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Exploring the molecular mechanisms underlying insulin analogs is important for protein engineering to design innovative drug proteins. Insulin aspart (IAsp) and insulin degludec (IDeg) are representative examples of insulin analogs with distinct release profiles synthesized by targeted mutagenesis in protein engineering. Despite their importance in diabetes treatment, there remains a gap in our understanding of the molecular basis for their differential release mechanisms. In this study, ordinary molecular dynamics simulation and steered molecular dynamics are utilized to investigate the structural stability, solubility analysis, and monomer interactions of these insulins, with the aim to explain the mesoscale differences between the two insulin release mechanisms. Simulation findings have further been validated through experimental verification, shedding light on the intricate mechanisms underlying insulin release and providing valuable insights into pharmaceutical implications and potential advancements in the design of insulin therapy. [ABSTRACT FROM AUTHOR]

Insulin is essential for treating type 1 diabetes and insulin-requiring type 2 diabetes. Background/Objectives: Diabetes is a widespread condition that can lead to multiple and severe complications. Rapid-acting insulin analogs (RAIAs) and long-acting insulin analogs are prescribed for the effective management of diabetes. RAIAs are expected to be associated with a higher number of dosing errors because of their rapid onset, short duration of action, and the need for frequent dosing, compared to other insulin analogs. There are three approved RAIAs on the market: insulin lispro (LIS), insulin aspart (ASP), and insulin glulisine (GLU). The aim of this study is to evaluate the real-world evidence on dosing errors reported for RAIAs in EudraVigilance (EV), an established pharmacovigilance database, in comparison to other insulin analogs and human insulins. Methods: A descriptive analysis and a disproportionality analysis were conducted. Results: ASP and LIS were associated with high percentages of adverse drug reactions (ADRs) (22% and 17%, respectively), with over 70% of the reports involving serious ADRs. A higher frequency of cardiac and eye disorder ADRs was observed for LIS compared with ASP and GLU. GLU showed a higher frequency of ADRs in the skin and subcutaneous tissue disorders category. LIS dosing errors accounted for 5% of the total number of cases, while dosing errors for ASP and GLU were less than 3%. The most frequently reported dosing errors involved improper dosing (49%). Conclusions: Although there were fewer dosing errors of RAIAs in comparison to other insulins, the severity of the potential outcome highlights the importance of precise dosing and timing. Improved the monitoring and reporting of these dosing errors could enhance diabetes patient care. Additionally, smart medical devices could improve therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is one of the most prevalent diseases in the world and a leading cause of many cardiovascular diseases. Today, there is a wide range of options available to treat diabetes. Over the last few decades, the clinical field has gone through a major shift in the direction of genetic engineering and synthetic biology. This has led to many new techniques and treatments that can help manage diabetes. The purpose of this study is to summarize the advancement of diabetic treatments from old, conventional methods to new-age treatments which hold the potential to cure diabetes. While reviewing published research and review articles, we found that over the last few decades, there has been a surge in more handy devices to monitor and manage blood glucose levels. With advancements in the field of science, techniques such as genetic engineering, nanotechnology and synthetic biology are being used to design new devices or artificially engineer cells to relieve the symptoms associated with the disease. While the old conventional ways of taking medications or managing glycaemic levels using insulin syringes are more common, new-age treatments like insulin patches, synthetic cells, and synthetic receptors will likely gain popularity in the coming years. [ABSTRACT FROM AUTHOR]

Insulin is essential for treating type 1 diabetes and insulin-requiring type 2 diabetes. Background/Objectives: Diabetes is a widespread condition that can lead to multiple and severe complications. Rapid-acting insulin analogs (RAIAs) and long-acting insulin analogs are prescribed for the effective management of diabetes. RAIAs are expected to be associated with a higher number of dosing errors because of their rapid onset, short duration of action, and the need for frequent dosing, compared to other insulin analogs. There are three approved RAIAs on the market: insulin lispro (LIS), insulin aspart (ASP), and insulin glulisine (GLU). The aim of this study is to evaluate the real-world evidence on dosing errors reported for RAIAs in EudraVigilance (EV), an established pharmacovigilance database, in comparison to other insulin analogs and human insulins. Methods: A descriptive analysis and a disproportionality analysis were conducted. Results: ASP and LIS were associated with high percentages of adverse drug reactions (ADRs) (22% and 17%, respectively), with over 70% of the reports involving serious ADRs. A higher frequency of cardiac and eye disorder ADRs was observed for LIS compared with ASP and GLU. GLU showed a higher frequency of ADRs in the skin and subcutaneous tissue disorders category. LIS dosing errors accounted for 5% of the total number of cases, while dosing errors for ASP and GLU were less than 3%. The most frequently reported dosing errors involved improper dosing (49%). Conclusions: Although there were fewer dosing errors of RAIAs in comparison to other insulins, the severity of the potential outcome highlights the importance of precise dosing and timing. Improved the monitoring and reporting of these dosing errors could enhance diabetes patient care. Additionally, smart medical devices could improve therapeutic outcomes.

Type 1 diabetes is characterized by insulin deficiency, and treatment is to supply insulin mimicking the physiological endogenous insulin secretion. Since its discovery, insulin therapy has evolved, and since the 1990s, an increasing number of insulin analogs with various pharmacokinetic and pharmacodynamic profiles have become available. Despite the improvement of insulin therapy, hypoglycemia remains the main side effect and is a daily concern for many people with diabetes and their families. A proportion of people with type 1 diabetes are at increased risk of hypoglycemia and experience recurring episodes. When designing insulin trials, this group of people is most often excluded in order to reduce the risk of adverse study outcomes, even though it may be the group that may benefit the most from treatment with new insulins. The results of the phase III trials, therefore, underestimate the clinical impact and pharmacoeconomic effect of the implementation of new insulins in the broader type 1 diabetes population. This paper reviews the four insulin trials that include people at increased risk of hypoglycemia. In general, the studies confirm the results from phase III trials in terms of similar reduction and maintenance of HbA1c, as well as relative rate reductions of hypoglycemia. However, the absolute treatment differences in the reduction of hypoglycemia are even greater in the trials, including people at high risk of hypoglycemia. This emphasizes the importance of including people at high risk of hypoglycemia to assess the full clinical and pharmacoeconomic benefit of new insulins. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is characterized by insulin deficiency, and treatment is to supply insulin mimicking the physiological endogenous insulin secretion. Since its discovery, insulin therapy has evolved, and since the 1990s, an increasing number of insulin analogs with various pharmacokinetic and pharmacodynamic profiles have become available. Despite the improvement of insulin therapy, hypoglycemia remains the main side effect and is a daily concern for many people with diabetes and their families. A proportion of people with type 1 diabetes are at increased risk of hypoglycemia and experience recurring episodes. When designing insulin trials, this group of people is most often excluded in order to reduce the risk of adverse study outcomes, even though it may be the group that may benefit the most from treatment with new insulins. The results of the phase III trials, therefore, underestimate the clinical impact and pharmacoeconomic effect of the implementation of new insulins in the broader type 1 diabetes population. This paper reviews the four insulin trials that include people at increased risk of hypoglycemia. In general, the studies confirm the results from phase III trials in terms of similar reduction and maintenance of HbA1c, as well as relative rate reductions of hypoglycemia. However, the absolute treatment differences in the reduction of hypoglycemia are even greater in the trials, including people at high risk of hypoglycemia. This emphasizes the importance of including people at high risk of hypoglycemia to assess the full clinical and pharmacoeconomic benefit of new insulins.

Abstract In Brazil, insulin analogs stand out as one of the most demanded medications by judicial means. However, the guarantee of judicial access does not guarantee rational use. In context, pharmacotherapeutic follow-up (PF) is shown to be clinical effective strategy for patients with diabetes. To evaluate direct medical costs one year after performing PF in patients with type 1 diabetes mellitus using insulin analogs ordered by court in Public Health System (Sistema Único de Saúde - SUS). This is a partial economic analysis, nested within a quasi-experimental study. Patients with T1DM who receive insulin analogs by judicialization in a medium-sized Brazilian city participated. The PF was conducted following the method adapted from the Pharmacotherapy workup (PW). Data were collected considering the period of one year before the start of the intervention and one year after the start of the intervention. Direct medical costs were evaluated and the difference in costs was calculated. 28 patients participated in the intervention. After PF, direct costs were -$3,696.78. Sensitivity analysis showed that there is a 33.4 % chance for PF to present cost savings when compared to baseline. The PF has the potential to reduce direct medical costs from the perspective of the SUS.

Diabetes mellitus represents a significant global health threat characterized by hyperglycemia caused by inadequate insulin secretion and/or insulin resistance. Exogenous insulin supplements had been recognized as a crucial treatment for achieving successful glycemic control in patients with Type 1 and most patients with Type 2 diabetes. Over the past century, substantial progress has been made in the development of novel insulin formulations, including the super‐fast‐acting and long‐acting basal insulin analogs, of which the latter is indispensable for the management of nocturnal fasting and intraprandial blood glucose within the normal physiological range. Recently, combining chemical and genetic engineering with drug optimization have resulted in a formidable evolution in ultra‐long‐acting weekly insulin. Here, the current state of once‐weekly insulin analogs and the euglycemic clamp technique used in the early clinical development to elucidate the pharmacokinetics and pharmacodynamics of this type of novel weekly insulin analogs were systematically overviewed. [ABSTRACT FROM AUTHOR]

Abstract Background Hypoglycemic syndrome is a potentially life-threatening condition that can lead to the disruption of brain and internal organ functions, and in severe cases to irreparable consequences or death. Factitious hypoglycemia (FH) is the deliberate use of insulin preparations or oral hypoglycemic drugs with the aim of lowering blood glucose levels into the pathologically-hypoglycemic range. Deliberate administration of insulin analogs may be difficult to prove because they might not have epitopes or containing low affinity epitopes that are the targets of antibodies used in particular assay kits. Case presentation A 34 years old woman was admitted to the Endocrinology Research Centre in September 2021 with a diagnosis of hypothyroidism and diabetes mellitus. Upon admission she complained of high glycemia indexes up to a maximum of 34 mmol/l ( 612 mg/dl), high TSH and low free T4 ( fT4) concentrations, despite reporting regular levothyroxine administration at a dose of 200 mcg per day. Under nursing supervision, her fT4 was rapidly normalized suggesting non-compliance as the cause of low thyroid hormone milieu. Glycemic fluctuations from 33 to 2.1 mmol/l (594 to 38 mg/dl) according to glucometer measurements were observed against the background of Lis-Pro insulin therapy, while no hyperglycemia was registered in venous blood and in the interstitial fluid concomitantly with the values found by glucometer. It was assumed that the patient’s fingers were intentionally contaminated with glucose solution. Factitious hypo- and hyperglycemia were suspected. During yet another episode of hypoglycemia (1.86 mmol/L, 33 mg/dl) venous blood was drawn. Low to low-normal insulin and C-peptide values were found: 2.2 µU/ml (Roche kit) and 1.18 ng/ml, respectively. Therefore, insulin concentration in the same sample was re-tested with another kit (Abbott) and a significantly elevated value of 89.9 µU/ml was detected. Based on these results, FH was confirmed due to exogenous administration of an insulin analog undetectable by the Roche kit. Conclusion This clinical example illustrates to draw attention to multiple manipulations employed by subjects with Munchhausen Syndrome. In addition, this diagnosis may be further complicated by the laboratory use of immunoassay kits incapable of detecting some insulin analogs.

Purpose: The higher costs of insulin analogs including short-acting insulin aspart (IAsp) and long-acting insulin glargine (IGla) have restricted their widespread uptake despite having improved pharmacokinetic and pharmacodynamic properties and patient convenience. This study aims to evaluate the cost-effectiveness of IAsp versus Regular Insulin (RI) and IGla versus NPH Insulin in type 1 and 2 diabetes from the perspective of the Iranian healthcare system. Methods: Clinical data including HbA1c levels, hypoglycemia, weight gain, and health-related quality of life were derived from the included systematic review and meta-analysis studies. Different methods of pharmacoeconomic evaluation were used for an annual time horizon. Utility decrements for diabetes-related complications were extracted from the literature. Direct medical costs were calculated in 2022 prices. A one-way sensitivity analysis was also performed. Results: In type 1 diabetes, IAsp was associated with more costs and effects in terms of reducing HbA1c compared with RI. An incremental cost of $83 was estimated to obtain an additional 1% reduction in HbA1c per patient per year. Similarly, an incremental cost of $16 was estimated for IGla compared with NPH. In type 2 diabetes, IAsp and RI were associated with equal efficacy and safety. For IGla versus NPH, the incremental cost-effectiveness ratio was calculated at $1975 per quality-adjusted life-year. The robustness of the result was confirmed through sensitivity analysis. Conclusion: Insulin analogs, IAsp and IGla, are cost-effective for type 1 diabetes versus human insulins, RI and NPH. For type 2 diabetes, IAsp is not cost-effective when compared with RI. For IGla versus NPH, however, the incremental cost-effectiveness ratio seems to be within the accepted thresholds. [ABSTRACT FROM AUTHOR]

Introduction: Use of continuous glucose monitoring (CGM) in people with diabetes may provide a more complete picture of glycemic control than glycated hemoglobin (HbA1c) measurements, which do not capture day-to-day fluctuations in blood glucose levels. The randomized, crossover, phase IV SWITCH PRO study assessed time in range (TIR), derived from CGM, following treatment with insulin degludec or insulin glargine U100 in patients with type 2 diabetes at risk for hypoglycemia. This post hoc analysis evaluated the relationship between TIR and HbA1c, following treatment intensification during the SWITCH PRO study. Methods: Correlation between absolute values for TIR (assessed over 2-week intervals) and HbA1c, at baseline and at the end of maintenance period 1 (M1; week 18) or maintenance period 2 (M2; week 36), were assessed by linear regression and using the Spearman correlation coefficient (rs). These methods were also used to assess correlation between change in TIR and change in HbA1c from baseline to the end of M1, both in the full cohort and in subgroups stratified by baseline median HbA1c (≥ 7.5% [≥ 58.5 mmol/mol] or < 7.5% [< 58.5 mmol/mol]). Results: A total of 419 participants were included in the analysis. A moderate inverse linear correlation was observed between TIR and HbA1c at baseline (rs −0.54), becoming stronger following treatment intensification during maintenance periods M1 (weeks 17–18: rs −0.59) and M2 (weeks 35–36: rs −0.60). Changes in TIR and HbA1c from baseline to end of M1 were also linearly inversely correlated in the full cohort (rs –0.40) and the subgroup with baseline HbA1c ≥ 7.5% (rs −0.43). This was less apparent in the subgroup with baseline HbA1c < 7.5% (rs −0.17) (p-interaction = 0.07). Conclusion: Results from this post hoc analysis of data from SWITCH PRO, one of the first large interventional clinical studies to use TIR as the primary outcome, further support TIR as a valid clinical indicator of glycemic control. Trial registration: ClinicalTrials.gov identifier, NCT03687827. [ABSTRACT FROM AUTHOR]

Context: Hypoglycemia in people with diabetes is common, especially in those taking medications such as insulin and sulfonylureas (SU) that place them at higher risk. Hypoglycemia is associated with distress in those with diabetes and their families, medication nonadherence, and disruption of life and work, and it leads to costly emergency department visits and hospitalizations, morbidity, and mortality. Objective: To review and update the diabetes-specific parts of the 2009 Evaluation and Management of Adult Hypoglycemic Disorders: Endocrine Society Clinical Practice Guideline and to address developing issues surrounding hypoglycemia in both adults and children living with diabetes. The overriding objectives are to reduce and prevent hypoglycemia. Methods: A multidisciplinary panel of clinician experts, together with a patient representative, and methodologists with expertise in evidence synthesis and guideline development, identified and prioritized 10 clinical questions related to hypoglycemia in people living with diabetes. Systematic reviews were conducted to address all the questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. Results: The panel agreed on 10 questions specific to hypoglycemia risk and prevention in people with diabetes for which 10 recommendations were made. The guideline includes conditional recommendations for use of real-time continuous glucose monitoring (CGM) and algorithm-driven insulin pumps in people with type 1 diabetes (T1D), use of CGM for outpatients with type 2 diabetes at high risk for hypoglycemia, use of long-acting and rapid-acting insulin analogs, and initiation of and continuation of CGM for select inpatient populations at high risk for hypoglycemia. Strong recommendations were made for structured diabetes education programs for those at high risk for hypoglycemia, use of glucagon preparations that do not require reconstitution vs those that do for managing severe outpatient hypoglycemia for adults and children, use of real-time CGM for individuals with T1D receiving multiple daily injections, and the use of inpatient glycemic management programs leveraging electronic health record data to reduce the risk of hypoglycemia. Conclusion: The recommendations are based on the consideration of critical outcomes as well as implementation factors such as feasibility and values and preferences of people with diabetes. These recommendations can be used to inform clinical practice and health care system improvement for this important complication for people living with diabetes. [ABSTRACT FROM AUTHOR]

The destruction of β-cells of the pancreas leads to either insulin shortage or the complete absence of insulin, which in turn causes diabetes Mellitus. For treating diabetes, many trials have been conducted since the 19th century until now. In ancient times, insulin from an animal’s extract was taken to treat human beings. However, this resulted in some serious allergic reactions. Therefore, scientists and researchers have tried their best to find alternative ways for managing diabetes with progressive advancements in biotechnology. However, a lot of research trials have been conducted, and they discovered more progressed strategies and approaches to treat type I and II diabetes with satisfaction. Still, investigators are finding more appropriate ways to treat diabetes accurately. They formulated insulin analogs that mimic the naturally produced human insulin through recombinant DNA technology and devised many methods for appropriate delivery of insulin. This review will address the following questions: What is insulin preparation? How were these devised and what are the impacts (both positive and negative) of such insulin analogs against TIDM (type-I diabetes mellitus) and TIIDM (type-II diabetes mellitus)? This review article will also demonstrate approaches for the delivery of insulin analogs into the human body and some future directions for further improvement of insulin treatment.

The insulin receptor (IR), the insulin‐like growth factor‐1 receptor (IGF1R), and the insulin/IGF1 hybrid receptors (hybR) are homologous transmembrane receptors. The peptide ligands, insulin and IGF1, exhibit significant structural homology and can bind to each receptor via site‐1 and site‐2 residues with distinct affinities. The variants of the Iridoviridae virus family show capability in expressing single‐chain insulin/IGF1 like proteins, termed viral insulin‐like peptides (VILPs), which can stimulate receptors from the insulin family. The sequences of VILPs lacking the central C‐domain (dcVILPs) are known, but their structures in unbound and receptor‐bound states have not been resolved to date. We report all‐atom structural models of three dcVILPs (dcGIV, dcSGIV, and dcLCDV1) and their complexes with the receptors (μIR, μIGF1R, and μhybR), and probed the peptide/receptor interactions in each system using all‐atom molecular dynamics (MD) simulations. Based on the nonbonded interaction energies computed between each residue of peptides (insulin and dcVILPs) and the receptors, we provide details on residues establishing significant interactions. The observed site‐1 insulin/μIR interactions are consistent with previous experimental studies, and a residue‐level comparison of interactions of peptides (insulin and dcVILPs) with the receptors revealed that, due to sequence differences, dcVILPs also establish some interactions distinct from those between insulin and IR. We also designed insulin analogs and report enhanced interactions between some analogs and the receptors. [ABSTRACT FROM AUTHOR]

Objective: Insulin icodec (icodec), a once-weekly basal insulin analog, has been investigated in the phase 3a ONWARDS clinical trial program. This pharmacokinetic (PK)/pharmacodynamic (PD) modeling analysis of data from the ONWARDS 2 and 4 trials investigated efficacy outcomes and hypoglycemia rate in insulin-experienced individuals with type 2 diabetes when switching from daily basal insulin to icodec without or with a 50% one-time additional dose for the first injection only., Methods: Data from two randomized, 26-week, phase 3a trials of insulin-experienced individuals with type 2 diabetes on a basal (ONWARDS 2) or basal-bolus (ONWARDS 4) insulin regimen were used for PK/PD model development and validation. The effect of switching to icodec without versus with a 50% one-time additional dose on prebreakfast self-measured blood glucose (SMBG), glycated hemoglobin (HbA1c), weekly insulin dose, and clinically significant hypoglycemia was assessed., Results: Model predictions suggested that switching to icodec without versus with a 50% one-time additional dose would result in a mild, transient (1-2 weeks) increase in prebreakfast SMBG after treatment initiation, that would decrease to matching levels between groups by week 4 and remain similar between groups until end of treatment (week 26). There were no model-predicted differences between groups in HbA1c reduction or clinically significant hypoglycemia over the 26-week study period or in weekly icodec dose at week 26., Conclusions: This PK/PD model analysis suggests that omitting administration of a 50% one-time additional dose when switching to icodec from daily basal insulin would not be predicted to result in any sustained effects., (Copyright © 2024. Published by Elsevier Inc.)

Background and Aims: Nocturnal hypoglycemia is mainly a consequence of inappropriate basal insulin therapy in type 1 diabetes (T1D) and may compromise optimal glycemic control. Insulin degludec is associated with a lower risk of nocturnal hypoglycemia in T1D. As nocturnal hypoglycemia is often asymptomatic, we applied continuous glucose monitoring (CGM) to detect a more precise occurrence of nocturnal hypoglycemia in the HypoDeg trial, comparing insulin degludec with insulin glargine U100 in people with T1D and previous nocturnal severe hypoglycemia. Materials and Methods: In the HypoDeg trial, 149 people with T1D were included in an open-label randomized cross-over trial. Sixty-seven participants accepted optional participation in the predefined substudy of 4 × 6 days of blinded CGM requiring completion of at least one CGM period in each treatment arm. CGM data were reviewed for hypoglycemic events. Results: Treatment with insulin degludec resulted in a relative rate reduction (RRR) of 36% (95% confidence interval [CI]: 10%-54%; P < 0.05) in nocturnal CGM-recorded hypoglycemia (≤3.9 mmol/L), corresponding to an absolute rate reduction (ARR) of 0.85 events per person-week. In nocturnal CGM-recorded hypoglycemia (≤3.0 mmol/L), we found an RRR of 53% (95% CI: 36%-65%; P < 0.001), corresponding to an ARR of 0.75 events per person-week. At the lower detection limit of the CGM (≤2.2 mmol/L), treatment with insulin degludec resulted in a significant RRR of 58% (95% CI: 23%-77%; P = 0.005). The reductions were primarily due to significant RRRs in asymptomatic hypoglycemia. Conclusion: In people with T1D, prone to nocturnal severe hypoglycemia, insulin degludec compared with insulin glargine U100 significantly reduces nocturnal CGM-recorded hypoglycemia. www.clinicaltrials.gov (#NCT02192450). [ABSTRACT FROM AUTHOR]

[Display omitted] • PK predictions. • Inter-drug approach. • Comparison of translation methods. • Single animal translation. • in vitro - in vivo. An inter-drug approach, applying pharmacokinetic information for insulin analogs in different animal species, rat, dog and pig, performed better compared to allometric scaling for human translation of intra-venous half-life and only required data from a single animal species for reliable predictions. Average fold error (AFE) between 1.2–1.7 were determined for all species and for multispecies allometric scaling AFE was 1.9. A slightly larger prediction error for human half-life was determined from in vitro human insulin receptor affinity data (AFE on 2.3–2.6). The requirements for the inter-drug approach were shown to be a span of at least 2 orders of magnitude in half-life for the included drugs and a shared clearance mechanism. The insulin analogs in this study were the five fatty acid protracted analogs: Insulin degludec, insulin icodec, insulin 320, insulin 338 and insulin 362, as well as the non-acylated analog insulin aspart. [ABSTRACT FROM AUTHOR]

BackgroundThe speed of insulin absorption after subcutaneous delivery is highly variable. Incorrect assumptions about insulin pharmacokinetics compromise effective glycemic regulation. Our ultimate goal is to develop a system to monitor insulin levels in vivo continuously, allowing pharmacokinetic parameters to be calculated in real time. We hypothesize that a bead-based detection system can be run on a flow-through microfluidic platform to measure insulin in subcutaneous fluid sampled via microdialysis. As a first step in development, we focused on microsphere-based measurement of insulin.MethodsPolystyrene microspheres coated with an anti-insulin monoclonal antibody were exposed to insulin-containing solutions, and after addition of a fluorescently labeled anti-insulin monoclonal antibody with a distinct epitope, bead-associated fluorescence was detected by fluorescence microscopy in 96-well plates or in a flow-through, microfluidic platform.ResultsThe bead detection system in plates had a linear range in buffer for regular human insulin (RHI), insulin lispro, and insulin aspart of 15-1115 µIU/ml, 14-976 µIU/ml, and 25-836 µIU/ml, respectively. Measurement on plasma samples demonstrated proportionality between basal and peak insulin levels similar to the laboratory reference method. Preliminary results in a polydimethylsiloxane-based, flow-through, microfluidic platform showed a strong signal at peak insulin levels.ConclusionsWe have developed a microsphere-based system to rapidly measure levels of insulin and insulin analogs. We have further demonstrated proof of concept that this bead detection system can be implemented in a lab-on-a-chip format, which will be further developed and combined with microdialysis for real-time monitoring of insulin in vivo.

Introduction: Lipoatrophy (LA) is one of the complications of insulin treatment. It has become rare thanks to insulin analogues but it can still be observed in patients with diabetes type 1(T1DM). No effective treatment exists. Herein, we report for the first time two children with T1DM and LA successfully treated with laser treatment. Clinical cases: A 6-year-old child with T1DM presented with LA 4 months post-diagnosis. He was on continuous subcutaneous insulin infusion (CSII). LA presented on body sites where insulin catheter was never inserted. He underwent different treatment options with no positive effect. Laser treatment was tried with impressive improvement. The second 9-year-old child presented with LA 5 years postdiagnosis. He changed the insulin type, the site of insulin injection, and tried topical use of sodium chromoglycate cream with partial improvement. Laser treatment was finally used with remarkable outcome. Conclusion: Insulin-induced LA is now a rare skin complication with no effective treatment up to now. Laser treatment seems to be an effective treatment option. [ABSTRACT FROM AUTHOR]

The venomous insulin‐like peptides released by certain cone snails stimulate hypoglycemic shock to immobilize fish and catch the prey. Compared to human insulin (hIns), the cone snail insulins (Con‐Ins) are typically monomeric and shorter in sequence, yet they exhibit moderate hIns‐like biological activity. We have modeled six variants of Con‐Ins (G3, K1, K2, T1A, T1B, and T2) and carried out explicit‐solvent molecular dynamics (MD) simulations of eight types of insulins, two with known structures (hIns and Con‐Ins‐G1) and six Con‐Ins with modeled structures, to characterize key residues of each insulin that interact with the truncated human insulin receptor (μIR). We show that each insulin/μIR complex is stable during explicit‐solvent MD simulations and hIns interactions indicate the highest affinity for the "site 1" of IR. The residue contact maps reveal that each insulin preferably interacts with the αCT peptide than the L1 domain of IR. Through analysis of the average nonbonded interaction energy contribution of every residue of each insulin for the μIR, we probe the residues establishing favorable interactions with the receptor. We compared the interaction energy of each residue of every Con‐Ins to the μIR and observed that γ‐carboxylated glutamate (Gla), His, Thr, Tyr, Tyr/His, and Asn in Con‐Ins are favorable substitutions for GluA4, AsnA21, ValB12, LeuB15, GlyB20, and ArgB22 in hIns, respectively. The identified insulin analogs, although lacking the last eight residues of the B‐chain of hIns, bind strongly to μIR. Our findings are potentially useful in designing potent fast‐acting therapeutic insulin. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is characterized by chronic hyperglycemia and varying degrees of insulin resistance and insulinopenia. Achieving targeted glycemic control in diabetic patients is important to reduce the risk of late complications, and many patients with type 2 diabetes ultimately require insulin therapy to maintain adequate glycemic control. Timely administration of insulin can prevent the progression of diabetes, reduce the development of complications, and have fewer side effects. Basal insulin is the preferred option in most cases when glycemic control is not achieved. However, there is considerable therapeutic inertia in clinical practice, both with respect to initiation of insulin therapy and titration of the basal insulin dose. The longer duration of action, reduced glucose variability and a lower risk of hypoglycemia seen with the latest generation of basal insulin analogs compared to the previous generation simplify titration and may increase patient compliance.

BackgroundEstimation of insulin sensitivity factor (ISF) is essential for correction insulin doses calculation. This study aimed to assess real-life ISF among children and adolescents with type 1 diabetes using ultra-long-acting basal insulin analogs and to detect factors associated with ISF among those patients.MethodsThis prospective observational study was conducted at Sohag University Hospital, Egypt, and included 93 participants aged 6–18 years, diagnosed with T1DM for at least 1 year and using insulin glargine 300 Units/mL or insulin degludec 100 Units/mL as basal insulin. The ISF, insulin-to-carbohydrate ratio (ICR) and insulin doses were initially assessed then adjusted as required. The participants were regularly contacted throughout the follow-up period. Glycemic control parameters were assessed after 3 months.ResultsThe ISF showed diurnal variation with higher correction dose requirements for the morning than for the rest of the day (p < 0.001). This pattern of diurnal variation was found in participants with different pubertal stages and in participants using either type of ultra-long acting basal insulin analogs. There was no significant difference between the ISF calculated according to the 1800 rule [1800/Total daily insulin dose (TDD)] and the morning ISF (p = 0.25). The 1800 rule-calculated ISF was significantly lower than the actual ISF for the afternoon (p < 0.001) and the evening (p < 0.001). ISF at different times of the day were significantly correlated with age, body mass index, pubertal stage, diabetes duration, TDD, and ICR. Multiple regression analysis revealed that ICR was the most significant factor associated with ISF. Linear regression analysis revealed that the ISF (in mg/dL) for any time of the day could be estimated as 5.14 × ICR for the same time of the day (coefficient = 5.14, 95% confidence interval: 5.10–5.19, R2 = 0.95, p < 0.001).ConclusionDiurnal variation of ISF that had to be considered for proper calculation of correction doses. This diurnal variation was found in children and adolescents with different pubertal stages. The 1800 rule was appropriate for the morning correction doses but not in the afternoon or the evening. The TDD and the ICR could be used for ISF estimation.

Introduction: there is a lack of research evaluating the impact of therapeutic switching from human insulin to analogues, particularly in paediatric populations from low- and middle-income countries., Aim: The study aimed to retrospectively assess the effectiveness and safety of transitioning from human insulin to insulin analogs in Tunisian children with diabetes., Methods: This retrospective descriptive study included children with type 1 diabetes who changed their insulin therapy protocol after at least one year of treatment with human insulin. Clinical, therapeutic, and glycaemic homeostasis parameters were assessed following the transition from human insulin (NPH + rapid-acting insulin) to the Basal-Bolus insulin analog- protocol., Results: The study included 60 patients. Following the switch, all patients showed a significant reduction in mean fasting blood glucose levels (11.11 mmol/l vs. 8.62 mmol/l; p=0.024). Glycated haemoglobin A1C levels decreased notably in children who adhered to their diet (from 9.93% to 8.38%; p=0.06) and/or engaged in regular physical activity (from 10.40% to 8.61%; p=0.043). The average number of hypoglycemic events per year decreased from 4.03 events/year to 2.36 events/year (p=0.006), along with a decrease in the rate of patients hospitalized for acid-ketotic decompensation (from 27% to 10%; p=0.001). Financial constraints led to 82% of patients reusing microfine needles ≥2 times per day, and 12% were compelled to revert to the initial insulin therapy protocol due to a lack of access to self-financed microfine needles or discontinued social coverage., Conclusions: Although insulin analogues offer clear benefits, their use poses challenges as a therapeutic choice for children with diabetes in low- to middle-income countries. These challenges hinder the achievement of optimal glycemic control goals.

Human insulin regulates carbohydrate metabolism to maintain the blood glucose level and this peptide hormone has been considered an important biomarker in diabetic management. Several fast-acting and long-acting insulin analogs have also emerged to improve insulin dose regimes for chronic diabetic patients. The administration of insulin is currently based on some glucose-insulin models; however, simultaneous measurement of glucose and insulin enables better glucose control and circumvents abnormal levels of blood insulin. Reliable quantification of glucose is well served by glucose meters, which have become less invasive and more powerful, and even non-invasive devices for continuous monitoring of glucose have emerged. However, the measurement of insulin and its analogs is more difficult and complicated due to their large size (> MW 5.8 kDa) and picomolar levels in the blood as well as the presence of endogenous interfering molecules. In clinical and hospital settings, insulin detection is performed by fully automated immunoassay platforms with high throughput and reliability. Chromatographic techniques equipped with tandem mass spectrometry perform the separation of insulin from its analogs. Albeit insulin can be electrochemically oxidized, electroanalysis still lacks detection sensitivity and selectivity without sample pre-treatment. Biosensing based on aptamers and molecular imprinted polymers (MIP) shows great promise to overcome these two key drawbacks. Future developments will focus on robust antibodies, aptamers, and insulin selective biorecognition elements with high selectivity, stability, and capacity. Such robust aptamers might open the possibility for the development of Point-of-Care (POC) devices to measure ultra-low levels of insulin in blood with high selectivity and reliability.

The life-saving discovery of insulin in Toronto in 1921 is one of the most impactful achievements in medical history, at the time being hailed as a miracle treatment for diabetes. The insulin molecule itself, however, is poorly amenable as a pharmacological intervention, and the formidable challenge of optimizing insulin therapy has been ongoing for a century. We review early academic insights into insulin structure and its relation to self-association and receptor binding, as well as recombinant biotechnology, which have all been seminal for drug design. Recent developments have focused on combining genetic and chemical engineering with pharmaceutical optimization to generate ultra-rapid and ultra-long-acting, tissue-selective, or orally delivered insulin analogs. We further discuss these developments and propose that future scientific efforts in molecular engineering include realizing the dream of glucose-responsive insulin delivery. Pharmacokinetically tailored insulin has been rationally designed by molecular structural engineering and/or pharmaceutical formulation to improve glucose control and convenience for people with diabetes. Novel mechanisms for protracted insulin action based on reduced plasma clearance hold promise to enable once-weekly subcutaneous and once-daily oral basal insulin delivery. Hepato-preferential insulin analogs can be designed by tailoring molecular size and receptor affinity to provide more physiological insulin replacement. Successful oral insulin delivery has been achieved in early clinical trials but is still hampered by low bioavailability. Clinical trials have been initiated with glucose-sensitive analogs chemically engineered to switch between active and inactive conformations or to undergo glucose-dependent clearance, thus giving hope that a 'smart insulin' is within reach. [ABSTRACT FROM AUTHOR]

The discovery of insulin in 1921 and the progress achieved in the ensuing century highlight the promise and challenge of biochemically modifying the molecule to achieve optimization of its delivery and therapeutic efficacy. Normal endogenous insulin secretion consists of a highly orchestrated physiologic loop wherein multiple metabolic signals trigger the pancreatic β cells to secrete the precise amount of insulin into the portal system required to maintain euglycemia. Accordingly, in the treatment of diabetes, attempting to replicate this complex physiology with exogenous insulin therapy given subcutaneously presents a clinical challenge. In this context, recombinant DNA-based technology has enabled the development of insulin analogs that have been specifically designed to confer advantageous pharmacodynamic features that can better mimic endogenous insulin secretion. In this review, we discuss the development of the most widely available insulin preparations and provide evidence-based insight into their use in clinical practice. The discovery of insulin in 1921 and the progress achieved in the ensuing century highlight the promise and challenge of biochemically modifying the molecule to achieve optimization of its delivery and therapeutic efficacy. In this review, Kramer et al. discuss the development of the most widely available insulin preparations and provide evidence-based insight into their use in clinical practice. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a disease of metabolic dysregulation, most notably abnormal glucose metabolism, accompanied by characteristic long-term complications. The complications that are specific to diabetes include retinopathy, nephropathy, and neuropathy. To achieve glycemic goals in patients with Type 2 diabetes when multiple pharmacologic agents are failing, the early introduction of insulin is key. Our objective is to assist clinicians in designing individualized management plans for insulin therapy in patients with Type 2 diabetes mellitus. We searched Medline, PubMed, journal articles, WHO publications, and reputable textbooks relating to diabetes mellitus and insulin therapy using publications from 1992 to 2016. With the progression of Type 2 diabetes, there is ultimately progressive loss of pancreatic beta-cell function and endogenous insulin secretion. At this stage, most patients require exogenous insulin therapy to achieve optimal glucose control. Choosing from the wide variety of glucose-lowering interventions currently available could be a challenge for the health-care provider and the patients in terms of effectiveness, tolerability, and cost of the various diabetes treatments. However, these should not be the case as risk reductions in long-term complications were related to the levels of glycemic control achieved, rather than to a specific glucose-lowering agent. The challenges of initiating and intensifying insulin therapy are quite enormous and could be daunting to health-care givers. Glycemic treatment should be stepwise with swift introduction of successive interventions after treatment failure (i.e., A1C ≥7.0%). Insulin should be initiated when A1C is ≥7.0% after 2–3 months of dual oral therapy.

IntroductionThe goal of insulin therapy in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) is to match as closely as possible normal physiologic insulin secretion to control fasting and postprandial plasma glucose. Modifications of the insulin molecule have resulted in two long-acting insulin analogs (glargine and detemir) and three rapid-acting insulins (aspart, lispro, and glulisine) with improved pharmacokinetic/pharmacodynamic (PK/PD) profiles. These agents can be used together in basal-bolus therapy to more closely mimic physiologic insulin secretion patterns.MethodsThis study reviews effects of the multiple demographic and clinical parameters in the insulin analogs glargine, detemir, lispro, aspart, and glulisine in patients with T2DM. A search was conducted on PubMed for each major topic considered (effects of injection site, age, race/ethnicity, obesity, renal or hepatic dysfunction, pregnancy, exercise, drug interactions) using the topic words and name of each type of insulin analog. Information was also obtained from the prescribing information for each insulin analog.ResultsThe PK/PD profiles for insulin analogs may be influenced by many variables including age, weight, and hepatic and renal function. However, these variables do not have equivalent effects on all long-acting or rapid-acting insulin analogs.ConclusionRapid-acting and long-acting insulin analogs represent major advances in treatment for patients with T2DM who require insulin therapy. However, there are potentially important PK and PD differences between the two long-acting agents and among the three rapid-acting insulin analogs, which should be considered when designing treatment regimens for special patient groups.

The quantification of peptide hormones by means of liquid chromatography (LC) coupled to mass spectrometry (MS) or other techniques (e.g. immunoassays) has been a challenging task in modern analytical chemistry. Especially for insulin, its synthetic analogs, and C‐peptide, reliable determinations are urgently needed due to their diagnostic value in the management of diabetes and insulin resistance and because of the illicit use of insulin as a performance‐enhancing agent in professional sports or as an effective toxin in forensic toxicology. The concomitant measurement of C‐peptide and insulin offers an established tool for the diagnostic workup of hypoglycemia (endogenous vs. exogenous hyperinsulinemia), characterizing hepatic insulin clearance, and the assessment of beta‐cell function (insulin secretion). Thus, the present approach offers the possibility to determine human insulin and its synthetic analogs (lispro, glulisine, aspart, glargine metabolite, degludec, detemir, porcine, and bovine) and C‐peptide simultaneously after sample preparation utilizing protein precipitation and a mixed‐mode cation‐exchange solid‐phase extraction, and subsequent detection by LC‐high resolution MS. The method was fully validated regarding the following parameters: specificity, limit of detection (0.2 ng/mL), limit of quantification (0.6 ng/mL), recovery (40–90%), accuracy (78–128%), linearity, precision (< 21%), carry over, robustness, and matrix effects. The proof‐of‐concept was shown by analyzing authentic plasma samples from adults with class II obesity and prediabetes collected in the course of an oral glucose tolerance test. All sample preparation steps were controlled by two stable isotope‐labeled internal standards, namely [[2H10] Leu B6, B11, B15, B17]‐insulin, and [[13C6] Leu 26, 30] C‐peptide. [ABSTRACT FROM AUTHOR]

Andrzej Kokoszka1,2 1II Department of Psychiatry, Medical University of Warsaw, 2Department of Psychology, SWPS University of Social Sciences and Humanities, Warsaw, Poland Background: Insulin analogs are regarded as more convenient to use than human insulin; however, they require a different administration scheme due to their unique pharmacokinetic and pharmacodynamic properties. This study aimed to assess difficulties with adherence to treatment with insulin analogs in patients with type 2 diabetes mellitus (T2DM), who had previously been treated with human insulin. The associations between difficulties with adherence and clinical, demographic, and psychological characteristics were also evaluated.Patients and methods: The study was conducted on 3,467 consecutively enrolled patients with T2DM (54.4% women), mean age 63.9 years (SD =9.57), who had recently undergone a physician-directed change in treatment from human insulin to insulin analogs. The questionnaires addressed difficulties with switching the therapy, coping styles, well-being, and perception of self-influence on the disease.Results: No adherence problems in switching therapy were reported in 56.6% of patients. Specific moderate difficulties were reported in 10.4%–22.1% of patients, major difficulties in 0.7%–6.9% of patients, and very significant difficulties in 0.03%–1.3% of patients. Overall, remembering to modify the insulin dose in the case of additional meals was the most frequently reported difficulty, and problems with identifying hypoglycemic symptoms were the least frequently reported. The increased risk of difficulties was moderately related to low perception of self-influence on diabetes and poor well-being. The intensity of problems was higher among those who were less-educated, lived in rural areas, had complications, and/or reported maladaptive coping styles.Conclusion: Switching from human insulin to an insulin analog did not cause adherence problems in more than half of the patients. In the remaining patients, difficulties in adherence correlated with maladaptive coping styles, low perception of self-influence on disease course, and depressive symptoms. Keywords: adherence, type 2 diabetes mellitus, insulin, insulin analogs, treatment adherence

Diabetes is a medical condition associated with impaired glucose regulation caused either due to insufficient insulin production or resistance to insulin (Type 2 diabetes, gestational diabetes) or the absence of insulin through the selective killing of beta cells in the pancreas (Type 1 diabetes). Irregular insulin production leads to various health complications. To prevent such complications, patients must adhere to medical recommendations before availing of any advanced insulin therapy(ies), considered productive for the treatment. Natural insulin, although highly effective in controlling blood glucose levels, patients are often at risk of developing hypoglycemia and many other complications. This has led to the development of insulin analogs, the modified variants of natural insulin having a minimal risk of causing hypoglycemia. Besides the development of analogs, the mode of insulin delivery is also considered critical in achieving better glycemic control in diabetic patients. Until recently, various exogenous insulin delivery methods were practiced, but effective glycemic control without any associated risk and ease of delivery remains a subject of paramount concern. It countered attenuation or delayed onset of diabetes-associated complications without a permanent cure, raising an unmet demand for insulin formulations and delivery methods that offer stability, biocompatibility, reproducibility, precision dosing, non-immunogenicity, and safety. The current practice utilizes non-physiological delivery methods with less invasive administration routes, offering glycemic stability and therapeutic effectiveness. This review focuses on the recent advances made and future perspectives envisioned about newer insulin therapies and delivery methods that tend to improve the management of diabetes by inculcating ideas to reduce the disease's severity and improve the quality of life., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Reliable detection and measurement of cell proliferation are essential in the preclinical assessment of carcinogenic risk of therapeutics. In this context, the assessment of mitogenic potential on mammary glands is crucial in the preclinical safety evaluation of novel insulins. The existing manual counting is time-consuming and subject to operator bias. To standardize the processes, make it faster, and resistant to errors, we developed a semiautomated image analysis system (CEPA software, which is open-source) for counting of proliferating cells in photomicrographs of mammary gland sections of rats labeled with Ki-67. We validated the software and met the predefined targets for specificity, accuracy, and reproducibility. In comparison to manual counting, the respective mean differences in absolute labeling indices (LIs) for CEPA software were 3.12% for user 1 and 3.05% for user 2. The respective regression analysis revealed a good correlation between the CEPA software user and manual counting. Moreover, the CEPA software showed enhanced reproducibility between independent users. The interuser variability is centered around 0 and the absolute difference was about 0.53% LI. Based on validation data, our software has superiority to the manual counting and is a valid and reliable tool for the routine analysis of cell proliferation in mammary glands from rats exposed to insulin analogs. [ABSTRACT FROM AUTHOR]

We investigated the pharmacodynamics (PD) and pharmacokinetics (PK) of BioChaperone insulin Lispro (BCLIS), faster insulin aspart (FIA) and insulin aspart (ASP) in patients with type 1 diabetes using an insulin pump. In this randomized, double‐blind, three‐way crossover glucose clamp study, 43 patients received a bolus dose of each insulin (0.15 U/kg) in addition to a basal rate (0.01 U/kg/h), delivered via an insulin pump. With BCLIS, the AUC‐GIR,0–60 minutes (primary endpoint) was improved compared to ASP (least square means ratio, 1.63; 95% CI, 1.44–1.88; P < 0.0001) and was similar compared to FIA (least square means ratio, 1.06; 95% CI, 0.94–1.18; P = 0.4609). BCLIS showed faster‐on PD (tearly0.5GIRmax) than ASP and faster‐off PD (tlate0.5GIRmax) than both FIA and ASP. BCLIS also demonstrated significantly higher early exposure (AUCins, 0–60 minutes) and lower late exposure (AUCins,120–600 minutes) than both other insulins. In patients with type 1 diabetes using an insulin pump, BCLIS better mimics prandial insulin secretion and action than ASP and shows a faster off‐PD than FIA. [ABSTRACT FROM AUTHOR]

Abstract Insulin remains a predominant life-saving medication for type 1 and type 2 Diabetes Mellites. Natural insulin secretion limits the fluctuation of the narrow and high surge of blood glucose levels. However, imitating the same by external insulin remains a challenge as a variety of insulin analogs (rapid acting, short acting, intermediate acting and long-acting) have different pharmacokinetic (PK) and pharmacodynamic (PD) properties. Inconsistent reduction in overall hyperglycemia level and nocturnal hypoglycemia due to variable absorption time and time action profile predominantly highlights the need of revisiting the PK/PD of insulin analogs as single analog is not yet sufficed to replace internal insulin exogenously. Combination therapy with basal and prandial insulins or intensification of hypoglycemic therapy with premixed insulins are of prime importance in managing diabetes effectively, imitating the natural insulin secretion. Therefore, the knowledge of PK/PD properties might help a practitioner to design, implement and manage insulin replacement therapy effectively and averting adverse events. Present study reports the comparative analysis of PK/PD profile of various insulin analogs based on the concurrent information about clinical aspects. Moreover, study interlinks the major concerns of therapeutic efficacy of insulin analogs with their respective onset of action and duration of effectiveness and reported adverse drug reaction which explore the scope of improvement. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

[Display omitted] Insulin therapy is the mainstay to treat diabetes characterizedd by hyperglycemia. However, its short half-life of only 4–6 min limits its effectiveness in treating chronic diabetes. Advances in recombinant DNA technology and protein engineering have led to several insulin analogue products that have up to 42 h of glycemic control. However, these insulin analogues still require once- or twice-daily injections for optimal glycemic control and have poor patient compliance and adherence issues. To achieve insulin release for more than one day, different injectable delivery systems including microspheres, in situ forming depots, nanoparticles and composite systems have been developed. Several of these delivery systems have advanced to clinical trials for once-weekly insulin injection. This review comprehensively summarizes the developments of injectable insulin analogs and delivery systems covering the whole field of injectable long-lasting insulin technologies from prototype design, preclinical studies, clinical trials to marketed products for the treatment of diabetes. [ABSTRACT FROM AUTHOR]

Dilek Gogas Yavuz,1 Habip Bilen,2 Seda Sancak,3 Tayfun Garip,4 Zeliha Hekimsoy,5 Ibrahim Sahin,6 Murat Yilmaz,7 Hasan Aydin,8 Aysegul Atmaca,9 Murat Sert,10 Pinar Karakaya,11 Dilek Arpaci,4 Aytekin Oguz,12 Nilgun Guvener13 On behalf of the Dropout Study Group 1Department of Endocrinology and Metabolism, Marmara University Faculty of Medicine, Istanbul, 2Department of Endocrinology and Metabolism, Ataturk University Faculty of Medicine, Erzurum, 3Clinic of Endocrinology and Metabolism, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, 4Clinic of Endocrinology and Metabolism, Sakarya State Hospital, Sakarya, 5Department of Endocrinology and Metabolism, Celal Bayar University Faculty of Medicine, Manisa, 6Department of Endocrinology and Metabolism, Inonu University Faculty of Medicine, Malatya, 7Department of Endocrinology and Metabolism, Namik Kemal University Faculty of Medicine, Tekirdag, 8Department of Endocrinology and Metabolism, Yeditepe University Faculty of Medicine, Istanbul, 9Department of Endocrinology and Metabolism, Ondokuzmayis University Faculty of Medicine, Samsun, 10Department of Endocrinology and Metabolism, Cukurova University Faculty of Medicine, Adana, 11Clinic of Endocrinology and Metabolism, Bakirkoy Training and Research Hospital, Istanbul, 12Department of Internal Medicine, Medeniyet University Faculty of Medicine, Istanbul, 13Department of Endocrinology and Metabolism, Baskent University Faculty of Medicine, Istanbul, Turkey Objective: The objective of this study is to evaluate the impact of sequential telephonic interviews on treatment persistence and daily adherence to insulin injections among insulin-naïve type 2 diabetes patients initiated on different insulin regimens in a 3-month period.Methods: A total of 1,456 insulin-naïve patients with type 2 diabetes (mean [standard deviation, SD] age: 56.0 [12.0] years, 49.1% were females) initiated on insulin therapy and consecutively randomized to sequential (n=733) and single (n=723) telephonic interview groups were included. Data on insulin treatment and self-reported blood glucose values were obtained via telephone interview. Logistic regression analysis was performed for factors predicting increased likelihood of persistence and skipping an injection.Results: Overall, 76.8% patients (83.2% in sequential vs 70.3% in single interview group, (P

Lipohypertrophy has been suggested as an outcome of lipogenic action of insulin and/or injection-related tissue trauma. In a cross-sectional study, we evaluated the predictors of lipohypertrophy in 372 type 1 diabetes patients (mean age 17.1 years) receiving subcutaneous insulin with pen and/or syringes for ≥3 months. On examining injection sites with inspection and palpation technique, 62.1% patients demonstrated lipohypertrophy. Univariate analysis showed that gender, BMI, HbA1c, injection device, rotation, injection area, needle length, insulin regimen, and total daily dose of insulin were associated with lipohypertrophy (p < 0.05). Notably, the mean needle reuse was comparable in patients with or without lipohypertrophy (8.1 vs. 7.2, p = 0.534). In multivariate logistic regression, gender, HbA1c, TDD, injection devices, and needle length lost its significance. Further, injections over smaller area (≤8.5 × 5.5 cm) and non-rotation of sites were found to be strongest independent predictor of lipohypertrophy (p < 0.0005 for both) with increased odds of 23.2 (95% CI 9.1–59.2) and 6.3 (95% CI 3.4–11.9) times, respectively. Being underweight was also a significant independent predictor (odds ratio [OR] 13.0 [95% CI 2.2–75.2], p = 0.004). Compared to rapid plus long-acting analogs, regular insulin plus long-acting analogs and conventional premixed insulin users had 3.2 (95% CI 1.5–6.8, p = 0.003) and 4.6 (95% CI 1.4–15.7, p = 0.014) fold higher risk of lipohypertrophy (mean injection frequency 4.01 vs. 4.01 vs. 2.09, respectively). Sub-group analysis showed that lipohypertrophy was 79% less likely in patients with multiple daily injections (≥4) than twice-daily regimen (OR 0.21, p < 0.0005). Moreover, lipohypertrophy was reduced to half with bolus doses of rapid-acting insulin analogs than regular insulin (p = 0.003), even though mean injection frequency was comparable (4.01 vs. 3.93, p = 0.229). This difference was statistically insignificant for basal doses with NPH or long-acting analogs (p = 0.069). Therefore, injection area, rotation, BMI, and insulin regimen are the best predictors of lipohypertrophy and together could correctly identify lipohypertrophy status in 84.4% patients with excellent discrimination capability (AUC = 0.906, p < 0.0005). In conclusion, findings of our study suggest that delivering rapidly absorbed insulin analogs over large injection area along with greater split of total daily doses reduce insulin-induced lipogenesis and outplay tissue trauma added through frequent injections and needle reuse.

Background: Hypoglycemia is an increasingly important endpoint in clinical diabetes trials. The assessment of hypoglycemia should therefore be as complete as possible. Blinded continuous glucose monitoring (CGM) provides an improved opportunity to capture asymptomatic and nocturnal events. Here we report results from the HypoAna trial comparing all-analog-insulin therapy (aspart/detemir) with all-human-insulin therapy (neutral protamine Hagedorn/regular) on non-severe hypoglycemia (symptomatic and asymptomatic hypoglycemia) as assessed by blinded CGM and compared with data obtained by self-monitoring of blood glucose (SMBG) in patients with type 1 diabetes and recurrent severe hypoglycemia.Methods: Fifty-three patients completed a substudy of 4 × 3 days of blinded CGM. CGM traces were reviewed for hypoglycemic events lasting 15 min or longer.Results: At the threshold ≤3.9 mmol/L, the per-protocol analysis demonstrated a 40% rate reduction (95% confidence interval [CI] 20%-60%; P = 0.002) in nocturnal non-severe hypoglycemia during analog treatment, mainly due to a 40% rate reduction (95% CI 0%-70%; P = 0.03) of nocturnal asymptomatic hypoglycemia. Similar nonsignificant trends were seen at the glucose threshold ≤3.0 mmol/L. Overall CGM-detected that nocturnal asymptomatic hypoglycemia ≤3.9 mmol/L was ∼17 times more frequent than SMBG-detected episodes (52 vs. 3 events/patient-year). This translates into a time needed to treat one patient with insulin analogs to prevent one episode that is 34 times shorter using CGM data than SMBG data (1.4 vs. 47 weeks).Conclusions: Capturing hypoglycemic events by the conventional method of SMBG in patients with impaired awareness reveals only a limited number of events. Blinded CGM can provide more complete data, particularly in terms of asymptomatic and nocturnal events. [ABSTRACT FROM AUTHOR]

As injectable therapies such as human insulin, insulin analogs, and glucagon-like peptide-1 receptor agonists are used to manage diabetes, correct injection technique is vital for the achievement of glycemic control. The forum for injection technique India acknowledged this need for the first time in India and worked to develop evidence-based recommendations on insulin injection technique, to assist healthcare practitioners in their clinical practice.

A 56-year-old middle-eastern male with a long-standing history of poorly controlled type 2 diabetes mellitus presented to us complaining of severely painful bilateral upper and lower extremity cramps occurring shortly after his rapid-acting insulin analog injection(s). The cramps had started 6 months ago and have been occurring intermittently in non-predictable episodes since then. He had otherwise never experienced any insulin-related adverse reaction(s) before. His cramps are very painful and debilitating, interfering with his daily activities and placing him in a state of constant fear/anxiety of re-experiencing them. This caused him to become non-adherent with his prescribed treatment and poorly compliant with his follow-up regimens. Thorough examination showed a diffuse loss of sensation over the lower limbs. This was subsequently confirmed with a combined electromyography–nerve conduction study which indicated extensive diabetic axonal polyneuropathy. By contrast, lower extremity segmental arterial pressures were negative for peripheral vasculo-occlusive disease, ruling out vascular insufficiency as a possible etiology of the cramps. We then measured the levels of serum electrolytes right-before and 30 min right-after injecting the patient with his insulin. Potassium dropped by about 16% from its initial level, compared to a drop of only around 4% for calcium and none (0%) for magnesium. Thus, we speculated this insulin-induced sharp drop in serum potassium levels as potentiating the patient’s already existing advanced diabetic neuropathy, thereby leading to muscle cramping. However, attempting potassium supplementation for a brief period of time led to a rapid resolution of cramps when they occurred and an overall reduction in their frequency of recurrence. This tilted our diagnosis toward the insulin-induced acute drop in serum potassium levels as the most likely etiology underlying the patient’s cramps. Such an observation has been made only once previously within the literature, back in 1992, at the Duke University Medical Center.