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Purpose: We undertook a study to investigate the relationship between duration of medication use and prevalence of impaired awareness of hypoglycemia (IAH) among patients with insulin-treated or sulfonylurea-treated type 2 diabetes in Taiwan., Methods: A total of 898 patients (41.0% insulin users, 65.1% sulfonylurea users; mean [SD] age = 59.9 [12.3] years, 50.7% female) were enrolled in pharmacies, clinics, and health bureaus of Tainan City, Taiwan. Presence of IAH was determined with Chinese versions of the Gold questionnaire (Gold-TW) and Clarke questionnaire (Clarke-TW). Sociodemographics, disease and treatment histories, diabetes-related medical care, and health status were collected. We used multiple logistic regression models to assess the relationship between duration of medication use and IAH., Results: Overall IAH prevalence was 41.0% (Gold-TW) and 28.2% (Clarke-TW) among insulin users, and 65.3% (Gold-TW) and 51.3% (Clarke-TW) among sulfonylurea users. Prevalence increased with the duration of sulfonylurea use, whereas it decreased with the duration of insulin use. After controlling for potential confounders, 5 or more years of sulfonylurea use was significantly associated with 3.50-fold (95% CI, 2.39-5.13) and 3.06-fold (95% CI, 2.11-4.44) increases in the odds of IAH based on the Gold-TW and Clarke-TW criteria, respectively. On the other hand, regular blood glucose testing and retinal examinations were associated with reduced odds in both insulin users and sulfonylurea users., Conclusions: The prevalence of IAH was high among patients using sulfonylureas long term, but the odds of this complication were attenuated for those who received regular diabetes-related medical care. Our study suggests that long-term sulfonylurea use and irregular follow-up increase risk for IAH. Further prospective studies are needed to confirm the observed associations. Annals Early Access article., (© 2024 Annals of Family Medicine, Inc.)

Aim: To evaluate whether both bolus insulin injection frequency and smart pen engagement were associated with changes in glycaemic control, using real-world data from adults with type 1 diabetes (T1D)., Materials and Methods: Adults using a smart pen (NovoPen 6) to administer bolus insulin (fast-acting insulin aspart or insulin aspart) alongside continuous glucose monitoring were eligible for inclusion. Smart pen engagement was characterized by number of days with pen data uploads over the previous 14 days. Glycaemic control was evaluated by analysing glucose metrics., Results: Overall, data from 1194 individuals were analysed. The number of daily bolus injections was significantly associated with time in range (TIR; 3.9-10.0 mmol/L [70-180 mg/dL]; P < 0.0001). Individuals administering, on average, three daily bolus insulin injections had an estimated 11% chance of achieving >70% TIR. The probability of achieving >70% TIR increased with the mean number of daily bolus injections. However, the percentage of TIR was lower on days when individuals administered higher-than-average numbers of injections. The observed mean number of daily bolus injections administered across the study population was lower than the optimal number required to reach glycaemic targets (4.8 injections vs. 6-8 injections). Smart pen engagement was significantly associated with improved TIR., Conclusions: Glycaemic control was associated with daily bolus insulin injection frequency and smart pen engagement. A treatment regimen combining an optimal bolus injection strategy, and effective smart pen engagement, may improve glycaemic control among adults with T1D., (© 2023 Novo Nordisk A/S and The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

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.

Objective: Insulin resistance is characterized by ectopic fat accumulation leading to cardiac diastolic dysfunction and nonalcoholic fatty liver disease. The objective of this study was to determine whether treatment with the peroxisome proliferator-activated receptor-α (PPARα) agonist ciprofibrate has direct effects on cardiac and hepatic metabolism and can improve insulin sensitivity and cardiac function in insulin-resistant volunteers., Methods: Ten insulin-resistant male volunteers received 100 mg/d of ciprofibrate and placebo for 5 weeks in a randomized double-blind crossover study. Insulin-stimulated metabolic rate of glucose (MRgluc) was measured using dynamic 18 F-fluorodeoxyglucose-positron emission tomography ( 18 F-FDG-PET). Additionally, cardiac function, whole-body insulin sensitivity, intrahepatic lipid content, skeletal muscle gene expression, 24-hour blood pressure, and substrate metabolism were measured., Results: Whole-body insulin sensitivity, energy metabolism, and body composition were unchanged after ciprofibrate treatment. Ciprofibrate treatment decreased insulin-stimulated hepatic MRgluc and increased hepatic lipid content. Myocardial net MRgluc tended to decrease after ciprofibrate treatment, but ciprofibrate treatment had no effect on cardiac function and cardiac energy status. In addition, no changes in PPAR-related gene expression in muscle were found., Conclusions: Ciprofibrate treatment increased hepatic lipid accumulation and lowered MRgluc, without affecting whole-body insulin sensitivity. Furthermore, parameters of cardiac function or cardiac energy status were not altered upon ciprofibrate treatment., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Recent in vitro experiments with patch pumps (PP) Omnipod (OP), Omnipod DASH (OP-D), A6 TouchCare (A6), and Accu-Chek Solo (ACS) have observed periodic fluctuations in the delivered amount of insulin during basal rate and consecutive bolus delivery in some PP, calling for a more systematic characterization of these periodic delivery patterns. Here, it was found that during basal rate delivery of 1 U/h, some devices of OP, OP-D, and A6 showed deviations of up to ±30% from target delivery that consistently repeated every 5 hours, whereas ACS showed no clear periodicity with considerably lower deviations. Similar results were found during consecutive bolus delivery of 1 U, where deviations repeated consistently every five boluses in some devices of OP, OP-D, and A6. However, there was a large variability in the periodic delivery patterns between individual devices of the same PP model. Examining their pumping techniques indicated a connection between the insulin delivery mechanism and observed delivery patterns of the PP. However, the clinical impact of such patterns is unclear.

Aim: To establish the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of proposed biosimilar Insulin N (Biocon's Insulin-N; Biocon Biologics Ltd., Bangalore, India) and US-licensed Humulin® N (Humulin-N; Eli Lilly and Company, Indianapolis, IN, USA) in healthy subjects., Materials and Methods: This was a phase-1, single-centre, double-blind, randomized, three-period, six-sequence, partially replicated, crossover, 24-h euglycaemic clamp study. Overall, 90 healthy subjects were randomized, of whom 85 completed the study. The subjects received either two single doses of Biocon's Insulin-N and a single dose of Humulin-N or two single doses of Humulin-N and a single dose of Biocon's Insulin-N subcutaneously at a dose of 0.4 IU/kg. The primary PK endpoints were the area under the insulin concentration-time curve from 0 to 24 h (AUC ins.0-24h ) and the maximum insulin concentration (C ins.max ). The primary PD endpoints were the area under the glucose infusion rate (GIR) curve from 0 to 24 h (AUC GIR.0-24h ) and the maximum GIR (GIR max )., Results: Biocon's Insulin-N was found to be equivalent to Humulin-N for the primary PK (geometric 90% confidence interval for the least squares mean ratio: AUC ins.0-24h , 100.98%-115.66% and C ins.max , 95.91%-110.16%) and PD endpoints (intra-subject variability ≥0.294; 95% upper confidence interval [(μT - μR) 2  - θσ 2 WR] <0; point estimates of geometric least squares mean ratio: AUC GIR.0-24h , 104.61% and GIR max , 100.81%). The safety profile of Biocon's Insulin-N was similar to that of Humulin-N, and no serious adverse events were reported., Conclusion: PK and PD equivalence was shown between Biocon's Insulin-N and Humulin-N in healthy subjects, and both treatments were well tolerated and considered safe., (© 2023 John Wiley & Sons Ltd.)

Objective: We evaluated the safety and feasibility of open-source automated insulin delivery AndroidAPS in adolescents and young adults with type 1 diabetes (T1D) and compared its efficacy in three different scenarios: hybrid closed loop (HCL) with meal boluses, meal announcement only (MA), and full closed loop (FCL). Research Design and Methods: In an open-label, prospective, randomized crossover trial (clinicaltrials.gov NCT04835350), 16 adolescents with T1D (10 females) with mean age of 17 years (range 15-20), glycated hemoglobin 56 mmol/mol (range 43-75), and mean duration of diabetes 5.9 years (9-15) underwent three distinct 3-day periods of camp living, comparing the above-mentioned scenarios of AndroidAPS. We used modified and locked version of AndroidAPS 3.1.03, which was called Pancreas4ALL for study purposes. The order of MA and FCL periods was assigned randomly. The primary endpoints were feasibility and safety of the system represented by percentage of time of glucose control by the system and time in hypoglycemia below 3 mmol/L. Results: The glycemia was controlled by the system 95% time of the study and the proportion of time below 3 mmol/L did not exceed 1% over the whole study period (0.72%). The HCL scenario reached significantly higher percentage of time below 3 mmol/L (HCL 1.05% vs. MA 0.0% vs. FCL 0.0%; P  = 0.05) compared to other scenarios. No difference was observed among the scenarios in the percentage of time between 3.9 and 10 mmol/L (HCL 83.3% vs. MA 79.85% vs. FCL 81.03%, P  = 0.58) corresponding to mean glycemia (HCL 6.65 mmol/L vs. MA 7.34 mmol/L vs. FCL 7.05 mmol/L, P  = 0.28). No difference was observed in the mean daily dose of insulin or in the daily carbohydrate intake. No serious adverse event occurred during the study period. Conclusions: Our pilot study showed that FCL might be a realistic mode of treatment for people with T1D.

Background: Elective surgery in patients with insulin-treated type 2 diabetes mellitus (T2D) and the admission period in the hospital, comprise a distinctive and challenging situation for physicians, nurses, as well as for the patients themselves. There is a lack of widely accepted evidence-based and standardized approach of care in regard to perioperative management of patients with insulin-treated T2D., Methods: The main purpose of this proof-of-concept study was to investigate whether a standardized insulin and meal regimen on the day of surgery leads to a better management of diabetes in terms of blood glucose (BG) levels. Two different insulin and meal regimens-group A with half of insulin dose given with a standardized postoperative meal and group B with a custom preoperative breakfast and full insulin dose-were compared with Group C with routine care (no meal and no insulin injection on the day of surgery). Each group consisted of 12 to 15 patients. BG measurements were performed pre- and immediately postoperatively, before meals and at bedtime., Results: Both standardized and well-defined insulin and meal regimens resulted in better average BG levels in the perioperative period, especially in the morning after the surgery., Conclusions: In this study, we observed that a standardized perioperative insulin regimen efficiently lowered postoperative BG levels. Providing a custom breakfast and a full insulin dose resulted in lower postoperative BG levels. These approaches were not associated with an increase in hypoglycemic events. Physicians and nursing staff gave positive feedback to the structured and well-defined approaches.

Objectives: The study aimed to evaluate dual liquid chromatography (LC) coupled to high-resolution mass spectrometry (HRMS) for the simultaneous analysis of small and large molecule drugs by development and application of a validated bioanalytical method., Methods: The oral antihyperglycemic drugs (OAD) dapagliflozin, empagliflozin, glibenclamide, glimepiride, metformin, pioglitazone, repaglinide, saxagliptin, sitagliptin, and vildagliptin, as well as the antihyperglycemic peptides exenatide, human insulin, insulin aspart, insulin degludec, insulin detemir, insulin glargine, insulin glulisine, insulin lispro, and semaglutide were included in the analytical procedure. Analytes were extracted using a combination of protein precipitation and solid-phase extraction. Two identical reversed-phase columns were used for separation followed by Orbitrap high-resolution mass spectrometry. The whole procedure was validated according to international recommendations., Results: Different MS parameters had to be used for the two analyte groups, but dual LC separation allowed elution of all analytes within 12 min using the same column type. The analytical procedure was accurate and precise for most of the compounds except for exenatide, semaglutide, and insulin glargine, which were included qualitatively in the method. Analysis of proof-of-concept samples revealed OAD concentrations mostly within their therapeutic range, insulins could be detected in five cases but at concentrations below the lower limit of quantification except for one case., Conclusions: Dual LC in combination with HRMS was shown to be a suitable platform to analyze small and large molecules in parallel and the current method allowed the determination of a total of 19 antihyperglycemic drugs in blood plasma within 12 min., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Aim: We aimed to examine the effect of Ramadan fasting on interstitial glucose control and variability before, during, and after Ramadan in type 2 diabetes patients receiving insulin therapy., Methods: Participants received a flash glucose monitoring (FGM) system one week before Ramadan that was removed on the sixth or seventh day (pre- and early Ramadan periods) of Ramadan and a second FGM system one week before the end of Ramadan that was removed one week after the end of Ramadan (late and post-Ramadan periods). Fasting blood samples were collected during the pre-, early, and late Ramadan study visits and tested for HbA1c, serum creatinine, and plasma glucose levels., Results: Thirty-four patients were prospectively included. The standard deviation and coefficient of variation of glucose concentrations were higher in the early Ramadan period than in the pre-Ramadan period, but did not differ in the late or post-Ramadan periods. Changes in the early Ramadan period were restricted to males and patients aged <55 years. No significant changes were observed in the average glucose level, glucose management indicator, time in range, time in hyperglycemia, or time in hypoglycemia at any time point., Conclusions: Ramadan fasting in patients with insulin-treated type 2 diabetes is associated with an initial increase in glucose variability that quickly returned to pre-Ramadan levels. Ramadan fasting was not associated with any significant changes in glycemic control measures., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest regarding the research, authorship, and/or publication of this article., (Copyright © 2023 Research Trust of DiabetesIndia (DiabetesIndia) and National Diabetes Obesity and Cholesterol Foundation (N-DOC). Published by Elsevier Ltd. All rights reserved.)

Background: Insulin treatment is an essential hormone replacement therapy for the survival of people with type 1 diabetes and is often used for treatment in type 2 diabetes, particularly as the disease progresses. Advances in insulin therapy have been made since its discovery, including production of human insulin and development of insulin analogs with improved efficacy and safety profiles. The different types of available insulin formulations allow health care professionals to personalize treatment to an individual's needs. Generally, insulin requires parenteral administration via subcutaneous injection owing to very low oral bioavailability., Methods: This article reviews the human, technological, economical, and regulatory factors affecting the performance of insulin pens and the relationship between them. Opportunities and challenges that insulin pen injections may encounter in the future are also considered., Results: Insulin delivery devices, together with other factors, influence dose accuracy, convenience, and quality of life, contributing to easier medication administration with high efficacy and safety. For patients, ease of use, fast and accurate drug delivery, and painless injection are the most valuable features of an insulin injection device. For manufacturers, technological feasibility and economic viability also need to be considered when developing injection devices., Conclusion: Insulin pen injectors are generally preferred over vial and syringe, although access may be limited in some health care systems. Insulin pen injectors can adapt to different insulin regimens and formulations and have the potential to acquire dosing data in real time.

Introduction: Automated insulin delivery (AID) has become a well-known research topic devoted to achieving better glycemic outcomes. AID systems consist primarily of three components: the continuous glucose monitoring system, the insulin delivery system, either tethered or patch pump, and the control system (algorithm). A key component in the tethered pump AID system is the insulin infusion set (IIS). This Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) study was conducted to evaluate the IIS evolution in the era of AID and to provide future perspectives of IIS clinical use., Methods: Literature searches for articles published from January 2016 to July 2022 were performed in Embase/Medline and PubMed. Data were extracted following PRISMA guidelines. Primary meta-analysis outcomes were IIS wear duration, total daily dose of insulin, and IIS failure reasons/modes., Results: We identified 387 publications, of which 15 eligible studies compared various IISs comprising over 1400 participants and >53 000 wears. Half of the studies published in 2022 were focused on extended IISs designed for wear durations of seven days or more. Three clinical trials have demonstrated the safe use of extended IISs to seven days of wear in individuals with type 1 diabetes, and two also demonstrated good glycemic control throughout the seven-day use., Conclusions: Research in insulin infusion technology has increased in the last six years, and extended IISs have demonstrated improved overall performance, particularly in duration of wear. Paths for future products are discussed with an emphasis on understanding the existing barriers related to both technical and nontechnical issues.

Background: We evaluated the effect of meloxicam on insulin lispro pharmacokinetics and glucose pharmacodynamics over 10 days of continuous subcutaneous insulin infusion (CSII) at one infusion site in people with type 1 diabetes (T1D)., Method: This phase 1, randomized, double-blind, single-center, two-way crossover study enrolled adults with T1D for ≥1 year on stable CSII for ≥3 months. Participants randomly received U100 insulin lispro and LY900027 (U100 insulin lispro + 0.25 mg/mL meloxicam). Primary end points were area under the insulin lispro curve from 0 to 5 hours (AUC Ins.0-5h ) after bolus administration prior to a mixed-meal tolerance test (MMTT) and maximum observed concentration of insulin lispro (C Ins.max ) on days 5, 7, and 10, versus day 3 (baseline)., Results: A total of 20 participants were randomized. Insulin absorption was accelerated for insulin lispro and LY900027 from days 1 to 7. The AUC Ins.0-5h was significantly lower on day 10 versus day 3 for LY900027 (-19%) and insulin lispro (-14%); the AUC Ins.0-5h did not differ significantly between treatments. The C Ins.max increased with LY900027 and insulin lispro (by ~14%-23% and ~16%-51%) on days 5, 7, and 10 versus day 3. The C Ins.max of LY900027 was ~14%-23% lower than insulin lispro C Ins.max on days 7 and 10 ( P ≤ .0805). Accelerated insulin absorption and a modest loss of total insulin exposure led to a loss of MMTT glycemic control at later time points., Conclusions: The pharmacokinetics of insulin changed over catheter wear time even when an anti-inflammatory agent was present. Postprandial glycemic control was adversely affected by the accelerated insulin absorption and decreased insulin exposure.

Insulin aspart (NovoRapid®, NovoMix®, Novolog® and Fiasp®) is a fast-acting analog of human insulin, indicated in the treatment of type I and II diabetes. It is administered before meals to mimic the physiological insulin secretion that follows a rise in blood glucose. Its misuse for the purposes of suicide and murder and in the context of factitious order has often been described. In forensic medicine, the identification of insulin in biological samples has always been complex. In this paper, we present a case of suicide of a 64-year-old man who died after the injection of insulin aspart. He was suffering from terminal lung cancer and left a letter explaining the reasons for his suicide. Four empty NovoRapid® pens were found near the body. Body examination was unremarkable, and the femoral blood was collected in two dry Vacutainer™ tubes (red cap) and two sodium fluoride (NaF) tubes (gray cap). A liquid chromatography coupled to high-resolution mass spectrometry method was used to identify and discriminate insulin aspart from human insulin after immunopurification in the blood samples and in the pens. Blood specimens tested positive for insulin aspart with the concentrations of 36 and 37 ng/mL in dry tubes and 58 and 71 ng/mL in tubes containing NaF when tested ∼3 weeks after the collection of the specimens. The contents of the pens also matched with insulin aspart. The stability of insulin in blood is a critical point in the interpretation of the concentrations due to their rapid decrease caused by the activity of proteases in blood. During a degradation study implemented to compare three preservatives and dry tubes, suitable insulin aspart stability was observed with disodium salt of ethylenediaminetetracetic acid and NaF. Given that NaF is standard in forensic toxicology for measuring blood alcohol concentrations, the authors suggest its use for blood collection when insulin intoxication is suspected., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Since the discovery of insulin, continuous developments of this peptide have led to better management of diabetes mellitus, thus leading to a decrease in diabetes-related mortality. Despite these developments, we have seen an increase in diabetes cases, which has further necessitated more innovative methods for diabetes management. The subcutaneous administration of insulin remains the mainstay therapy for type 1 diabetes mellitus. However, despite the availability of insulin analogues with improved pharmacokinetics, challenges with conventional administration exist. The challenges associated with insulin injections include hypoglycaemic episodes, needle phobia, and injection-site inflammation, which all have been reported to reduce patient compliance. Ongoing research on diabetes management strives to develop therapies that provide improved glycaemic control with minimal side effects. In part, for these reasons, we have seen an increase in the search and development of alternative insulin delivery systems that are envisaged to circumvent the shortfalls associated with the conventional administration route. Several alternative drug delivery systems, such as oral, pulmonary, buccal, nasal, and transdermal, have been explored in the last century. These efforts have not been without victory, as we have seen the emergence of pulmonary (Exubera and Afrezza) and buccal insulin delivery systems licenced for therapeutic use. Despite the success seen in these two systems, their marketability and popularity have been severely compromised due to reported safety concerns. Although oral insulin delivery has always shown promise in the past decades; however, it was only limited to preclinical trials. The main challenge associated with this delivery route is poor bioavailability, which necessitates high insulin concentration to be administered. Due to recent developments, oral insulin has reached phase 3 clinical trials. It is believed that patients would prefer oral insulin as their preference is often observed for oral antidiabetics over injected ones. In the last decade, transdermal insulin has also gained interest, where delivery of insulin with a concomitant reduction in blood glucose concentration has been demonstrated in vivo. However, at present, there are no clinical studies that have reported the efficacy of transdermal insulin administration. With technological advancement, there is a potential to develop yet another insulin delivery system that would likely enter the markets. As these novel delivery systems have been found to be effective, emerging competing products should be welcome and appreciated., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Competing Interests: Competing interests: None declared.

Competing Interests: None declared

Background: This study aimed at assessing the long-term effects of intranasal insulin (INI) on cognition and gait in older people with and without type 2 diabetes mellitus (T2DM)., Methods: Phase 2 randomized, double-blinded trial consisted of 24 week treatment with 40 IU of INI (Novolin ® R, off-label use) or placebo (sterile saline) once daily and 24 week follow-up. Primary outcomes were cognition, normal (NW), and dual-task (DTW) walking speeds. Of 244 randomized, 223 completed baseline (51 DM-INI, 55 DM-Placebo, 58 Control-INI, 59 Control-Placebo; 109 female, 65.8 ± 9.1; 50-85 years old); 174 completed treatment (84 DM, 90 Controls); 156 completed follow-up (69 DM)., Results: DM-INI had faster NW (~ 7 cm/s; p = 0.025) and DTW on-treatment (p = 0.007; p = 0.812 adjusted for baseline difference) than DM-Placebo. Control-INI had better executive functioning on-treatment (p = 0.008) and post-treatment (p = 0.007) and verbal memory post-treatment (p = 0.004) than Control-Placebo. DM-INI increased cerebral blood flow in medio-prefrontal cortex (p < 0.001) on MRI. Better vasoreactivity was associated with faster DTW (p < 0.008). In DM-INI, plasma insulin (p = 0.006) and HOMA-IR (p < 0.013) decreased post-treatment. Overall INI effect demonstrated faster walking (p = 0.002) and better executive function (p = 0.002) and verbal memory (p = 0.02) (combined DM-INI and Control-INI cohort, hemoglobin A1c-adjusted). INI was not associated with serious adverse events, hypoglycemic episodes, or weight gain., Conclusion: There is evidence for positive INI effects on cognition and gait. INI-treated T2DM participants walked faster, showed increased cerebral blood flow and decreased plasma insulin, while controls improved executive functioning and verbal memory. The MemAID trial provides proof-of-concept for preliminary safety and efficacy and supports future evaluation of INI role to treat T2DM and age-related functional decline., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

The technology needed to "close the loop," that is, a system for continuous glucose monitoring and a pump that infuses insulin, are only 2 of the 3 components needed for each system for automated insulin delivery (AID), the other is a "translation" of the glucose information into the appropriate amount of insulin to be applied at a given point in time to keep glucose levels in the body in the target range. It might look straightforward to calculate the required insulin dose and control the pump to apply this immediately; however, once a given amount of insulin is in the body, it will be absorbed and become metabolically active. To avoid lowering glucose levels toward too low levels, the algorithms used to calculate the insulin dose have to take a number of other factors into account. This is needed to make sure that AID systems are not only efficient but also safe, that is, not only Time-in-Range should be maximal, also Time-below-Range should be minimal. The review characterizes the different types of AID algorithms that were developed in the last decades. Using a structured approach, the different algorithms are classified. A systematic evaluation of the performance of the different algorithms is missing, not only during the clinical development of AID systems, but also in daily practice. However, it might very well be that other factors determine which AID algorithms will be used in practice.

Background: The safety and efficacy of intravenous insulin injection coupled with subsequent milk consumption was evaluated for high-quality cardiac viability F-18-fluorodeoxyglucose ( 18 F-FDG) images., Methods and Results: A total of 328 patients with known/suspected coronary artery disease received intravenous insulin injection with or without subsequent milk consumption for cardiac 18 F-FDG imaging. When blood glucose levels had decreased by ≥ 20%, 18 F-FDG was injected. Patients were scored for hypoglycemic symptoms using a 10-point scale (discomfort: 0, none; 1 to 3, mild; 4 to 6, moderate; 7 to 9, severe). An insulin-related hypoglycemic event was defined as an increased symptomatic score following insulin injection. The number of hypoglycemic events was significantly lower in the milk consumption group than in the group that did not (24/164 vs. 51/164, P < .01). Maximal and averaged standardized uptake value of the left ventricular myocardium (MyoSUVmax and MyoSUVmean) were also measured. The milk and control groups had similar mean hypoglycemic symptom scores (4.2 ± 4.0 vs. 3.3 ± 3.1, respectively), MyoSUVmax, and MyoSUVmean (11.1 ± 4.8, 7.3 ± 3.2 vs. 11.4 ± 4.5, 7.4 ± 3.2, respectively)., Conclusion: Intravenous insulin injection supplemented with subsequent milk consumption is a safer formulation for cardiac viability 18 F-FDG imaging without impairing image quality., (© 2021. American Society of Nuclear Cardiology.)

Objective: To evaluate the health economics of using continuous subcutaneous insulin infusion (CSII) therapy versus multiple daily injections (MDI) therapy in children and adolescent patients with type 1 diabetes (T1D) in Qingdao, China., Methods: A long-term cost-effectiveness analysis was conducted using the IQVIA Core Diabetes Model (CDM). The baseline characteristics of the simulated cohorts were obtained from 213 pediatric T1D patients who received care with CSII(104 cases) or MDI(109 cases) in Qingdao from 1 January 2015 to 31 March 2019. In the essential case, the expenditure of the complications and treatment of the disease with both therapies were evaluated in Chinese currency from the perspective of healthcare system. In a secondary analysis, the model used a 70-year time horizon, and a discount rate of 5% was applied to all future health outcomes and costs. A one-way sensitivity analysis was conducted on delta HbA1c, different prices of insulin pump, price of each upgrade cycle rates and different discount rates. Uncertainty was also evaluated by the probability sensitivity analysis and scenario analysis., Results: In the base-case analysis, the lifetime total costs were lower for CSII group at ¥630,871 per patient compared with ¥672,672 for MDI group. The quality-adjusted life years (QALYs) gained were 11.612 and 11.197 for patients treated with CSII group and MDI group, respectively. The CSII group was cost-saving compared to MDI group. The feasibility of CSII group being cost-effective was 100% under the threshold of 3 times per capita GDP of China in 2019 (¥212,676) which was indicated from the probabilistic sensitivity analysis. Regarding scenario analysis, the ICER of the CSII group compared to MDI was between -151,583 and 153,366 RMB/QALYs, which is cost-effective., Conclusions: This economic evaluation compared CSII therapy versus MDI therapy for T1D children and adolescent patients in China and findings indicate that CSII should be considered a preferred treatment modality to MDI.

Background: Combination of insulin and GLP-1RAs have shown reductions in the HbA1c, body weight, and the risk of hypoglycemia. To date, there are conflicting data regarding the effect of GLP-1RAs on insulin dosage(s)., Objective: The objective of this study was to evaluate adjustments of insulin doses upon initiation of GLP-1RAs., Methods: This was a retrospective chart review of patients on insulin therapy initiated on GLP-1RAs at NYU Langone Health. Patients were included in the study if they were at least 18 years of age, history of type 2 diabetes, and were on concurrent basal or mixed insulin therapy. 45 patients met inclusion criteria and were included in the study analysis. The primary endpoint was the median change in overall basal insulin doses. Secondary endpoints included median changes in total basal, mixed, and bolus insulin doses, oral antidiabetic medications and GLP-1RA doses, HbA1c, body weight, fasting glucose, and creatinine clearance. Safety results included any adverse reactions to insulin and/or GLP-1RA., Results: In the per-protocol analysis, there was a significant reduction in overall total basal insulin doses from baseline to week 24 (50 units vs. 44 units, p < 0.05). There was a median reduction in patients receiving glargine (50 units vs. 44 units) and detemir (29 units vs. 21.5 units)., Conclusions: Use of GLP-1RAs after 24 weeks resulted in a statistically significant reduction in overall total basal insulin dosages from baseline. The median HbA1C in our patient population was >8%. Consider a ≥10% reduction in the overall basal insulin dose upon initiation of GLP-1RA in patients with a HbA1C >8%.

Background: Blood glucose and insulin exhibit coordinated daily and hourly rhythms in people without diabetes (nonT1D). Although the presence and stability of these rhythms are associated with euglycemia, it is unknown if they (1) are preserved in individuals with type 1 diabetes (T1D) and (2) vary by therapy type. In particular, Hybrid Closed Loop (HCL) systems improve glycemia in T1D compared to Sensor Augmented Pump (SAP) therapies, but the extent to which either recapitulates coupled glucose and insulin rhythmicity is not well described. In HCL systems, more rapid modulation of glucose via automated insulin delivery may result in greater rhythmic coordination and euglycemia. Such precision may not be possible in SAP systems. We hypothesized that HCL users would exhibit fewer hyperglycemic event, superior rhythmicity, and coordination relative to SAP users., Methods: Wavelet and coherence analyses were used to compare glucose and insulin delivery rate (IDR) within-day and daily rhythms, and their coordination, in 3 datasets: HCL (n = 150), SAP (n = 89), and nonT1D glucose (n = 16)., Results: Glycemia, correlation between normalized glucose and IDR, daily coherence of glucose and IDR, and amplitude of glucose oscillations differed significantly between SAP and HCL users. Daily glucose rhythms differed significantly between SAP, but not HCL, users and nonT1D individuals., Conclusions: SAP use is associated with greater hyperglycemia, higher amplitude glucose fluctuations, and a less stably coordinated rhythmic phenotype compared to HCL use. Improvements in glucose and IDR rhythmicity may contribute to the overall effectiveness of HCL systems.

Diabetes is an increasing public health problem, and insulin is the mainstay for treatment of type 1 diabetes. In type 2 diabetes treatment, insulin therapy is used after oral or other injectable agents become inadequate to achieve glycemic control. Despite the advances in insulin therapy, management of diabetes remains challenging. Numerous studies have reported low adherence and persistence to insulin therapy, which acts as a barrier to successful glycemic control and diabetes management. The aim of this targeted review article is to provide an overview of adherence and persistence to insulin therapy in people with diabetes and to discuss the impact of the emergence of a new connected ecosystem of increasingly sophisticated insulin pens, glucose monitoring systems, telemedicine, and mHealth on diabetes management. With the emergence of a connected diabetes ecosystem, we have entered an era of advanced personalized insulin delivery, which will have the potential to enhance diabetes self-management and clinical management. Early systems promise to unlock the potential to address missed or late bolus insulin delivery, which should help to address non-adherence and non-persistence. Over time, improvements in this ecosystem have the potential to combine insulin data with previously missing contextualized patient data, including meal, glucose, and activity data to support personalized clinical decisions and ultimately revolutionize insulin therapy.

A new insulin patch pump for continuous subcutaneous insulin infusion was developed. The pump is composed of reusable and disposable parts and operates with a stepping motor. This pump was compared to a patch pump and a durable pump regarding basal rate and bolus accuracy. Using a microgravimetric method, boluses of 0.2 U, 1 U and 7 U, and a basal rate of 1 U/h were tested. For all pumps, bolus accuracy was higher when larger volumes were delivered. While median deviations were similar for all pumps, there were differences in the precision of individual boluses and when regarding basal rate delivery divided into 1-h windows.

Obesity is occurring due to continue taken high fat diet; this is the fast-growing problem reaching epidemic proportion globally. Ursolic acid altered the abnormal glucose metabolism in diabetic rats. In this experimental protocol, we examine ursolic acid (UA) anti-obesity effect against streptozotocin (STZ) and high-fat diet-induced obesity in rats. Orally administered the ursolic acid (2.5, 5 and 10 mg/kg) dose to the hyperglycemic rats for 8 weeks and estimated the blood glucose level at different time intervals. Biochemical, hepatic, lipid, renal and antioxidant parameters were estimated. Traf-4, Mapk-8, Traf-6 and genes such as Ins-1, ngn-3 and Pdx-1 mRNA expression were estimated using qRT-PCR to scrutinize the molecular mechanism in MAPK downstream JNK cascade and insulin pathway signalling pathways. Ursolic acid significantly (p<0.001) down-regulated the blood glucose level at dose dependent manner. Its also reduced the plasma insulin level, non-essential fatty acid and increased the level of adiponectin as compared to obese control group rats. Ursolic acid treated group rats reduced the level of total cholesterol and triglycerides. Ursolic-acid-treated rats have been shown to decrease oxidative stress in pancreatic tissue by restoring the free radical effect of scavenging, suppress the Traf-6, Mapk-8 and Traf-4 mRNA expression, enhance the expression of Pdx-1, Ins-1 and Ngn-3 and ensure the regeneration of pancreas β cells and therefore pancreas insulin. The current result suggested the anti-obese effect of ursolic acid against high fat diet (HFD) induced obese rats via alteration of insulin and JNK signaling pathway.

Administration of exogenous insulin or insulin analogs is a common cause of hypoglycemia. The etiology of hypoglycemic episodes can be investigated by the measurement of insulin. However, frequently used synthetic insulin analogs show variable reactivity with immunoassays designed for the quantification of human insulin and may produce misleading results. To overcome this challenge, mass spectrometric methods can be applied to differentiate and accurately quantify insulin and its analogs. Here we describe a liquid chromatography-tandem high-resolution accurate mass (LC-HRAM) for the highly specific and independent quantification of insulin and its synthetic analogs including aspart, detemir, glargine, glulisine, and lispro. This method utilizes antibody affinity extraction followed by analysis on a high-resolution accurate mass spectrometer., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Scholarly interest in the technosphere is exploding. Most analyses define the technosphere as massive, modern, and autonomous. This article constructively critiques these claims, focusing on scale, time, and power. First, it suggests that the technosphere exists at multiple scales that intersect in myriad ways. Second, it shows that the technosphere has a three-million-year history, meaning that Homo sapiens and the technosphere coevolved. This coevolution implies that the technosphere is a profoundly social entity. Third, its history is about how human groups (usually white, male ones) have used technology to build a physical world that works to their advantage and is thus also an issue of power. As histories of pollution, climate change, and many other things show, the technosphere does not exist outside a powerless, undifferentiated humanity. Social and technological formations are thoroughly interwoven. Clark and Szerszynski have urged scholars to "socialize the Anthropocene." This article urges scholars to "socialize" the technosphere, to interrogate and explore its social dimensions.

Impairment of adiponectin production and function is closely associated with insulin resistance and type 2 diabetes, which are linked to obesity. Studies in animal models have documented the anti-diabetic effects of tetrahydrocurcumin (THC). Although several possible mechanisms have been proposed, the contribution of adiponectin signaling on THC-mediated antihyperglycemic effects remains unknown. Here, we report that adiposity, steatosis, and hyperglycemia were potently attenuated in high-fat diet/streptozotocin-induced diabetic obese mice after they received 20 and 100 mg/kg THC for 14 weeks. THC upregulated UCP-1 in adipose tissue and elevated adiponectin levels in the circulation. THC upregulated the AdipoR1/R2-APPL1-mediated pathway in the liver and skeletal muscle, which contributes to improved insulin signaling, glucose utilization, and lipid metabolism. Furthermore, THC treatment significantly ( p < 0.05) preserved islet mass, reduced apoptosis, and restored defective insulin expression in the pancreatic β-cells of diabetic obese mice, which was accompanied by an elevation of AdipoR1 and APPL1. These results demonstrated a potential mechanism underlying the beneficial effects of THC against hyperglycemia via the adiponectin-AdipoR pathway, and thus, may lead to a novel therapeutic use for type 2 diabetes.

Automated Insulin Delivery (AID) are systems developed for daily use by people with type 1 diabetes (T1D). To ensure the safety of users, it is essential to consider how the human factor affects the performance and safety of these devices. While there are numerous publications on hardware-related failures of AID systems, there are few studies on the human component of the system. From a control point of view, people with T1D using AID systems are at the same time the plant to be controlled and the plant operator. Therefore, users may induce faults in the controller, sensors, actuators, and the plant itself. Strategies to cope with the human interaction in AID systems are needed for further development of the technology. In this paper, we present an analysis of potential faults introduced by AID users when the system is under normal operation. This is followed by a review of current fault tolerant control (FTC) approaches to identify missing areas of research. The paper concludes with a discussion on future directions for the new generation of FTC AID systems.

Background: Perioperative diabetes patients are often treated with sliding-scale insulin, despite a lack of evidence to support therapeutic effectiveness. We introduced an automated subcutaneous insulin algorithm (SQIA) to improve glycemic control in these patients while maintaining the simplicity of a q4 hour adjustable sliding-scale insulin order set., Methods: In this pilot study, we implemented a fully programmed, self-adjusting SQIA as part of a structured order set in the electronic medical record for adult patients who are nil per os, or on continuous enteral tube feedings or total parenteral nutrition. The nurse only enters the current glucose in the Medication Administration Record, and then the calculated dose is shown. The new dose is based on previous dose, and current and previous glucoses. The SQIA titrates the glucose to 120-180 mg/dL. For this pilot, this order set was utilized for complex perioperative oncologic patients., Results: The median duration on the SQIA was 58 hours. Glucoses at titration initiation were highest at 206 ± 63 mg/dL, and came down to 156 ± 29 mg/dL by 72 hours. The majority of measured glucoses (66.8%, n = 647) were maintained between 80 and 180 mg/dL. There were no glucoses lower than 60 mg/dL, and only 0.3% (n = 3) were below 70 mg/dL. There was a low rate of errors (1%)., Conclusions: A simple automated SQIA can be used to titrate insulin to meet the changing metabolic requirements of individuals perioperatively and maintain glucose within the target range for these hospitalized patients.

Aim: To examine blood glucose measurements recorded as part of the diabetes protocol operated by the UK, Ireland and Austria, which allows commercial airline pilots with insulin-treated diabetes to fly., Methods: An observational study was conducted in pilots with insulin-treated diabetes, granted medical certification to fly commercial or noncommercial aircraft, who recorded pre-flight and hourly in-flight blood glucose measurements. These values were correlated to a traffic light system (green 5.0 to 15.0 mmol/L; amber 4.0 to 4.9 mmol/L and 15.1 to 20.0 mmol/L; and red <4.0 mmol/L or >20.0 mmol/L) and studied for trends in glucose concentrations, time course within flight and any consequences. Pilot demographics were also analysed., Results: Forty-four pilots (90%) recorded one or more blood glucose value outside the green range during the 7 years of the study. Pilot age, diabetes type and duration, and follow-up period were comparable among subgroups, and mean glycated haemoglobin did not differ before and after certification in a way which would indicate poorer glycaemic control in any subgroup. A total of 892 blood glucose values (2.31%) were outside the green range, with half reported in-flight at various time intervals. There were 48 (0.12%) low red range values recorded, 14 (0.04%) of which occurred in-flight; all but four were restored to within the green range by the time of the next measurement. Appropriate corrective action was taken for all out-of-range values, with no reports of pilot incapacitation from any cause., Conclusions: The traffic light system appears effective in identifying and reducing the frequency and severity of out-of-range values., (© 2021 John Wiley & Sons Ltd.)

Objective: Advances in diabetes technology have transformed the treatment paradigm for type 1 diabetes, yet the burden of disease is significant. We report on a pivotal safety study of the first tubeless, on-body automated insulin delivery system with customizable glycemic targets., Research Design and Methods: This single-arm, multicenter, prospective study enrolled 112 children (age 6-13.9 years) and 129 adults (age 14-70 years). A 2-week standard therapy phase (usual insulin regimen) was followed by 3 months of automated insulin delivery. Primary safety outcomes were incidence of severe hypoglycemia and diabetic ketoacidosis. Primary effectiveness outcomes were change in HbA 1c and percent time in sensor glucose range 70-180 mg/dL ("time in range")., Results: A total of 235 participants (98% of enrolled, including 111 children and 124 adults) completed the study. HbA 1c was significantly reduced in children by 0.71% (7.8 mmol/mol) (mean ± SD: 7.67 ± 0.95% to 6.99 ± 0.63% [60 ± 10.4 mmol/mol to 53 ± 6.9 mmol/mol], P < 0.0001) and in adults by 0.38% (4.2 mmol/mol) (7.16 ± 0.86% to 6.78 ± 0.68% [55 ± 9.4 mmol/mol to 51 ± 7.4 mmol/mol], P < 0.0001). Time in range was improved from standard therapy by 15.6 ± 11.5% or 3.7 h/day in children and 9.3 ± 11.8% or 2.2 h/day in adults (both P < 0.0001). This was accomplished with a reduction in time in hypoglycemia <70 mg/dL among adults (median [interquartile range]: 2.00% [0.63, 4.06] to 1.09% [0.46, 1.75], P < 0.0001), while this parameter remained the same in children. There were three severe hypoglycemia events not attributable to automated insulin delivery malfunction and one diabetic ketoacidosis event from an infusion site failure., Conclusions: This tubeless automated insulin delivery system was safe and allowed participants to significantly improve HbA 1c levels and time in target glucose range with a very low occurrence of hypoglycemia., (© 2021 by the American Diabetes Association.)

Evidence suggests a major contribution of postprandial glucose (PPG) excursions to the increased risk of micro- and macro-vascular complications in individuals with type 2 diabetes mellitus (T2DM). Administration of bolus insulin remains a very effective therapeutic option for PPG control. The aim of this expert group recommendation document was to provide practical and easy-to-execute guidelines for physicians on the appropriate use of bolus insulin in the management of T2DM. A panel of key opinion leaders from India reviewed and discussed the available clinical evidence and guideline recommendations on the following topics: (1) optimum control of PPG; (2) choice of bolus insulin; and (3) special situations and practical considerations. The expert panel critically analyzed the current literature and clinical practice guidelines and factored their rich clinical experience to develop a set of nine expert group recommendations for the effective use of bolus insulin. These recommendations will not only result in a more evidence-based application of bolus insulin in the clinical setting but also trigger further research and provide a valuable base for the development of future guidelines on the use of bolus insulin in the management of individuals with T2DM.

Manufacturing of insulin and its analogues relied upon in vitro enzymatic cleavages of its precursor forms (single chain precursor, SCP) at both ends of a connecting peptide (C-peptide) that links the respective B-chain and A-chains to corresponding final forms. We have demonstrated a simplified approach of cleaving P. pastoris expressed SCP, distinctly at one site for conversion to insulin glargine. The design of the precursor was made in such a way that there is no C-peptide in the precursor which needs to be removed in the final product. Instead of traditional both side cleavage of the C-peptide and removing the C-peptide (by trypsin), followed by 2nd enzyme reaction (typically carboxipeptidase B), present work established only one side cleavage of the sequence by only trypsin converts the precursor to final insulin glargine product. The novel design of the precursor helped in producing insulin glargine in a single step with an application of single enzyme brought high degree of process efficiencies. Highly purified product was generated through two reversed phase high pressure chromatographic steps. Purified product was compared with the reference product Lantus®, for various physico-chemical and biological properties. Primary, secondary and tertiary structures as well as biological pharmaco-dynamic effects were found comparable. High cell density fermentation that gave a good yield of the SCP, a single step conversion to insulin glargine, enabled by a unique design of SCP and a distinct purification approach, has led to a simplified and economical manufacturing process of this important drug used to treat diabetes. KEY POINTS: • Novel concept for processing single chain precursor of insulin glargine • Simple and economic process for insulin glargine • Physicochemical characterization and animal Pharmacodynamics show similarity to Lantus.

Objective: To adjust for dynamic insulin requirements in critically ill patients, intravenous (IV) insulin infusions allow for titration of the dose according to a prespecified algorithm. Despite the adaptability of IV insulin protocols, human involvement in dose calculation allows for error. We integrated a previously validated IV insulin calculator into our electronic health record (Epic) and instituted it in the cardiovascular intensive care unit (CVICU). We aim to describe the design of the calculator, the implementation process, and evaluate the calculator's impact., Method: Employing an aggressive training program and user acceptance testing prior to significant elbow support at the time of institution, we successfully integrated the insulin calculator in our CVICU. We evaluated the glucometrics before and after implementation as well as nursing satisfaction following calculator implementation., Results: Overall, our implementation led to increased frequency of blood sugar at various glycemic targets, a trend toward less hypoglycemia or hyperglycemia. For severe hypoglycemia, our preintervention cohort had 0.02% of blood sugars less than 40 mg/dL but no blood sugars less than 40 mg/dL were identified in our patient's postintervention. For the CVICU target blood glucose of 70-180 mg/dL, 87.97% blood sugars at baseline met goal compared to 91.39% at one month, 91.24% at three months, and 90.87% at six months postintervention., Conclusion: By utilizing an aggressive education campaign championing superusers and making adjustments to the calculator based on early problems that were encountered, we were able to improve glycemic control and limit glucose variability at our institution.