Insulin Formulations Research Articles

Type 1 Diabetes in Pregnancy: A Review

Up to 10% of all pregnancies in the US are complicated by diabetes. Among them, 0.2 to 0.5 % of the individuals had type 1 diabetes (T1DM). Preterm birth, preeclampsia, macrosomia, shoulder dystocia, intrauterine fetal death, fetal growth restriction, cardiac and renal abnormalities, as well as uncommon neural disorders including sacral agenesis, are all heightened risks for pregnancies affected by T1DM. It has been demonstrated that preconception planning and intensive glycemic control can lower the rate of fetal loss and abnormalities in pregnancies complicated by T1DM. The number of alternatives available to the obstetric team has risen as a result of recent improvements in insulin formulations and delivery techniques. To promote compliance and guarantee optimal glucose control, insulin regimens should be customized for each patient. For effective care, intensive preconception counseling with regular follow-up visits that emphasize strict glucose control is advised.

Formulation Excipients and Their Role in Insulin Stability and Association State in Formulation.

While excipients are often overlooked as the "inactive" ingredients in pharmaceutical formulations, they often play a critical role in protein stability and absorption kinetics. Recent work has identified an ultrafast absorbing insulin formulation that is the result of excipient modifications. Specifically, the insulin monomer can be isolated by replacing zinc and the phenolic preservative metacresol with phenoxyethanol as an antimicrobial agent and an amphiphilic acrylamide copolymer excipient for stability. A greater understanding is needed of the interplay between excipients, insulin association state, and stability in order to optimize this formulation. Here, we formulated insulin with different preservatives and stabilizing excipient concentrations using both insulin lispro and regular human insulin and assessed the insulin association states using analytical ultracentrifugation as well as formulation stability. We determined that phenoxyethanol is required to eliminate hexamers and promote a high monomer content even in a zinc-free lispro formulation. There is also a concentration dependent relationship between the concentration of polyacrylamide-based copolymer excipient and insulin stability, where a concentration greater than 0.1g/mL copolymer is required for a mostly monomeric zinc-free lispro formulation to achieve stability exceeding that of Humalog in a stressed aging assay. Further, we determined that under the formulation conditions tested zinc-free regular human insulin remains primarily hexameric and is not at this time a promising candidate for rapid-acting formulations.

Poly(trehalose methacrylate) as an Excipient for Insulin Stabilization: Mechanism and Safety.

Insulin, the oldest U.S. Food and Drug Administration (FDA)-approved recombinant protein and a World Health Organization (WHO) essential medicine for treating diabetes globally, faces challenges due to its storage instability. One approach to stabilize insulin is the addition of poly(trehalose methacrylate) (pTrMA) as an excipient. The polymer increases the stability of the peptide to heat and mechanical agitation and has a low viscosity suitable for injection and pumps. However, the safety and stabilizing mechanism of pTrMA is not yet known and is required to understand the potential suitability of pTrMA as an insulin excipient. Herein is reported the immune response, biodistribution, and insulin plasma lifetime in mice, as well as investigation into insulin stabilization. pTrMA alone or formulated with ovalbumin did not elicit an antibody response over 3 weeks in mice, and there was no observable cytokine production in response to pTrMA. Micropositron emission tomography/microcomputer tomography of 64Cu-labeled pTrMA showed excretion of 78–79% ID/cc within 24 h and minimal liver accumulation at 6–8% ID/cc when studied out to 120 h. Further, the plasma lifetime of insulin in mice was not altered by added pTrMA. Formulating insulin with 2 mol equiv of pTrMA improved the stability of insulin to standard storage conditions: 46 weeks at 4 °C yielded 87.0% intact insulin with pTrMA present as compared to 7.8% intact insulin without the polymer. The mechanism by which pTrMA-stabilized insulin was revealed to be a combination of inhibiting deamidation of amino acid residues and preventing fibrillation, followed by aggregation of inactive and immunogenic amyloids all without complexing insulin into its hexameric state, which could delay the onset of insulin activity. Based on the data reported here, we suggest that pTrMA stabilizes insulin as an excipient without adverse effects in vivo and is promising to investigate further for the safe formulation of insulin.

The Effect of Two Different Insulin Formulations on Postprandial Hyperglycemia after High and Low Glycemic-Index Meal in Type 1 Diabetes.

Despite multiple pharmacological options, including rapid-acting insulin analogs, postprandial hyperglycemia is still highly prevalent in patients with type 1 and type 2 diabetes. We hypothesize that the new rapid-acting insulin formulation, the so-called faster-acting Aspart, may have a different effect in controlling postprandial hyperglycemic burden according to the quality of the meal compared to the traditional Aspart. Twenty-five patients with type 1 diabetes were consecutively recruited at the diabetes care center of the University Hospital affiliate of the Magna Græcia University of Catanzaro. Each patient performed four meal tests one week apart, two with a predefined high glycemic index (HGI) food and two with a low glycemic index (LGI) food using insulin Aspart once and Faster Aspart the other time. The 0–30 min, 0–60 min, and 0–120 min glucose Area Under the Curve (AUC) of postprandial glycemic excursion, calculated from continuous glucose monitoring data, were significantly lower with Faster Aspart administered before the HGI test meal as compared to Aspart. A significant difference in favor of Faster Aspart was also found when comparing the 0–60 min and 0–120 min AUC after the LGI meal. Faster Aspart may provide better postprandial glucose control than Aspart regardless of the glycemic index of the meal.

Counteractive Effects of Choline Geranate (CAGE) ILs and Ethanol on Insulin’s Stability—A Leap Forward towards Oral Insulin Formulation

Choline geranate (CAGE) ionic liquids (ILs) stabilize insulin, thereby aiding its oral delivery, whereas ethanol (EtOH) affects its stability by disrupting the hydrophobic interactions. In this study, cognizance of the stabilization mechanism of insulin dimer in the presence of both CAGE ILs and EtOH mixtures is achieved through biased and unbiased molecular dynamics (MD) simulations. Here, two order parameters are employed to study the insulin dimer dissociation using well-tempered metadynamics (WT-MetaD). The stability of insulin is found to be strongly maintained until a 0.20 mole fraction of EtOH. Besides, higher concentrations of EtOH marginally affect the insulin stability. Moreover, geranate anions form a higher number of H-bonding interactions with water molecules, which aids insulin stabilization. Conversely, the addition of EtOH minimizes the water-mediated H-bonding interactions of geranate. Additionally, geranate traps the EtOH molecules, thereby preventing the interactions between insulin and EtOH. Furthermore, the free energy landscape (FEL) reveals the absence of dimer dissociation along with noticeable deviations in the distances R and the number of contacts Q. The dimerization free energy of insulin was calculated to be −16.1 kcal/mol at a 0.20 mole fraction of EtOH. Moreover, increments in mole fractions of EtOH effectuate a decrease in the insulin stability. Thus, the present study represents CAGE ILs as efficient insulin dimer stabilizes at low concentrations of EtOH.

An amphiphilic small molecule drives insulin aggregation inhibition and amyloid disintegration

The aggregation of proteins into ordered fibrillar structures called amyloids, and their disintegration represent major unsolved problems that limit the therapeutic applications of several proteins. For example, insulin, commonly used for the treatment of diabetes, is susceptible to amyloid formation upon exposure to non-physiological conditions, resulting in a loss of its biological activity. Here, we report a novel amphiphilic molecule called PAD-S, which acts as a chemical chaperone and completely inhibits fibrillation of insulin and its biosimilars. Mechanistic investigations and molecular docking lead to the conclusion that PAD-S binds to key hydrophobic regions of native insulin, thereby preventing its self-assembly. PAD-S treated insulin was biologically active as indicated by its ability to phosphorylate Akt, a protein in the insulin signalling pathway. PAD-S is non-toxic and protects cells from insulin amyloid induced cytotoxicity. The high aqueous solubility and easy synthetic accessibility of PAD-S facilitates its potential use in commercial insulin formulations. Notably, PAD-S successfully disintegrated preformed insulin fibrils to non-toxic smaller fragments. Since the structural and mechanistic features of amyloids are common to several human pathologies, the understanding of the amyloid disaggregation activity of PAD-S will inform the development of small molecule disaggregators for other amyloids.

Insulin: evolution of insulin formulations and their application in clinical practice over 100years.

The first preparation of insulin extracted from a pancreas and made suitable for use in humans after purification was achieved 100 years ago in Toronto, an epoch-making achievement, which has ultimately provided a life-giving treatment for millions of people worldwide. The earliest animal-derived formulations were short-acting and contained many impurities that caused adverse reactions, thereby limiting their therapeutic potential. However, since then, insulin production and purification improved with enhanced technologies, along with a full understanding of the insulin molecule structure. The availability of radio-immunoassays contributed to the unravelling of the physiology of glucose homeostasis, ultimately leading to the adoption of rational models of insulin replacement. The introduction of recombinant DNA technologies has since resulted in the era of both rapid- and long-acting human insulin analogues administered via the subcutaneous route which better mimic the physiology of insulin secretion, leading to the modern basal-bolus regimen. These advances, in combination with improved education and technologies for glucose monitoring, enable people with diabetes to better meet individual glycaemic goals with a lower risk of hypoglycaemia. While the prevalence of diabetes continues to rise globally, it is important to recognise the scientific endeavour that has led to insulin remaining the cornerstone of diabetes management, on the centenary of its first successful use in humans.

Minimizing Hypoglycemia with Insulin Therapy

Iatrogenic hypoglycemia is the most feared and common complication of insulin therapy. Hypoglycemia can have serious consequences and can be potentially life-threatening. In addition to the neurological manifestations of severe hypoglycemia, hypoglycemia may be associated with cognitive dysfunction, cardiovascular events, arrhythmias, and increased mortality. Recurrent episodes of hypoglycemia may lead to hypoglycemia unawareness, which increases the risk of severe hypoglycemia. Therefore, prevention of hypoglycemia remains a priority in persons with diabetes on insulin therapy. The “THINK” strategy provides a comprehensive approach for diabetes care providers to minimize the risk of hypoglycemia related to insulin therapy by mitigating factors that increase the risk. This requires setting reasonable glycemic Targets keeping in mind a person's risk of hypoglycemia; choosing the right Tools such as insulin formulation and regimen with lower risk and adequate glucose monitoring; judicious Titration of insulin doses; use of modern Technology such as continuous glucose monitoring, continuous subcutaneous insulin infusion, and sensor augmented pumps in patients at high risk; maintaining Harmony between insulin dose, diet, physical activity, and changes in lifestyle; Individualization of diabetes therapy; ensuring there are No errors in insulin administration; and empowering patients with Knowledge about hypoglycemia. The THINK strategy offers a handy tool for tailoring insulin therapy to minimize hypoglycemia risk.

Efficacy and safety of oral insulin versus placebo for patients with diabetes mellitus: A systematic review and meta-analysis.

Compliance to insulin injections is poor due to difficulty in subcutaneous administration. Hence, there is a need of an oral formulation of insulin. Oral insulin is currently under investigation. The present analysis aimed to evaluate oral insulin versus placebo for patients with diabetes mellitus (type-1 and type-2). Results from PUBMED and MEDLINE were searched and compiled from January 1, 2000 to January 9, 2020. Postprandial blood glucose excursions (2PPG), glycated hemoglobin (HbA1c), C-peptide levels, and immune antibody (IAA) levels were compared between the arms. In addition, time to diabetes and safety of oral insulin were discussed. Thirteen out of 1778 trials were included to the analysis. Oral insulin was found to induce significant reduction in mean 2PPG excursion (standardized mean difference [SMD]: -1.94, 95% CI: -3.20 to -0.68, I² = 91.81, P < 0.005) and mean IAA levels (SMD:-0.49, 95% CI: -0.82 to -0.16, I² = 27.12, P < 0.005) compared with placebo. Mean C-peptide levels were notably lower in the oral insulin arm. However, the difference was not statistically significant. No significant difference was observed in mean HbA1c levels. The rate of development of type-1 diabetes was not significantly influenced by oral insulin. No deaths or treatment-related serious adverse events were reported. Oral insulin provided significant benefits for acute maintenance of diabetes mellitus. It elicited lower immune response and was well tolerated. This new formulation has potential to augment the management of diabetes mellitus. More studies are required to assess its long-term effects.

Identification and characterization of chemical and physical stability of insulin formulations utilizing degraded glycerol after repeated use and storage

Insulin treatment is currently considered to be the main strategy for controlling diabetes. Although the recombinant insulin formulation is relatively mature, we found that a batch of insulin formulation exhibited an unusual degradation rate in the stability experiment. The main purposes of this article are to identify the root cause for this phenomenon and characterize of chemical and physical degradation products. We compared the chemical and physical stability of two batches of insulin formulations prepared separately with simulated repeated use and freshly opened glycerol. The chemical stability of insulin was identified by liquid chromatography coupled with tandem mass spectrometry (LC- MS/MS). Micro-flow imaging (MFI), far-ultraviolet circular dichroism (Far-UV CD) and Thioflavin T (ThT) fluorescent assays were used to reveal protein aggregation and fibrosis. The chemical and physical stability of the insulin formulation with newly opened glycerol was much better than that with degraded glycerol, and both groups of formulations were extremely sensitive to light. The results indicated that the original batch insulin formulation with abnormal stability was indeed caused by the excipient glycerol after long-term storage and repeated usage. More attention should be paid to the quality changes of excipients during repeated usage and storage of excipients for the practical purpose. Moreover, we have discovered a novel degradation pathway for insulin and peptides in general. In addition, LC-MS/MS results suggested that the N-terminus of insulin B-chain was prone to chemical degradation which enlightens that it could be potentially modified to improve the stability of insulin formulations.

Combination Use of U-500 Regular Insulin via Insulin Pump and Rapid-Acting U-100 Prandial Injections for Treatment of Pre-Existing Type 2 Diabetes in Pregnancy.

The high-dose large-volume insulin injections that may become necessary during pregnancy due to marked pregnancy-induced insulin resistance may result in suboptimal therapeutic effectiveness. Use of U-500 insulin, a concentrated insulin formulation, has been suggested during pregnancy. However, the pharmacokinetic properties of U-500 insulin monotherapy can impede achievement of strict pregnancy glycemic targets. We propose a novel regimen for treatment of severe pregnancy-induced insulin resistance that enables precise delivery of U-500 basal insulin therapy through continuous subcutaneous insulin infusion (CSII) while maintaining the desired kinetics of prandial rapid-acting U-100 insulin therapy. This combination approach, guided by continuous glucose monitoring data, enabled achievement of pregnancy glycemic targets while reducing basal insulin requirements by approximately one-third. We report our method for (1) conversion to U-500 insulin delivery through CSII during pregnancy and (2) conversion from U-500 basal insulin delivery through CSII to U-100 intravenous insulin infusion therapy at delivery, to offer clinicians who encounter similar challenging scenarios a novel approach to diabetes management during pregnancy in the setting of marked insulin resistance.

Photoacoustic imaging reveals mechanisms of rapid-acting insulin formulations dynamics at the injection site

ObjectiveUltra-rapid insulin formulations control postprandial hyperglycemia; however, inadequate understanding of injection site absorption mechanisms is limiting further advancement. We used photoacoustic imaging to investigate the injection site dynamics of dye-labeled insulin lispro in the Humalog® and Lyumjev® formulations using the murine ear cutaneous model and correlated it with results from unlabeled insulin lispro in pig subcutaneous injection model. MethodsWe employed dual-wavelength optical-resolution photoacoustic microscopy to study the absorption and diffusion of the near-infrared dye-labeled insulin lispro in the Humalog and Lyumjev formulations in mouse ears. We mathematically modeled the experimental data to calculate the absorption rate constants and diffusion coefficients. We studied the pharmacokinetics of the unlabeled insulin lispro in both the Humalog and Lyumjev formulations as well as a formulation lacking both the zinc and phenolic preservative in pigs. The association state of insulin lispro in each of the formulations was characterized using SV-AUC and NMR spectroscopy. ResultsThrough experiments using murine and swine models, we show that the hexamer dissociation rate of insulin lispro is not the absorption rate-limiting step. We demonstrated that the excipients in the Lyumjev formulation produce local tissue expansion and speed both insulin diffusion and microvascular absorption. We also show that the diffusion of insulin lispro at the injection site drives its initial absorption; however, the rate at which the insulin lispro crosses the blood vessels is its overall absorption rate-limiting step. ConclusionsThis study provides insights into injection site dynamics of insulin lispro and the impact of formulation excipients. It also demonstrates photoacoustic microscopy as a promising tool for studying protein therapeutics. The results from this study address critical questions around the subcutaneous behavior of insulin lispro and the formulation excipients, which could be useful to make faster and better controlled insulin formulations in the future.

1205-P: Trends in Insulin Use and Glycemic Control in U.S. Adults with Diabetes, 1988–2020

Introduction: Insulin remains a last line therapy for type 2 diabetes, and formulations have improved significantly over the past 30 years. It is unknown whether these advancements have translated into better glycemic control in persons with diabetes. Methods: We conducted a trends analysis of cross-sectional data from the National Health and Nutrition Examination Survey (NHANES, 1988-2020) . Our analysis included 8,658 nonpregnant adults aged ≥20 with diagnosed diabetes. We examined trends in self-reported diabetes medication use (insulin or oral) and glycemic control (A1c<7.0%) , overall and by race/ethnicity. Results: From 1988-1994 to 2013-2020, there was an increase in the proportion of US adults with diabetes using only oral glucose-lowering medications (43.5% to 55.2%, p=0.003) . The proportion of patients using insulin did not change over the same period (30.5% to 28.2%, p=0.81) . Glycemic control improved among users of oral medications (p<0.001) (Figure 1a) . Among insulin users, glycemic control was unchanged (p=0.87) . Mexican American insulin users had a decrease in glycemic control (25.1% in 1988-94 to 9.9% in 2013-20, p=0.004) and had poorer glycemic control, overall, as compared to their non-Hispanic White or Black counterparts (Figure 1b-1d) . Conclusions: Despite improvements in insulin formulations, insulin users have not seen improved glycemic control. Disclosure S.Venkatraman: None. E.Selvin: Other Relationship; Wolters Kluwer. M.Fang: n/a.

1449-P: Reducing Ghrelin Levels as a Novel Method to Increase Pancreatic Beta-Cell Mass

Objective: Exogenous insulin remains the leading therapy for type 1 diabetes mellitus, T1D. However, current insulin formulations and delivery methods do not match the precision of functioning beta-cells, and even intensive monitoring of blood glucose and use of insulin pumps are not enough to halt frequent hypoglycemia, hyperglycemia and morbidity. Thus, regenerating beta-cells has become a major target of diabetes research to treat T1D. While the hormone ghrelin is well known to increase blood glucose, at least in part by inhibiting insulin secretion, ghrelin’s action on beta-cell mass and proliferation has heretofore not been explored in detail. Here, we sought to test the hypothesis that reducing ghrelin levels increases beta-cell mass. Methods: Using histologic methods, we compared islet anatomy in ghrelin-knockout (ghrelin-KO) mice vs. wildtype littermates at three different ages: newborns (P0-P2) , juveniles (4-week-old) , and adults (10-12-week-old) . We also compared islet anatomy in adult wildtype mice, 4 weeks following conditional ghrelin-cell ablation vs. wildtype mice with intact ghrelin-cells. n= 4-8 mice per group and 33-433 islets per mouse. Results: Ghrelin gene deletion or ghrelin-cell ablation increased mean islet area and mean islet insulin-immunoreactive (insulin-IR) area by 52-82 % and by 45-51 %, respectively, in juveniles and adults. Increased islet size was driven by an increased % of large islets. Increased insulin-IR area was associated with increased beta-cell number per islet. An increased % of large islets was also observed in newborn ghrelin-KO mice. Conclusions: In mice, ghrelin plays an important role in controlling beta-cell mass. Reducing ghrelin levels for even short periods can increase islet size by increasing beta-cell numbers. Disclosure D.Gupta: None. C.P.Richard: None. J.M.Zigman: Research Support; Novo Nordisk Research Center Indianapolis, Novo Nordisk Research Center Indianapolis, Stock/Shareholder; Medtronic, Medtronic. A.W.Burstein: None. K.Shankar: None. S.Varshney: None. O.Singh: None. S.Paul: None. S.B.Ogden: None. S.Osborne-lawrence: None. N.Metzger: None.

788-P: Development of an Extended-Wear Infusion Set with Angled Cannula

Objective: Medtronic Mio™ 30 infusion set (M30IS) is a single-use consumable for pump users with pre-loaded inserter, utilizing a 30° insertion angle, and labeled for 3-day use. The M30IS wear duration is impacted by initial local trauma caused by insertion & cannula and sustained inflammation mostly by insulin infusion (especially insulin aggregates and other impurities in the infusate) , with the latter being predominant. Recently, a 7-day Medtronic Extended Infusion Set (MEIS) based on 3-day Mio™ Advance IS with a 90° soft cannula was developed and commercialized in Europe, by improving insulin formulation stability in the fluid path. This study is focused on applying the extended wear (EW) technology from MEIS to the M30IS to develop an EW set with angled cannula (the EM30IS) . Method: This is a cross over study of M30IS and EM30IS on drug-induced Type 1 diabetic Yucatan pigs. Each animal wore both sets multiple times with one each time on the abdomen that was continuously infused with Novolog™ subcutaneously via a pump for 1-week or until failure. Blood glucose were measured 5 times/day. Physical examination and serum panel tests were conducted for safety evaluation. Result: Fourteen wears were completed for each device. No significant safety concern was identified. Compared to the 90° cannula sets tested on the same model having occlusion alarm rate of 0∼20% for MEIS and ∼40% for 3-day sets at 7 days, no occlusion alarm was detected in either M30IS or EM30IS. Survival rate of EM30IS (86%, similar to MEIS) trended higher than that of M30IS (71%) . Average total daily dose of insulin increased with time for M30IS (Day 1: 14.4 U, Day 6: 18.1U) , whereas remained nearly unchanged for EM30IS (Day 1: 14.9 U, Day 6: 15.6 U) . Conclusion: The data indicated that the EM30IS is safe and efficacious on the diabetic porcine model for subcutaneous insulin infusion for 7 days. The EW technology is equally safe and effective on extending the wear duration of M30IS. The EM30IS is moving to the next phase of product development. Disclosure G.Zhang: Employee; Medtronic. E.Anselmo: Employee; Medtronic. J.L.Ortigoza: Employee; Medtronic. S.Chattaraj: Employee; Medtronic.

Formation of subvisible particles in commercial insulin formulations

The conformation and assembly of insulin are sensitive to physical and chemical variables. Insulin can misfold and form both amorphous and amyloid aggregates. Localized cutaneous amyloidosis due to insulin usage has been reported, and question remains regarding its stability in the original flasks due to storage and handling. Here we report the evaluation of the formation of aggregates in insulin formulations upon once-weekly handling and storage of the in-use cartridges at 4 °C or 37 °C for 5 weeks. Electrospray ionization mass spectrometry showed no obvious chemical decomposition. No major changes in oligomeric distribution were observed by size-exclusion chromatography. Dynamic light scattering allowed the identification of particles with high hydrodynamic radius formed during storage at 4 °C and 37 °C. Transmission electron microscopy analysis revealed the formation of amorphous material, with no clear evidence for amyloid material up to 28 days of incubation. These data support evidences for the formation of subvisible and submicrometer amorphous particulate matter in insulin formulations shortly upon use.

One hundred years of insulin: Is it time for smart?

Smarter understanding of diabetes pathophysiology and pharmacology of insulin therapy can lead to better clinical outcomes. Rather than looking for an insulin formulation that is considered "best" for a general population, it could be appropriate to seek the "smart" insulin choice, tailored to the specific clinical situation. Different treatment goals should be considered, with pros and cons to each. Ideally, insulin therapy in most diabetic dogs should mimic a "basal-bolus" pattern. The "intermediate"-acting insulin formulations might provide better "bolus" treatment in dogs than the rapid-acting formulations used in people. In patients with some residual beta cell function such as many diabetic cats, administering only a "basal" insulin might lead to complete normalisation of blood glucose concentrations. Insulin suspensions (neutral protamine Hagedorn, neutral protamine Hagedorn/regular mixes, lente and protamine zinc insulin) as well as insulin glargine U100 and detemir are "intermediate"-acting formulations that are administered twice daily. For a formulation to be an effective and safe "basal" insulin, its action should be roughly the same every hour of the day. Currently, only insulin glargine U300 and insulin degludec meet this standard in dogs, whereas in cats, insulin glargine U300 is the closest option.

L’insulina alla luce delle nuove linee guida italiane per il trattamento del diabete di tipo 2: quando, in chi e perché?

Aim: this editorial is aimed at providing a reference for the insulin treatment of type 2 diabetes in adults. Methods and results: the present paper revised the recently published Italian guidelines for the treatment of type 2 diabetes (outpatients), either in primary care or specialist referral. The guideline has been developed following the methods described in the Manual of the National Guideline System (http://www.snlg-iss.it) by a panel nominated by the Società Italiana di Diabetologia (SID) and Associazione Medici Diabetologi (AMD). Prior cardiovascular events, heart failure, hypoglycemic risk, and other conditions have been considered as factors capable of modifying treatment strategies. The following areas have been assessed: 1) position of the insulin therapy in the new algorithms; 2) type of formulations (insulin analogues or human insulin); 3) use of insulin infusion pumps. Conclusions: insulin should be used only as a second/thirdline therapy due to its lower efficacy on long-term HbA1c, higher risk of hypoglycemia, and neutral effects on cardiorenal outcomes. Human insulin formulations should be avoided for safety concerns (higher hypoglycemic risk) with no preference among different insulin analogues. Insulin pumps are not recommended for the treatment of type 2 diabetes.

Insulin analogs in the treatment of type II diabetes and future perspectives

The discovery of insulin by Banting and Best marked 100 years in 2021, and it was a life-saving treatment modality for type II diabetes mellitus (T2DM). Insulin is a natural hormone that has been used extensively in T2DM patients since its discovery. Currently, insulin analogs are also available in different formulations for T2DM management, overcoming the limitations of human insulin with better safety and side effect profiles. The insulin analogs like the rapid-acting analogs (Aspart, lispro, glulisine), the long-acting basal analogs (Glargine, detemir), the ultra-long acting (Insulin degludec), and the premixed insulin analog formulations (75% Neutral protamine lispro, 25% lispro; 50% neutral protamine lispro, 50% lispro; 70% protamine aspart, 30% aspart) have been prepared through genetic engineering while preserving the basic insulin profile. A large number of studies have demonstrated their clinical effects on glycated hemoglobin test (HbA1c) in achieving glycemic control and thereby lowering the microvascular and macrovascular complications of T2DM with less traditional side effects of regular human insulin, mainly the risk of hypoglycemia, postprandial glycemic excursions, and weight gain. This review explores the currently available insulin analogs, their clinical implications, pharmacokinetics (PK), pharmacodynamics (PD), safety profile, and cost-effectiveness. We also discuss the future developments in the management of T2DM, especially the scientific advancements surrounding the novel insulin formulations, including the biosimilar insulin, and the innovative insulin delivery methods, such as oral and inhaled insulin.

Insulin for topical use in wound healing: opportunities and limitations

Aims: The role of insulin in the regulation of energy metabolism, protein synthesis, proliferation, migration, secretion by keratinocytes, endothelial cells, and fibroblasts suggests that its presence is essential for wound healing (WH). The present study aims to explore the opportunities and limitations of topical insulin (TI) formulations. Methods: To obtain a complete picture of the challenges of the local insulin formulation a chronological review of previous publications in electronic databases was performed, applying data collection and selection criteria. Results: The opportunity of topically applied insulin has shown active interest over time. According to studies, regular insulin and isophane are suitable for local use, but currently there is no consensus on the appropriate concentration. Insulin can be incorporated into cutaneous liquid, semisolid, and solid dosage forms, either by itself, or by prior nano-or microencapsulation methods. The most important limiting factors to be evaluated are the stability of the peptide and the sterility of the obtained products. Conclusion: Examination of the balance of opportunities and limitations of TI formulations, it can be concluded that the range of applicable technological methods is wide. A high-quality, safe, and efficacious form of TI would have great value from a socio-economic point of view.