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Objective: To compare the effect of pre-mixed human insulin with insulin analogue in diabetic control among type-2 Diabetes mellitus patients at tertiary care hospital. Study Design: Comparative cross-sectional study. Place and Duration of Study: Department of Medicine, Pak Emirates Military Hospital, Rawalpindi, Pakistan, from Jun 2021 to Apr 2022. Methodology: Eleven hundred and fifty-six patients with poorly controlled type-2 diabetes on oral hypoglycemic agents requiring insulin were recruited for the study. Patients were divided into two groups via a lottery method. Group-A received the pre-mixed human insulin, while Group-B received the Insulin analogue advised by the consultant endocrinologist or medical specialist according to the requirements based on recent investigations. Diabetes control was compared in both groups at the end of twelve weeks of treatment. Results: Out of 1156 patients with type-2 diabetes mellitus included in the study, 810(70.1%) were male, while 346(29.9%) were female. The mean duration of DM in the study participants was 3.42±4.44 years. At the end of three months, 978(84.6%) patients had good glycemic control, while 178(15.4%) patients had poor glycemic control. Statistical analysis revealed that the type of insulin used to manage these patients had no significant relationship with glycemic control in our study participants (p-value>0.05). Conclusion: No statistically significant difference was observed in the number of patients achieving adequate glycemic control between those using pre-mixed human insulin and those using insulin analogue in our study.

Objectives: INS068 is a novel, soluble, and long-acting insulin analog. In this study, we evaluated the pharmacokinetics and relative bioavailability of two formulations of INS068 in healthy Chinese subjects: a reference formulation packaged in vials and administered via syringe (R), and a test formulation packaged and administered via pen injector (T).Methods: A randomized, open-label, two-period, two-sequence crossover study was conducted with 24 healthy Chinese subjects. Subjects were randomized and administered subcutaneously in the abdomen at 0.4 U/kg of test or reference INS068 injection according to an open crossover design. INS068 concentrations in the serum were measured using LC-MS/MS, and the pharmacokinetic parameters of maximum concentration (Cmax) and area under the concentration-time curve (AUC0–t and AUC0–∞) were used to evaluate relative bioavailability.Results: After a single dose at 0.4 U/kg, the median Tmax of INS068 was 12 h for both formulations, and the mean t1/2 for T and R was 13.0 h and 12.6 h, respectively. The geometric means of Cmax and AUC0–∞ were 3.99 nmol/L and 120 h·nmol/L for the T, and 4.05 nmol/L and 117 h·nmol/L for the R, respectively. The geometric mean ratios of Cmax, AUC0–t and AUC0–∞ of T over R were 98.7% (90% CI: 92.7%–105.2%), 102.6% (90% CI: 100.0%–105.3%) and 102.8% (90% CI: 100.1%–105.5%).Conclusion: The overall PK profile of the two formulations of INS068 injection was comparable in healthy subjects, and the pen injector of INS068 had adequate safety and tolerability, supporting it as a new formulation in a phase III study and bridging PK data from early phase clinical trials.Clinical Trial Registration:clinicaltrials.gov, identifier: NCT05336071

Insulin therapy in the setting of type 1 and advanced type 2 diabetes is complicated by increased risk of hypoglycemia. This potentially fatal complication could be mitigated by a glucose-responsive insulin analog. We report an insulin-facilitated glucose transporter (Glut) inhibitor conjugate, in which the insulin molecule is rendered glucose-responsive via conjugation to an inhibitor of Glut. The binding affinity of this insulin analog to endogenous Glut is modulated by plasma and tissue glucose levels. In hyperglycemic conditions (e.g., uncontrolled diabetes or the postprandial state), the in situ-generated insulin analog-Glut complex is driven to dissociate, freeing the insulin analog and glucose-accessible Glut to restore normoglycemia. Upon overdose, enhanced binding of insulin analog to Glut suppresses the glucose transport activity of Glut to attenuate further uptake of glucose. We demonstrate the ability of this insulin conjugate to regulate blood glucose levels within a normal range while mitigating the risk of hypoglycemia in a type 1 diabetic mouse model.

This phase 1 study compared the pharmacokinetic (PK) and glucose pharmacodynamic (PD) characteristics of biosimilar SAR342434 insulin lispro and Japan‐reference Humalog insulin lispro. This was a randomized, double‐blind, 2‐period, crossover study. Thirty‐six healthy Japanese male subjects underwent a 10‐hour euglycemic clamp following a single subcutaneous 0.3‐U/kg dose of SAR342434 or Humalog. Insulin lispro concentration and blood glucose were measured, and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. Primary PK end points were maximum plasma insulin lispro concentration and area under the plasma insulin concentration–time curve (AUC) from time 0 to the last quantifiable concentration. Primary PD end points were area under the GIR–time curve from time 0 to 10 hours and maximum GIR. PK exposure (maximum plasma concentration and AUC from time 0 to the last quantifiable concentration) and PD activity (GIR‐AUC from time 0 to 10 hours and maximum GIR) were similar between treatments. Geometric mean ratios were close to 1, and the corresponding 90% and 95%CIs (PK and PD activity, respectively) were within the 0.80 to 1.25 equivalence range. SAR342434 and Humalog were well tolerated. In healthy Japanese males, SAR342434 and Humalog showed similar PK exposure profiles and PD potency, in support of SAR342434 use as a biosimilar product. [ABSTRACT FROM AUTHOR]

Background:Diabetic ketoacidosis (DKA) is an acute metabolic healthcare crisis in patients with diabetes mellitus. The current study aimed to compare the effectiveness of rapid-acting insulin analog administered subcutaneously with regular insulin infused intravenously among the DKA patients.Methodology:In this prospective open labelled study, 100 consecutive DKA patients were randomly assigned to two groups. Group 1 patients were admitted to the intensive care unit (ICU) and treated with intravenous regular insulin infusion. Group 2 patients were managed in the emergency medical ward with subcutaneous rapid-acting insulin. Response to the therapy was assessed by the follow-up investigations of the biochemical parameters, including blood glucose concentration, serum ketones, pH, serum electrolytes including bicarbonates, sodium and potassium concentration until the resolution of DKA. Furthermore, the overall duration of therapy (blood glucose level < 250 mg/dl), time and amount of insulin administered until the resolution of DKA, were also assessed.Results:The baseline clinical and biochemical parameters were similar between the two treatment groups except for blood glucose and sodium concentration. The mean random blood sugar (RBS), acid-base parameters and concentration of ketone bodies were significantly improved from admission until the resolution of DKA. There was no significant difference in the duration of therapy (p=0.07). While the time and amount of insulin therapy required until resolution of DKA were significantly reduced among the patients treated subcutaneously with rapid-acting insulin, i.e. 16.36 ± 6.92 hrs and59.28 ± 30.05 units (p

Background: To address the challenges posed by inconsistent detection of analog insulin in commercially available insulin immunoassays, resulting in potential discrepancies in clinical findings and misdiagnosis during the investigation of factitious hypoglycemia., we aimed to evaluate the ability of the Siemens Atellica automated immunoassay to detect insulin analogs compared with LC-MS/MS., Methods: Five insulin analogs were analyzed at 10 ng/mL spiked into serum samples, with recombinant human insulin as positive controls. Insulin and C-peptide assays were performed using Siemens Atellica and LC-MS/MS. Recovery rates were calculated., Results: Siemens Atellica immunoassay demonstrated robust cross-reactivity (92-121%) of insulin analogs. In contrast, glargine was detected by LC-MS/MS but other analogs were not observed (<10% recovery)., Conclusion: Our results indicate that the insulin assay conducted on the Siemens Atellica platform could be used to diagnose factitious hypoglycemia by detecting the specific insulin analogs involved. The findings from our studies indicate the suitability of this method for clinical laboratory use in cases where factitious hypoglycemia is under consideration as a potential diagnosis. Clinicians should take these results into account when interpreting insulin measurements, particularly in instances where insulin analog overdose is suspected., (© 2024. The Author(s).)

Data from the Social Security Administrator for Health (BPJS Kesehatan) in 2014 to 2019 shows that the use of analog insulin (99.5% of DM cases) in Indonesia is higher than that of human insulin. The high use of insulin in the treatment of type 2 DM causes high costs for purchasing insulin. Therefore a policy is needed in the selection and use of insulin in the treatment for type 2 DM patients. This research aimed to evaluate the treatment profile, costs, and clinical outcomes of the use of human and analog insulin in type 2 DM patients in RSUPN Cipto Mangunkusumo. The longitudinal time-series research methods and data collection were conducted retrospectively. The independent variables of the research were human and analog insulin. While the dependent variables were the profile of treatment, direct treatment costs, and clinical outcomes. The research sample consisted of 291 patients, with exclusion samples of 185 patients and inclusion samples of 106 patients. The research showed that the average cost of a 30-day for single human insulin treatment was Rp.637.748.00. while for single analog insulin was Rp792,493.00. The results of the differences test in the cost of single human insulin treatment and single analog insulin show significant differences with a p value = 0.048. Based on the results of the study it can be concluded that there is significant difference in the cost of treatment in single human insulin and single analog insulin. [ABSTRACT FROM AUTHOR]

Abstract Background Multiple daily subcutaneous injections (MDSIs) are mainly used for formulating an insulin therapy for diabetic patients; however, they also cause insulin-derived amyloidosis (IDA) and lead to poor glycemic control. In addition, for the continuous subcutaneous insulin infusion system (CSII), precipitation frequently causes catheter occlusion and, if the precipitate in the formulations is amyloid, the injection of the insoluble amyloid into the subcutaneous tissue leads to IDA. The aim of this study was to conduct in vitro experiments and present a situation where insulin formulations cause precipitation and amyloid formation. Methods Humulin®R and NovoRapid® were used as model formulations for MDSIs and CSII, respectively. The generation of the precipitation was evaluated by measuring turbidity, and amyloid formation was evaluated by using Thioflavin T. Humulin®R was mixed with saline buffer solutions and glucose solutions to evaluate the effect of dilution. In addition, we created an experimental system to consider the effect of the time course of condition changes, and investigated the effects of insulin concentration, m-cresol existence, and pH change on the generation of the precipitate and amyloid in the formulation. Results In both the original and diluted formulations, physical stimulation resulted in the formation of a precipitate, which in most cases was an amyloid. The amyloid was likely to be formed at a near neutral pH. On the contrary, although a precipitate formed when the pH was decreased to near the isoelectric point, this precipitate was not an amyloid. Further decreases in pH resulted in the formation of amyloids, suggesting that both the positive and negative charged states of insulin tended to form amyloids. The formulation additive m-cresol suppressed amyloid formation. When additives were removed from the formulation, the amyloid-containing gel was formed in the field of substance exchange. Conclusions To consider changes in conditions that may occur for insulin formulations, the relationship between the formation of precipitates and amyloids was demonstrated in vitro by using insulin formulations. From the in vitro study, m-cresol was shown to have an inhibitory effect on amyloid formation.

Insulin therapy has advanced remarkably over the past few decades. Ultra-rapid-acting and ultra-long-acting insulin analogs are now commercially available. Many additional insulin formulations are in development. This review outlines recent advances in insulin therapy and novel therapies in development. [ABSTRACT FROM AUTHOR]

Fast-acting insulins are central to the regulation of prandial glucose in diabetic patients. Current fast-acting insulins require 20–30 min for the onset and longer for the peak blood concentrations. The recent work by Mann et al. used high-throughput synthesis and screening of polyacrylamide-based excipients to yield a formulation with pharmacokinetics that is faster than the currently available fast-acting insulins. [ABSTRACT FROM AUTHOR]

Objective: To compare the effect of pre-mixed human insulin with insulin analogue in diabetic control among type-2 Diabetes mellitus patients at tertiary care hospital. Study Design: Comparative cross-sectional study. Place and Duration of Study: Department of Medicine, Pak Emirates Military Hospital, Rawalpindi, Pakistan, from Jun 2021 to Apr 2022. Methodology: Eleven hundred and fifty-six patients with poorly controlled type-2 diabetes on oral hypoglycemic agents requiring insulin were recruited for the study. Patients were divided into two groups via a lottery method. Group-A received the pre-mixed human insulin, while Group-B received the Insulin analogue advised by the consultant endocrinologist or medical specialist according to the requirements based on recent investigations. Diabetes control was compared in both groups at the end of twelve weeks of treatment. Results: Out of 1156 patients with type-2 diabetes mellitus included in the study, 810(70.1%) were male, while 346(29.9%) were female. The mean duration of DM in the study participants was 3.42±4.44 years. At the end of three months, 978(84.6%) patients had good glycemic control, while 178(15.4%) patients had poor glycemic control. Statistical analysis revealed that the type of insulin used to manage these patients had no significant relationship with glycemic control in our study participants (p-value>0.05). Conclusion: No statistically significant difference was observed in the number of patients achieving adequate glycemic control between those using pre-mixed human insulin and those using insulin analogue in our study. [ABSTRACT FROM AUTHOR]

Abstract Background Rapid-acting insulin analogs (RAIs) have not been examined for long-term safety in randomized clinical trials. We performed a nationwide longitudinal cohort study among individuals with type 2 diabetes (T2DM) to address cardiovascular safety and mortality among users of lispro, aspart and glulisine insulins. Methods We used four national registers, following patients previously not treated with RAI but with continuous use of RAIs in 2005-2014 up to 6.4 years, to examine HbA1c and weight, and the occurrence of severe hyperglycemia or hypoglycemia, renal failure, cardiovascular events or death. The treatment groups were compared using a weighted Cox proportional hazards model. Results We included 17,620 patients, mean age slightly higher than 60 years, diabetes duration 9.9–11.7 years, mean BMI 30.5 kg/m2, HbA1c around 70 mmol/mol (8.6% NGSP), and 40.9–54.0% of the patients exhibiting eGFR

Insulin therapy in the setting of type 1 and advanced type 2 diabetes is complicated by increased risk of hypoglycemia. This potentially fatal complication could bemitigated by a glucose-responsive insulin analog. We report an insulin-facilitated glucose transporter (Glut) inhibitor conjugate, in which the insulin molecule is rendered glucose-responsive via conjugation to an inhibitor of Glut. The binding affinity of this insulin analog to endogenous Glut is modulated by plasma and tissue glucose levels. In hyperglycemic conditions (e.g., uncontrolled diabetes or the postprandial state), the in situ-generated insulin analog-Glut complex is driven to dissociate, freeing the insulin analog and glucose-accessible Glut to restore normoglycemia. Upon overdose, enhanced binding of insulin analog to Glut suppresses the glucose transport activity of Glut to attenuate further uptake of glucose. We demonstrate the ability of this insulin conjugate to regulate blood glucose levels within a normal range while mitigating the risk of hypoglycemia in a type 1 diabetic mouse model. [ABSTRACT FROM AUTHOR]

Despite the importance of insulin and insulin analogs as therapeutic agents for the treatment of type I and II diabetes mellitus (DM), bioanalysis to support regulatory submissions of analogs remains a challenging endeavor. In particular, quantitation of insulin lispro by immunoanalytical methods has largely been limited to assays that display a high degree of cross-reactivity to native insulin because this analog shares extensive primary sequence homology with endogenous insulin and its efficacious circulating concentrations are low. We report herein development of the first noncompetitive electrochemiluminescence-based immunoassay (ECLIA) for specific determination of insulin lispro in serum or plasma. The new sandwich ECLIA permits accurate assessment of insulin lispro pharmacokinetics without interference from endogenous insulin. Integral to the development of this specific immunoassay was establishment of a proprietary process for affinity production of an oligoclonal monospecific guinea pig antiserum to the unique subtle structural modification in insulin lispro. We specifically optimized the ECLIA to provide reliable performance for supporting pharmacokinetic assessments in the pharmacologically relevant concentration range from 50.0 to 5,000 pM with robust performance up to 100,000 pM upon dilution. We concluded the new noncompetitive ECLIA represents a useful and convenient immunoassay for accurate quantitation of insulin lispro during pharmacokinetic assessments. [ABSTRACT FROM AUTHOR]

Background: Treatment for type 1 diabetes mellitus (T1DM) has greatly changed by the general use of insulin analogs and continuous subcutaneous insulin infusion (CSII). To investigate whether these advances have been translated into continued improvement in glycemic control in Japanese children and adolescents, we analyzed the registration data of the two consecutive recent cohorts of Japanese childhood-onset T1DM patients. Methods: The registration data including hemoglobin A1c (HbA1c), hypoglycemia and insulin regimen were compared between the two cohorts (862 patients in the 2008 cohort and 1090 in the 2013 cohort). Results: The proportion of subjects with multiple daily insulin injection therapy (MDI) and CSII significantly increased (p<0.0001) from 67.4% and 9.7% to 71.8% and 23.4%, respectively. In the 2013 cohort, almost all patients were treated with basal-bolus treatment using insulin analogs. The use of CSII increased in all age groups, especially in the age group 0–5 years. The rates of overall, moderate and severe hypoglycemia significantly declined from 10.24, 10.18 and 0.056 events/100 persons/period in the 2008 cohort to 0.66, 0.62 and 0.033 in the 2013 cohort (p<0.0001, <0.0001, 0.04), respectively. Contrarily, there were no significant changes in HbA1c values between the two cohorts. Conclusions: The popularization of the basal-bolus treatment using insulin analogs hascontributed to a significant decrease in hypoglycemia. In contrast, the intensive insulin treatment may not be enough for the satisfactory improvement of glycemic control in Japanese children and adolescents with T1DM. Considerable points remain, such as diabetic education and support to motivate patients. [ABSTRACT FROM AUTHOR]

Keywords: Aged society; Hypoglycemia; Insulin analog EN Aged society Hypoglycemia Insulin analog 795 797 3 07/27/20 20200701 NES 200701 Insulin was discovered by Banting and Best in 1921, and was subsequently applied for the treatment of diabetes. The Japan Diabetes Society reported the results of a survey of severe hypoglycemia showing that 60.8% of patients who experienced severe hypoglycemia were insulin users, and their mean age was 74.0 years (Figure 1)12. Therefore, educating elderly diabetes patients about diabetes management, including the insulin self-injection technique and countermeasure methods for hypoglycemia, is very important. [Extracted from the article]

Objectives: INS068 is a novel, soluble, and long-acting insulin analog. In this study, we evaluated the pharmacokinetics and relative bioavailability of two formulations of INS068 in healthy Chinese subjects: a reference formulation packaged in vials and administered via syringe (R), and a test formulation packaged and administered via pen injector (T). Methods: A randomized, open-label, two-period, two-sequence crossover study was conducted with 24 healthy Chinese subjects. Subjects were randomized and administered subcutaneously in the abdomen at 0.4 U/kg of test or reference INS068 injection according to an open crossover design. INS068 concentrations in the serum were measured using LC-MS/MS, and the pharmacokinetic parameters of maximum concentration (C max ) and area under the concentration-time curve (AUC 0-t and AUC 0-∞ ) were used to evaluate relative bioavailability. Results: After a single dose at 0.4 U/kg, the median T max of INS068 was 12 h for both formulations, and the mean t 1/2 for T and R was 13.0 h and 12.6 h, respectively. The geometric means of C max and AUC 0-∞ were 3.99 nmol/L and 120 h·nmol/L for the T, and 4.05 nmol/L and 117 h·nmol/L for the R, respectively. The geometric mean ratios of C max , AUC 0-t and AUC 0-∞ of T over R were 98.7% (90% CI: 92.7%-105.2%), 102.6% (90% CI: 100.0%-105.3%) and 102.8% (90% CI: 100.1%-105.5%). Conclusion: The overall PK profile of the two formulations of INS068 injection was comparable in healthy subjects, and the pen injector of INS068 had adequate safety and tolerability, supporting it as a new formulation in a phase III study and bridging PK data from early phase clinical trials. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT05336071., Competing Interests: Authors X-HG, KS, and SF were employed by the Jiangsu Hengrui Medicine Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Zhang, Ye, Gao, Song, Zhou, Li, Zhao, Shi, Yang, Shen, Feng and Zhao.)

The goals of Type 2 diabetes treatment are to eliminate the hyperglycemia resulting from insulin insufficiency and/or insulin resistance, delay beta cell damage/depletion, and prevent other metabolic co-morbidities and complications. In the current treatment algorithms, lifestyle changes (medical nutrition therapy, physical exercise) and oral anti-diabetics are followed by insulin therapy, which is considered a replacement therapy for Type 2 diabetes. Pre-mixed insulin preparations, which are an option for patients with poor blood glucose level control under oral anti-diabetics treatment, have been developed to meet both basal and prandial insulin needs by simulating the physiological changes in insulin levels. The consensus on the necessity of individualizing insulin therapy requires physicians to have a detailed knowledge of the various uses of insulin. Therefore, this comprehensive consensus statement has been prepared by a panel of expert endocrinologists from different regions of Turkey to help physicians use biphasic insulin aspart 30 in suitable patients at the right time. In this statement, expert panel opinions on (a) Recommendations for the appropriate initiation, titration, and intensification of insulin treatment, and (b) The treatment algorithms in initiation, titration, and intensification of biphasic insulin aspart 30 treatment and special conditions specific to changing treatment regimen are presented. [ABSTRACT FROM AUTHOR]

Background Poor treatment persistence can affect the realworld effectiveness of insulin therapy. A cross-sectional online survey in 942 patients with type 2 diabetes from 7 different countries evaluated patient experience when initiating basal insulin and the reasons behind insulin persistence patterns. Here, we report the quantitative results for the subset of patients from Germany. Methods Adults with type 2 diabetes who had initiated basal insulin during the last 3-24 months, identified from marketresearch panels, participated in the survey. Patients were asked if they had ≥ 7-day gaps in basal insulin treatment, and were then classified as "continuers" (no gap since starting insulin), "interrupters" ( ≥ 1 gap within the first 6 months after starting insulin and subsequently restarted insulin), or "discontinuers" (stopped insulin within the first 6 months after starting and had not restarted at the time of the survey). For each country, 50 participants were planned per persistence category. Enrollment ended if the target quota was reached or enrollment plateaued. Data were analyzed overall and separately for each persistence cohort. Results The 131 participants from Germany included 55 (42.0 %) continuers, 50 (38.2 %) interrupters and 26 (19.9 %) discontinuers. The most common motivations to initiate basal insulin therapy were encouragement by physician or other healthcare provider (HCP; 54.2 %) and expectation to improve glycemic control (42.0 %). More than 95 % of participants received training before and during insulin initiation (considered as helpful by 81.7 %); most (67.2 %) preferred in-person training. Continuers more frequently felt that insulin would help to manage diabetes and that their own views were considered when initiating insulin, they reported less concerns and challenges before and during insulin initiation than interrupters or discontinuers. The most common motivations to continue basal insulin were improved glycemic control (72.7 %), improved physical well-being (49.1 %), and instruction by physician or other HCP (45.5 %). The most common reasons contributing to interruption/discontinuation were perceived weight gain (52.0 %/50.0 %), hypoglycemia (22.0 %/38.5 %), and potential adverse effects (30.0 %/26.9 %). Conclusions Quality interactions between physicians or other HCPs and their patients before and during the initiation of basal insulin may help to manage patient expectations and to improve persistence to insulin therapy. [ABSTRACT FROM AUTHOR]

We have demonstrated the use of conductive polylactic acid (PLA) filament for dose monitoring in a syringe-less wearable infusion pump. A channel reservoir is inlaid with conductive PLA filament. As the liquid medium is dispensed via gas pressurization by an built-in electrolysis chamber, the effective impedance of the conductive PLA filament/liquid medium column changes as well. This allows the dispensed volume to be monitored via the output voltage across a series resistor. Using 5 V sinusoidal input voltage, the output voltage decreased from ∼1.3 to ∼0.13 V as the dispensed volume of 0.1 mol/L PBS increased from 0 to 1000 μL. Similarly, the output voltage for insulin analog decreased from ∼0.64 to 0.126 V for the same volume displaced. Repeated dispensing runs with 0.1 mol/L PBS showed good consistency (standard deviation less than 10 mV). The rate of change of the output voltage with elapsed time varied accordingly for the different flow rates (0.25–1.00 mL/h or ∼4–17 μL/min). At electrolysis voltages of 1.5 and 5 V, the respective output voltage were 1.04 and 0.33 V. These corresponded to flow rates of ∼3 and 10 mL/h (∼50 and 160 μL/ min). [ABSTRACT FROM AUTHOR]

INTRODUCTION: To assess and compare per-day anti-diabetic medication costs for Chinese type-2 diabetes mellitus (T2DM) insulin-naïve patients between those who initiated premixed insulin analogs ("premixed group") and those who initiated long-acting insulin analogs ("long-acting group"). METHODS: Data were obtained from an electronic medical record database between 2010.01.01 and 2015.06.30 covering medical encounter records from all general hospitals in a district from Shanghai, China. Insulin-naïve T2DM patients who were aged ≥ 18 years, treated with an oral anti-diabetic drug (OAD) only during the baseline period (3 months prior to insulin initiation), and initiated premixed or long-acting insulin analogs were included. Patients were followed until index insulin discontinuation or 12 months after initiation, whichever came first. The t test and generalized linear models adjusting for propensity score (PS) (including baseline demographics, number of OAD classes, comorbidities, costs, and healthcare resource utilization) were used to examine the differences between the two insulin groups. RESULTS: A total of 570 and 185 patients were identified for the premixed and long-acting groups, with mean (SD) ages of 63.0 (12.8) and 61.1 (11.9) (P = 0.08) and male proportions of 47.4% and 51.4% (P = 0.35), respectively. During the baseline period, 19.3% of the premixed users had T2DM-related hospitalizations, while the rate was 12.4% in the long-acting group (P = 0.03). The mean number of T2DM-related outpatient visits was 0.98 and 1.23 for the premixed and long-acting groups, respectively (P = 0.07). During the follow-up period, the per-day insulin dose averaged 31.7 and 15.3 international units (IU) for the premixed and long-acting groups, respectively. Compared with the patients on premixed insulin, the mean per-day cost for patients on long-acting insulin was 37.3% higher [15.3 vs 11.2 Chinese yuan (RMB); mean difference (MD) (95% CI): 4.2 (3.2, 5.1)] for the overall anti-diabetes medication, 81.3% higher [3.3 vs 1.8 RMB; MD (95% CI): 1.5 (0.8, 2.2)] for OAD, and 28.6% higher [12.0 vs 9.3 RMB; MD (95% CI): 2.7 (2.1, 3.3)] for insulin. The results were consistent after adjusting for the PS. CONCLUSION: Among Chinese T2DM insulin-naïve patients, those who initiated premixed insulin had a lower per-day antidiabetic medication cost than those who initiated long-acting insulin. [ABSTRACT FROM AUTHOR]

Recent estimates indicate that diabetes occurs in 16.5% of the Turkish population, which is in keeping with the increasing global prevalence of diabetes. Following rapid economic growth, increase in life expectancy and changes in lifestyle over the past decade have resulted in the placement of a tremendous cost burden on the Turkish economy by diabetes and associated co-morbidities, representing 20% of overall spending on healthcare. Maintaining good glycemic control is vital for effective diabetes management. Long-term studies have demonstrated the ability of intensive glucose-lowering strategies to prevent or delay co-morbidities associated with diabetes. However, insulin intensification is commonly associated with hypoglycemia, which is regarded as the most significant barrier to attaining and maintaining good glycemic control. Patients are often unaware of the potential negative impact of hypoglycemia on their long-term health, as well as on daily functions. In addition, hypoglycemia and its associated symptoms or co-morbidities greatly influence adherence and dosing behavior, patients' quality of life (QoL), and significantly affect economic productivity. The aim of this study is to review the impact of hypoglycemia in patients with diabetes, focusing on the implications of findings from international and Turkish studies for the management of hypoglycemia in Turkish patients. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the pharmacodynamics (PD) and pharmacokinetics (PK) of insulin aspart in healthy cats following intramuscular (IM) and subcutaneous (SC) injection. Eight healthy, purpose-bred cats were used in a randomized, crossover study design. Each cat had 2 isoglycemic clamps performed, one after receiving 0.25 IU/kg of insulin aspart by IM injection and one after receiving the same dose by SC injection. The two isoglycemic clamps were performed on different days, at least 48 h apart. The blood glucose, plasma endogenous insulin, and plasma insulin aspart concentrations were measured and the glucose infusion rate (GIR) was recorded during the clamp. The GIR over time was used to create a time-action curve for each clamp which was used to describe the PD of insulin aspart. Data that are normally distributed are reported as mean ± SD, while data that are not normally distributed are reported as median (25–75 percentile). When compared to the PD data that have been reported for regular insulin in healthy cats, insulin aspart had a more rapid onset (IM: 10 min [10–21.25 min], SC: 12.5 min [10–18.75 min]) and shorter duration of action (IM: 182.5 ± 34.33 min, SC: 159.38 ± 41.87 min). The onset of action ( P = 0.795), time to peak action ( P = 0.499), duration of action ( P = 0.301), and total metabolic effect ( P = 0.603) did not differ with route of administration; however, SC administration did result in a higher maximum plasma insulin aspart concentration (IM: 1,265.17 pmol/L [999.69–1,433.89 pmol/L], SC: 3,278.19 pmol/L [2,485.29–4,132.01 pmol/L], P = 0.000) and larger area under the insulin aspart vs time curve (IM: 82,662 ± 30,565 pmol/L, SC: 135,060 ± 39,026 pmol/L, P = 0.010). Insulin aspart has a rapid onset of action and short duration of effect in healthy cats when administered by IM and SC injection. Although it cannot be assumed that the PD and PK of insulin aspart will be the same in cats with diabetic ketoacidosis (DKA), our data support further investigation into the use of SC insulin aspart as an alternative to regular insulin for the treatment of DKA in cats. [ABSTRACT FROM AUTHOR]

A significant drawback of the exogenous administration of insulin to diabetics is the non-physiological profile of insulin action resulting in the insufficient suppression of hepatic glucose production, which is the main contributing factor to diabetic hyperglycemia under fasting conditions and the basis of the challenge to restore a more physiological glucose profile in diabetes. The insulin receptor (IR) exists in two alternatively spliced variants, IR-A and IR-B, with different tissue distribution. While peripheral tissues contain different proportions of both isoforms, hepatic cells almost exclusively contain IR-B. In this respect, IR-B-selective insulin analogs would be of great interest for their potential to restore more natural metabolic homeostasis in diabetes. Recent advances in the structural biology of insulin and IR have provided new clues for understanding the interaction of both proteins. This article discusses and offers some structural perspectives for the design of specific insulin analogs with a preferential binding to IR-B.

Purpose: Comparison of the dissociation kinetics of rapid-acting insulins lispro, aspart, glulisine and human insulin under physiologically relevant conditions. Methods: Dissociation kinetics after dilution were monitored directly in terms of the average molecular mass using combined static and dynamic light scattering. Changes in tertiary structure were detected by near-UV circular dichroism. Results: Glulisine forms compact hexamers in formulation even in the absence of Zn. Upon severe dilution, these rapidly dissociate into monomers in less than 10 s. In contrast, in formulations of lispro and aspart, the presence of Zn and phenolic compounds is essential for formation of compact R6 hexamers. These slowly dissociate in times ranging from seconds to one hour depending on the concentration of phenolic additives. The disadvantage of the long dissociation times of lispro and aspart can be diminished by a rapid depletion of the concentration of phenolic additives independent of the insulin dilution. This is especially important in conditions similar to those after subcutaneous injection, where only minor dilution of the insulins occurs. Conclusion: Knowledge of the diverging dissociation mechanisms of lispro and aspart compared to glulisine will be helpful for optimizing formulation conditions of rapid-acting insulins. [ABSTRACT FROM AUTHOR]

A significant drawback of the exogenous administration of insulin to diabetics is the non-physiological profile of insulin action resulting in the insufficient suppression of hepatic glucose production, which is the main contributing factor to diabetic hyperglycemia under fasting conditions and the basis of the challenge to restore a more physiological glucose profile in diabetes. The insulin receptor (IR) exists in two alternatively spliced variants, IR-A and IR-B, with different tissue distribution. While peripheral tissues contain different proportions of both isoforms, hepatic cells almost exclusively contain IR-B. In this respect, IR-B-selective insulin analogs would be of great interest for their potential to restore more natural metabolic homeostasis in diabetes. Recent advances in the structural biology of insulin and IR have provided new clues for understanding the interaction of both proteins. This article discusses and offers some structural perspectives for the design of specific insulin analogs with a preferential binding to IR-B. [ABSTRACT FROM AUTHOR]

Aims: Centrally administered insulin improves cognitive functions in patients with Alzheimer's disease; however, it remains unknown whether long-acting insulin analogs exert more pronounced effects than insulin. In the present study, we directly compared the effects of insulin and its analogs on neural functions in vitro and in vivo.Methods: Cultured rat cerebral cortical neurons were treated with insulin, insulin glargine U100 (Gla), insulin detemir (Det), or insulin degludec (Deg). Moreover, these drugs were intracerebroventricularly administered to mice. Their efficacies were evaluated by biochemical and behavioral analyses.Results: In cultured neurons, insulin, Gla, and Det increased phosphorylation of Akt and enhanced gene expression of brain-derived neurotrophic factor to a similar extent, although Deg was less effective. The effects of Det and Deg, but not insulin and Gla were suppressed by addition of albumin. When the drug was centrally administered, the increasing effects of insulin on the Akt phosphorylation were comparable to those of Gla but greater than those of Det in hippocampus and cerebral cortex of diabetic db/db and non-diabetic db/m+ mice. Moreover, insulin and Gla enhanced memory functions in Y-maze test and suppressed depression-like behavior in forced swim test in normal mice to a similar extent, and these effects were more potent than those of Det.Conclusions: Insulin and Gla have greater impacts on central nervous system than insulin analogs with high albumin sensitivity, such as Det and Deg. These pharmacological profiles should be taken into account for developing an insulin-based therapy to treat Alzheimer's disease. [ABSTRACT FROM AUTHOR]

With the expiration of patent protection for several originator insulin analog molecules, the availability of insulin analog copies is set to increase. Many regulatory authorities have developed, and continue to refine, guidelines for the approval of biosimilar insulin analogs. Aspects such as the structure, pharmacokinetics and pharmacodynamics, efficacy, safety, and immunogenicity of biosimilar insulin analogs are extensively addressed in these guidelines, but how the biosimilar insulin analog is administered to people with diabetes is not usually a topic. The aim of this article is to highlight that the delivery device-drug combination is of particular importance. Regulatory, legal, and practical aspects of the delivery device, be it a syringe, pen, or pump, have to be considered in the context of biosimilar insulin analogs. Although the safety and efficacy of biosimilar insulin analogs per se are of primary importance for physicians and people with diabetes, functions and features of the devices used for administration also require attention from a practical point of view. Unfortunately, although there are several clinical studies investigating the technical aspects of and patient preference for the originator insulin analog pens, there are currently very little published data for nonoriginator or biosimilar insulin analog pens. In addition, it is not known if it is safe to assume that a biosimilar insulin analog cartridge is compatible with an existing originator insulin analog pen. We believe that there is a need for more discussion on the role of devices for administration of biosimilar insulin analogs. [ABSTRACT FROM AUTHOR]