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Aims: Despite the evidence exhibited that diabetes during gestation (DDG) is linked with reproductive dysfunction in offspring, the underlying cellular mechanisms involved are not precisely defined. This study was designed to assess the impact of voluntary exercise and insulin glargine on DDG-induced metabolic and reproductive disorders in male offspring., Main Methods: Fifty female Wistar rats (three weeks old) received a control diet (n = 10) or high-fat-high-sucrose diet (to induce DDG; n = 40) for six weeks before breeding. From the 7th day of pregnancy onwards, blood glucose over 140 mg/dL was characterized as DDG. Then, the DDG animals were randomly divided into four subgroups with/without voluntary exercise and/or insulin glargine. To evaluate insulin resistance, a glucose tolerance test was performed on the 15th day of pregnancy. After three weeks, male offspring were weaned, and fed a control diet until 12 weeks old. At the end of the experiment, the lipid profile, sex hormones, and apelin-13 in the serum, mRNA expression of apelin receptors (APJ) in the testis and sperm analysis were assessed., Key Findings: Our results indicated that voluntary exercise and/or insulin glargine administration in mothers with DDG ameliorated lipid profile, and sex hormones alterations, reduced the serum level of apelin-13, as well as increased APJ expression in testis, and quality of sperm in offspring., Significance: Combined administration of voluntary exercise and insulin glargine during pregnancy by regulating of apelinergic system and inhibiting the metabolic and reproductive complications induced by DDG, can be considered as a suitable therapeutic strategy for improving sub-or in-fertility in the male offspring., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: This study investigated the effects of insulin glargine and exenatide on the muscle mass of patients with newly diagnosed type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD)., Methods: We performed a post-hoc analysis of our previously study, a 24-week randomized controlled multicenter clinical trial (ClinicalTrials.gov, NCT02303730). Seventy-six patients were randomly assigned 1:1 to receive insulin glargine or exenatide treatment. The changes in psoas muscle area (PMA) (mm 2 ) were obtained with the cross-sectional Dixonfat magnetic resonance images at the fourth lumber vertebra., Results: There were no significant differences in age, BMI, gender, and PMA in insulin glargine and exenatide groups at baseline. After treatment, PMA tended to increase by 13.13 (-215.52, 280.80) mm 2 in the insulin glargine group and decrease by 149.09 (322.90-56.39) mm 2 in the exenatide group (both p> 0.05). Subgroup analysis showed a 560.64 (77.88, 1043.40) (mm 2 ) increase of PMA in the insulin group relative to the Exenatide group in patients with BMI<28 kg/m 2 ( p 0.031) after adjusting for gender, age, and research center. Interaction analysis showed an interaction between BMI and treatment ( p 0.009). However, no interaction was observed among subgroups with a BMI≥28 kg/m 2 or with different genders and ages., Conclusion: Compared to exenatide, insulin glargine can relativity increase PMA in patients with T2DM having BMI<28 kg/m 2 and NAFLD., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Type 2 diabetes mellitus (T2DM) related bone fracture. The effects of glucagon-like peptide-1 receptor analogs for the treatment of T2DM on bone are controversial in human studies. This study aimed to compare the effects of GLP-1 receptor analogs exenatide and insulin glargine treatment on bone turnover marker levels and bone mineral density (BMD) in postmenopausal female patients with T2DM. Thirty female patients with T2DM who were naive to insulin and incretin-based treatments, with spontaneous postmenopause, were randomized to exenatide or insulin glargine arms and were followed up for 24 weeks. BMD was evaluated using dual-energy X-ray absorptiometry and bone turnover markers by serum enzyme-linked immunosorbent assay. The body mass index significantly decreased in the exenatide group compared to the glargine group (P < .001). Receptor activator of nuclear factor kappa-B (RANK) and RANK ligand (RANKL) levels were significantly decreased with exenatide treatment (P = .009 and P = .015, respectively). Osteoprotegerin (OPG) level significantly increased with exenatide treatment (P = .02). OPG, RANK, RANKL levels did not change with insulin glargine treatment. No statistically significant difference was found between the pre- and posttreatment BMD, alkaline phosphatase, bone-specific alkaline phosphatase, and type 1 crosslinked N-telopeptide levels in both treatment arms. Despite significant weight loss with exenatide treatment, BMD did not decrease, OPG increased, and the resorption markers of RANK and RANKL decreased, which may reflect early antiresorptive effects of exenatide via the OPG/RANK/RANKL pathway., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To study the antioxidant protective effects of different low-dose of insulin glargine on organs of burned rats with delayed resuscitation., Methods: Forty male Sprague-Dawley (SD) rats were randomly divided into sham group, delayed resuscitation control group, and insulin glargine 0.5, 1.0, and 2.0 U groups, with 8 rats in each group. The rats were immersed in hot water (95.0±0.5) centigrade for 15 s to establish the third-degree scald model with 30% total body surface area. The rats in the sham group were immersed in a 37 centigrade water bath for 15 s. Insulin glargine (0.5, 1.0, 2.0 U×kg -1 ×d -1 ) was injected subcutaneously in corresponding insulin glargine group 2 hours after injury, and the same amount of normal saline was injected intraperitoneally in the delayed resuscitation control group. Intraperitoneal injection of normal saline 40 mL/kg simulated delayed resuscitation 6 hours after injury in all groups. Abdominal aortic blood samples, heart and kidney tissue were collected immediately after simulating burn in the sham group, and 24 hours after burn in other four groups. The blood glucose, myocardial enzymes [lactate dehydrogenase (LDH), creatine kinase (CK), α-hydroxybutyrate dehydrogenase (α-HBDH), and aspartate aminotransferase (AST)] and renal function indexes [blood urea nitrogen (BUN) and serum creatinine (SCr)] were measured by spectrophotometry, and the isoenzyme MB of creatine kinase (CK-MB) level was determined by immunosuppression method to evaluate the effects of different low-dose insulin glargine intervention on blood glucose, cardiac and renal functions in scalded rats with delayed resuscitation. The oxidative and antioxidant indices [xanthine oxidase (XOD), myeloperoxidase (MPO), copper-zinc superoxide dismutase (CuZn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC)] from the heart and kidney tissues of rats were detected by spectrophotometry to analyze the antioxidant effects of different low-dose insulin glargine interventions., Results: Compared with the sham group, the blood glucose of the rats in the delayed resuscitation control group was significantly increased, the heart and kidney functions were significantly reduced, the oxidation capacity was enhanced, and the antioxidant indicators were significantly reduced. After the intervention of insulin glargine, with the increase of insulin glargine dose, the blood glucose, myocardial enzyme and renal function indicators of rats showed a gradual downward trend, the oxidation indicators continued to decrease, and the antioxidant indicators showed a gradual upward trend. When the dose was 2.0 U×kg -1 ×d -1 , the blood glucose, LDH, CK, CK-MB, α-HBDH, AST, BUN, SCr, XOD and MPO were significantly lower than those in the delayed resuscitation control group [blood glucose (mmol/L): 5.91±0.25 vs. 11.76±0.36, LDH (U/L): 3 332.12±51.61 vs. 5 008.94±490.12, CK (kU/L): 0.49±0.03 vs. 0.85±0.04, CK-MB (U/L): 125.40±12.19 vs. 267.52±11.63, α-HBDH (U/L): 122.99±5.37 vs. 240.85±13.99, AST (U/L): 11.95±1.81 vs. 17.87±1.57, BUN (mmol/L): 4.72±0.15 vs. 7.16±0.34, SCr (μmol/L): 87.11±6.51 vs. 137.50±11.36, XOD (U/g): 166.29±3.27 vs. 204.90±4.82 in heart tissue, 63.51±1.46 vs. 79.69±1.75 in kidney tissue, MPO (U/g): 1.05±0.02 vs. 1.55±0.06 in heart tissue, 1.04±0.04 vs. 1.87±0.01 in kidney tissue, all P < 0.05], and CuZn-SOD, CAT, GSH-Px and T-AOC were significantly higher than those in the delayed resuscitation control group [CuZn-SOD (kU/g): 82.95±2.69 vs. 56.52±2.26 in heart tissue, 94.50±2.73 vs. 62.02±1.66 in kidney tissue, CAT (U/g): 36.07±2.01 vs. 15.15±2.22 in heart tissue, 184.49±4.53 vs. 156.02±3.96 in kidney tissue, GSH-Px (kU/g): 231.93±8.03 vs. 179.48±3.15 in heart tissue, 239.63±7.30 vs. 172.20±2.09 in kidney tissue, T-AOC (kU/g): 4.85±0.23 vs. 2.71±0.11 in heart tissue, 5.51±0.08 vs. 3.50±0.07 in kidney tissue, all P < 0.05]., Conclusions: Different low-dose of insulin glargine (≤ 2.0 U×kg -1 ×d -1 ) could exert antioxidant protection on the heart and kidney of rats with delayed resuscitation after burns, with a dose-dependent manner.

Introduction: To determine whether the local administration of insulin glargine compared with placebo in nondiabetic patients with venous ulcers (VUs) leads to increased wound healing., Methods: A randomized controlled trial using a split-plot design was performed in 36 adults with leg VUs >25 cm 2 and more than 3 mo of evolution. Each hemi-wound received either 10 UI insulin glargine or saline solution once a day for 7 d. Size of the wounds, thermal asymmetry, the number of blood vessels, and the percentage area of collagen content in wound biopsies were assessed at baseline and after 7 d of treatment. Blood capillary glucose was monitored once a day after the insulin injection., Results: After 7 d of treatment, the hemi-wounds treated with insulin glargine were significantly smaller, had less thermal asymmetry, more blood vessels, and more collagen content than the saline-treated side. Correlation between thermal asymmetry and the number of blood vessels was also found (r 2  = 66.2, P < 0.001). No patient presented capillary glucose levels ≤3.3 mmol/L nor any adverse effects., Conclusions: In nondiabetic patients with chronic VUs, the topical administration of insulin glargine seems to be safe and promotes wound healing and tissue repair after 7 d of treatment., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (© 2022 British Small Animal Veterinary Association.)

Insulin treatment was confirmed to reduce insulin resistance, but the underlying mechanism remains unknown. Caveolin-1 (Cav-1) is a functional protein of the membrane lipid rafts, known as caveolae, and is widely expressed in mammalian adipose tissue. There is increasing evidence that show the involvement of Cav-1 in the AKT activation, which is responsible for insulin sensitivity. Our aim was to investigate the effect of Cav-1 depletion on insulin sensitivity and AKT activation in glargine-treated type 2 diabetic mice. Mice were exposed to a high-fat diet and subject to intraperitoneal injection of streptozotocin to induce diabetes. Next, glargine was administered to treat T2DM mice for 3 weeks (insulin group). The expression of Cav-1 was then silenced by injecting lentiviral-vectored short hairpin RNA (shRNA) through the tail vein of glargine-treated T2DM mice (CAV1-shRNA group), while scramble virus injection was used as a negative control (Ctrl-shRNA group). The results showed that glargine was able to upregulate the expression of PI3K and activate serine phosphorylation of AKT through the upregulation of Cav-1 expression in paraepididymal adipose tissue of the insulin group. However, glargine treatment could not activate AKT pathway in Cav-1 silenced diabetic mice. These results suggest that Cav-1 is essential for the activation of AKT and improving insulin sensitivity in type 2 diabetic mice during glargine treatment., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Hangya Peng et al.)

Introduction: Hypoglycemic drugs affect the bone quality and the risk of fractures in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and insulin on bone mineral density (BMD) in T2DM., Methods: In this single-blinded study, a total of 65 patients with T2DM were randomly assigned into four groups for 52 weeks: the exenatide group ( n = 19), dulaglutide group ( n = 19), insulin glargine group ( n = 10), and placebo ( n = 17). General clinical data were collected, and BMD was measured by dual-energy X-ray absorptiometry., Results: Compared with baseline, the glycosylated hemoglobin (HbA1c) decreased significantly in the exenatide (8.11 ± 0.24% vs. 7.40 ± 0.16%, P = 0.007), dulaglutide (8.77 ± 0.37% vs. 7.06 ± 0.28%, P < 0.001), and insulin glargine (8.57 ± 0.24% vs. 7.23 ± 0.25%, P < 0.001) groups after treatment. In the exenatide group, the BMD of the total hip increased. In the dulaglutide group, only the BMD of the femoral neck decreased ( P = 0.027), but the magnitude of decrease was less than that in the placebo group; the BMD of L1-L4, femoral neck, and total hip decreased significantly ( P < 0.05) in the placebo group, while in the insulin glargine group, the BMD of L2, L4, and L1-4 increased ( P < 0.05). Compared with the placebo group, the BMD of the femoral neck and total hip in the exenatide group and the insulin glargine group were increased significantly ( P < 0.05); compared with the exenatide group, the BMD of L4 in the insulin glargine group was also increased ( P = 0.001)., Conclusions: Compared with the placebo, GLP-1RAs demonstrated an increase of BMD at multiple sites of the body after treatment, which may not exacerbate the consequences of bone fragility. Therefore, GLP-1RAs might be considered for patients with T2DM. This trial is registered with ClinicalTrials.gov NCT01648582., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Ting-ting Cai et al.)

Aims/introduction: This study compares the effects of two different insulin regimens - basal versus bolus insulin - on metabolic and cardiovascular autonomic function in Japanese participants with type 2 diabetes., Materials and Methods: Participants were randomly assigned to groups for therapy with insulin glulisine (IGlu) or insulin glargine (IGla). The primary efficacy end-point was glycemic variability, including M-values, mean of glucose levels, and a blood glucose profile of seven time points before and after the intervention. The secondary end-points included pleiotropic effects, including endothelial and cardiac autonomic nerve functions., Results: Blood glucose levels at all time points significantly decreased in both groups. Post-lunch, post-dinner, and bedtime blood glucose levels were significantly lower in the IGlu group than in the IGla group. Nadir fasting blood glucose levels at the end-point were significantly lower in the IGla group than in the IGlu group. The M-value and mean blood glucose levels were significantly decreased from baseline in both groups, although the former was significantly lower in the IGlu group than in the IGla group. IGla, but not IGlu, was found to elevate 24-h parasympathetic tone, especially during night-time, and it decreased 24-h sympathetic nerve activity, especially at dawn., Conclusions: Both IGlu and IGla regimens reduced glucose variability, with IGlu bringing a greater reduction in M-value. IGla, but not IGlu, increased parasympathetic tone during night-time and decreased sympathetic nerve activity at dawn. These findings shed light on the previously unrecognized role of night-time basal insulin supplementation on sympathovagal activity in type 2 diabetes patients., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: MYL-1501D is a proposed biosimilar to insulin glargine. The noninferiority of MYL-1501D was demonstrated in patients with type 1 diabetes and type 2 diabetes in 2 phase 3 trials. Immunogenicity of MYL-1501D and reference insulin glargine was examined in both studies., Methods: INSTRIDE 1 and INSTRIDE 2 were multicenter, open-label, randomized, parallel-group studies. In INSTRIDE 1, patients with type 1 diabetes received MYL-1501D or insulin glargine over a 52-week period. In INSTRIDE 2, patients with type 2 diabetes treated with oral antidiabetic drugs, insulin naive or not, received MYL-1501D or reference insulin glargine over a 24-week period. Incidence rates and change from baseline in relative levels of antidrug antibodies (ADA) and anti-host cell protein (anti-HCP) antibodies in both treatment groups were determined by a radioimmunoprecipitation assay and a bridging immunoassay, respectively. Results were analyzed using a mixed-effects model (INSTRIDE 1) or a nonparametric Wilcoxon rank sum test (INSTRIDE 2)., Results: Total enrollment was 558 patients in INSTRIDE 1 and 560 patients in INSTRIDE 2. The incidence of total and cross-reactive ADA was comparable between treatment groups in INSTRIDE 1 and INSTRIDE 2 (P > 0.05 for both). A similar proportion of patients had anti-HCP antibodies in both treatment groups in INSTRIDE 1 at week 52 (MYL-1501D, 93.9 %; reference insulin glargine, 89.6 %; P = 0.213) and in INSTRIDE 2 at week 24 (MYL-1501D, 87.3 %; reference insulin glargine, 86.9 %; P > 0.999)., Conclusions: In INSTRIDE 1 and INSTRIDE 2, similar immunogenicity profiles were observed for MYL-1501D and reference insulin glargine in patients with type 1 diabetes and type 2 diabetes, respectively., Trial Registration: ClinicalTrials.gov, INSTRIDE 1 ( NCT02227862 ; date of registration, August 28, 2014); INSTRIDE 2 ( NCT02227875 ; date of registration, August 28, 2014).

Insulin glargine is a long-acting analogue of human insulin that has been used to manage hyperglycemia in patients with diabetes mellitus (DM) for nearly 20 years. Insulin glargine has a relatively constant concentration-time profile that mimics basal levels of insulin and allows for once-daily administration. MYL-1501D is a biosimilar insulin glargine designed to offer greater access of insulin glargine to patients, with comparable efficacy and safety to the marketed reference product. We conducted a comprehensive panel of studies based on a formal analysis of critical quality attributes to characterize the structural and functional properties of MYL-1501D and reference insulin glargine products available in the United States and European Union. MYL-1501D was comprehensively shown to have high similarity to the reference products in terms of protein structure, metabolic activity (both in vitro cell-based assays and in vivo rabbit bioassays), and in vitro cell-based assays for mitogenic activity. The structural analyses demonstrated that the primary protein sequence was identical, and secondary and tertiary structures are similar between the proposed biosimilar and the reference products. Insulin receptor binding affinity and phosphorylation studies also established analytical similarity. MYL-1501D demonstrated high similarity in different metabolic assays of glucose uptake, adipogenesis activity, and inhibition of stimulated lipolysis. Rabbit bioassay studies showed MYL-1501D and EU-approved insulin glargine are highly similar to US-licensed insulin glargine. These product quality studies show high similarity between MYL-1501D and licensed or approved insulin glargine products and suggest the potential of MYL-1501D as an alternative cost-effective treatment option for patients and clinicians., Competing Interests: P Goyal, B Vats, S Gouda, DJ Ranayhossaini, JP Smith, A Barve, and R Ullanat are paid employees of Viatris Inc and may hold stock in the company. HV Pai, P Kodali, N Vajpai, S Annegowda, K Mane, S Mohan, S Saxena, AB Veerabhadraia, M Palande, PS Nair, DC More, UR Karudumpa, K Jyothirmai, A Bhattacharya, F Almeida, SG Khyade, PR Moole, and R Melarkode are paid employees of Biocon Research Limited and may hold stock in the company. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Insulin glargine (IGla) is a synthetic human-recombinant insulin analog that is used routinely in people as a q24h basal insulin. The 300 U/mL (U300) formulation of IGla is associated with longer duration of action and less within-day variability, making it a better basal insulin compared with the 100 U/mL (U100) formulation. We hypothesized that in healthy cats, IGlaU300 has a flatter time-action profile and longer duration of action compared with IGlaU100. Seven healthy neutered male, purpose-bred cats were studied in a randomized, crossover design. Pharmacodynamics of IGlaU100 and IGlaU300 (0.8 U/kg, subcutaneous) were determined by the isoglycemic clamp method. The time-action profile of IGlaU300 was flatter compared with IGlaU100 as demonstrated by lower peak (5.6 ± 1.1 mg/kg/min vs 8.3 ± 1.9 mg/kg/min, respectively; P = 0.04) with no difference in total metabolic effect (ME; P = 0.7) or duration of action (16.8 h ± 4.7 h vs 13.4 h ± 2.6 h; P = 0.2). The greater fraction of ME in the 12- to 24-h period postinjection (35 ± 23% vs 7 ± 8% respectively; P = 0.048) and lower intraday GIR% variability (7.8 ± 3.7% vs 17.4 ± 8.2% respectively; P = 0.03) supports a flatter time-action profile of IGlaU300. There were no differences in onset and end of the action. In summary, although both formulations have a similar duration of action that is well below 24 h, the ME of IGlaU300 is more evenly distributed over a 24 h period in healthy cats, making it a better candidate for once-daily injection in diabetics compared with IGlaU100., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Recombinant insulin Lisargine is a new type of insulin. In this study, we aimed to compare its pharmacodynamic (PD) and pharmacokinetic (PK) with Lantus., Methods: The PD test was performed by exploring the effect of single administration on blood glucose of normal rats and STZ-induced diabetic rats, and the effect of multiple administrations on blood glucose of STZ-induced diabetic rats. Further PD tests include receptor affinity test, receptor autophosphorylation test and adipocyte glucose uptake test. Four IU and 8 IU per dog Lisargine was used for PK test, insulin was measured and area under curve (AUC) was calculated., Results: With single injection, Lisargine 1.5 IU/kg had significant hypoglycemic effects at 1 and 2 h, similar to that of Lantus. Lisargine 5 IU/kg and 10 IU/kg lowered the blood glucose of STZ-induced diabetic rats at 1, 2, 4 & 6 h significantly. With multiple injections, Lantus lowered blood glucose at 2, 4 & 6 h, Lisargine 2.5 IU/kg, 5 IU/kg, and 10 IU/kg lowered blood glucose at 2 & 4 h significantly, compared with vehicle. There was no difference for receptor affinity test, receptor autophosphorylation test and adipocyte glucose uptake test between Lisargine and Lantus. The PK of Lisargine and Lantus of healthy Beagle dogs was very similar., Conclusions: This animal study demonstrated that PK and PD of Lisargine and Lantus were similar, suggesting the bioequivalence of these products.

A rabbit blood sugar bioidentity assay is required by the FDA to evaluate biological activity for all insulin and its analogs per USP<121> guideline. Not only are a large number of live animals used, but the rabbit blood sugar method is also highly variable and expensive. Our goal is to develop a functional cell-based assay to replace rabbit blood sugar method. An H4IIE G6P-Luc reporter assay was developed by utilizing insulin's role in regulating hepatic gluconeogenesis pathway. It is known that Glucose 6-phosphatase is a rate-limiting enzyme in the gluconeogenesis pathway, and the mRNA expression of its catalytic subunit, G6PC, is highly regulated by insulin. A G6P-Luc stable cell line in H4IIE hepatocytes was first generated by stably expressing luciferase reporter gene driven by human G6PC promoter via lentivirus technology. The cell-based assay was developed and optimized to demonstrate good dose-dependent responsiveness to insulin. We further qualified the assay with two analysts through multiple runs, and demonstrated excellent performance characteristics of linearity, accuracy, and precision. A robustness study was then conducted to define critical factors for assay performance. We compared this newly developed assay with a previously established cell-based pIR MSD assay, which measures insulin receptor phosphorylation (pIR) in HepG2 cell line using Meso-Scale Discovery (MSD) technology. The comparability study was conducted to compare the two assays using samples generated from forced degradation. This study showed high correlation between assays, and both are stability indicating. Compared with the pIR MSD assay, the G6P-Luc assay not only has a significantly lower variability in qualification studies, but also offers many other advantages, including ease of use in a quality control laboratory with fewer steps, lower cost, and does not depend on a single vendor. In conclusion, we have developed a physiologically relevant and robust functional cell-based assay that is suitable to replace rabbit blood sugar method., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: The main objective of this experimental study was to evaluate the feasibility of diabetes induction by total pancreatectomy and pancreatic allotransplant after diabetes induction by total pancreatectomy. The secondary objective was to evaluate metabolic (C-peptide, glycemia) and inflammatory (lactate and platelet levels) parameters after diabetes induction by total pancreatectomy and pancreatic allotransplant after total pancreatectomy., Materials and Methods: The study protocol was approved by the French Minister of Research (APAFiS no.18169). Insulin-dependent diabetes was induced by total pancreatectomy in one male Sus scrofa pig, and pancreatic allotransplant was performed, after total pancreatectomy, in 3 male Sus scrofa pigs. Total pancreatectomy was performed under general anesthesia,with meticulous dissection of the portal vein and the splenic vein to preserve the spleen. Concerning pancreas procurement, extensive pancreas preparation occurred during thewarm phase,before coldperfusion. Pancreatic allotransplant was performed using donor aorta (with superior mesenteric artery and celiac trunk)., Results: Diabetes induction was successful, with negative C-peptide values at 3 hours after total pancreatectomy. Glycemic control without hypoglycemic events was obtained with the use of long-acting insulin administered once per day. No rapid-acting insulin was used. In animals that received pancreatic allotransplant, after enteral feeding was started, glycemic control without hypoglycemic events and without insulin was obtained in 2 animals., Conclusions: In an experimental porcine model, diabetes induction by total pancreatectomy and pancreatic allotransplant after total pancreatectomy are feasible and effective. The development of these models offers the potential for new investigations into ischemia-reperfusion injuries, improvement of pancreas procurement methods, and preservation techniques.

Subcutaneous MYL1501D insulin glargine 100 U/mL (hereafter referred to as MYL1501D insulin glargine) [Semglee ® ] is a long-acting human insulin analogue approved as a biosimilar of insulin glargine 100 U/mL (hereafter referred to as reference insulin glargine 100 U/mL) [Lantus ® ] in various countries, including those of the EU for the treatment of diabetes mellitus in patients aged ≥ 2 years, as well as Japan for diabetes where insulin therapy is indicated. MYL1501D insulin glargine has similar physicochemical characteristics and biological properties to those of EU- and US-sourced reference insulin glargine 100 U/mL, with the bioequivalence of pharmacodynamic and pharmacokinetic parameters between these agents shown in adults with type 1 diabetes. Once-daily MYL1501D insulin glargine demonstrated noninferior glycaemic efficacy to that of once-daily reference insulin glargine 100 U/mL in adults with type 1 or 2 diabetes, with its glycated haemoglobin-lowering benefits maintained over the longer-term (52 weeks) and unaffected by previous insulin exposure. Switching between MYL1501D insulin glargine and reference insulin glargine 100 U/mL did not appear to impact glycaemic efficacy in adults with type 1 diabetes. MYL1501D insulin glargine was well tolerated, demonstrating a safety and immunogenicity profile similar to that of reference insulin glargine 100 U/mL in patients with type 1 and 2 diabetes, and in those with type 1 diabetes switching between the two agents. As expected, hypoglycaemia was the most frequently reported treatment-emergent adverse event. Thus, MYL1501D insulin glargine provides an effective biosimilar alternative for patients requiring insulin glargine therapy.

Background: Insulin therapy is the mainstay of treatment for type 1 diabetes and may be necessary in type 2 diabetes. Current insulin analogues present a more physiological profile, are effective, and with less risk of hypoglycemia, but they are expensive. Biosimilar insulins should offer the advantages of insulin analogues at reduced costs. In addition, current rapid-acting insulin analogues are not fast enough to control excessive postprandial glucose excursions in many patients., Areas of Uncertainty: Biosimilar insulins demonstrated that are safe and effective, but interchangeability and automatic substitution remain an issue. Ultrafast-acting insulins should reduce postprandial hyperglycemia and improve flexibility in insulin dosing., Data Sources: This systematic review was conducted following widely recommended methods. We searched for each topic in Medline, Embase, the Cochrane Library, and SCISEARCH for relevant citations for the appropriate period., Therapeutic Advances: LY2963016 and MK-1293 are biosimilar insulins of insulin glargine, and SAR342434 is a biosimilar of insulin lispro. The abbreviated developed program demonstrated comparable efficacy and safety and supports their use for treatment of people with diabetes but no interchangeability. Faster-acting insulin aspart is a new formulation of insulin aspart with accelerated subcutaneous absorption. Faster aspart demonstrated noninferiority in reducing HbA1c as compared to insulin aspart with superiority in controlling postprandial hyperglycemia without increasing hypoglycemia, and flexible insulin dosing., Conclusions: Biosimilar insulins have comparable PK-PD profiles and equivalent efficacy and safety to original insulins at a lower price, making them available for more people with diabetes. Faster aspart is the first ultrafast-acting insulin. New upcoming clinical trials and more clinical experience with faster aspart will show the real potential of this new insulin.

Background: In type 1 diabetes (T1D), closed-loop systems provide excellent overnight fasting blood glucose control by adjusting the insulin infusion rate based on corresponding changes in sensor glucose levels. In patients on multiple daily insulin (MDI) injections, such control in overnight glucose levels has not been possible due to the inability to alter the absorption rate of long-acting insulin after injection. In this study, we tested the hypothesis that increases/decreases of fasting glucose levels could be achieved by cooling/warming the skin around the injection site, which would result in lower/higher Glargine absorption rates from its subcutaneous depot., Methods: Fourteen subjects with T1D (4 females; age 39.6 ± 16.7 years, HbA1c 7.8 ± 1.1%, BMI 25.4 ± 2.8 kg/m 2 ) on MDI therapy underwent fasting pharmacokinetic and pharmacodynamic studies that started at ~8 am and lasted 240 min on 3 separate days in random order: a control day without warming or cooling of the injection site and two experimental days, one day with injection site warming and the other with cooling., Results: Cooling the skin around the glargine injection site reduced insulin concentrations by >40% ( P < .01 versus the warming study, P = .21 versus the control study), accompanied by a 55 mg/dL increase in serum glucose ( P < .01 versus the control study). Conversely, skin warming prevented the fall in serum insulin ( P = .2 versus the control study; P < .01 versus the cooling study), resulting in a 40 mg/dL reduction in serum glucose ( P < .001 versus the cooling study, P = .11 versus the control study)., Conclusions: This proof of concept study has shown that cooling and warming the skin around the injection site provides a means to decrease and increase the rate of absorption and action of insulin glargine from its subcutaneous depot.

Insulin glargine 300 U/mL (IGla-U300) and insulin degludec (IDeg) are synthetic insulin analogs designed as basal insulin formulations. In people, IGla-U300 is more predictable and longer acting compared with glargine 100 U/mL. The duration of action of IDeg in people is > 42 h, allowing flexibility in daily administration. We hypothesized that IDeg would have longer duration of action compared with IGla-U300 in healthy purpose-bred cats. Seven cats received 0.4 U/kg (subcutaneous) of IDeg and IGla-U300 on two different days, >1 wk apart. Exogenous insulin was measured and pharmacodynamic parameters were derived from glucose infusion rates during isoglycemic clamps and suppression of endogenous insulin. The Shapiro-Wilk test was used to assess normality, and normally distributed parameters were compared using paired t-tests. There was no difference between IDeg and IGla-U300 in onset, peak action, or total metabolic effect. On average, time to peak action (T PEAK ) of IGla-U300 was 145 ± 114 min (95% confidence interval [CI] = 25-264) longer than T PEAK of IDeg (P = 0.03) and duration of action (T DUR ) of IGla-U300 was 250 ± 173 min (95% CI = 68-432) longer than T DUR of IDeg (P = 0.02). The "flatness" of the time-action profile (as represented by the quotient of peak action/T DUR ) was significantly greater for IGla-U300 compared with IDeg (P = 0.04). Overall, insulin concentration measurements concurred with findings from isoglycemic clamps. Based on these data, IDeg is not suitable for once-daily administration in cats. The efficacy of once-daily IGla-U300 in diabetic cats should be further investigated., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To explore the beneficial effects of dapagliflozin and/or insulin glargine on the pancreatic beta cell mass and hepatic steatosis in db/db mice., Methods: Six-week-old db/db mice were assigned to one of four groups: untreated (Placebo), treated with dapagliflozin (Dapa), treated with insulin glargine (Gla), or treated with dapagliflozin and insulin glargine (Dapa+Gla). After 8 weeks of treatment, we determined glucose tolerance, beta cell mass, hepatic lipid content and gene expression., Results: Glucose tolerance was significantly ameliorated in the three treated groups to the same degree compared with the Placebo group. Immunohistochemical analysis revealed that the pancreatic beta cell mass was significantly maintained in the Dapa and Dapa+Gla groups, but not in the Gla group, compared with the Placebo group (Placebo 2.25 ± 1.44 mg, Dapa 5.01 ± 1.63 mg, Gla 3.79 ± 0.96 mg, Dapa+Gla 5.19 ± 1.78 mg). However, the triglyceride content of the liver was markedly elevated in the Gla group compared with that in the other three groups (Placebo 24.1 ± 11.5 mg, Dapa 30.6 ± 12.9 mg, Gla 128 ± 49.7 mg, Dapa+Gla 54.4 ± 14.1 mg per gram liver). The expression levels of genes related to fatty acid synthesis and lipid storage were significantly upregulated in the Gla group., Conclusions: Our results showed that beta cell mass was sustained and hepatic steatosis was prevented, after 8 weeks of treatment with either dapagliflozin or dapagliflozin plus insulin glargine, but not with insulin glargine alone, in db/db mice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This report describes novel clinical data assessing the pharmacodynamics of insulin glargine/lixisenatide (iGlarLixi) compared with placebo and insulin glargine alone, to determine pharmacokinetics of lixisenatide, and to assess safety of iGlarLixi in Japanese people with type 2 diabetes mellitus (T2DM). In a single-centre, open-label, randomized, placebo-controlled cross-over study, participants received subcutaneous iGlarLixi 5 U/5 μg and 10 U/10 μg, placebo, and 5 U insulin glargine. The primary endpoint was area under the postprandial plasma glucose (PPG) curve (AUC 0-2h ). A total of 20 participants completed all study periods. iGlarLixi 5 U/5 μg and 10 U/10 μg reduced mean PPG dose-dependently compared with placebo and insulin glargine 5 U. Both combinations significantly reduced PPG-AUC 0-2h dose-dependently compared with placebo (least squares mean difference -7.48 mmol h/L for 5 U/5 μg, -10.75 mmol h/L for 10 U/10 μg; P < 0.0001). iGlarLixi 5 U/5 μg reduced PPG-AUC 0-2h significantly compared with insulin glargine 5 U (-0.76 mmol h/L; P < 0.0001). No symptomatic hypoglycaemia occurred during the study. iGlarLixi single subcutaneous injections significantly and dose-dependently reduced PPG compared to placebo or insulin glargine in Japanese participants with T2DM. iGlarLixi was safe and well tolerated, and would be expected to provide the 24-hour plasma glucose-lowering effects of insulin glargine and the postprandial antihyperglycaemic effects of lixisenatide., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To compare the effects of long-term treatment with the GLP-1RA exenatide twice-daily versus titrated insulin glargine (iGlar) on renal function and albuminuria in type 2 diabetes (T2DM) patients., Methods: We post-hoc evaluated renal outcome-data of 54 overweight T2DM patients (mean  ± SD age 60 ± 8 years, HbA1c 7.5 ± 0.9%, eGFR 86 ± 16 mL/min/1.73 m 2 , median [IQR] urinary albumin-to-creatinine-ratio (UACR) 0.75 [0.44-1.29] mg/mmol) randomised to exenatide 10 µg twice-daily or titrated iGlar on-top-of metformin for 52-weeks. Renal efficacy endpoints were change in creatinine clearance (CrCl) and albuminuria (urinary albumin-excretion [UAE] and UACR) based on 24-h urines, collected at baseline and Week-52. eGFR and exploratory endpoints were collected throughout the intervention-period, and after a 4-week wash-out., Results: HbA1c-reductions were similar with exenatide (mean ± SEM -0.80 ± 0.10%) and iGlar (-0.79 ± 0.14%; treatment-difference 0.02%; 95% CI -0.31 to 0.42%). Change from baseline to Week-52 in CrCl, UAE or UACR did not statistically differ; only iGlar reduced albuminuria (P < 0.05; within-group). eGFR decreased from baseline to Week-4 with exenatide (-3.9 ± 2.1 mL/min/1.73 m 2 ; P = 0.069) and iGlar (-2.7 ± 1.2 mL/min/1.73 m 2 ; P = 0.034), without treatment-differences in ensuing trajectory. Exenatide versus iGlar reduced bodyweight (-5.4 kg; 2.9-7.9; P < 0.001), but did not affect blood pressure, lipids or plasma uric acid., Conclusions: Among T2DM patients without overt nephropathy, one-year treatment with exenatide twice-daily does not affect renal function-decline or onset/progression of albuminuria compared to titrated iGlar., Trial Registration: ClinicalTrials.gov ID: NCT00097500., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Insulin-treated patients with type 2 diabetes (T2D) and obesity are challenged in achieving body weight stability or reduction, in addition to glycaemic control. Post-hoc analyses of body weight and insulin dose data from the AWARD-4 trial involved comparison of treatment with once-weekly dulaglutide 1.5 mg (N = 295) or 0.75 mg (N = 293) and treatment with daily insulin glargine (N = 296), each with prandial insulin lispro (± metformin)., Materials and Methods: Changes in weight and in the proportion of patients without weight gain or with weight loss of at least 3%, 5% or 10% or composites of HbA1c less than 7% without weight gain and weight loss of at least 3% after 52 weeks were compared between the dulaglutide (either dose) groups and the insulin glargine group, overall and by baseline BMI (<30, 30-<35, ≥35 kg/m 2 ), using analysis of covariance and logistic regression, including interaction terms., Results: The following parameters were statistically significant (P < 0.01) in favour of the dulaglutide-treated groups, at lower mean total daily insulin doses, vs the insulin glargine group. The achieved targets were more pronounced with dulaglutide 1.5 mg than with insulin glargine: LSM weight change difference, -3.23 kg; proportion of patients without weight gain, 49.0% vs 19.0%; proportion of patients with weight loss ≥3%, 21.7% vs 5.7% or with weight loss ≥5%, 10.5% vs 2.4%; proportion of patients with HbA1c <7% without weight gain, 26.2% vs 7.9%; proportion of patients with HbA1c <7% and weight loss ≥3%, 11.9% vs 1.4%, respectively. Treatment effect for these parameters was not significantly different across BMI categories., Conclusions: Larger proportions of patients in late-stage T2D needing treatment intensification achieved glycemic control without weight gain or with weight loss at lower insulin doses with once-weekly dulaglutide plus daily prandial insulin than with a basal-bolus insulin regimen, overall and across all three BMI subgroups., (© 2019 John Wiley & Sons Ltd.)

Aims: A post-hoc analysis to assess the impact in people with type 2 diabetes, of increasing doses of basal insulin on glycaemic measures, body weight and hypoglycaemia., Research Design and Methods: We included data from prospective, randomized controlled treat-to-target trials of ≥24 weeks' duration in people with type 2 diabetes, uncontrolled on metformin and sulphonylureas, and treated with insulin glargine 100 units/mL (U100), who had at least six fasting plasma glucose (FPG) measurements. The impact of insulin dose on glycated haemoglobin (HbA1c) values, FPG, hypoglycaemia incidence (<3.9 mmol/L [70 mg/dL]), and body weight was analysed. A total of 458 participants from three eligible trials were included., Results: The observed relationship between higher basal insulin doses and glycaemic control was non-linear, with increasing insulin dose leading to smaller reductions in FPG and HbA1c for doses >0.3 IU/kg/d, with a plateauing effect at 0.5 IU/kg/d. Total daily dose of insulin >0.5 IU/kg/d resulted in greater weight gain, but without higher rates of hypoglycaemia, compared with insulin doses ≤0.5 IU/kg/d., Conclusions: This analysis indicates that basal insulin doses >0.5 IU/kg/d have diminishing additional impact on improving glycaemic measures, with the disadvantage of additional weight gain. Clinicians should consider anti-hyperglycaemic treatment intensification at doses approaching 0.5 IU/kg/d., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Amylin analogs are important adjunctive drugs in the treatment of diabetes mellitus. However, a dual therapy with insulin involves inconvenient multiple injections. Here we describe a novel n-terminal PEGylated human amylin analog - BZ043 - and its potential to improve the control of glycemia using lower doses of insulin. The effect of BZ043 over the insulin-mediated control of fed-glycemia was investigated in rats with streptozotocin-induced diabetes treated with the basal analog glargine (GLAR). Fasted rats (3 h) received a single treatment of BZ043 (16, 64 or 128 nmol/kg), GLAR (1.5 IU or 6.0 IU) or BZ043 plus GLAR low dose (1.5 IU) in separate injections, and had free access to 5% glucose rich chow and water. BZ043 dose-proportionally prevented the meal-related increase of glycemia, and the co-treatment (64 or 128 nmol/kg) with GLAR restored normoglycemia without abrupt variations of glycemia. BZ043 showed a prolonged anti-hyperglycemic effect and, together with GLAR, promoted a long-lasting normoglycemia, in vivo. We conceive that combining BZ043 and GLAR in a fixed-ratio co-formulation might conveniently improve the control of diabetes mellitus., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Diabetes has recently been identified as a risk factor for a variety of cancers, possibly due to hyperinsulinemia or exogenous insulin use. Thyroid cancer is the most common endocrine malignancy, and its incidence has been exponentially increasing worldwide at an alarming rate. The aim of this study was to establish whether insulin use affects thyroid cancer development and progression, specifically cell proliferation and migration in vitro., Methods: In this study, we investigated the effects of the insulin agents most commonly used in the clinic, regular human insulin (HI) and insulin glargine (IG), on the proliferation and migration of thyroid cells., Results: Both HI and IG affected the thyroid cells in a dose-dependent manner and at high concentrations significantly promoted thyroid cell proliferation and tumor cell migration. The promoting effect might be elicited by activation of the insulin receptor and insulin-like growth factor-1 receptor and through the downstream Akt-signaling pathway, which inhibits the activity of the tumor-suppressor FoxO3a. In particular, MAPK-signaling cascades were activated in papillary thyroid carcinoma cell-1 cells but not in follicular rat thyroid-5 cells., Conclusion: The in vitro evidence demonstrated that HI and IG can promote thyroid cell proliferation and tumor cell migration at supraphysiological concentrations, but the effect was not significant at low concentrations. Whether high-dose insulins could affect diabetic patients with thyroid cancer or undetected (pre)cancerous lesions needs further in vivo study., Abbreviations: HI: human regular insulin; IG: insulin glargine; IR: insulin receptor; IGF-1R: insulin-like growth factor-1 receptor; Akt: protein kinase B (PKB); MAPK: mitogen-activated protein kinase; FoxO3a: the forkhead box-containing protein: class O 3a.

Aims: To confirm non-inferiority of insulin degludec/insulin aspart (IDegAsp) once-daily (OD) versus insulin glargine (IGlar) U100 OD + insulin aspart (IAsp) OD for HbA 1c after 26 weeks, and compare efficacy and safety between groups at W26 + W38., Methods: A 38-week, randomised, open-label, treat-to-target (HbA 1c  < 7.0%) trial in adults with type 2 diabetes mellitus (on basal insulin ± oral antidiabetic drugs; HbA 1c 7.0-10.0%). Randomisation (1:1): IDegAsp or IGlar U100 + IAsp. Intensification to IDegAsp twice daily (BID) was permitted at W26 + W32, or with additional IAsp injections at W26 (maximum IAsp BID) or W32 (maximum IAsp three-times daily)., Results: For W0-W26, mean percentage-change (standard deviation) HbA 1c was: IDegAsp, -1.1 (0.9); IGlar U100 + IAsp, -1.1 (0.8); estimated treatment difference: 0.07% (95% confidence interval [CI]: -0.06; 0.21) confirmed non-inferiority. At W26 and W38, target HbA 1c achievement, and mean fasting and postprandial glucose were similar across groups. At W38, more subjects achieved target HbA 1c without hypoglycaemia with IDegAsp (22.5%) than with IGlar U100 + IAsp (21.1%), with significantly fewer nocturnal episodes (W0-W38, estimated rate ratio: 0.61 [95% CI: 0.40; 0.93]). Safety profiles were similar across treatment groups throughout., Conclusions: IDegAsp OD/BID are effective treatment intensification options versus multiple injection basal-bolus therapies, achieving similar glycaemic control, with significantly less nocturnal hypoglycaemia., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The purpose of this study was to compare the efficacy and safety of intensive insulin therapy (premixed insulin lispro vs. insulin glargine) in patients with type 2 diabetes mellitus (T2DM)., Methods: MEDLINE, EMBASE, the Cochrane Library, and www.clinicaltrials.gov were systematically searched for randomized clinical trials (RCTs) of patients with T2DM treated with either premixed insulin lispro or insulin glargine for a duration of 24 weeks., Results: A total of 13 RCTs and 5401 patients were included in this study. In parallel trials and crossover trials, premixed insulin lispro was found to be superior to insulin glargine at reducing glycosylated hemoglobin (HbA1c) (parallel trials: weighted mean difference [WMD] -0.18%; 95% confidence interval [CI] -0.31 to -0.06; P = 0.004; crossover trials: WMD 0.37%; 95% CI -0.51 to -0.23; P < 0.00001). Premixed insulin lispro resulted in more weight gain than insulin glargine (parallel trials: WMD +0.64 kg; 95% CI +0.14 to +1.15; P = 0.01; crossover trials: WMD +0.74 kg; 95% CI +0.19 to +1.29; P = 0.009), and premixed insulin lispro was associated with a higher risk of hypoglycemia than insulin glargine (parallel trials: odds ratio [OR] 1.20; 95% CI 1.06-1.36; P = 0.005; crossover trials: OR 2.24; 95% CI 1.45-3.46; P = 0.0003)., Conclusions: Premixed insulin lispro provides a larger reduction in HbA1c and is associated with a significantly higher risk of hypoglycemia and greater weight gain in patients with T2DM. These findings may be helpful in selecting therapy for individual subjects.

Aims: To assess the impact of duration of prior basal insulin therapy on study outcomes in people with type 2 diabetes mellitus receiving insulin glargine 300 U/mL (Gla-300) or insulin glargine 100 U/mL (Gla-100) for 6 months., Methods: A post hoc patient-level meta-analysis of data from the EDITION 1 and 2 studies. Outcomes included: HbA 1c , percentage of participants with ≥1 confirmed or severe hypoglycaemic event at night (00:00-05:59 h) or any time (24 h), and body weight change. Data were analysed according to duration of prior basal insulin use: >0-≤2 years, >2-≤5 years, >5 years., Results: This meta-analysis included 1618 participants. HbA 1c change from baseline to month 6 was comparable between Gla-300 and Gla-100 groups, regardless of duration of prior basal insulin therapy. The lower risk with Gla-300 versus Gla-100 of ≥1 confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemic event, at night or any time (24 h), was unaffected by duration of prior basal insulin therapy. Similarly, weight change was unaffected by duration of prior basal insulin therapy., Conclusions: Switching to Gla-300 from other basal insulin therapies provided comparable glycaemic control with lower risk of hypoglycaemia versus Gla-100, regardless of duration of prior basal insulin therapy., Clinical Trial Registration: NCT01499082, NCT01499095 (ClinicalTrials.gov)., (Copyright © 2018. Published by Elsevier B.V.)

Aims: The aim of this study was to evaluate whether a combination drug therapy that consists of dapagliflozin with three other oral hypoglycemic agents (OHAs) would have a beneficial safety and efficacy profile in T2DM patients who have uncontrolled glucose levels compared to a treatment regimen that contains of basal insulin with two different OHAs., Methods: A total of 162 type 2 diabetic patients who are unable to control glucose on their current therapy consisting of 3 OHAs were enrolled in dapagliflozin group and 148 patients in insulin glargine group for the 24-week study period., Results: The mean changes in HbA1c level were comparable as -0.97 ± 1.29% in dapagliflozin group and -0.95 ± 1.41% in insulin glargine group (p = 0.911). Also, the fasting plasma glucose or post-prandial 2 h glucose were comparably decreased in dapagliflozin or insulin glargine. In terms of the body-weight, there was a significant decrease of -2.36 ± 0.51 kg following treatment of dapagliflozin, whereas the increment of 1.93 ± 0.49 kg was in insulin glargine (p < 0.001). In terms of adverse events, hypoglycemic events were higher in insulin glargine rather than dapagliflozin (15.1% vs. 1.6%, p < 0.05)., Conclusions: Our findings demonstrated that the addition of dapagliflozin to an existing drug regimen consisting of three different OHAs in patients exhibiting inadequate blood glucose control could be alternate treatment modality in T2D who hesitate to initiate insulin therapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: The aims of this study were to use real-world treatment results to compare changes in estimated glomerular filtration rate (eGFR) and glycosylated hemoglobin (HbA 1c ) among patients with type 2 diabetes who initiated treatment with dulaglutide or insulin glargine and to determine the proportions of patients with renal impairment who initiate each treatment., Methods: The study used data from the Practice Fusion electronic health records database from October 2013 through June 2017. Adults with type 2 diabetes who initiated dulaglutide or insulin glargine therapy and had multiple recorded serum creatinine and/or HbA 1c laboratory test results were included in the study. The dulaglutide cohort (n = 1222) was matched to the insulin glargine cohort (n = 13,869) using Mahalanobis distance matching with propensity score calipers. Multivariable analyses of the matched cohorts of individuals with serum creatinine results (n = 1183 dulaglutide and 1183 insulin glargine) examined the association between intent-to-treat therapy and changes in eGFR. In addition, multivariable analyses were also conducted on a subset of these patients who also had recorded HbA 1c tests (n = 1088 dulaglutide and 1088 insulin glargine) to examine the association between changes in HbA 1c during the 1 year postperiod., Findings: Among patients who initiated dulaglutide therapy, only 0.9% of patients had an index eGFR <30 and ≥15 mL/min/1.73 m 2 and 0.1% had an index eGFR <15 mL/min/1.73 m 2 . In contrast, 4.1% of insulin glargine-treated patients had an index eGFR <30 and ≥15 mL/min/1.73 m 2 and 1.2% had an index eGFR <15 mL/min/1.73 m 2 . Compared with patients who initiated therapy with insulin glargine, initiation of dulaglutide therapy was associated with a significantly smaller decrease in eGFR (-0.4 vs -0.9 mL/min/1.73 m 2 ; P = 0.0024), a significantly smaller likelihood of having a 30% or greater reduction in eGFR (3.3% vs 4.1%; P < 0.0001), and a significantly larger reduction in HbA 1c (-0.5% vs -0.2%; P < 0.0001)., Implications: In clinical practice, the use of dulaglutide was relatively more limited in patients with a higher degree of renal impairment compared with use of insulin glargine. However, initiation of dulaglutide therapy, compared with insulin glargine therapy, was associated with a significantly smaller decrease in eGFR and a larger reduction in HbA 1c during the 1 year postperiod., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

BACKGROUND The aim of this study was to compare the effects of liraglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, and insulin glargine, a long-acting insulin analog, on glycemic control and pancreatic β-cell function in db/db mice. MATERIAL AND METHODS Eight-week-old male db/db mice (n=40) were divided into five groups: the vehicle-treated group (VG) (n=8); the insulin glargine-treated group (GG) (dose, 450 mg/kg) (n=8), the low-dose liraglutide-treated group (LLG) (dose, 75 μg/kg) (n=8), the mid-dose liraglutide-treated group (MLG) (150 μg/kg) (n=8), and the high-dose liraglutide-treated group (HLG) (300 μg/kg) (n=8), treated with subcutaneous injection once daily, from 8-14 weeks-of-age. Body weight, pancreatic weight, levels of blood glucose, triacylglycerol, C-peptide, and the intraperitoneal glucose tolerance test (IPGTT) were used. Expression levels of the INS1 gene were measured using reverse transcription polymerase chain reaction (RT-PCR), and pancreatic and duodenal homeobox 1 (Pdx1), paired box 4 (Pax4), and paired box 6 (Pax6) mRNA expression were measured. RESULTS Both insulin glargine and liraglutide improved glycemic control of db/db mice when compared with vehicle. The following were significantly increased in the HLG compared with the GG: the receiver operating characteristic (ROC) area under the curve (AUC) for the IPGTT; C-peptide levels; the pancreas to body weight coefficient; expression levels of the INS1 gene and pancreatic transcription factors Pdx1, Pax4 and Pax6. Liraglutide treatment was without hypoglycemic effects. CONCLUSIONS Liraglutide acted in a dose-dependent manner on glycemic control of db/db mice, and was more effective than insulin glargine, when administered at a high dose.

The inability to achieve optimal diabetes glucose control in people with diabetes is multifactorial, but one contributor may be inadequate control of postprandial glucose. In patients treated with multiple daily injections of insulin, both the dose and timing of meal-related rapid-acting insulin are key factors in this. There are conflicting opinions and evidence on the optimal time to administer mealtime insulin. We performed a comprehensive literature search to review the published data, focusing on the use of rapid-acting insulin analogues in patients with Type 1 diabetes. Pharmacokinetic and pharmacodynamic studies of rapid-acting insulin analogues, together with postprandial glucose excursion data, suggest that administering these 15-20 min before food would provide optimal postprandial glucose control. Data from clinical studies involving people with Type 1 diabetes receiving structured meals and rapid-acting insulin analogues support this, showing a reduction in post-meal glucose levels of ~30% and less hypoglycaemia when meal insulin was taken 15-20 min before a meal compared with immediately before the meal. Importantly, there was also a greater risk of postprandial hypoglycaemia when patients took rapid-acting analogues after eating compared with before eating., (© 2017 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Subcutaneous once-daily LY2963016 insulin glargine (LY insulin glargine) [Abasaglar ® (EU); Basaglar ® (USA)] has been approved in the EU as a biosimilar to reference insulin glargine (Lantus ® ), and in the USA as a follow-on biologic to reference insulin glargine, for use in patients with type 1 or 2 diabetes. Structural and functional characterization of LY insulin glargine in preclinical studies showed that it is similar to reference insulin glargine. In phase I euglycaemic clamp studies, LY insulin glargine demonstrated similar pharmacodynamic (including duration of action) and pharmacokinetic parameters to reference insulin glargine. In the phase III ELEMENT trials, LY insulin glargine and reference insulin glargine were noninferior to each other with respect to glycaemic control, indicating their equivalent efficacy, when administered with mealtime insulin in adults with type 1 diabetes or with oral antiglycaemic medications in adults with type 2 diabetes. LY insulin glargine was generally well tolerated, with a safety profile (including the risk of hypoglycaemia and immunogenicity) similar to that of reference insulin glargine and without any additional safety concerns identified. Basal insulin treatment status at baseline did not impact the relative efficacy, safety and immunogenicity of LY insulin glargine versus reference insulin glargine in the ELEMENT 1 and 2 trials. In conclusion, LY insulin glargine offers an additional basal insulin option for patients with type 1 or 2 diabetes, potentially at a lower cost.

Aims: To identify baseline characteristics associated with better efficacy and safety responses to twice-daily insulin lispro low mixture (LM) or once-daily insulin glargine (IG) in insulin-naïve patients with type 2 diabetes (T2D)., Methods: This post hoc analysis of the DURABLE study used the gradient-boosting method to generate hypothetical outcomes with the alternative treatment to assigned study drug to evaluate the potential additional benefit of one insulin over the other in association with influential baseline covariates in the same patient. The magnitude of additional benefit was further quantified by the generalized linear model and recursive partitioning regression tree method., Results: Baseline characteristics with the highest relative influence on 24-week outcomes in the overall population (LM, n = 1045; IG, n = 1046) were: for HbA1c change: fasting plasma glucose (FPG) (29.31%), age (28.57%); for reaching target HbA1c <7% (<53 mmol/mol): weight (22.41%); for weight change: weight (18.54%); for FPG: FPG (43.66%), age (20.8%); for 30-day hypoglycemia: FPG (57.09%), weight (10.1%). LM showed superiority over IG for HbA1c reduction and reaching HbA1c <7% overall, with clinically significant differences in HbA1c reduction (>0.4%) in some subpopulations. IG was superior over LM in most patients for less weight gain and hypoglycemia and lower FPG., Conclusions: Differences in magnitude of response to twice-daily LM and once-daily IG in association with baseline characteristics of insulin-naïve patients with T2D were found. Future real-world studies using these statistical methods could help identify patients who respond better to certain insulin regimens to help guide clinicians in treatment decisions., (Copyright © 2017 Eli Lilly and Company. Published by Elsevier B.V. All rights reserved.)

Background: Diabetes mellitus is a disease that affects millions of Americans, and its prevalence is only anticipated to increase in coming years. It is estimated that diabetes-related visits account for 1% of all emergency department (ED) encounters. In recent years, there have been several new categories of medications approved for the treatment of diabetes, including new insulins, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, an amylin analogue, and sodium-glucose cotransporter-2 inhibitors., Objective of the Review: This review presents recently approved agents to treat diabetes, with a focus on basic mechanism, place in therapy, and toxicities the ED provider may encounter., Discussion: Many of these new therapies have been incorporated as first- and second-line agents for the management of diabetes. Recently approved diabetes medications often have different mechanisms of action and adverse effect and overdose profiles compared to traditional agents, such as sulfonylureas and metformin., Conclusions: Emergency providers will encounter patients taking these newly approved medications, as well as treat those presenting with adverse effects and overdoses from them. As such, emergency providers must have a basic understanding of these new therapies so that they can optimally care for diabetic patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: To compare outcomes between Asian and non-Asian patients with type 2 diabetes (T2D) inadequately controlled on oral antidiabetic drugs (OADs) initiating insulin glargine 100 units (U)/mL (Gla-100) in randomised controlled clinical trials., Methods: Post hoc analysis of patient-level data (Asian n = 235; non-Asian n = 3351) from 16 trials., Results: At baseline, Asian patients were younger with lower body mass index (BMI), fasting C-peptide, and fasting plasma glucose (FPG) than non-Asian patients (all P < .001). Asian patients had a higher mean glycosylated haemoglobin (HbA1c) at Week 24 and less reduction in HbA1c from baseline (7.4% vs. 7.2%; -1.3% vs. -1.6%, respectively; P = .0001), and were less likely to achieve HbA1c <7.0% (40% vs. 47%; P = .002) than non-Asian patients. Reductions in FPG and rates of hypoglycaemia were similar between Asian and non-Asian patients. Asian patients had less weight gain than non-Asian patients (+1.3 vs. +1.9 kg, respectively, P = .013)., Conclusions: In our post hoc meta-analysis, Gla-100 effectively lowers HbA1c and FPG in Asian patients with T2D uncontrolled on OADs with similar incidence of hypoglycaemia and less absolute weight gain compared with non-Asian patients. At a similar FPG reduction, fewer Asian patients achieved HbA1c target <7.0%, suggesting that prandial glucose needs to be addressed., (Copyright © 2017. Published by Elsevier B.V.)

Background: Subclinical myocardial injury, as measured by high-sensitivity cardiac troponin T (hsTnT), and myocardial stress, as measured by N-terminal pro-B-type natriuretic peptide (NT-proBNP), are related to glycemic control in patients with type 2 diabetes mellitus, and are strong predictors of adverse cardiovascular outcomes. We sought to determine whether antihyperglycemic therapy improves measures of myocardial injury and myocardial stress in patients with type 2 diabetes mellitus., Methods and Results: We randomized, in a 2×2 factorial fashion, 438 patients with type 2 diabetes mellitus to insulin glargine, metformin, the combination, or placebo and measured changes in NT-proBNP and hsTnT after 12 weeks of therapy. At baseline, the median (Q1-Q3) plasma concentration was 35.4 (15.7-86.3) ng/L for NT-proBNP and 6.7 (4.6-10.1) ng/L for hsTnT. The adjusted (95% confidence interval) change in NT-proBNP concentration was 20.7% (7.9-35.0) in the insulin arm compared with 0.13% (-10.8 to 12.5) in the no-insulin arm ( P =0.03 for comparison). These changes were not related to changes in fasting or postprandial glucose, glycated hemoglobin, weight, blood pressure, or inflammation. In the metformin arm, the adjusted change in NT-proBNP was 7.8% (-3.7 to 20.7) compared with 13.0% (0.72-26.8) in the no-metformin arm ( P =0.58). No significant changes in hsTnT concentrations were observed for any of the treatment arms., Conclusions: Insulin glargine was associated with a significant 20.7% increase in NT-proBNP, a marker of myocardial stress, after 12 weeks of therapy. No change in hsTnT, a marker of myocardial injury, was observed. The changes were independent of substantial improvements in glucose control., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00366301., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

The goal of insulin therapy in people affected by type 1 diabetes mellitus consists in achieving an optimal metabolic control and so HbA1c levels below 7.5%, according to the conclusions of relevant scientific studies. In any case it seems that this target is far from being achieved, mostly in the pediatric population. However, many important pharmacological, technological and cultural milestones have been placed both in therapy and management of insulin-dependent diabetes even if the gap between growing knowledge in these fields and its application in daily clinical practice appears still too wide. A fundamental component of these advancements concerns the design of new insulin basal analogues; molecules used to realize a basal-bolus model of therapy with MDI scheme. Degludec insulin has been recently approved for the pediatric utilization (aged 1 to 17 years). A registration trial for pediatric population (aged 6 to 17 years) is in progress for glargine U-300 insulin. These two insulin types have different biochemical and pharmacological properties and they represent two different ways to achieve the ideal basal analogue. Insulin degludec and insulin glargine U-300 are the newest basal analogues and each of them has proper pharmacokinetic and pharmacodynamic characteristics. Their characteristics represent an effort to create the ideal solution. The aim of this review is to summarize the pharmacokinetic and pharmacodynamic properties of these new insulins, to list the most significant scientific findings regarding their pharmacology as well as clinical uses, with particular reference to the pediatric population in order to declare them to clinical experience and to report data on an initial experience with these analogues, especially with degludec insulin. Once again, evolution goes through the specialized training of the staff involved in the care of the diabetic patient and the constant education of the latter.

Aim: To evaluate the efficacy and adverse effects of IDegLira and IGlarLixi treatment and to perform a comparison between two strategies., Methods: The registration number is CRD42017053952. Randomized controlled trials of IGlarLixi treatment or IDegLira treatment compared with placebo or active hypoglycemic agents in type 2 diabetes were included., Results: Eight trials were included. The absolute HbA1c change relative to baseline after IGlarLixi treatment was -1.50% with significance (95% CI, -1.89% to -1.12%, p < 0.01); the absolute HbA1c change after IDegLira treatment was -1.89% with significance (95% CI, -2.04% to -1.73%, p < 0.01). Comparisons between IGlarLixi treatment and IDegLira treatment indicated no significant differences between groups. The absolute weight change after IGlarLixi treatment significantly decreased (weighted mean difference (WMD), -0.62 kg; 95% CI, -0.93 to -0.31 kg, p = < 0.01), but the absolute weight change after IDegLira treatment was not significantly changed (WMD, -0.81 kg; 95% CI, -3.26 to 1.65 kg, p = 0.52). There were no significant differences between groups., Conclusion: Glucose control of IGlarLixi treatment or IDegLira treatment was significantly lower than that at baseline. Comparisons between the two treatment groups indicated no significant differences between groups in absolute HbA1c changes or body weight changes relative to baseline.

LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products with identical amino acid sequences. This was a phase 1 single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period crossover study to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties of LY IGlar and IGlar at 2 different doses. Fasted healthy subjects were randomly assigned to receive 2 single doses of LY IGlar and IGlar (0.3 and 0.6 U/kg for each product). Blood samples were collected up to 24 hours postdose to assess PK, and a euglycemic clamp lasting up to 24 hours postdose was conducted to assess PD. Twenty-four healthy subjects aged 23 to 52 years participated in the study. The primary PK parameters (area under the concentration versus time curve from 0 to 24 hours [AUC 0-24 ] and maximum observed drug concentration [C max ]) and PD parameters (total amount of glucose infused during the clamp [G tot ] and maximum glucose infusion rate [R max ]) were not statistically different between LY IGlar and IGlar at either dose. No safety concerns were noted with either drug. The study demonstrated that the PK and PD parameters for LY IGlar and IGlar were comparable following single doses at both 0.3 and 0.6 U/kg., (© 2017, The American College of Clinical Pharmacology.)

Objective: To compare the safety and efficacy of insulin degludec (IDeg) with those of insulin glargine (IGlar) in insulin-naive subjects with type 2 diabetes (T2DM). Methods: This was a 26-week, randomized, open-label, parallel-group, treat-to-target trial in 560 Chinese subjects with T2DM (men/women: 274/263, mean age 56 years, mean diabetes duration 7 years) inadequately controlled on oral antidiabetic drugs (OADs). Subjects were randomized 2∶1 to once-daily IDeg (373 subjects) or IGlar(187 subjects), both in combination with metformin. The primary endpoint was changes from baseline in glycosylated hemoglobin(HbA1c) after 26 weeks. Results: Mean HbA1c decreased from 8.2% in both groups to 6.9% in IDeg and 7.0% in IGlar, respectively. Estimated treatment difference (ETD) of IDeg-IGlar in change from baseline was -0.10% points (95% CI -0.25-0.05). The proportion of subjects achieving HbA1c<7.0% was 56.3%and 49.7% with IDeg and IGlar, respectively [estimated odds ratio of IDeg/IGlar: 1.26(95% CI 0.88-1.82)]. Numerically lower rateof overall confirmed hypoglycaemia and statistically significantly lower nocturnal confirmed hypoglycemia were associated with IDeg compared with IGlar, respectively [estimated rateratio of IDeg/IGlar 0.69(95% CI 0.46-1.03), and 0.43(95% CI 0.19-0.97)]. No differences in other safety parameters were found between the two groups. Conclusions: IDeg was non-inferior to IGlar in terms of glycaemic control, and was associated with a statistically significantly lower rate of nocturnal confirmed hypoglycaemia. IDeg is considered to be suitable for initiating insulin therapy in Chinese T2DM patients on OADs requiring intensified treatment. Clinical trail registration: Clinicaltrials.gov, NCT01849289.

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Insulin glargine 300 units/mL: Insulin glargine 300 units/mL (Gla-300) is a formulation of insulin glargine that delivers the same number of insulin units in one-third of the injectable volume of insulin glargine 100 units/mL (Gla-100). Glucose control: Recently approved in the United States and in Europe for use in type 1 and type 2 diabetes, Gla-300 has a more constant and evenly distributed glucose-lowering effect compared with Gla-100, with a duration of action beyond 24 hours and lower within-day and between-day intra-individual variability in blood glucose levels. These benefits translate into predictable and sustained glucose control from a once-daily injection, with potential for fewer hypoglycemia episodes and less weight gain., Case Studies: Case studies are presented to highlight the potential clinical benefits and considerations associated with initiating treatment with Gla-300 in people with type 1 and type 2 diabetes.

Fibroblast growth factor 21 (FGF21) is a promising regulator of glucose and lipid metabolism with multiple beneficial effects including hypoglycemic and lipid-lowering. Previous studies have reported that FGF21 is expected to become a new drug for treatment of diabetes. Liraglutide and insulin glargine are the two representative anti-diabetic biological drugs. In the current study, we aim to compare the long-term pharmacological efficacy of mFGF21 (an FGF21 analogue), liraglutide and insulin glargine in type 2 diabetic db/db mice. Db/db mice were initially treated with three kinds of proteins (25nmol/kg/day) by subcutaneous injection once a day for 4weeks, then subsequently be treated with once every two days for next 4weeks. After 8weeks of treatments, the blood glucose levels, body weights, glycosylated hemoglobin levels, fasting insulin levels, serum lipid profiles, hepatic biochemical parameters, oral glucose tolerance tests and hepatic mRNA expression levels of several proteins (GK, G6P, GLUT-1 and GLUT-4) associated with glucose metabolism of the experimental mice were detected. Results demonstrated that three proteins could significantly decrease the fed blood glucose levels of db/db mice. After treatment for 1week, the fed blood glucose levels of db/db mice in liraglutide group were significantly lower than those in mFGF21 and insulin glargine groups. However, after 2weeks of administration, the long-lasting hypoglycemic effect of mFGF21 was superior to liraglutide and insulin glargine up to the end of the experiments. Compared with liraglutide and insulin glargine, mFGF21 significantly reduced the glycosylated hemoglobin levels and improved the ability on glycemic control, insulin resistance, serum lipid and liver function states in db/db mice after 8weeks treatments. In addition, mFGF21 regulated glucose metabolism through increasing the mRNA expression levels of GK and GLUT-1, and decreasing the mRNA expression level of G6P. But liraglutide and insulin glargine could only up-regulate the mRNA expression of GLUT-4. In summary, as a hypoglycemic drug for long-term treatment, mFGF21 has the potential to be an ideal drug candidate for the therapy of type 2 diabetes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes, but with identical amino acid sequences. This study compared the duration of action of LY IGlar and IGlar in subjects with type 1 diabetes mellitus (T1DM)., Materials and Methods: This was a randomized, double-blind, single-dose, two-period, crossover study. Twenty subjects underwent 42-hour euglycaemic clamps after a single subcutaneous 0.3-U/kg dose of LY IGlar or IGlar. In this study, the duration of action was defined as the time required for blood glucose levels to rise consistently above a predefined cut-off of 8.3 mmol/L (150 mg/dL) from a state of euglycaemia. Blood samples were collected to measure blood glucose for pharmacodynamic (PD) evaluations., Results: End of action was reached within 42 hours in 26 of 40 clamps (13 LY IGlar and 13 IGlar). The median duration of action for all subjects was 37.1 and 40.0 hours, and the mean duration of action (calculated using only patients who reached end of action) was 23.8 and 25.5 hours for LY IGlar and IGlar, respectively. The duration of action was demonstrated to be similar between the treatments using time-to-event analysis (log-rank test of equality p = .859). Following administration of LY IGlar and IGlar, the PD parameters of maximum glucose infusion rate (R max ) and total glucose infusion during the clamp (G tot ) were comparable., Conclusion: LY IGlar and IGlar had similar duration of action and comparable PD parameters in subjects with T1DM., (© 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Manufacturers of insulin products for diabetes therapy have long sought ways to modify the absorption rate of exogenously administered insulins in an effort to better reproduce the naturally occurring pharmacokinetics of endogenous insulin secretion. Several mechanisms of protraction have been used in pursuit of a basal insulin, for which a low injection frequency would provide tolerable and reproducible glucose control; these mechanisms have met with varying degrees of success. Before the advent of recombinant DNA technology, development focused on modifications to the formulation that increased insulin self-association, such as supplementation with zinc or the development of preformed precipitates using protamine. Indeed, NPH insulin remains widely used today despite a frequent need for a twice-daily dosing and a relatively high incidence of hypoglycaemia. The early insulin analogues used post-injection precipitation (insulin glargine U100) or dimerization and albumin binding (insulin detemir) as methods of increasing therapeutic duration. These products approached a 24-hour glucose-lowering effect with decreased variability in insulin action. Newer basal insulin analogues have used up-concentration in addition to precipitation (insulin glargine U300), and multihexamer formation in addition to albumin binding (insulin degludec), to further increase duration of action and/or decrease the day-to-day variability of the glucose-lowering profile. Clinically, the major advantage of these recent analogues has been a reduction in hypoglycaemia with similar glycated haemoglobin control when compared with earlier products. Future therapies may bring clinical benefits through hepato-preferential insulin receptor binding or very long durations of action, perhaps enabling once-weekly administration and the potential for further clinical benefits., (© 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: Hypoglycemia remains one of the main challenges of insulin therapy. To reduce insulin-related hypoglycemia at our institution, we restricted inpatient ordering of high glargine doses (≥0.5 U/kg/day) to endocrine staff in May 2013. This retrospective cohort study assesses its effect on hypoglycemia and glycemic control within 48 hours of admission (ADM)., Methods: We identified 692 adult patients hospitalized at Boston Medical Center who received glargine upon ADM from November 1, 2012 through April 30, 2013 as the pre-intervention group, and 651 adult patients admitted between November 1, 2013 and April 30, 2014 as the postintervention group. Demographics, medical history, home insulin regimen, concurrent oral diabetes medications or glucocorticoid administration, ADM serum creatinine, all blood glucose levels (BG) ≤48 hours of ADM, and hemoglobin A1c values ≤3 months were assessed. Hypoglycemia was defined as BG ≤70 mg/dL, and hyperglycemia as BG ≥200 mg/dL. Multivariable regression models assessed potential associations between covariates and incidence of hypoglycemia and average BG ≤48 hours of ADM., Results: Demographics were similar between groups. Significantly less patients received high-dose glargine in the post-intervention group (5.2% vs. 0.3%, P<.001). Incidences of hypoglycemia were significantly lower in the postintervention group (20.9% vs. 17.8%, P<.001 per ADM; 3.4% vs. 2.3%, P = .001 per BG measurements [BGM]). Mean BG levels ≤48 hours of ADM and incidence of hyperglycemia were not significantly different. The adjusted incident rate ratio of hypoglycemia was 0.63 per ADM and 0.74 per BGM in the postintervention group compared to the pre-intervention group (P = .001 and P = .063, respectively)., Conclusion: We found that implementation of a restriction on high doses of glargine resulted in lower rates of hypoglycemia without worsening glycemic control., Abbreviations: ADM = admission BG = blood glucose BGM = blood glucose measurements BMC = Boston Medical Center BMI = body mass index EMR = electronic medical record HgbA1c = hemoglobin A1c IRR = incidence rate ratio NPH = neutral protamine Hagedorn TDD = total daily dose T2D = type 2 diabetes.

Newer insulin products have advanced the evolution of insulin replacement options to more accurately mimic natural insulin action. There are new, modified, and concentrated insulins; administration devices calibrated for both increased concentrations and administration accuracy to improve adherence and safety; and inhaled insulin. There are new combinations of longer-acting basal insulin and rapid-acting insulin or glucagon like protein-1 receptor agonists. Existing insulin replacement designs and methods can be updated using these tools to improve efficacy and safety. Individualized decisions to use them should be based on patient physiologic needs, self-care ability, comorbidities, and cost considerations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Basal insulin peglispro (BIL) is a novel basal insulin with hepato-preferential action resulting from reduced peripheral effects. This report provides an integrated summary of lipid changes at 26 weeks with BIL and comparator insulins (glargine, NPH) from phase III studies in type 1 diabetes (T1D), insulin-naïve patients with type 2 diabetes (T2D), patients with T2D on basal insulin only and patients with T2D on basal-bolus therapy. BIL treatment had little effect on HDL cholesterol and LDL cholesterol in all patients. The effect of both BIL and glargine treatment on triglycerides (TG) depended on whether patients had been previously treated with insulin. When BIL replaced conventional insulin glargine or NPH treatments, increases in TG levels were observed. When BIL or comparator insulins were given for 26 weeks to insulin-naïve patients with T2D, TG levels were unchanged from baseline with BIL but decreased with either glargine or NPH. The decreased peripheral action of BIL may reduce suppression of lipolysis in peripheral adipose tissue resulting in increased free fatty acid delivery to the liver and, hence, increased hepatic TG synthesis and secretion., (© 2016 John Wiley & Sons Ltd.)