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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]

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.