Practical aspects of usage of insulin in India: Descriptive review and key recommendations.

BACKGROUND AND AIMS: Insulin therapy is an integral part of diabetes management. However, reliable and easily accessible information on a number of basic facts concerning insulin therapy, including storage of insulin, managing insulin therapy during travel, nuances of insulin use while driving, and dose adjustments during sick days is lacking. This document aims to make readily available, reliable, and easy to implement information on these essential but relatively less discussed aspects of insulin therapy. METHOD: Literature search was performed using PubMed and Cochrane Library from inception till 1st of July 2019. The relevant topics were reviewed by a panel of 5 specialists and 23 contributing physicians and endocrinologists, who had assembled at Bengaluru, India for the 13th National Insulin Summit. After a thorough review of the literature, and following detailed discussions, the committee arrived at these recommendations. RESULTS: Unopened vials and cartridges of insulin should be stored at 2 °C-8 °C in a refrigerator and protected from direct sunlight. For opened vials and in-use cartridges, manufacturer's instructions must be followed at all times. While traveling by air, dose adjustments are required only when flying across more than five time zones in the east or west directions. Insulin therapy should not be omitted or stopped during an acute illness; rather the doses need careful adjustments based on self-monitoring of blood glucose. CONCLUSION: Recommendations and guidelines, covering many common aspects of insulin therapy are readily available. This consensus document aims to make recommendations for those essential aspects of insulin therapy that are crucial for its success but are relatively less known and less discussed.

A standardized glucose-insulin-potassium infusion protocol in surgical patients: Use of real clinical data from a clinical data warehouse.

AIMS: We evaluated the clinical usefulness of a new unified glucose-insulin-potassium (GIK) regimen in a general surgical department. METHODS: Surgical patients treated under the previous diverse GIK regimens (September 2016 to August 2017) and the new unified GIK regimen (September 2017 to August 2018) were identified in records of the Clinical Data Warehouse of Seoul National University Bundang Hospital. Serial and area under the curve (AUC) glucose levels, and percentages of time within the target glucose levels were compared in propensity score matched patients in the diverse GIK regimen and in the unified GIK regimen (n = 227 in each group). RESULTS: The AUC of glucose at 6 h and 12 h was lower under the unified GIK regimen than the diverse GIK regimen. The percentage of target glucose levels was higher in the unified GIK regimen compared to the diverse GIK regimen (81.5% vs. 75.0%, P = 0.026), but the occurrence of hypoglycaemia did not differ significantly between groups. CONCLUSIONS: The unified GIK regimen was more effective than the diverse GIK regimen for glycaemic control and did not increase the number of patients developing hypoglycaemia. This validated written GIK regimen can be safely used in a general surgical department.

A Case for Expanding Thermochromic Vial Monitor Technology to Insulin and Other Biologics.

Insulin quality and efficacy determine glycemic control, which determines quality of life for people with diabetes. Insulin efficacy is reduced by heat exposure, especially in tropical climates, remote areas, and with improper handling. Insulin doses can be adjusted based on blood glucose monitoring, which may compensate for lack of viability. However, a measured response may be difficult with other biopharmaceuticals. Thermochromic vial monitor technology developed for oral polio vaccines (vaccine vial monitors) is an inexpensive, easily available, visible modality which can be used for insulin and other biopharmaceuticals to detect excessive heat exposure and thus reduced potency at any point in the cold-chain, till the end-users, thus improving patient care. Regulatory authorities must urgently consider the need to impose mandatory use of this technology for all biopharmaceuticals, including insulin, to ensure efficacy till end usage.

Faster Compared With Standard Insulin Aspart During Day-and-Night Fully Closed-Loop Insulin Therapy in Type 1 Diabetes: A Double-Blind Randomized Crossover Trial.

OBJECTIVE: We evaluated the safety and efficacy of day-and-night fully closed-loop insulin therapy using faster (Faster-CL) compared with standard insulin aspart (Standard-CL) in young adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: In a double-blind, randomized, crossover trial, 20 participants with type 1 diabetes on insulin pump therapy (11 females, aged 21.3 ± 2.3 years, HbA1c 7.5 ± 0.5% [58.5 ± 5.5 mmol/mol]) underwent two 27-h inpatient periods with unannounced afternoon moderate-vigorous exercise and unannounced/uncovered meals. We compared Faster-CL and Standard-CL in random order. During both interventions, the fuzzy-logic control algorithm DreaMed GlucoSitter was used. Glucose sensor data were analyzed by intention-to-treat principle with the difference (between Faster-CL and Standard-CL) in proportion of time in range 70-180 mg/dL (TIR) over 27 h as the primary end point. RESULTS: The proportion of TIR was similar for both arms: 53.3% (83% overnight) in Faster-CL and 57.9% (88% overnight) in Standard-CL (P = 0.170). The proportion of time in hypoglycemia <70 mg/dL was 0.0% for both groups. Baseline-adjusted interstitial prandial glucose increments 1 h after meals were greater in Faster-CL compared with Standard-CL (P = 0.017). The gaps between measured plasma insulin and estimated insulin-on-board levels at the beginning, at the end, and 2 h after the exercise were smaller in the Standard-CL group (P = 0.029, P = 0.003, and P = 0.004, respectively). No severe adverse events occurred. CONCLUSIONS: Fully closed-loop insulin delivery using either faster or standard insulin aspart was safe and efficient in achieving near-normal glucose concentrations outside postprandial periods. The closed-loop algorithm was better adjusted to the standard insulin aspart.

Recent advances in the determination of insulins from biological fluids.

The qualitative and quantitative determination of insulin and its related substances (e. g., C-peptide) is of great importance in many different areas of analytical chemistry. In particular, due to the steadily increasing prevalence of metabolic disorders such as diabetes mellitus, an adequate control of the circulating amount of insulin is desirable. In addition, also in forensics and doping control analysis, the determination of insulin in blood, urine or other biological matrices plays a major role. However, in order to establish general reference values for insulin and C-peptide for diabetology, the comparability of measured concentrations is indispensable. This has not yet been fully implemented, although enormous progress has been made in recent years, and the search for a "gold standard" method is still ongoing. In addition to established ligand-binding assays, an increasing number of mass-spectrometric methods have been developed and employed as the to-date available systems (for example, high-resolution/high accuracy mass spectrometers) provide the sensitivity required to determine analyte concentrations in the sub-ng/mL (sub-100pmol/L) level. Meanwhile, also high-throughput measurements have been realized to meet the requirement of testing a high number of samples in a short period of time. Further developments aim at enabling the online measurement of insulin in the blood with the help of an insulin sensor and, in the following, in addition to a brief review, today's state of the art testing developments are summarized.

Pharmacological control of inflammation in wound healing.

Wound inflammation is a rapid and highly orchestrated process that significantly impacts the wound healing cascade. Consequent to injury, a series of events set off that include inflammatory, proliferation and maturation phases leading to wound closure and restoration of normal skin integrity. Stimuli causing stress to host immune system or induce inflammatory response include tissue damage and pathogenic microbial infection.Several evidences points towards the positive role of inflammation as it essential to fight against the attack of invading pathogens and to remove dead tissues from the site of injury. Besides its positive role, prolonged inflammation is injurious and may result in deregulated stages of the wound healing which may lead to excessive scarring. Achieving balance in inflammatory cascade is one of the challenging tasks for development of a wound healing drug. This review mainly focuses on the pharmacological control of inflammation by agents which critically balance the inflammatory cascade. However, none of the agent is available in the healthcare market which exclusively plays a role in wound repair. In this review we shall explore different factors or agents affecting inflammation in wound healing. This information might be helpful in designing and development new process, technologies or drugs for better management of wound care. In addition, understanding the effect of inflammation on the outcome of the healing process will serve as a significant milestone in the area of pathological tissue repair.

How often patients on insulin therapy measure postprandial glycemia and modify insulin doses accordingly? From an on-line survey in insulin-treated diabetes patients in Spain.

INTRODUCTION: Controlling postprandial glycemia (PPG) is important to achieve optimal glycemic control, but few studies have evaluated how often is measured and evaluated. OBJECTIVES: To evaluate how often patients on insulin therapy measure PPG and modify insulin doses accordantly. As secondary objectives, we evaluated the factors conditioning elevated PPG and associated issues. MATERIAL AND METHODS: Cross-sectional observational study based on a web-based survey from an unselected sample of adult insulin-treated patients. A p-value of < 0.05 was significant. RESULTS: 1251 patients (68% women, 38.9 ±â€¯13 years [mean ±â€¯SD], body mass index (BMI) 24.2 ±â€¯4.2 kg/m2, diabetes duration 17.4 ±â€¯12.8 years, insulin dose 38 ±â€¯18 IU) participated, 1104 with autoinmmune disease (AD) and 147 with non-autoinmmune diabetes (NAD). 59% of patients had HbA1c ≤ 7%, 92.7% of patients with AD and 55.8% with NAD were attended by specialists (p < 0.001). People with AD did more often blood glucose monitoring (BGM) (p < 0.0001) and used continuous glucose monitoring systems (CGMS) (p < 0.0001). 90.1% with AD and 68.0% with NAD received instructions on measuring PPG (p < 0.001), and more with AD received specific training to change the treatment (87% vs. 61.2%, p < 0.0001) and were more proactive. However, more with NAD discussed their postprandial glucose levels with their healthcare team during clinical visits (92.5% vs. 74.1%, p < 0.0001). Regarding bolus administration, 88.6% with AD and 68.7% with NAD injected the insulin bolus before meals (p < 0.001). CONCLUSIONS: Patients with AD determine PPG more frequently. Diabetes type, follow-up setting, number of injections and CGMS use were the most important predictive factors for PPG measurement. Diabetes education programs should address how to best monitor PPG and appropriate corrective actions.

Assessment of optimal insulin administration timing for standard carbohydrates-rich meals using continuous glucose monitoring in children with type 1 diabetes: A cross-over randomized study.

AIMS/INTRODUCTION: The present study was an assessment of postprandial glucose concentration after carbohydrates-rich meals using continuous glucose monitoring in 30 children with type 1 diabetes treated using continuous subcutaneous insulin infusion with a rapid-acting insulin analog. MATERIALS AND METHODS: Over a period of 3 days, participants administered simple boluses with different delay times between insulin administration and the beginning of carbohydrates-rich meal consumption (meal no. 1 containing 197 kcal, no. 2 containing 247 kcal and meal no. 3 containing 323 kcal; containing practically no protein and fat). In the present cross-over randomized study, we analyzed the average glucose concentration profiles in 5-min intervals, mean glucose at insulin administration, mean glucose after 120 and 180 min, mean and peak glucose, glucose peak time, areas under the glucose and glucose increase curves, and time period lengths with glucose <50, 70 mg/dL, and >140 and 200 mg/dL. RESULTS: For test meals at 20-min versus 0-min delay time, the study exposed a longer median time period to reach peak glucose (95 vs 65 min, P = 0.01) after meals. A tendency to the lowest peak and mean glucose, and the longest time with glucose within a normal range was observed in patients who administered bolus insulin 20 min before a meal. CONCLUSIONS: For carbohydrates-rich meals, administration of a proper dose of a rapid-acting insulin analog is crucial. The influence of rapid-acting insulin analog administration timing seems to be of minor importance in comparison with correct insulin dose adjustment; however, a tendency to achieve more balanced glucose profiles was found in a group who administered insulin 20 min before a meal.

Molecularly imprinted polymer based quartz crystal microbalance sensor for the clinical detection of insulin.

In this study, quartz crystal microbalance sensors based on molecular imprinting technology were fabricated for real-time detection of insulin in aqueous solution and artificial plasma. This study describes the preparation of insulin imprinted poly(hydroxyethyl methacrylate)-N-methacryloyl-(l)-histidine methyl ester based quartz crystal microbalance sensor for insulin determination. Poly(hydroxyethyl methacrylate)-N-methacryloyl-(l)-histidine methyl ester based film on chip surface was synthesized by ultra violet (UV) polymerization for the detection of insulin at low concentrations. At the first step, N-methacryloyl-(l)-histidine methyl ester complex was formed with insulin and then, the insulin imprinted film has been prepared. The characterization of the polymeric film has been conducted with ellipsometry, contact angle, Fourier transform infrared-attenuated total reflectance and atomic force microscopy measurements. Langmuir, Freundlich and Langmuir-Freundlich adsorption isotherm models were applied for this system. The best fitted model to explain the interactions between molecular imprinted chip and insulin molecules was the Langmuir adsorption isotherm (R2: 0.999). The repeatability of insulin imprinted chip was investigated by using of equilibration-binding-regeneration cycles for four times. The detection limit was found as 0.00158 ng/mL. According to the results, the QCM sensor has showed low-detection limit, high selectivity and sensitivity for insulin assay.

Formulary Considerations for Insulins Approved Through the 505(b)(2) "Follow-on" Pathway.

OBJECTIVE: To summarize formulary-relevant issues for follow-on insulins approved through the Food and Drug Administration (FDA) 505(b)(2) approval pathway (Basaglar and Admelog). DATA SOURCES: A search of the MEDLINE database was performed for articles pertaining to clinical and formulary considerations for follow-on insulin products through July 2018. STUDY SELECTION AND DATA EXTRACTION: All clinical trials used in the 505(b)(2) approval process for follow-on insulin glargine and insulin lispro products were included and summarized. DATA SYNTHESIS: Follow-on insulin glargine and insulin lispro products have been recently approved as the first lower-cost alternatives to innovator insulin products. The follow-on insulins were approved via the 505(b)(2) pathway, making them neither generics nor biosimilars. Current data do not suggest any clinically relevant differences between the follow-on insulins and their respective innovator products. Clinicians should be aware that follow-on insulins will be reclassified as biologic products in the year 2020. Relevance to Patient Care and Clinical Practice: This article provides information about currently available follow-on insulin products that were approved through the 505(b)(2) pathway, including product characteristics and efficacy and safety data. These products will likely be considered for both clinical use and formulary placement because of their potentially lower cost compared with innovator products. CONCLUSIONS: Follow-on insulin products approved through the 505(b)(2) pathway are supported by robust efficacy and safety data. As new follow-on insulins are approved and the regulatory change that will occur with these products in 2020 approaches, formulary decisions and clinical policies (eg, substitution) will continue to be revisited.

The association of basal insulin treatment versus standard care with outcomes in anti-GAD positive and negative subjects: A post-hoc analysis of the ORIGIN trial.

We compared cardiovascular and other outcomes in patients with dysglycaemia with or without anti-glutamic acid dehydrogenase (GAD) antibodies participating in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. Of the 12 537 participants, 8162 had anti-GAD measured at baseline and 267 were anti-GAD positive. The effects of insulin glargine versus standard care and of n-3 fatty acids supplements versus placebo were compared by testing the interaction of the treatment effects and anti-GAD status. The effect of glargine on development of new diabetes was assessed in participants without previous diabetes at baseline. The overall incidence of outcomes did not differ between anti-GAD positive and anti-GAD negative subjects. The incidence of the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke did not differ between anti-GAD positive participants randomized to insulin glargine or to standard care, with a hazard ratio (HR) (95% confidence interval [CI]) of 0.80 (0.44-1.44) or in anti-GAD negative participants with a HR of 1.07 (0.96-1.20) (P for interaction = 0.20).

Concentrations of Intact Insulin Concurs With FDA and EMA Standards When Measured by HPLC in Different Parts of the Distribution Cold Chain.

BACKGROUND: The article by Carter and Heinemann raised serious concerns about the concentrations of insulin in vials being sold in US pharmacies. To study the claims made in the manuscript, we reviewed Novo Nordisk data on insulin concentration. METHODS: Insulin concentrations within vials from three different sources along the distribution chain were evaluated utilizing currently accepted US Pharmacopeia methodology: (1) insulin content and stability based on production batches covering 7 years of insulin production, (2) insulin content in samples returned to Novo Nordisk over the last three years in the United States, and (3) data from eight years of independent EMA testing. RESULTS: The data demonstrated that without exception (1) insulin quality based on stability data was maintained, even in scenarios that stressed the normal recommendations for temperature storage conditions, (2) insulin content from the last three years of samples returned to Novo Nordisk from patients in the United States (233 vials) was within USP requirements recognized by FDA, and (3) ten years of independent EMA sampling of products obtained at wholesalers and pharmacies across the EU confirmed compliance (n = 43). CONCLUSIONS: The study by Carter and Heinemann utilized an LC-MS technique, which has not been validated for the quantification of insulin in pharmaceutical preparations. It appears likely that their findings are the result of the method utilized and not due to decreased insulin content in samples. However, recognizing the importance of maintaining Insulin content from production to the patient, Novo Nordisk supports continued evaluation of insulin distributed to pharmacies and patients utilizing validated techniques compliant with international pharmacopeias.

Clinical Utility and Cross-Reactivity of Insulin and C-Peptide Assays by the Lumipulse G1200 System.

BACKGROUND: Measurement of insulin and C-peptide concentrations is important for deciding whether insulin treatment is required in diabetic patients. We aimed to investigate the analytical performance of insulin and C-peptide assays using the Lumipulse G1200 system (Fujirebio Inc., Tokyo, Japan). METHODS: We examined the precision, linearity, and cross-reactivity of insulin and C-peptide using five insulin analogues and purified proinsulin. A method comparison was conducted between the Lumipulse G1200 and Roche E170 (Roche Diagnostics, Mannheim, Germany) systems in 200 diabetic patients on insulin treatment. Reference intervals for insulin and C-peptide concentrations were determined in 279 healthy individuals. RESULTS: For insulin and C-peptide assays, within-laboratory precision (% CV) was 3.78-4.14 and 2.89-3.35%, respectively. The linearity of the insulin assay in the range of 0-2,778 pmol/L was R²=0.9997, and that of the C-peptide assay in the range of 0-10 nmol/L was R²=0.9996. The correlation coefficient (r) between the Roche E170 and Lumipulse G1200 results was 0.943 (P<0.001) for insulin and 0.996 (P<0.001) for C-peptide. The mean differences in insulin and C-peptide between Lumipulse G1200 and the Roche E170 were 19.4 pmol/L and 0.2 nmol/L, respectively. None of the insulin analogues or proinsulin showed significant cross-reactivity with the Lumipulse G1200. Reference intervals of insulin and C-peptide were 7.64-70.14 pmol/L and 0.17-0.85 nmol/L, respectively. CONCLUSIONS: Insulin and C-peptide tests on the Lumipulse G1200 show adequate analytical performance and are expected to be acceptable for use in clinical areas.

Development and validation of a mass spectrometry-based assay for quantification of insulin-like factor 3 in human serum.

BACKGROUND: The circulating level of the peptide hormone insulin-like factor 3 (INSL3) is a promising diagnostic marker reflecting Leydig cell function in the male. Few commercial immunoassays of varying quality exist. Therefore, we decided to develop and validate a precise method for quantification of INSL3 by mass spectrometry. METHODS: We developed an assay in which the INSL3 A-chain is released from the INSL3 A-B heterodimer by chemical reduction and alkylation. The alkylated INSL3 A-chain is quantitated by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as substitute for serum INSL3. The method was compared to a validated and sensitive in-house serum INSL3 immunoassay using 97 serum samples from 12 healthy boys during pubertal transition. Adult levels were determined based on sera from 72 adult healthy males aged 18-40 years. RESULTS: An LC-MS/MS assay with limit of detection and limit of quantification (LOQ) of 0.06 and 0.15 ng/mL, respectively, and intra-assay CVs <9% in the relevant ranges was obtained. The LC-MS/MS compared well with the in-house immunoassay (Deming regression slope: 1.28; Pearson correlation: R=0.86). INSL3 concentrations increased with pubertal maturation in healthy boys. INSL3 concentrations were above the LOQ in all samples from the adult men. The mean (±2 SD range)for serum INSL3 concentrations in the adult men was 2.2 (0.5-3.9) ng/mL. CONCLUSIONS: We have developed a robust and sensitive method suitable for quantitation of serum INSL3 in a clinical setting using LC-MS/MS instrumentation available in modern clinical laboratories. The method paves the way for future studies into the clinical role of serum INSL3 measurements.

Top-down mass spectrometric immunoassay for human insulin and its therapeutic analogs.

Measurement of insulin and its therapeutic analogs is important in diabetes, hypoglycemia, sports anti-doping and toxicology. Commercial insulin immunoassays fail to detect commonly prescribed insulin analogs. Because of their unique sequences and masses, these analogs are readily measured and distinguished with mass spectrometric (MS) assays. Reviewed here is an insulin mass spectrometric immunoassay (MSIA) that combines micro-scale immunoaffinity capture with sensitive MS detection of insulin and its therapeutic analogs. An antibody reactive to all insulin analogs was used to affinity capture the insulin analogs. Following elution, insulins were detected with MALDI-TOF MS or LC-MS analysis. Isotopic resolution for insulin was achieved for both MS techniques, and several insulin analogs were detected at unique m/z signals. Porcine insulin, spiked in all samples, served as an internal reference standard for quantification. Linear standard curves spanning three orders of magnitude were obtained, with limits of detection of 15pM for the MALDI-TOF MS and 1.5pM for the LC-MS. This insulin assay was capable of detecting and quantifying not only human endogenous insulin, but also most of the therapeutic insulin analogs, which could find use in diagnosis of severe hypoglycemia and in sports anti-doping. SIGNIFICANCE: Insulin replacement therapy consists of injection of long- or fast-acting insulin analogs with slightly modified primary sequences compared to human insulin. Assays that are capable of detecting all insulin analogs are desired, not only for medical management of diabetes and severe hypoglycemia but also for sports anti-doping and toxicology.

Can the gold standard be beaten? How reliable are various modifications of the Synacthen test compared to the insulin tolerance test.

Criteria for the evaluation of the insulin tolerance test (ITT) and Synacthen test are still a matter of debate. The objective of the study was to make a comparison of serum and salivary cortisol during four stimulation tests. Sixty four healthy volunteers underwent the ITT, the Synacthen test with 1 (LDST), 10 (MDST) and 250 (HDST) microg dose of ACTH. Maximum serum cortisol response was observed at the 90 min of the ITT (49 %), HDST (89 %) and MDST (56 %) and at the 40 min of the LDST (44 %). Results expressed as 95 % confidence intervals: 408.0-843.6 and 289.5-868.1 nmol/l in the IIT at 60 and 90 min. In the HDST and the MDST serum cortisol reached the maximum at 90 min 542.6-1245.5 and 444.2-871.3 nmol/l. Levels of salivary cortisol followed the same pattern as serum cortisol. Salivary cortisol reached the maximum response in the HDST and the MDST at 90 min and at 40 min in the LDST. We confirmed good reliability of all tests with respect to timing of response and maximum response compared to the ITT. We proved that the MDST test can provide the similar response in serum cortisol to the HDST. Measuring either salivary cortisol or ACTH levels did not provide any additional benefit then measuring serum cortisol by itself.