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Introduction: People with diabetes require insulin to regulate blood glucose (BG); rapid-acting insulin analogs (RAIA) represent one approach for BG management. New fast-acting RAIA administered at the start of a meal suppress postprandial BG better than conventional RAIA. New RAIA are expected to confer higher treatment satisfaction and improved quality of life (QOL) than conventional RAIA. Methods: This cross-sectional, web-based survey in Japan (November 2022) included people with diabetes (type 1/2), aged ≥ 18 years, registered in the Rakuten Insight Diabetes Panel, using new and/or conventional RAIA. RAIA-specific satisfaction was evaluated by questions on RAIA use (scores: 1 [not at all satisfied]; 7 [very satisfied]) and QOL by the Diabetes Therapy-Related (DTR)-QOL questionnaire (scores: 0–100, 100 = best) for the whole population (primary endpoint) and for new versus conventional RAIA users (secondary endpoint). Multiple regression models were used to compare new versus conventional RAIA users. Results: The analysis population comprised 217 people with diabetes (new RAIA, n = 109; conventional RAIA, n = 108). Mean (standard deviation) RAIA-specific satisfaction scores ranged from 5.1 (1.2) to 5.4 (1.2); DTR-QOL total score was 51.6 (20.4). RAIA satisfaction scores were numerically higher for new versus conventional RAIA users; no difference in DTR-QOL total score was observed. DTR-QOL satisfaction with treatment domain score was significantly higher in new versus conventional RAIA users (least squares mean difference [standard error]: 7.3 [3.1]; 95% confidence interval: 1.2, 13.4; P = 0.0197). RAIA-specific satisfaction was higher among patients who discussed BG sufficiently with their doctor versus those who did not. Conclusions: New RAIA users have greater treatment satisfaction than conventional RAIA users. QOL was similar among new and conventional RAIA users, except for satisfaction with treatment, which was significantly higher among new RAIA users. Detailed explanations from the doctor to the person with diabetes about the relationship between new RAIA and BG status are essential. A graphical plain language summary is available with this article. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. Methods: This was a phase 3, multicenter, open‐label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment‐induced anti‐insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment‐induced AIA development to the prespecified margins. Results: The percentages of participants positive for treatment‐induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of −2.1 percentage points and a 90% CI (−7.6%, 3.5%) (predefined similarity margins: −10.7%, 10.7%). The difference in glycated haemoglobin was −0.08% (90% CI, −0.23, 0.06). The overall percentage of participants with any treatment‐emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. Conclusions: GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy, and safety, based on the current study. [ABSTRACT FROM AUTHOR]

Chromatographic modeling software packages are valuable tools during method optimization steps. These are well established for reversed‐phase applications utilizing retention time (RT) prediction to optimize separations and receive robust methods, which is of high interest for the analysis of pharmaceuticals. In contrast to liquid chromatography, the knowledge of RT prediction in supercritical fluid chromatography is limited to a manageable number of studies. This study uses the software DryLab to predict the RTs of the peptides bacitracin (Bac), colistin, tyrothricin (Tyro), and insulin analogs. Gradient time, column temperature, and the ternary composition (terC) of carbon dioxide, methanol (MeOH), and acetonitrile (ACN) in the gradient elution are varied in a feasibility approach using a neutral (Viridis BEH) and an amino‐derivatized aromatic (Torus 2‐PIC) stationary phase. In the second part, chromatographic optimization is performed in silico through gradient adjustments to optimize the separation of the fingerprint of Bac. The final gradient method utilizes a Viridis BEH column (100 × 3.0 mm, 1.7 μm), carbon dioxide, and a modifier consisting of ACN/MeOH/water/methanesulfonic acid (60:40:2:0.1, v:v:v:v). In addition, changes in the retention order of Tyro compounds with the proportion of the terC in combination with a Torus Diol column are investigated. [ABSTRACT FROM AUTHOR]

Background: This analysis assessed the cost‐effectiveness of insulin glargine 300 units/mL (Gla‐300) versus insulin glargine 100 units/mL (Gla‐100) in insulin‐naïve adults with type 2 diabetes (T2D) inadequately controlled with oral antidiabetic drugs (OADs). Methods: Costs and outcomes for Gla‐300 versus Gla‐100 from a US healthcare payer perspective were assessed using the BRAVO diabetes model. Baseline clinical data were derived from EDITION‐3, a 12‐month randomized controlled trial comparing Gla‐300 with Gla‐100 in insulin‐naïve adults with inadequately controlled T2D on OADs. Treatment costs were calculated based on doses observed in EDITION‐3 and 2020 US net prices, while costs for complications were based on published literature. Lifetime costs ($US) and quality‐adjusted life‐years (QALYs) were predicted and used to calculate incremental cost‐effectiveness ratio (ICER) estimates; extensive scenario and sensitivity analyses were conducted. Results: Lifetime medical costs were estimated to be $353,441 and $352,858 for individuals receiving Gla‐300 and Gla‐100 respectively; insulin costs were $52,613 and $50,818. Gla‐300 was associated with a gain of 8.97 QALYs and 21.12 life‐years, while Gla‐100 was associated with a gain of 8.89 QALYs and 21.07 life‐years. This resulted in an ICER of $7522/QALY gained for Gla‐300 versus Gla‐100. Thus, Gla‐300 was cost‐effective versus Gla‐100 based on a willingness‐to‐pay threshold of $50,000/QALY. Compared with Gla‐100, Gla‐300 provided a net monetary benefit of $3290. Scenario and sensitivity analyses confirmed the robustness of the base case. Conclusion: Gla‐300 may be a cost‐effective treatment option versus Gla‐100 over a lifetime horizon for insulin‐naïve people in the United States with T2D inadequately controlled on OADs. [ABSTRACT FROM AUTHOR]

Aims: Combining insulin with a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) to treat type 2 diabetes (T2D) is common. While many studies have investigated concomitant therapy with basal insulin+GLP‐1RA, few have reported on premixed insulin+GLP‐1RA. We aimed to address this gap using data from the Clinical Practice Research Datalink Aurum database in England. Methods: This retrospective cohort study with propensity score matching assessed glycaemic levels and other clinical outcomes in people with T2D, comparing biphasic insulin aspart 30/70 (BIAsp 30) + GLP‐1RA with basal insulin (insulin detemir/glargine U100) + GLP‐1RA (from 2006 to 2021). Results: In total, 4770 eligible people were identified; 1511 had a BIAsp 30 + GLP‐1RA regimen and were propensity score‐matched to an equal number receiving basal+GLP‐1RA. There was no significant difference in glycated haemoglobin (HbA1c) reduction between cohorts at 6 months (p = 0.15), with a decrease of −1.07 (95% CI: −1.16; −0.98) %‐points (−11.7 mmol/mol [95% CI: −12.7; –10.7]) in the BIAsp 30 + GLP‐1RA cohort, versus −0.97 (95% CI: −1.07; −0.88) %‐points (−10.6 mmol/mol [95% CI: −11.7; –9.6]) in the basal+GLP‐1RA cohort. Body mass index (BMI) decreased by −0.35 kg/m2 (95% CI: −0.52;−0.18) at 6 months with BIAsp 30 + GLP‐1RA, versus −0.72 kg/m2 (95% CI: −0.90;−0.54) with basal+GLP‐1RA (p = 0.003). BMI was influenced by the initiation sequence of GLP‐1RA in relation to insulin (p < 0.0001). Hypoglycaemia rates were low and not significantly different between cohorts. Conclusions: Combining BIAsp 30 + GLP‐1RA provides glycaemic control with no significant difference to that of propensity score‐matched people receiving basal insulin+GLP‐1RA, with no increase in hypoglycaemia risk or weight gain. [ABSTRACT FROM AUTHOR]

This article presents a study comparing the effectiveness of two types of insulin, Gla-300 and IDeg-100, in managing glucose levels in patients with type 1 diabetes. The study used a glucodensity approach to analyze continuous glucose monitoring (CGM) data and found that Gla-300 users had a higher percentage of time within the target glucose range (TIR) and lower glucose variability compared to IDeg-100 users, particularly during the nocturnal period. The results suggest that Gla-300 may be a more effective insulin for managing glucose levels in patients with type 1 diabetes, but further research is needed to confirm these findings. It is important to note that the study has limitations, such as its retrospective nature and small sample size. [Extracted from the article]

This study evaluated the effect of 24-week Taichi training and Taichi plus resistance band training on pulmonary diffusion capacity and glycemic control in patients with Type 2 diabetes mellitus (T2DM). Forty-eight patients with T2DM were randomly divided into three groups: Group A—Taichi training: practiced Taichi 60 min/day, 6 days/week for 24 weeks; Group B—Taichi plus resistance band training: practiced 60-min Taichi 4 days/week plus 60-min resistance band training 2 days/week for 24 weeks; and Group C–controls: maintaining their daily lifestyles. Stepwise multiple regression analysis was applied to predict diffusion capacity of the lungs for carbon monoxide (DLCO) by fasting blood glucose, insulin, glycosylated hemoglobin (HbA1c), tumour necrosis factor alpha (TNF-α), von Willebrand Factor (vWF), interleukin-6 (IL-6), intercellular adhesion molecule 1 (ICAM-1), endothelial nitric oxide synthase (eNOS), nitric oxide (NO), endothelin-1 (ET-1), vascular endothelial growth factor, and prostaglandin I-2. Taichi with or without resistance band training significantly improved DLCO, increased insulin sensitivity, eNOS and NO, and reduced fasting blood glucose, insulin, HbA1c, TNF-α, vWF, IL-6, ICAM-1, and ET-1. There was no change in any of these variables in the control group. DLCO was significantly predicted (R2 = 0.82) by insulin sensitivity (standard-β = 0.415, P<0.001), eNOS (standard-β = 0.128, P = 0.017), TNF-α (standard-β = -0.259, P = 0.001), vWF (standard-β = -0.201, P = 0.007), and IL-6 (standard-β = -0.175, P = 0.032) in patients with T2DM. The impact of insulin sensitivity was the most important predictor for the variation of DLCO based on the multiple regression modeling. This study demonstrates that 24-week Taichi training and Taichi plus resistance band training effectively improve pulmonary diffusion capacity and blood glycemic control in patients with T2DM. Variation of DLCO is explained by improved insulin sensitivity and endothelial function, and reduced inflammatory markers, including TNF-α, vWF, and IL-6. [ABSTRACT FROM AUTHOR]

Background//Objective: Diabetes affects millions of people globally, despite treatment options, adherence and other factors pose obstacles. Once-weekly Insulin Icodec, a novel basal Insulin analog with a week-long half-life, offers potential benefits, enhancing convenience, adherence, and quality of life for improved glycemic control. This systematic review and meta-analysis aimed to assess the efficacy and safety of once-weekly Insulin Icodec compared to once-daily Insulin Glargine U-100 in individuals with type II diabetes (T2D). Methods: A comprehensive literature search was conducted using PubMed, and Cochrane Library databases before September 2023 to identify relevant Randomized control trials (RCTs) with no language restrictions following PRISMA guidelines. The Cochrane risk-of-bias tool was used for quality assessment. All statistical analyses were conducted using RevMan (version 5.4; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Result: Four RCTs published from 2020 to 2023 with a cumulative sample size of 1035 were included. The pooled mean difference (MD) revealed a 4.68% longer TIR (%) with Insulin Icodec compared to Insulin Glargine U-100 [{95% CI (0.69, 8.68), p = 0.02}], the estimated mean changes in HbA1c (%) and FPG (mg%) were found to be insignificant between the two groups [MD = − 0.12 {95% CI (− 0.26, 0.01), p = 0.07}] and [MD = − 2.59 {95% CI (− 6.95, 1.78), p = 0.25}], respectively. The overall OR for hypoglycemia was also nonsignificant between the two regimens 1.04 [{95% CI (0.71, 1.52), p = 0.84}]. Other safety parameters were similar between the two groups. Conclusions: Switching from daily Insulin Glargine U-100 to weekly Insulin Icodec showed longer TIR (%) as well as similar blood glycemic control and safety profile. Hence, it may be a good alternate option for management of longstanding T2D. [ABSTRACT FROM AUTHOR]

While many studies compared multiple daily injections (MDI) and insulin pump therapy on various clinical outcomes, the results remain inconclusive. This multicenter retrospective cohort study included 175 patients and aimed to evaluate the effects of different insulin therapy methods on various clinical outcomes, including hemoglobin A1c (HbA1c), total daily insulin dosage, body mass index, glomerular filtration rate, in pediatric patients with type 1 diabetes. In a linear mixed-effects regression analysis, a statistically significant interaction between time and treatment type on HbA1c was found. It suggested significantly higher reduction of HbA1c values between 12-month visit and baseline in the group receiving MDIs compared to insulin pump therapy. Patients using MDIs observed higher reduction of HbA1c levels and lower total daily insulin dose relative to insulin pump therapy group. Other changes of clinical indicators were the same for group of patients. Various studies report controversial results on long term effects of these treatments on HbA1c values necessitating large population-based cohort studies in this field. [ABSTRACT FROM AUTHOR]

Despite advances in the management of type 2 diabetes mellitus (T2DM), one-third of patients with diabetes do not achieve the desired glycemic goal. Considering this inadequacy, many agents that activate glucokinase have been investigated over the last two decades but were withdrawn before submission for marketing permission. Dorzagliatin is the first glucokinase activator that has been granted approval for T2DM, only in China. As overstimulation of glucokinase is linked with pathophysiological disturbances such as fatty liver and cardiovascular issues and a loss of therapeutic efficacy with time. This review aims to highlight the benefits of glucokinase activators vis-à-vis the risks associated with chronic enzymatic activation. We discuss the multisystem disturbances expected with chronic activation of the enzyme, the lessons learned with glucokinase activators of the past, the major efficacy and safety findings with dorzagliatin and its pharmacological properties, and the status of other glucokinase activators in the pipeline. The approval of dorzagliatin in China was based on the SEED and the DAWN trials, the major pivotal phase III trials that enrolled patients with T2DM with a mean glycosylated hemoglobin of 8.3–8.4%, and a mean age of 53–54.5 years from multiple sites in China. Patients with uncontrolled diabetes, cardiac diseases, organ dysfunction, and a history of severe hypoglycemia were excluded. Both trials had a randomized double-blind placebo-controlled phase of 24 weeks followed by an open-label phase of 28 weeks with dorzagliatin. Drug-naïve patients with T2DM with a disease duration of 11.7 months were enrolled in the SEED trial while the DAWN trial involved patients with T2DM with a mean duration of 71.5 months and receiving background metformin therapy. Compared with placebo, the decline in glycosylated hemoglobin at 24 weeks was more with dorzagliatin with an estimated treatment difference of − 0.57% in the SEED trial and − 0.66% in the DAWN trial. The desired glycosylated hemoglobin (< 7%) was also attained at more than two times higher rates with dorzagliatin. The glycemic improvement was sustained in the SEED trial but decreased over 52 weeks in the DAWN trial. Hyperlipidemia was observed in 12–14% of patients taking dorzagliatin versus 9–11% of patients receiving a placebo. Additional adverse effects noticed over 52 weeks with dorzagliatin included an elevation in liver enzymes, hyperuricemia, hyperlacticacidemia, renal dysfunction, and cardiovascular disturbances. Considering the statistically significant improvement in glycosylated hemoglobin with dorzagliatin in patients with T2DM, the drug may be given a chance in treatment-naïve patients with a shorter disease history. However, with the waning therapeutic efficacy witnessed in patients with long-standing diabetes, which was also one of the potential concerns with previously tested molecules, extended studies involving patients with chronic and uncontrolled diabetes are needed to comment upon the long-term therapeutic performance of dorzagliatin. Likewise, evidence needs to be generated from other countries, patients with organ dysfunction, a history of severe hypoglycemia, cardiac diseases, and elderly patients before extending the use of dorzagliatin. Apart from monitoring lipid profiles, long-term safety studies of dorzagliatin should involve the assessment of serum uric acid, lactate, renal function, liver function, and cardiovascular parameters. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This post hoc analysis assessed continuous glucose monitoring (CGM)–based metrics and hypoglycemia duration with once-weekly insulin icodec versus once-daily basal insulin analogs in insulin-experienced individuals with long-standing type 2 diabetes from two 26-week phase 3a trials (ONWARDS 2 and ONWARDS 4). RESEARCH DESIGN AND METHODS: Time in range (TIR) (3.9–10.0 mmol/L), time above range (TAR) (>10.0 mmol/L), and time below range (TBR) (<3.9 mmol/L and <3.0 mmol/L) were assessed during three CGM time periods (switch [weeks 0–4], end of treatment [weeks 22–26], and follow-up [weeks 27–31]) for icodec versus comparators (ONWARDS 2, insulin degludec [basal regimen]; ONWARDS 4, insulin glargine U100 [basal-bolus regimen]) using double-blind CGM data. CGM-derived hypoglycemic episode duration (<3.9 mmol/L) was assessed. RESULTS: In both trials, there were no statistically significant differences in TIR, TAR, or TBR (<3.0 mmol/L) for icodec versus comparators across all time periods. In the end-of-treatment period, mean TIR was 63.1% (icodec) vs. 59.5% (degludec) in ONWARDS 2 and 66.9% (icodec) vs. 66.4% (glargine U100) in ONWARDS 4. Mean TBR <3.9 mmol/L and <3.0 mmol/L remained within recommended targets (<4% and <1%, respectively) across time periods and treatment arms. Hypoglycemic episode duration (<3.9 mmol/L) was comparable across time periods and treatment arms (median duration ≤40 min). CONCLUSIONS: In insulin-experienced participants with long-standing type 2 diabetes, CGM-based TIR, TAR, and CGM-derived hypoglycemia duration (<3.9 mmol/L) were comparable for icodec and once-daily basal insulin analogs during all time periods. TBR remained within recommended targets. [ABSTRACT FROM AUTHOR]

The majority of cases of chronic kidney disease (CKD) worldwide are driven by the presence of type 2 diabetes (T2D), resulting in an increase in CKD rates over the past few decades. The existence of CKD alongside diabetes is associated with increased burden of cardiovascular disease and increased risk of death. Optimal glycaemic control is essential to prevent progression of CKD, but achieving glycaemic targets in people with CKD and diabetes can be challenging because of increased risk of hypoglycaemia and limitations on glucose‐lowering therapeutic options. This review considers the challenges in management of T2D in people with impaired kidney function and assesses evidence for use of basal insulin analogues in people with CKD. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of age and disease duration on the efficacy and safety of iGlarLixi versus insulin glargine 100 units/ml (iGlar) or lixisenatide (Lixi) alone in Asian people with type 2 diabetes (T2D) uncontrolled on oral antidiabetic drugs (LixiLan‐O‐AP) or basal insulin ± oral antidiabetic drugs (LixiLan‐L‐CN). Materials and Methods: In this post hoc analysis, the glycated haemoglobin (HbA1c) changes were assessed from baseline to week 24 (LixiLan‐O‐AP) or 30 (LixiLan‐L‐CN) in subgroups defined by baseline age (<65, ≥65 years) and duration of T2D. The proportion who achieved the composite of HbA1c <7% (<53.0 mmol/mol) without weight gain and without symptomatic hypoglycaemia (plasma glucose ≤3.9 mmol/L) and the incidences of hypoglycaemia and gastrointestinal disorders were also analysed. Results: HbA1c reductions were consistently greater with iGlarLixi versus iGlar or Lixi across all subgroups, including participants aged ≥65 years and those with T2D for ≥15 or ≥20 years. Greater proportions of participants achieved HbA1c <7% (<53.0 mmol/mol) without weight gain or hypoglycaemia with iGlarLixi versus iGlar or Lixi, regardless of age or T2D duration. Hypoglycaemia incidence was similar with iGlarLixi versus iGlar across most subgroups; the incidence of gastrointestinal disorders was lower with iGlarLixi versus Lixi in all subgroups. Conclusions: iGlarLixi showed consistent efficacy and safety across all age and disease duration subgroups in Asian people with uncontrolled T2D, including older individuals and those with longstanding disease. [ABSTRACT FROM AUTHOR]

This article presents the findings of a study on the effectiveness of dulaglutide, a medication for type 2 diabetes, in Chinese patients. The study found that dulaglutide improved glycemic control, reduced body weight, and decreased insulin dosage compared to a placebo. The researchers also analyzed how patient characteristics influenced the medication's efficacy. The study was conducted ethically and registered with ClinicalTrials.gov. The results suggest that patients with higher baseline HbA1c levels may experience greater improvements in glycemic control, while those with higher baseline fasting serum glucose levels may experience greater weight loss. However, the study has limitations and further research is needed to fully understand these findings. [Extracted from the article]

Background: Achieving good glycaemic control is essential to reducing the risk of diabetes complications. Insulin is the most effective therapy for achieving good glycaemic control; however, it is associated with a higher risk of hypoglycaemia, especially with human insulin. This study aimed to evaluate the efficacy of intensification from human to analogue insulin and its added cost. Methods: This retrospective study was conducted at the Hospital Universiti Sains Malaysia (HUSM). Patients with type 2 diabetes mellitus (T2DM) who underwent intensification for at least 3 months from human to analogue insulin were included in this study. The patients' medical records, haemoglobin A1c (Hba1c) and fasting blood sugar (FBS) were retrieved. The total cost pre- and post-intensification of insulin was obtained from the pharmacy database. Differences in HbA1c, FBS and total insulin cost pre- and post-intensification were analysed. Results: A total of 163 patients with T2DM who had intensification from human to analogue insulin were included in this study. HbA1c and FBS levels were significantly lower in analogue insulin. However, the differences were not clinically significant, as the mean reduction in HbA1c was less than 0.5%. Meanwhile, the total costs of analogue insulin for 3 months were higher. Conclusion: There were no clinically significant improvements in patients' HbA1c and FBS after the intensification of insulin, despite the extra costs spent. Hence, it is vital to choose the right group of patients to receive an insulin analogue to maximise its benefit but at the most optimal cost. [ABSTRACT FROM AUTHOR]

Objective: The association of insulin glargine with overall and site-specific cancer risk remains uncertain. This study aims to provide relevant evidence from mainland China. Methods: Based on the Shanghai Link Healthcare Database, patients newly treated with insulin glargine or neutral protamine Hagedorn (NPH) insulin between January 1, 2013 and December 31, 2020 were identified and followed up until December 31, 2021. In addition to the original cohort, we created a 1:1 propensity score-matched cohort with balanced baseline characteristics. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident cancers, comparing insulin glargine with NPH insulin. Results: A total of 26,810 insulin glargine users and 47,765 NPH insulin users were enrolled in the final analysis. During a median follow-up of 4.18 years, 3903 patients developed cancer. Including a 1-year lag period, insulin glargine use was not associated with increased cancer risk compared to NPH insulin use in both the original cohort (HR 1.02, 95% CI 0.95–1.10) and the propensity score-matched cohort (HR 1.01, 95% CI 0.94–1.09). In stratified analyses by sex, age, and cancer site, as well as in sensitivity analyses at different lag periods, the estimated cancer risk, although fluctuating, remained uncorrelated without any substantial change. Conclusion: Insulin glargine is not associated with the risk of overall and site-specific cancers compared to NPH insulin among patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Hyperglycemia is a hallmark of type 2 diabetes (T2D). Metformin, the first-line drug used to treat T2D, maintains blood glucose within a normal range by suppressing hepatic glucose production (HGP). However, resistance to metformin treatment is developed in most T2D patients over time. Transforming growth factor beta 1 (TGF-β1) levels are elevated both in the liver and serum of T2D humans and mice. Here, we found that TGF-β1 treatment impairs metformin action on suppressing HGP via inhibiting AMPK phosphorylation at Threonine 172 (T172). Hepatic TGF-β1 deficiency improves metformin action on glycemic control in high fat diet (HFD)-induced obese mice. In our hepatic insulin resistant mouse model (hepatic insulin receptor substrate 1 (IRS1) and IRS2 double knockout (DKO)), metformin action on glycemic control was impaired, which is largely improved by further deletion of hepatic TGF-β1 (TKObeta1) or hepatic Foxo1 (TKOfoxo1). Moreover, blockade of TGF-β1 signaling by chemical inhibitor of TGF-β1 type I receptor LY2157299 improves to metformin sensitivity in mice. Taken together, our current study suggests that hepatic TGF-β1 signaling impairs metformin action on glycemic control, and suppression of TGF-β1 signaling could serve as part of combination therapy with metformin for T2D treatment. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus has become increasingly prevalent and a considerable health risk in the United States. Early introduction of insulin can improve overall health outcomes of patients with diabetes. With the development of long-acting insulin analogs, such as insulin glargine, limitations such as variable absorption and hypoglycemia were reduced. Majority of reported adverse drug effects secondary to insulin glargine include injection site reaction and hypoglycemia. There is limited data on gastrointestinal adverse effects, including nausea, of insulin glargine. Case Presentation : A 51-year-old female with a past medical history of type 2 diabetes was referred to the collaborative drug therapy management pharmacist for diabetes education and management. The patient was initiated on insulin glargine (Lantus®) and began to experience episodes of nausea and emesis over a 9 week period. Once the patient was switched from insulin glargine (Lantus®) to insulin detemir, symptoms subsided. Upon re-trial of insulin glargine (Lantus®), nausea and emesis-like symptoms resumed. A probable relationship between insulin glargine (Lantus®) and the reaction was estimated using the Naranjo Adverse Drug Reaction Probability Scale. Conclusion: Potential mechanisms behind the relationship of insulin glargine (Lantus®) and nausea are hypothesized, however there is limited literature supporting this claim and further investigation is warranted. [ABSTRACT FROM AUTHOR]

Semaglutide is the first oral glucagon-like peptide-1 (GLP-1) analog commercially available for the treatment of type 2 diabetes. In this work, semaglutide was incorporated into poly(lactic- co -glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles (NPs) to improve its delivery across the intestinal barrier. The nanocarriers were surface-decorated with either a peptide or an affibody that target the human neonatal Fc receptor (hFcRn), located on the luminal cell surface of the enterocytes. Both ligands were successfully conjugated with the PLGA-PEG via maleimide-thiol chemistry and thereafter, the functionalized polymers were used to produce semaglutide-loaded NPs. Monodisperse NPs with an average size of 170 nm, neutral surface charge and 3% of semaglutide loading were obtained. Both FcRn-targeted NPs exhibited improved interaction and association with Caco-2 cells (cells that endogenously express the hFcRn), compared to non-targeted NPs. Additionally, the uptake of FcRn-targeted NPs was also observed to occur in human intestinal organoids (HIOs) expressing hFcRn through microinjection into the lumen of HIOs, resulting in potential increase of semaglutide permeability for both ligand-functionalized nanocarriers. Herein, our study demonstrates valuable data and insights that the FcRn-targeted NPs has the capacity to promote intestinal absorption of therapeutic peptides. [Display omitted] • Semaglutide was successfully incorporated into FcRn-targeted polymeric nanoparticles. • FcRn-targeted nanoparticles bound to hFcRn in a pH-dependent manner, with a stronger interaction at pH 6 than at pH 7.4. • FcRn-targeted nanoparticles showed higher interaction with in vitro intestinal models than non-targeted nanoparticles. • Injection of nanomedicines into intestinal organoids' lumen is a promising tool to evaluate cell-nanopartices interaction. [ABSTRACT FROM AUTHOR]

Aim: Despite global recommendations for type 2 diabetes mellitus treatment to maintain optimal glycaemic targets, a significant proportion of people remain in suboptimal glycaemic control. Our objective was to investigate the impact of intensification delay after basal insulin (BI) initiation on long‐term complications in people with suboptimal glycaemia. Materials and Methods: We conducted a retrospective cohort study in individuals with type 2 diabetes mellitus initiated on BI. Those with suboptimal glycaemia (glycated haemoglobin ≥7% or ≥53 mmol/mol) within 12 months of BI initiation were divided into early (treatment intensified within 5 years), or late (≥5 years) intensification groups. We estimated the age‐stratified risks of micro‐ and macrovascular complications among these groups compared with those with optimal glycaemia (glycated haemoglobin <7%). Results: Of the 13 916 people with suboptimal glycaemia, 52.5% (n = 7304) did not receive any treatment intensification. In those aged <65 years, compared with the optimal glycaemia group late intensification was associated with a 56% higher risk of macrovascular complications (adjusted hazard ratio 1.56; 95% confidence intervals 1.08, 2.26). In elderly people (≥65 years), late intensification was associated with a higher risk of cardiovascular‐related death (1.62; 1.03, 2.54) and a lower risk of microvascular complications (0.26; 0.08, 0.83). Conclusions: Those who had late intensification were at an increased risk of cardiovascular death if they were ≥65 years and an increased risk of macrovascular complications if they were <65 years. These findings highlight the critical need for earlier intensification of treatment and adopting personalized treatment strategies to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Introduction: To compare responses to basal insulin glargine 300 U/ml (IGlar‐300) and 100 U/ml (IGlar‐100) in newly defined subphenotypes of type 2 diabetes. Methods: Insulin‐naive participants (n = 858) from the EDITION 3 trial were assigned to subphenotypes 'Mild Age‐Related Diabetes (MARD)', 'Mild Obesity Diabetes (MOD)', 'Severe Insulin Resistant Diabetes (SIRD)' and 'Severe Insulin Deficient Diabetes (SIDD)'. Key variables were analysed at baseline and 26 weeks. Results: Participants were comprised of MOD 56.1% (n = 481), SIDD 22.1% (n = 190), MARD 18.2% (n = 156) and SIRD 3.0% (n = 26). After 26 weeks a similar decrease in glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) of 16‐19 mmol/mol and 1.4‐1.7 mmol/L, respectively, occurred in MARD and MOD with both insulins. SIDD had the most elevated HbA1c and FPG (80‐83 mmol/mol/11.1‐11.4 mmol/L) and reduction in both HbA1c and FPG was greater with IGlar‐100 than with IGlar‐300 (−18 vs. −15 mmol/mol and −1.6 vs. −1.3 mmol/L, respectively; each p =.03). In SIDD, despite receiving the highest basal insulin doses, HbA1c decline (57‐60 mmol/mol/7.3‐7.6%) was suboptimal at week 26. In MOD and SIDD lower incidences with IGlar‐300 were found for level 1 nocturnal hypoglycaemia [odds ratio (OR) 0.59, 95% confidence intervals (CI) 0.36‐0.97; OR 0.49, 95% CI 0.24‐0.99]. In addition, fewer level 2 hypoglycaemia episodes occurred at any time with IGlar‐300 in SIDD (OR 0.31, 95% CI 0.13‐0.77). Conclusion: Both insulins produce comparable outcomes in type 2 diabetes subphenotypes, but in SIDD, add‐on treatment to basal insulin is required to achieve glycaemic targets. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to evaluate the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) in insulin-naive patients with type 2 diabetes mellitus (T2DM) inadequately controlled on oral antidiabetic drug (OADs) treatment in Turkey. Methods: One hundred eight patients from 20 centers enrolled in the study. Starting from baseline, Gla-300 was self-administered subcutaneously and once daily in the evening. The primary outcome was the mean change in glycated hemoglobin A1c (HbA1c) from baseline to week 24. Results: The mean (±SD) Hb1Ac level of 9.4% (±0.8) at baseline decreased to 7.5% (±0.9) at week 12 (P < .1) and to 7.3% (±0.9) at week 24 (P < .1). Although none of the patients were within the target Hb1Ac level of ≤7% at baseline, the percentage of patients who achieved the target Hb1Ac level was 30.4% at week 12 and increased to 42.9% at week 24. Gla-300 treatment achieved the Hb1Ac target in 21 (19.4%) patients without experiencing a hypoglycemic event and in 27 (25.0%) patients who experienced at least one hypoglycemic event. For each self-monitoring blood glucose time point, significant improvements were observed as compared to baseline (P < .001). Statistically significant improvement (P < .001) was seen in the treatment satisfaction questionnaire - status version scores between baseline and week 24. Conclusion: This study indicated that Gla-300 is effective to provide a successful glycemic control with low risk of hypoglycemia added to OADs in insulin-naive patients with T2DM, and it has the potential to improve the quality of life of patients. [ABSTRACT FROM AUTHOR]

Acute hyperkalemia is characterized by high concentrations of potassium in the blood that can potentially lead to life-threatening arrhythmias that require emergent treatment. Therapy involves the utilization of a constellation of different agents, all targeting different goals of care. The first, andmost important step in the treatment of severe hyperkalemia with electrocardiographic (ECG) changes, is to stabilize the myocardium with calcium in order to resolve or mitigate the development of arrythmias. Next, it is vital to target the underlying etiology of any ECG changes by redistributing potassium from the extracellular space with the use of intravenous regular insulin and inhaled beta-2 agonists. Finally, the focus should shift to the elimination of excess potassium from the body through the use of intravenous furosemide, oral potassium-binding agents, or renal replacement therapy. Multiple nuances and controversies exist with these therapies, and it is important to have a robust understanding of the underlying support and recommendations for each of these agents to ensure optimal efficacy and minimize the potential for adverse effects and medication errors. [ABSTRACT FROM AUTHOR]

Peptides with a molecular mass between 2 and 10 kDa that are prohibited in elite sports usually require dedicated sample preparation and mass spectrometric detection that commonly cannot be combined with other (lower molecular mass) substances. In most instances, the physicochemical differences are too significant to allow for a generic analytical procedure. A simplification of established and comparably complex analytical approaches is therefore desirable and has been accomplished in the context of this study. With urine samples representing still the most frequently collected doping control specimens, efficient extraction of peptidic analytes from this matrix was a major goal of this method, as demonstrated for the included compounds such as insulins (human, lispro, aspart, glulisine, tresiba, glargine metabolite, bovine insulin, porcine insulin), growth hormone‐releasing hormones (sermorelin, CJC‐1295, tesamorelin) incl. their respective metabolites, insulin‐like‐growth factors (long‐R3‐IGF‐I, R3‐IGF‐I, des1–3‐IGF‐I), synacthen, gonadorelin and mechano growth factors (human MGF, MGF‐Goldspink). Sample preparation and detection are controlled by five internal standards, covering all five included peptide drug categories. Nearly all requirements of the recent technical documents from the World Anti‐Doping Agency (WADA) considering their minimum required performance levels (MRPL) are fulfilled, and the method was validated for its utilisation as initial testing procedure in doping controls. Finally, the approach was applied to authentic post‐administration study urine samples (for insulins and gonadorelin) in order to provide proof of principle. [ABSTRACT FROM AUTHOR]

A balanced and healthy diet is very important in type 1 diabetes mellitus (T1DM) in childhood. In addition to regulating blood glucose with diet, diet should also support optimal growth. Low-carbohydrate diet aims to provide daily energy from fats and was originally used for childhood epilepsy. We present a patient with T1DM who experienced unfavorable effects when on a low-carbohydrate diet. [ABSTRACT FROM AUTHOR]

Biphasic insulin aspart 30 is a premixed formulation containing a soluble fraction of insulin aspart (30%) and a protamine‐crystallized fraction (70%) that was developed to combine the rapid‐acting and prolonged advantages of commercially available insulins. The aim of this bioequivalence study was to compare the pharmacokinetics (PKs) of GP‐bi‐asp and Novo‐bi‐asp, and evaluate the pharmacodynamic (PD) properties as well as the safety of these drugs in the hyperinsulinemic euglycemic clamp (HEC) procedure. This was a phase 1, randomized, double‐blind, 2‐sequence, 2‐period crossover study. Thirty‐four male volunteers who met the inclusion criteria underwent the HEC procedure following a single subcutaneous injection of 0.4 IU/kg of either GP‐bi‐asp or Novo‐bi‐asp in the abdomen. After the treatment, the subjects' plasma glucose levels were monitored for 24 hours and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. The PD parameters were calculated using GIR values. Insulin aspart concentrations were measured in blood plasma using validated ELISA assays to evaluate the PK parameters of the investigated drugs. The 90% confidence intervals for the geometric mean ratios of PK (Cins and AUCins–T) parameters of Gp‐bi‐asp and Novo‐bi‐asp were close to 100% and within the 80%‐125% limits for establishing bioequivalence. The safety profiles of both drugs were also comparable. [ABSTRACT FROM AUTHOR]

Aims: To characterize the pharmacokinetic and pharmacodynamic properties of once‐weekly insulin icodec in type 2 diabetes (T2D). Materials and Methods: In an open‐label trial, 46 individuals with T2D (18‐75 years; body mass index 18.0‐38.0 kg/m2; glycated haemoglobin ≤75 mmol/mol [≤9%]; basal insulin‐treated) received subcutaneous once‐weekly icodec for ≥8 weeks at individualized doses, aiming at a pre‐breakfast plasma glucose concentration of 4.4 to 7.0 mmol/L (80‐126 mg/dL) on the last three mornings of each weekly dosing interval. Frequent blood sampling to assess total serum icodec concentration (ie, albumin‐bound and unbound) occurred from first icodec dose until 35 days after last dose. Icodec trough concentrations following initiation of once‐weekly dosing were predicted by pharmacokinetic modelling. During the final 3 weeks of icodec treatment, while at steady state, the icodec glucose‐lowering effect was assessed in three glucose clamps (target 7.5 mmol/L [135 mg/dL]): 0 to 36, 40 to 64 and 144 to 168 h post‐dose, thus covering the initial, middle and last part of the 1‐week dosing interval. Glucose‐lowering effect during a complete dosing interval was predicted by pharmacokinetic‐pharmacodynamic modelling. Results: Model‐predicted icodec steady state was attained after 3 to 4 weeks. At steady state, model‐predicted daily proportions of glucose‐lowering effect on days 1 to 7 of the 1‐week dosing interval were 14.1%, 16.1%, 15.8%, 15.0%, 14.0%, 13.0% and 12.0%, respectively. Icodec duration of action was at least 1 week in all participants. Once‐weekly icodec was overall safe and well tolerated in the current trial. Conclusions: The pharmacokinetic and pharmacodynamic characteristics of icodec in individuals with T2D support its potential as a once‐weekly basal insulin. [ABSTRACT FROM AUTHOR]

Seleno-insulin, a class of artificial insulin analogs, in which one of the three disulfide-bonds (S-S's) of wild-type insulin (Ins) is replaced by a diselenide-bond (Se-Se), is attracting attention for its unique chemical and physiological properties that differ from those of Ins. Previously, we pioneered the development of a [C7UA,C7UB] analog of bovine pancreatic insulin (SeIns) as the first example, and demonstrated its high resistance against insulin-degrading enzyme (IDE). In this study, the conditions for the synthesis of SeIns via native chain assembly (NCA) were optimized to attain a maximum yield of 72%, which is comparable to the in vitro folding efficiency for single-chain proinsulin. When the resistance of BPIns to IDE was evaluated in the presence of SeIns, the degradation rate of BPIns became significantly slower than that of BPIns alone. Furthermore, the investigation on the intermolecular association properties of SeIns and BPIns using analytical ultracentrifugation suggested that SeIns readily forms oligomers not only with its own but also with BPIns. The hypoglycemic effect of SeIns on diabetic rats was observed at a dose of 150 μg/300 g rat. The strategy of replacing the solvent-exposed S-S with Se-Se provides new guidance for the design of long-acting insulin formulations. Seleno-insulins (SeIns) are known to exhibit different in vitro properties from wild-type insulin, upon replacement of one of the three disulfide bonds with diselenide bonds; however, the in vivo hypoglycemic effect remains poorly understood. Here, the authors optimize the synthesis of SeIns via native chain assembly and reveal in vitro resistance against the insulin-degrading enzyme, as well as the in vivo hypoglycemic effect in diabetic rats at a dose of 150 μg/300 g rat. [ABSTRACT FROM AUTHOR]

The purity analysis of therapeutic peptides can often be challenging, demanding the application of more than a single analytical technique. Supercritical fluid chromatography nowadays is a promising alternative to reversed‐phase liquid chromatography, providing orthogonal and complementary information. This study investigated its applicability for the separation of human insulin, its analogs and degradation products. A previously published method development protocol for peptides up to 2000 Da was successfully applied to the higher molecular weight insulins (6 kDa). A single gradient method was optimized for all insulins using a Torus DEA column (100 × 3.0 mm, 1.7 μm), carbon dioxide and a modifier consisting of methanol/acetonitrile/water/methanesulfonic acid (65:35:2:0.1, v/v/v/v). Consecutively, the crown ether 18‐crown‐6, which is well known to complex charged lysine sidechains and other amino functionalities, was added to the modifier to evaluate its impact on selectivity. A decreased retention and a shift in the elution order for the insulins were observed. An inverse effect on retention was found when combined with a neutral stationary phase chemistry (Viridis BEH). [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a chronic disease of carbohydrate metabolism characterized by uncontrolled hyperglycemia due to the body's impaired ability to produce or respond to insulin. Oral or injectable exogenous insulin and its analogs cannot mimic endogenous insulin secreted by healthy individuals, and pancreatic and islet transplants face a severe shortage of sources and transplant complications, all of which limit the widespread use of traditional strategies in diabetes treatment. We are now in the era of stem cells and their potential in ameliorating human disease. At the same time, the rapid development of gene editing and cell-encapsulation technologies has added to the wings of stem cell therapy. However, there are still many unanswered questions before stem cell therapy can be applied clinically to patients with diabetes. In this review, we discuss the progress of strategies to obtain insulin-producing cells from different types of stem cells, the application of gene editing in stem cell therapy for diabetes, as well as summarize the current advanced cell encapsulation technologies in diabetes therapy and look forward to the future development of stem cell therapy in diabetes. [ABSTRACT FROM AUTHOR]

The insulin hormone is stored in the hexameric form and dissociates to the dimeric form and finally to the active monomeric form. When insulin secretion is impaired, thereby affecting various metabolic processes, as a final response, insulin analogs are subcutaneously injected before meals to facilitate glucose metabolism. Depending on the molecular details, analogs are rapid or slow acting based on the dissociation rate of the dimer to monomer. Insulin aspart is a recombinant human insulin analog, acting faster than regular human insulin. Despite its practical and elementary importance, the process of insulin aspart dimer dissociation is relatively unknown. Here, we combined molecular dynamics simulations and umbrella sampling to characterize the energetic and structural features of dissociation of the insulin aspart dimer. Like previous studies on human insulin (another well studied analog), insulin aspart can also display a wide spectrum of pathways for dimer dissociation from dissociation happening without a major change in the monomer structure to dissociation that is coupled with unfolding of a protein. Additionally, water plays a vital role in the dissociation of the insulin aspart by stabilizing the monomers in the dissociated state. Our study shows the molecular details, such as the variation in the structure and orientation and conformational changes along the minimum energy pathways in the process of dissociation of the insulin aspart dimer. [ABSTRACT FROM AUTHOR]

The article offers information on the association between obstructive sleep apnea (OSA) and type 2 diabetes, exploring the impact of continuous positive airway pressure (CPAP) therapy on glucose metabolism. Topics include the link between OSA and nocturnal hyperglycemia in patients with type 2 diabetes, the controversial data on CPAP's effect on glucose metabolism, and a case presentation of a patient with refractory fasting hyperglycemia and OSA.

Context. There are evidences that excessive production of reactive oxygen species is one of important abnormalities that contribute to development of chronic diabetic complications. Objective. To test the effect of intensive insulin therapy with analogues through the examining the level of oxidative stress parameters. Subjects and Methods. Comparison of data obtained by prospective analysis in 49 patients with T1DM was used, before and after six months of intensive insulin analog therapy. Results. The values of all three investigated parameters of oxidative stress malondialdehyde (MDA); xanthine oxidase (XO) and nitrates and nitrites (NOx) in our population with T1DM compared to the control (group of 42 voluntary blood donors) are statistically higher. The levels of antioxidant protection parameters compared to the control group also differ; the activities of catalase and glutathione peroxidase (GPx) are statistically higher in our population of T1DM patients compared to the control and superoxide dismutase (SOD) activities are statistically lower. The values of all three examined parameters of oxidative stress decrease after six months of intensive insulin analog therapy and were statistically lower after the therapy: for MDA p<0.001, for XO p<0.01 and for NOx p<0.05. The activities of catalase (p<0.001) and GPx (p<0.01) both decrease with therapy, while the activity of SOD is highest after the sixth month of therapy (p<0.001). Conclusion. In our patients with T1DM compared to the control the level of oxidative stress is significantly higher. Intensive insulin analog therapy with aspart and glargine promotes predominantly the improvement of oxidative stress, and in a less degree antioxidant protection. [ABSTRACT FROM AUTHOR]

Background: In youth with type 1 diabetes (T1D), high haemoglobin A1c (HbA1c) levels are associated with an increased risk for diabetic ketoacidosis (DKA). Aims: This study examined whether daily school‐supervised basal insulin injections were feasible and if they reduced the risk of morning ketosis in children and adolescents with high HbA1c levels. We hypothesized that supervised glargine and degludec would reduce the risk of ketosis and that the prolonged action of degludec would protect from ketosis after consecutive days of unsupervised injections. Materials & Methods: After a 2–4‐week run‐in, youth (10–18 years, HbA1c ≥ 8.5%) managing T1D with injections were randomized to school‐supervised administration of degludec or glargine for 4 months. School nurses observed daily blood β‐hydroxybutyrate (BHB) and glucose checks. During COVID closures, the research team supervised procedures remotely. Results: Data from 28 youth (age 14.3 ± 2.3 years, HbA1c 11.4 ± 1.9%, 64% F) were analysed. School‐supervised injections of both basal insulins for 1–4 days progressively lowered the percent of participants with elevated BHB. The percent of participants with elevated BHB (≥0.6 mmol/L) after 2 days of unsupervised basal insulin doses at home was greater in the glargine than degludec group but had a high p‐value (17.2% vs. 9.0%, p = 0.3). HbA1c was unchanged in both groups. Discussion: In youth with T1D at high risk for DKA, daily supervised long‐acting insulin administration decreased the probability of elevated ketone levels on subsequent school days, regardless of basal insulin type. A larger sample size may have demonstrated that the longer action profile of degludec would offer additional protection from ketosis during days of not attending school. Conclusion: Engaging school‐based caregivers in management of youth with T1D on injected insulin may decrease clinically significant ketosis and minimize acute complications of diabetes. [ABSTRACT FROM AUTHOR]

Galantamine, a centrally acting acetylcholinesterase inhibitor, has been shown to attenuate inflammation and insulin resistance in patients with metabolic syndrome. We investigated the effects of galantamine on glycemic control and development of diabetic nephropathy (DN) in Leprdb/db mice. Galantamine significantly reduced food intake, body weight, blood glucose and HbA1c levels. Insulin resistance (HOMA-IR, QUICKI), HOMA-β and elevations in plasma inflammatory cytokine levels (TNF-α, IL-6 and HMGB-1) were all attenuated by galantamine. Galantamine also ameliorated diabetes-induced kidney injury as evidenced by improvements in renal function (BUN, creatinine, albuminuria), histologic injury and apoptosis. Improved glycemic control and nephropathy were associated with increased circulating GLP-1, decreased renal P-38 MAPK and caspase-1 activation and reduced SGLT-2 expression. These findings provide insights into the mechanisms by which galantamine improves glycemic control and attenuates DN in the Leprdb/db mouse model. [ABSTRACT FROM AUTHOR]

In patients with Type 2 diabetes, a combination of Alogliptin and Pioglitazone medications, together with diet and physical activity, are used to improve glycemic control. Eco-friendly, cost-effective, and precise stability-indicating RP-HPLC method was developed and validated for the identification and quantification of Alogliptin and Pioglitazone in their tablet dosage form, as well as implementation to in vitro dissolution studies and uniformity of dosage unit. Isocratic separation is conducted at ambient temperature on the InertSustain C18 Analytical Column (150 × 4.6 mm, 5 μm) using mobile phase comprising 50 mM of ammonium dihydrogen phosphate and 5.0 mM of heptane sulfonic acid:acetonitrile (45:55, v/v) at a flow rate of 1.3 mL/minute. Calibration curves are conducted in the linearity range of 1–40 μg/mL of Alogliptin and 2.5–75 μg/mL of Pioglitazone with a correlation value >0.9995 and satisfactory recovery findings between 99 and 100%. The degraded samples are analyzed under relevant stress conditions as acidity, alkalinity, thermal and oxidation. The active components in finished products were subjected to a content uniformity test, which showed that they achieved the declared claim's acceptance standards (85–115%). Comparative in vitro dissolution studies are performed for generic products Inhibazone 12.5/30 mg FCT and Inhibazone 25/15 mg FCT against innovator products Oseni 12.5/30 mg FCT and Oseni 25/15 mg FCT at suitable FDA dissolution medium and different USP dissolution media and the results are similar. The metrics of the designed method were assessed according to ICH requirements, and all metrics, such as system suitability, linearity, recovery, robustness, LOD, LOQ, specificity and precision, were found to be within required tolerances and no overlapping was found for degradation peaks. Thence, the method can be used in quality control for the analysis of raw material, bulk, finish and stability. [ABSTRACT FROM AUTHOR]

Few studies have examined the molecular alterations in the auditory pathway of infants of diabetic mothers, notwithstanding the fact that maternal diabetes may have an impact on the development of the neonatal peripheral and central nervous systems. Male newborn rats were studied to determine how maternal diabetes affected the expression of gamma-aminobutyric acid (GABAAα1 and GABAB1) and metabotropic glutamate (mGlu2) receptors in the inferior colliculus (IC) in this research. Female rats were given a single intraperitoneal injection of streptozotocin (STZ) at a 65 mg/kg dose to develop a model of diabetic mothers. The study population was split into sham, diabetes without treatment, and diabetes with insulin groups. Their male neonatal rats were anesthetized on P0, P7, and P14 after mating and delivery. The receptors' distribution pattern was studied using immunohistochemistry (IHC). Pairwise comparison in the groups revealed that the GABA receptors (Aα1 and B1) were significantly downregulated in the diabetes without treatment group (p<0.001). Furthermore, pairwise comparison in the groups indicated significant mGlu2 upregulation in the diabetes without treatment group (p<0.001). Regarding the concentration of all receptors, there was no discernible distinction between the diabetes with insulin and sham groups. This investigation showed that the concentration of GABAAα1 and GABAB1 receptors decreased significantly over time, whereas the concentration of mGlu2 receptors increased significantly over time in male neonatal rats born to streptozotocin-induced diabetic mothers. [ABSTRACT FROM AUTHOR]

Aims: A cost‐effectiveness analysis was conducted to compare insulin glargine 300 U/mL (Gla‐300) versus insulin degludec 100 U/mL (IDeg‐100) in insulin‐naïve adults with type 2 diabetes (T2D) sub‐optimally controlled with oral anti‐diabetic drugs (OADs). Methods: The BRAVO diabetes model was used to assess costs and outcomes for once‐daily Gla‐300 versus once‐daily IDeg‐100 from a US healthcare sector perspective. Baseline clinical data were based on BRIGHT, a 24‐week, non‐inferiority, randomised control trial comparing Gla‐300 and IDeg‐100 in adults with T2D sub‐optimally controlled with OADs (with or without glucagon‐like peptide‐1 receptor agonists). Treatment costs were based on doses observed in BRIGHT as well as net prices. Costs associated with complications were based on published literature. Lifetime costs (US$) and quality‐adjusted life‐years (QALYs) were predicted and used to calculate incremental cost‐effectiveness ratio estimates; extensive scenario and sensitivity analyses were conducted. Results: Overall lifetime medical costs were estimated to be $327,904 and $330,154 for people receiving Gla‐300 and IDeg‐100, respectively; insulin costs were $43,477 and $44,367, respectively. People receiving Gla‐300 gained 8.024 QALYs and 18.55 life‐years, while people receiving IDeg‐100 gained 7.997 QALYs and 18.52 life‐years. Because Gla‐300 was associated with a cost‐saving of $2250 and 0.027 additional QALYs, it was considered to be dominant compared with IDeg‐100. Results of the scenario and sensitivity analyses confirmed the robustness of the base case results. Conclusion: Gla‐300 was the dominant treatment option compared with IDeg‐100 based on the willingness‐to‐pay threshold of $50,000/QALY. Results remained robust against a wide range of alternative assumptions on key parameters. [ABSTRACT FROM AUTHOR]

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

Background: Several studies have proved the advantages of second-generation insulin analogs in lowering intra-individual variability in plasma insulin levels, flexibility in dosing, a sustained glucose-lowering effect, and decreasing the risk of hypoglycemia. Glargine 300 is one of the newer second-generation basal insulin analogs to have been approved for both type 1 and 2 diabetes. The present study aims to assess the real-world clinical effectiveness and safety of Glargine U300 (Toujeo®) initiation after oral antidiabetic drug failure in insulin-naïve patients with T2DM. Methods: A prospective, observational study was conducted where participants were interviewed regarding their basic demographics, body weight, and treatment details. Glycemic parameters (HbA1C%, Fasting Plasma Glucose, and Post Prandial Blood Glucose) were observed in the initial 6 months, and changes were noted and compared. Any hypoglycemic events or other complications were also noted. Data collected were statistically analyzed. Results: The study included a total of 188 patients. Treatment with glargine 300 significantly reduced the mean HbA1C level from 9.78% at baseline to 7.90% at the end of 6 months of treatment (p < 0.001). 10.60% of patients achieved the glycemic target of ≤7.0% by the end of 6 months, while only 6.90% were within the target range at baseline. Similarly, significant reduction in FPG was observed at the end of 6 months treatment period with Glargine U300. A significant increase in dose requirement was observed throughout the study phase (p < 0.001). Incidence of hypoglycemia was noted in 2.12% of subjects. Conclusion: The lower incidence statistics of hypoglycemia coupled with sustained positive glycemic effects, stands out to be a prominent advantage of Glargine U300 over its other congeners. [ABSTRACT FROM AUTHOR]

Diabetes has been listed as one of the three major diseases that endanger human health. Accurately injecting insulin (Ins) depending on the level of blood glucose (LBG) is the standard treatment, especially controlling LBG in the long‐term by a single injection. Herein, the pH‐responsive hexa‐histidine metal assembly (HmA) encapsulated with enzymes (GOx and CAT) and Ins (HmA@GCI) is engineered as the vehicle for glucose‐mediated insulin delivery. HmA not only shows high proteins loading efficiency, but also well retained proteins activity and protect proteins from protease damage. Within HmA, the biocatalytic activities of enzymes and the efficiency of the cascade reaction between GOx and CAT are enhanced, leading to a super response to the change of LBG with insulin release and efficient clearance of harmful byproducts of GOx (H2O2). In the treatment of diabetic mice, HmA@GCI reduces LBG to normal in half an hour and maintains for more than 5 days by a single subcutaneous injection, and nearly 24 days with four consecutive injections. During the test period, no symptoms of hypoglycemia and toxicity to tissues and organs are observed. These results indicate that HmA@GCI is a safe and long‐acting hypoglycemic agent with prospective clinical application. [ABSTRACT FROM AUTHOR]

The neurotensin subtype 1 receptor (NTS1R) is overexpressed in a number of human tumors, thereby representing a valid target for cancer theranostics with radiolabeled neurotensin (NT) analogs like [99mTc]Tc-DT1 (DT1, N4-Gly7-NT(8-13)). Thus far, the fast degradation of intravenously injected NT–radioligands by neprilysin (NEP) and angiotensin-converting enzyme (ACE) has compromised their clinical applicability. Aiming at metabolic stability enhancements, we herein introduce (i) DT7 ([DAsn14]DT1) and (ii) DT8 ([β-Homoleucine13]DT1), modified at the C-terminus, along with (iii) DT9 ([(palmitoyl)Lys7]DT1), carrying an albumin-binding domain (ABD) at Lys7. The biological profiles of the new [99mTc]Tc–radioligands were compared with [99mTc]Tc-DT1, using NTS1R-expressing AsPC-1 cells and mice models without or during NEP/ACE inhibition. The radioligands showed enhanced in vivo stability vs. [99mTc]Tc-DT1, with [99mTc]Tc-DT9 displaying full resistance to both peptidases. Furthermore, [99mTc]Tc-DT9 achieved the highest cell internalization and tumor uptake even without NEP/ACE-inhibition but with unfavorably high background radioactivity levels. Hence, unlike C-terminal modification, the introduction of a pendant ABD group in the linker turned out to be the most promising strategy toward metabolic stability, cell uptake, and tumor accumulation of [99mTc]Tc-DT1 mimics. To improve the observed suboptimal pharmacokinetics of [99mTc]Tc-DT9, the replacement of palmitoyl on Lys7 by other ABD groups is currently being pursued. [ABSTRACT FROM AUTHOR]

Background: Insulin degludec/insulin aspart (IDegAsp) is the first dual combination that acts separately (basal and prandial actions). Different insulin regimens can be switched to IDegAsp. Several studies have been conducted evaluating the effectiveness and safety of IDegAsp. The purpose of this real-life study was to determine the effects of IDegAsp on metabolic control and hypoglycemia in patients who were switched from different insulin regimens to IDegAsp therapy. Methods: We retrospectively analysed the data of 401 patients. Comorbid conditions, metabolic parameters, total insulin dose, injection frequency and hypoglycemia events were recorded. Baseline data were compared with post-IDegAsp data. Results: Of the 401 patients, 208 were females and 193 were males, with a mean age of 64.8 ± 10.5 years. The number of injections per day and total insulin doses decreased significantly (p < 0.001) at follow-up. Furthermore, a significant improvement in fasting blood glucose and HbA1c was observed 3, 6, 12 and 24 months after IDegAsp. The frequency of minor hypoglycemia decreased after switching to IDegAsp. Conclusions: IDegAsp reduces the frequency of hypoglycemia with fewer injections and less insulin dose and helps provide metabolic control safely. [ABSTRACT FROM AUTHOR]

B 5.3 Glucose-lowering therapy in patients with type 2 diabetes and previous cardiovascular events without heart failure b Which glucose-lowering agents should be considered as first-, second-, and third-line therapies for glycemic control in patients with type 2 diabetes and previous cardiovascular events and without heart failure? B 5.6 Choice of long-acting basal insulin b Question: Should long-acting basal insulin with longer duration (glargine U300 and degludec) be preferred to long-acting basal insulin with shorter duration (detemir and glargine U100) in patients with type 2 diabetes needing treatment with basal insulin? B 4.2 Group- and individual-based educational therapy b Question: Should group-based educational therapy be preferable in comparison with individual therapy for diabetes control in patients with type 2 diabetes? PHARMACOLOGICAL THERAPY b B 5.1 Glucose-lowering therapy in patients with type 2 diabetes and no previous cardiovascular events or chronic renal failure b Which glucose-lowering agents should be considered as first-, second-, and third-line therapies for glycemic control in patients with type 2 diabetes and no previous cardiovascular events or chronic renal failure? B 5.4 Glucose-lowering therapy in patients with type 2 diabetes and heart failure b Which glucose-lowering agents should be considered as first-, second-, and third-line therapies for glycemic control in patients with type 2 diabetes and heart failure?. [Extracted from the article]

Apart from advances in pharmaceutical antidiabetic agents, efforts are being made toward hypoglycemic agents derived from natural sources. Cinnamon has been reported to have significant benefits for human health, particularly as an anti-inflammatory, antidiabetic, and anti-hypertriglyceridemic agent. The phytochemicals in cinnamon can be extracted from different parts of plant by distillation and solvent extraction. These chemicals help in decreasing insulin resistance and can act against hyperglycemia and dyslipidemia, inflammation and oxidative stress, obesity, overweight, and abnormal glycation of proteins. Cinnamon has shown to improve all of these conditions in in vitro, animal, and/or human studies. However, the mechanism of action of active ingredients found in cinnamon remains unclear. The current review presents the outstanding ability of cinnamon derivatives to control diabetes by various pathways modulating insulin release and insulin receptor signaling. It was also found that the type and dosage of cinnamon as well as subject characteristics including drug interactions are likely to affect the response to cinnamon. Future research directions based on this review include the synergistic usage of various cinnamon derivatives in managing and/or preventing diabetes and possible other relevant chronic diseases. [ABSTRACT FROM AUTHOR]

People with type 2 diabetes receiving a second-generation basal insulin (BI) analog may be switched to a first-generation formulation for financial reasons or changes in health insurance. However, because second-generation BI analogs have more even pharmacokinetic profiles, longer durations of action (>24 vs. ≤24 hours), and more stable action profiles than first-generation BI analogs, such a change may result in suboptimal treatment persistence and/or adherence. This study compared treatment persistence, treatment adherence, rates of hypoglycemia, and health care resource utilization outcomes in people with type 2 diabetes who either continued treatment with the second-generation BI Gla-300 or switched to a first-generation BI. The study showed that continuing with Gla-300 was associated with a lower risk of discontinuing therapy, fewer emergency department visits, and lower hypoglycemia event rates than switching to a first-generation BI. [ABSTRACT FROM AUTHOR]

The article focuses the high cost of insulin is a serious problem for many people with diabetes. It mentions analog insulins are more expensive than human insulins, but there is no evidence that they are more effective. It highlights multiple studies have shown that human insulins are just as effective as analog insulins.

Durvillaea antarctica is the seaweed that is the most consumed by the Chilean population. It is recognized worldwide for its high nutritional value in protein, vitamins, minerals, and dietary fiber. This is a narrative review in which an extensive search of the literature was performed to establish the immunomodulator, cardiometabolic, and gut microbiota composition modulation effect of Durvillaea antarctica. Several studies have shown the potential of Durvillaea antarctica to function as prebiotics and to positively modulate the gut microbiota, which is related to anti-obesity, anti-inflammatory, anticancer, lipid-lowering, and hypoglycemic effects. The quantity of Bacteroides was negatively correlated with that of inflammatory monocytes and positively correlated with the levels of several gut metabolites. Seaweed-derived polysaccharides modulate the quantity and diversity of beneficial intestinal microbiota, decreasing phenol and p-cresol, which are related to intestinal diseases and the loss of intestinal function. Additionally, a beneficial metabolic effect related to this seaweed was observed, mainly promoting the decrease in the glycemic levels, lower cholesterol levels and cardiovascular risk. Consuming Durvillaea antarctica has a positive impact on the immune system, and its bioactive compounds provide beneficial effects on glycemic control and other metabolic parameters. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy of iGlarLixi in the Asian Pacific (AP) population with type 2 diabetes (T2D) using derived time‐in‐ranges calculated from seven‐point self‐measured blood glucose. Methods: Two phase III trials were analysed. LixiLan‐O‐AP was performed in insulin‐naive T2D patients (n = 878) randomized to iGlarLixi, glargine 100 units/mL (iGlar) or lixisenatide (Lixi). LixiLan‐L‐CN was performed in insulin‐treated T2D patients (n = 426) randomized to iGlarLixi or iGlar. Changes in derived time‐in‐ranges from baseline to end‐of‐treatment (EOT) and estimated treatment differences (ETDs) were analysed. The proportions of patients achieving 70% or higher derived time‐in‐range (dTIR), 5% or higher dTIR improvement, and the composite triple target (≥ 70% dTIR, < 4% derived time‐below‐the‐range [dTBR] and < 25% derived time‐above‐the‐range [dTAR]) were calculated. Results: The changes from baseline to EOT in dTIR with iGlarLixi were greater versus iGlar (ETD1: 11.45% [95% CI, 7.66% to 15.24%]) or Lixi (ETD2: 20.54% [95% CI, 15.74% to 25.33%]) in LixiLan‐O‐AP, and versus iGlar (ETD: 16.59% [95% CI, 12.09% to 21.08%]) in LixiLan‐L‐CN. In LixiLan‐O‐AP, the proportions of patients achieving 70% or higher dTIR or 5% or higher dTIR improvement at EOT with iGlarLixi were 77.5% and 77.8%, respectively, higher than with iGlar (61.1% and 75.3%) or Lixi (47.0% and 53.0%). In LixiLan‐L‐CN, the proportions of patients achieving 70% or higher dTIR or 5% or higher dTIR improvement at EOT were 71.4% and 59.8% with iGlarLixi, greater than with iGlar (45.4% and 39.5%). More patients achieved the triple target with iGlarLixi compared with iGlar or Lixi. Conclusion: iGlarLixi achieved greater improvements in dTIR parameters versus iGlar or Lixi in insulin‐naïve and insulin‐experienced AP people with T2D. [ABSTRACT FROM AUTHOR]