17% to 65% ± 9%, P < 0.001), and mean glucose decreased by -18 ± 23 mg/dL (from 182 ± 32 to 164 ± 15 mg/dL, P < 0.001). The higher the baseline HbA1c level, the greater the change in HbA1c. Results were similar in the adult (N = 42) and pediatric (N = 48) cohorts. Time <70 mg/dL decreased from baseline over the 13 weeks by -0.50% ± 1.86% (P = 0.02), and time <54 mg/dL was similar (change from baseline -0.08% ± 0.59%, P = 0.24). Two severe hypoglycemia events (in same participant) and one diabetic ketoacidosis event occurred. Conclusions: Glycemic control improved after adult and pediatric participants in the SC arm in the Insulin-Only BP Pivotal Trial transitioned to use of the BP. Improvement using the BP was of similar magnitude to that observed during the RCT. ClinicalTrials.gov number, NCT04200313.

Positive Impact of the Bionic Pancreas on Diabetes Control in Youth 6-17 Years Old with Type 1 Diabetes: A Multicenter Randomized Trial.

Objective: To evaluate the insulin-only configuration of the iLet® bionic pancreas (BP) in youth 6-17 years old with type 1 diabetes (T1D). Research Design and Methods: In this multicenter, randomized, controlled trial, 165 youth with T1D (6-17 years old; baseline HbA1c 5.8%-12.2%; 35% using multiple daily injections, 36% using an insulin pump without automation, 4% using an insulin pump with low glucose suspend, and 25% using a hybrid closed-loop system before the study) were randomly assigned 2:1 to use BP (n = 112) with insulin aspart or insulin lispro (BP group) or to a control group (n = 53) using their personal standard care insulin delivery (SC group) plus real-time continuous glucose monitoring (CGM). The primary outcome was HbA1c at 13 weeks. Results: Mean HbA1c decreased from 8.1% ± 1.2% at baseline to 7.5% ± 0.7% at 13 weeks with BP versus 7.8% ± 1.1% at both baseline and 13 weeks with SC (adjusted difference = -0.5%, 95% CI -0.7% to -0.2%, P < 0.001). Participants with baseline HbA1c ≥9.0% (n = 34) decreased mean HbA1c from 9.7% ± 0.8% to 7.9% ± 0.6% after 13 weeks with BP compared with 9.7% ± 0.5% to 9.8% ± 0.8% with SC. Over 13 weeks, mean time in range (TIR) 70-180 mg/dL increased by 10% (2.4 h per day) and mean CGM glucose was reduced by 15 mg/dL with BP compared with SC (P < 0.001). Analyses of time >180 mg/dL, time >250 mg/dL, and standard deviation of CGM glucose favored BP (P < 0.001). Time <54 mg/dL was low at baseline (median 0.2%) and not significantly different between groups over 13 weeks (P = 0.24). A severe hypoglycemia event occurred in 3 (2.7%) participants in the BP group and in 1 (1.9%) in the SC group. Conclusions: In youth 6-17 years old with T1D, use of insulin-only configuration of BP improved HbA1c, TIR, and hyperglycemic metrics without increasing CGM-measured hypoglycemia compared with standard of care. Improvement in glycemic metrics was most pronounced in participants with high baseline HbA1c levels. Clinical Trial Registry: clinicaltrials.gov; NCT04200313.

The Bihormonal Bionic Pancreas Improves Glycemic Control in Individuals With Hyperinsulinism and Postpancreatectomy Diabetes: A Pilot Study.

OBJECTIVE: To determine whether the bihormonal bionic pancreas (BHBP) improves glycemic control and reduces hypoglycemia in individuals with congenital hyperinsulinism (HI) and postpancreatectomy diabetes (PPD) compared with usual care (UC). RESEARCH DESIGN AND METHODS: Ten subjects with HI and PPD completed this open-label, crossover pilot study. Coprimary outcomes were mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration <3.3 mmol/L. RESULTS: Mean (SD) CGM glucose concentration was 8.3 (0.7) mmol/L in the BHBP period versus 9 (1.8) mmol/L in the UC period (P = 0.13). Mean (SD) time with CGM glucose concentration <3.3 mmol/L was 0% (0.002) in the BHBP period vs. 1.3% (0.018) in the UC period (P = 0.11). CONCLUSIONS: Relative to UC, the BHBP resulted in comparable glycemic control in our population.

Improvements in Glycemic Control Achieved by Altering the tmax Setting in the iLet® Bionic Pancreas When Using Fast-Acting Insulin Aspart: A Randomized Trial.

INTRODUCTION: We investigated the safety of, and glucose control by, the insulin-only configuration of the iLet® bionic pancreas delivering fast-acting insulin aspart (faster aspart), using the same insulin-dosing algorithm but different time to maximal serum drug concentration (tmax) settings, in adults with type 1 diabetes. METHODS: We performed a single-center, single-blinded, crossover (two 7-day treatment periods) escalation trial over three sequential cohorts. Participants from each cohort were randomized to a default tmax setting (t65 [tmax = 65 min]) followed by a non-default tmax setting (t50 [tmax = 50 min; cohort 1], t40 [tmax = 40 min; cohort 2], t30 [tmax = 30 min; cohort 3]), or vice versa, all with faster aspart. Each cohort randomized eight new participants if escalation-stopping criteria were not met in the previous cohort. RESULTS: Overall, 24 participants were randomized into three cohorts. Two participants discontinued treatment, one due to reported 'low blood glucose' during the first treatment period of cohort 3 (t30). Mean time in low sensor glucose (< 54 mg/dl, primary endpoint) was < 1.0% for all tmax settings. Mean sensor glucose in cohorts 1 and 2 was significantly lower at non-default versus default tmax settings, with comparable insulin dosing. The mean time sensor glucose was in range (70-180 mg/dl) was > 70% for all cohorts, except the default tmax setting in cohort 1. No severe hypoglycemic episodes were reported. Furthermore, there were no clinically significant differences in adverse events between the groups. CONCLUSION: There were no safety concerns with faster aspart in the iLet at non-default tmax settings. Improvements were observed in mean sensor glucose without increases in low sensor glucose at non-default tmax settings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03816761.

One way to give insulin is to use an insulin delivery system. The iLet^® is a new type of insulin delivery system that works together with a continuous sugar monitoring tool (CGM). The CGM shows the blood sugar level in the body throughout the day. Based on this, the iLet automatically gives the insulin that is needed to control the blood sugar. Fast-acting insulin aspart (faster aspart) is a type of insulin that doctors can prescribe for use with insulin pens and insulin pumps. The researchers wanted to test the safety of faster aspart when given to people at different delivery settings in the iLet. Twenty-four men and women with type 1 diabetes from the USA took part. The different insulin delivery settings were the standard setting (t_max65 = 65 min) and new settings (t_max50 = 50 min; t_max40 = 40 min; t_max30 = 30 min). The shorter the t_max setting, the faster the insulin was assumed to be absorbed into the body by the iLet. People had good blood sugar control with faster aspart delivered using the iLet. The time with low blood sugar (i.e., < 54 mg/dl) was low for both the standard setting and the new settings. The average blood sugar was lower with the shorter, non-standard t_max settings. No people had serious side effects. No severe hypoglycemic episodes were reported. In this study, researchers found that it was safe to use faster aspart with the different settings in the iLet.

New and Emerging Technologies in Type 1 Diabetes.

There has been a rapid advancement in the pace of development of new diabetes technologies and therapies for the management of type 1 diabetes over the past decade. The Diabetes Control and Complications Trial conclusively established that tight glycemic control with intensive insulin therapy decreases the rates of diabetes complications in proportion to glycemic control, and diabetes technologies have accordingly been developed to help patients reach these goals. In this review, the authors discuss new diabetes therapeutics and technologies, including new insulin analogues, insulin pumps, continuous glucose monitoring systems, and automated insulin delivery systems."

A Three-Way Accuracy Comparison of the Dexcom G5, Abbott Freestyle Libre Pro, and Senseonics Eversense Continuous Glucose Monitoring Devices in a Home-Use Study of Subjects with Type 1 Diabetes.

Background: There is a dearth of comparative accuracy studies of continuous glucose monitoring (CGM) devices in the home-use setting, and none with the Eversense implantable CGM. Methods: We evaluated the accuracy of the Dexcom G5, Abbott Freestyle Libre Pro, and Senseonics Eversense during a 6-week free-living home-use bionic pancreas study involving 23 subjects with type 1 diabetes who wore all three devices concurrently. The primary outcome was the mean absolute relative difference (MARD) between CGM readings and point-of-care (POC) plasma-glucose (PG) values obtained approximately twice daily by the subjects. We compared PG values with CGM readings when available from all three CGMs in the 5 min preceding the PG values (n = 829 sets). Since the Libre Pro records readings every 15 min, we also did a two-way comparison between the G5 and the Eversense with a higher number of comparisons (n = 2277 sets). Results: All three CGM systems produced higher average MARDs than during in-clinic studies. However, since all three CGM systems were worn by the same individuals and used the same meter for comparator PG measurements, we could directly compare their performances. In the three-way comparison, Eversense achieved the lowest nominal MARD (14.8%) followed by Dexcom G5 (16.3%) and Libre Pro (18.0%) (Eversense vs. Libre Pro P = 0.004, other comparisons P = NS). There was a statistically significant difference (P = 0.008) in the two-way comparison of the MARDs for Eversense (15.1%) and G5 (16.9%). Conclusions: The point accuracy of the Eversense was better than two other CGMs when compared with POC PG values.

Automated glycemic control with the bionic pancreas in cystic fibrosis-related diabetes: A pilot study.

Cystic fibrosis-related diabetes (CFRD) is the most common extrapulmonary manifestation of cystic fibrosis. The current standard of care for CFRD involves treatment with insulin, typically via multiple daily injections. We conducted a small pilot study comparing usual care with automated glycemic control using the bihormonal (insulin and glucagon) and insulin-only configurations of the bionic pancreas. Both configurations of the bionic pancreas achieved good glycemic control, with mean glucose levels <150 mg/dl and minimal hypoglycemia. Subjects reported improved treatment satisfaction and reduced burden of diabetes management with the bionic pancreas. Further investigation of automated glycemic control in the treatment of CFRD is warranted.