Conventional Insulin Research Articles

A Randomized, Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Novel Insulin Dimer.

Insulin molecules of size much greater than natural insulin have been synthesized and studied with the intention of widening the therapeutic window between adequate glycemic control and hypoglycemia as compared with conventional insulins. MK-1092 is a synthetic insulin dimer with favorable properties demonstrated in preclinical studies. Here, we report the results of the first-in-human, randomized, double-blind, active-control, single ascending dose trial of MK-1092, conducted in healthy adults, adults with type 1 diabetes (T1D), and adults with type 2 diabetes (T2D). MK-1092 was well tolerated in all study populations, and no dose-related adverse events were identified across the evaluated dose range (4-64nmol/kg). Circulating concentrations of MK-1092 were approximately dose-proportional. Maximum glucose infusion rate (GIR) and 24-hour time-weighted average GIR were evaluated under euglycemic clamp conditions. These pharmacodynamic measurements were approximately dose-proportional in all study populations; at similar doses, the GIR parameters were lower in adults with T2D than in healthy adults or adults with T1D, likely due to the influence of insulin resistance. At doses ≥16nmol/kg, MK-1092 had similar or greater effects than glargine 3nmol/kg (0.5 units/kg) on increasing GIR in each study population and on suppressing free fatty acids and ketone generation in adults with T1D. MK-1092 did not prevent a subsequent high dose of lispro from increasing the GIR in healthy adults. Additional studies in adults with T1D and T2D are needed to further evaluate the safety, tolerability, and efficacy profile of MK-1092 and its potential for differentiation from more conventional insulins. (ClinicalTrials.gov: NCT03170544).

Effect of human insulin and insulin analogue on some inflammatory markers and total antioxidant capacity in a sample of Iraqi type 1 diabetic children and adolescents

Background: Both human insulin and insulin analogue used in the treatment of type 1 diabetes mellitus. The modification in amino acids sequences of human insulin lead to produce analogue form which have a pharmacokinetic and pharmacodynamics effect near to normal human endogenous
 
 insulin release.
 Aim of study: This study designed to compare between the effect of each type of insulin on high sensitive C-reactive protein and interleukin-6 and total antioxidant capacity in a sample of Iraqi type 1 diabetic children and adolescents.
 Study design: The study was enrolled on fifty-one Iraqi type 1 diabetic children and adolecence age range (6-18) year. The patients allocated into two groups, Group (1) includes 20 patients assigned to receive conventional human insulin (regular and NPH), and Group (2) includes 20 patients assigned to receive insulin analogue (insulin aspart and glargine) for three months. The inflammatory and antioxidant markers measured at baseline and after three months of intervention.
 Results: After three months of treatment, both insulin groups did not affect high sensetive C_reactive protein (hs-CRP) significantly from baseline to 3 months. Only insulin analogue reduced Interleukin-6 (IL-6) significantly, while human insulin reduced level of IL-6 but it was not statistically significant. Both therapies reduced total antioxidant capacity (TAOC) significantly; however, insulin analogue had higher reduction percentage (15.1% vs. 5.7%) compared to the conventional insulin.
 Conclusion: Only insulin analogue reduced IL-6 significantly. Both types of insulins did not effect on hs-CRP. Both therapies reduce TAOC significantly.

Current advances and future prospects in production of recombinant insulin and other proteins to treat diabetes mellitus.

Diabetes mellitus is the most prevalent deadly disease caused by the destruction and dysfunction of pancreatic β cells that consequentially increased blood glucose levels. The management of this disease via external administration of insulin/insulin analogs has been difficult and challenging due to their limited production and accessibility at affordable prices. The conventional insulin production platforms (Escherichia coli, Saccharomyces cerevisiae and mammalian cell lines) with limited scalability and high upstream process costs have not been successful in meeting the rapidly increasing insulin demands. However, plants have been used as safe, scalable, environmentally friendly and cost-effective high capacity production platforms for recombinant orally delivered insulin. Recent technological advances in genome engineering and editing technologies for adequate insulin and insulin analogs production, renewable cellular sources of insulin through transplantation of islets or insulin-producing cells and reprogramming or differentiation of non β cells into β-like cells, used either alone or in combination, for diabetes containment are reviewed here along with their future prospects.

Adjuvant Probiotics of Lactobacillus salivarius subsp. salicinius AP-32, L. johnsonii MH-68, and Bifidobacterium animalis subsp. lactis CP-9 Attenuate Glycemic Levels and Inflammatory Cytokines in Patients With Type 1 Diabetes Mellitus.

IntroductionType 1 diabetes mellitus (T1DM) is characterized by autoimmune destruction of pancreatic β cells. Previous study has discovered that probiotic strains residing in the gut play essential roles in host immune regulation. However, few clinical results demonstrated probiotic would actually benefit in attenuating glycated hemoglobin (HbA1c) along with inflammatory cytokine levels of the T1DM patients and analyzed their gut microbiota profile at the same time. In this clinical trial, we evaluated the therapeutic efficacy of probiotics on HbA1c along with inflammatory cytokine levels of T1DM patients to determine an alternative administration mode for T1DM medication. The probiotics changed T1DM gut microbiota profile will be measured by next-generation sequencing (NGS).Research Design and MethodsA randomized, double-blind, placebo-controlled trial was performed at China Medical University Hospital. T1DM patients between 6 and 18 years of age were enrolled. 27 patients were administered regular insulin therapy plus capsules containing probiotic strains Lactobacillus salivarius subsp. salicinius AP-32, L. johnsonii MH-68, and Bifidobacterium animalis subsp. lactis CP-9 daily for 6 months, and 29 patients were administered insulin therapy without extra probiotic supplement as placebo group. The variations of fasting blood glucose and HbA1c in these patients were analyzed. In addition, serum levels of inflammatory cytokines and anti-inflammatory cytokine were assessed using enzyme-linked immunosorbent assay. Patients’ stool microbiota were all subjects to NGS analysis.ResultsNGS data showed elevated populations of Bifidobacterium animalis, Akkermansia muciniphila and Lactobacillus salivarius in the gut of patients with T1DM who were taking probiotics. Patients with T1DM who were administered probiotics showed significantly reduced fasting blood glucose levels compared with the before-intervention levels. The HbA1c levels of the patients also improved after administration of probiotics. The concentrations of IL-8, IL-17, MIP-1β, RANTES, and TNF-α were significantly reduced and were associated with an increased TGF-β1 expression after probiotic intervention. The persistence effect of glycemic control and immunomodulation were observed even 3 months after discontinuation of the probiotics.ConclusionsHere, we found that conventional insulin therapy plus probiotics supplementation attenuated T1DM symptoms than receiving insulin treatment only. Probiotics supplementation with insulin treatment changed gut microbiota and revealed better outcome in stabilizing glycemic levels and reducing HbA1c levels in patients with T1DM through beneficial regulation of immune cytokines. Clinical Trial Registration ClinicalTrials.gov, identifier NCT03880760.

The effect of COVID-19 lockdown on the glycemic control of children with type 1 diabetes

BackgroundBetween March 18th and May 13th 2020, the COVID-19 pandemic outbreak in Finland resulted in the closure of schools and the limitation of daycare (i.e. lockdown). Social distancing changed the daily routines of children with type 1 diabetes (T1D). Healthcare professionals were forced to adapt to the pandemic by replacing physical outpatient visits with virtual visits. However, the influence of the lockdown on glycemic control in these patients remained unknown.MethodsIn this retrospective register study from a pediatric diabetes outpatient clinic, we analyzed the glycemic data of T1D patients (n = 245; aged 4 to 16 years) before and under the lockdown. All the participants used continuous glucose monitoring (rtCGM or iCGM), two-thirds were on insulin pumps (CSII), and one-third on multiple daily insulin injections (MDI) therapy.ResultsIn our patient cohort, time in range (TIR, n = 209) and mean glucose levels (n = 214) were similar prior to and under the lockdown (mean change 0.44% [95%CI: -1.1–2.0], p = 0.56 and -0.13 mmol/mol [95%CI: -0.3–0.1], p = 0.17, respectively). However, children treated with CSII improved their glycemic control significantly during the lockdown: TIR improved on average 2.4% [0.6–4.2] (p = 0.010) and mean blood glucose level decreased -0.3 mmol/mol [-0.6-(-0.1)] (p = 0.008). The difference was more pronounced in girls, adolescents and patients using conventional insulin pumps.ConclusionsThe glycemic control in T1D children did not deteriorate under the lockdown, and patients on CSII even improved their control, which suggests that social distancing might have allowed families to use the insulin pump more accurately as out-of-home activities were on hold.

Rapid-acting insulin analogues: Theory and best clinical practice in type 1 and type 2 diabetes.

Since the discovery of insulin 100 years ago, insulin preparations have improved significantly. Starting from purified animal insulins, evolving to human insulins produced by genetically modified organisms, and ultimately to insulin analogues, all in an attempt to mimic physiological insulin action profiles seen in individuals without diabetes. Achieving strict glucose control without hypoglycaemia and preventing chronic complications of diabetes while preserving quality of life remains a challenging goal, but the advent of newer ultra-rapid-acting insulin analogues may enable intensive insulin therapy without being too disruptive to daily life. Ultra-rapid-acting insulin analogues can be administered shortly before meals and give better coverage of mealtime-induced glucose excursions than conventional insulin preparations. They also increase convenience with timing of bolus dosing. In this review, we focus on the progress that has been made in rapid-acting insulins. We summarize pharmacokinetic and pharmacodynamic data, clinical trial data supporting the use of these new formulations as part of a basal-bolus regimen and continuous subcutaneous insulin infusion, and provide a clinical perspective to help guide healthcare professionals when and for whom to use ultra-fast-acting insulins.

Significance of the CGM metric of time in range in children and adolescents with type 1 diabetes.

Continuous glucose monitoring (CGM) has been widely used in children and adolescents as well as adults with type 1 diabetes. CGM metrics include three key measurements of target glucose: time in range (TIR: 70-180 mg/dL), time below range (TBR: <70 mg/dL), and time above range (TAR: >180 mg/dL). The primary goal of optimal glycemic control is to increase TIR to more than 70%, while simultaneously reducing TBR to less than 4%, while minimizing severe hypoglycemia to less than 1%, as proposed by the Advanced Technologies and Treatments for Diabetes (ATTD) panel. However, several studies have indicated that the TIR goal is quite difficult to achieve in pediatric patients who have remarkable interindividual and day-to-day glycemic variation due to their irregular lifestyles. Previous studies have demonstrated that patients without an automated insulin delivery system are unlikely to attain the recommended glycemic goals. On the other hand, reduction of hypoglycemia, particularly minimizing severe hypoglycemia, is a critical issue in the effective management of children with type 1 diabetes. Frequent episodes of severe hypoglycemia and hypoglycemia can cause lasting neurological damage. Accordingly, we propose reducing the TBR to less than 5%, rather than just targeting the TIR to more than 70%. In CGM metrics this should be the cardinal glycemic goal for pediatric patients who are either being treated with multiple daily injections of insulin or a conventional insulin pump, but who are not using an automated insulin delivery system.

Insulin dysregulation as a prominent driver of cell cycle re-entry in Alzheimer's disease.

Cell Cycle Re-entry (CCR) is observed in several neurological disorders and contributes to cognitive impairment in the early stages. The CCR markers were monitored and correlated functionally with upregulation of Insulin Receptor (INSR) and Insulin like Growth factor 1 Receptor (IGF1R) in Alzheimer's Disease (AD) cell model and mouse brain tissue. The AD cell model was developed as per Majumder et al. (2019) and checked for Cyclin A, D and E Levels after 6 and 11 hours of model development in differentiated SHSY5Y cell line (with 10 µM RA and BDNF for cholinergic neuron like cells) by qPCR. We then checked for expression and activity of INSR and IGF1R in these cells and mouse brain (extracted from FFPE slides) through western blot and qPCR. To assess the correlation of the two events, we exploited overexpression based in-vitro studies for real-time assessment. Levels of INSR and IGF1R both increase on mRNA and protein levels in both cell and animal model. The cyclins A2, D and E however decline when the receptors are overexpressed in a serum free media for 6 hours and 11 hours. The time points were chosen to mimic the average mammalian cell cycle and showed that the upregulation of the receptors negatively impact and reduce cyclin D levels up to 4 fold whereas Cyclin A levels and Cyclin E levels are marginally reduced by 0.48 and 0.5 fold respectively. However, when stimulated with conventional ligands, Insulin and IGF1 or amyloid beta (1-42) the receptors positively correlate with the Cyclin levels. Western blots show that amyloid beta binding phosphorylates the pY1135/1136 of IGF1R, pY1150/1151 of INSR rather than conventional pY1158, 1162 and 1163. The reduction in conventional ligands, Insulin and IGF1 with ageing and build-up of amyloid beta which preferentially phosphorylates a different site could have implications that determines cellular fate after the re-entry. Reference: Majumder, P., Roy, K., Bagh, S. and Mukhopadhyay, D., 2019. Receptor tyrosine kinases (RTKs) consociate in regulatory clusters in Alzheimer's disease and type 2 diabetes. Molecular and cellular biochemistry, 459(1), pp.171-182.

Clinical benefits of empagliflozin in very old patients with type 2 diabetes hospitalized for acute heart failure.

There is little evidence on the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in older patients with heart failure. This work analyzed the clinical efficacy and safety of empagliflozin continuation in very old patients with type 2 diabetes hospitalized for acute decompensated heart failure. We conducted a real-world observational study between September 2015 and June 2021. Patients ≥80 years were grouped by antihyperglycemic regimen: (1) continuation of preadmission empagliflozin combined with basal insulin regimen and (2) conventional basal-bolus insulin regimen. A propensity score matching analysis matched patients in both groups in a 1:1 manner. The primary outcome was differences in clinical efficacy measured by the visual analogue scale dyspnea score, NT-proBNP levels, diuretic response, and cumulative urine output. Safety endpoints such as adverse events, worsening heart failure, discontinuation of empagliflozin, length of hospital stay, and in-hospital deaths were also analyzed. After propensity score matching, 79 patients were included in each group. At discharge, the N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were lower in the empagliflozin continuation group than in the insulin group (1699 ± 522 vs. 2303 ± 598 pg/ml, p= 0.021). Both the diuretic response and cumulative urine output were greater in patients treated with empagliflozin than in patients with basal-bolus insulin during the hospitalization (at discharge: -0.14 ± -0.06 vs. -0.24 ± -0.10, p= 0.044; and 16,100 ± 1510 vs. 13,900 ± 1220 ml, p= 0.037, respectively). No differences were observed in safety outcomes. In very old patients with type 2 diabetes hospitalized for acute heart failure, continuing preadmission empagliflozin reduced NT-proBNP levels and increased diuretic response and urine output compared to a basal-bolus insulin regimen. The empagliflozin regimen also showed a good safety profile.

Size matters: Influence of center size on quality of diabetes control in children and adolescents with type 1 diabetes-A longitudinal analysis of the DPV cohort.

BackgroundTreatment of patients with type 1 diabetes requires experience and a specific infrastructure. Therefore, center size might influence outcome in diabetes treatment.ObjectiveTo analyze the influence of center size on the quality of diabetes treatment in children and adolescents in Germany and Austria.Patients and methodsIn 2009 and 2018, we analyzed metabolic control, acute complications, and rates of recommended screening tests in the DPV cohort. Diabetes centers were classified according to the number of patients from “XS” to “XL” (<20 [XS], ≥20 to <50 [S], ≥50 to <100 [M], ≥100 to <200 [L], ≥200 [XL]).ResultsOver the 10‐year period, metabolic control improved significantly in “M”, “L” and “XL” diabetes centers. Treatment targets are best achieved in “M” centers, while “XS” centers have the highest mean hemoglobin A1c. The relation between hemoglobin A1c and center size follows a “v‐shaped” curve. In 2009, conventional insulin therapy was most frequently used in “XS” centers, but in 2018, there was no difference in mode of insulin therapy according to center size. Use of CSII and sensor augmented CSII/hybrid closed loop increased with center size. Patients cared for in “XS” diabetes centers had the fewest follow‐up visits per year. The rates of severe hypoglycemia and DKA were lowest in “XL” diabetes centers, and the rate of DKA was highest in “XS” centers.ConclusionCenter size influences quality of care in pediatric patients with type 1 diabetes. Further investigations regarding contributing factors such as staffing and financial resources are required.

Temporal Trends for Diabetes Management and Glycemic Control Between 2010 and 2019 in Korean Children and Adolescents with Type 1 Diabetes.

Purpose: There is increasing use of modern devices in the management of patients with type 1 diabetes (T1D). We investigated temporal trends for diabetes management and outcomes in Korean pediatric T1D patients over 10 years. Methods: We retrospectively collected the data from 752 participants (boys: 311, 41.4%) diagnosed with T1D and aged ≤18 years, with ≥1 year of follow-up between 2010 and 2019 in any of the seven study hospitals in Korea. Results: Over the 10-year study period, use of continuous glucose monitoring (CGM) increased from 1.4% to 39.3%. From 2010 to 2019, there was an increased use of multiple daily insulin injections (MDI; 63.9%-77.0%, respectively) and continuous subcutaneous insulin infusion (CSII; 2.1%-14.0%, respectively), but decreased use of conventional insulin therapy (CIT, 33.9%-9.0%, respectively). Mean glycated hemoglobin (HbA1c) decreased from 8.56% to 8.01% (P < 0.001) and was lower in younger patients, boys, and CGM users (P < 0.001). MDI and CSII users had lower mean HbA1c levels than CIT users (P = 0.003). Regarding the acute complications of T1D, CGM use was associated with lower incidences of diabetic ketoacidosis (P = 0.015); CSII users were likely to experience less severe hypoglycemia (P = 0.008). Conclusions: The use of CSII and CGM increased ∼7- and 30-fold, respectively, over the 10-year study period. The glycemic control of pediatric T1D patients in Korea improved from 2010 to 2019, probably because of increased use of T1D technologies.

Effects of Metformin on Hepatic Steatosis in Adults with Nonalcoholic Fatty Liver Disease and Diabetes: Insights from the Cellular to Patient Levels.

Nonalcoholic fatty liver disease (NAFLD) patients with diabetes constitute a subgroup of patients with a high rate of liver-related complications. Currently, there are no specific drug recommendations for these patients. Metformin, a conventional insulin sensitizer agent, has been widely prescribed in patients with diabetes. Metformin treatment has been shown to be effective at alleviating hepatic lipogenesis in animal models of NAFLD, with a variety of mechanisms being deemed responsible. To date, most studies have enrolled diabetic patients who are treated with metformin, with the drug being taken continuously throughout the study. Although evidence exists regarding the benefits of metformin for NAFLD in preclinical studies, reports on the efficacy of metformin in adult NAFLD patients have had some discrepancies regarding changes in liver biochemistry and hepatic fat content. Evidence has also suggested possible effects of metformin as regards the prevention of hepatocellular carcinoma tumorigenesis. This review was performed to comprehensively summarize the available in vitro, in vivo and clinical studies regarding the effects of metformin on liver steatosis for the treatment of adult NAFLD patients with diabetes. Consistent reports as well as controversial findings are included in this review, and the mechanistic insights are also provided. In addition, this review focuses on the efficacy of metformin as a monotherapy and as a combined therapy with other antidiabetic medications.

A multifaceted approach in leveraging electronic health record tools for safe inpatient use of concentrated U-500 insulin.

The Institute for Safe Medication Practices classifies subcutaneous insulin as a high-risk medication. Concentrated U-500 insulin carries additional risks in comparison to conventional U-100 insulin, as the 5-fold more concentrated nature of this product, limitations to insulin pen dosing, and various devices for dose measurement may lead to miscommunication of patient-reported doses, resulting in downstream errors in ordering, verification, or administration. We describe a multifaceted approach to leveraging technical tools within the electronic health record (EHR) for U-500 insulin use. At Cleveland Clinic, the U-500 insulin use process evolved in a number of phases using EHR tools. Phase 1 included new clinical decision support and documentation tools during order entry, including a customized alert that fired during order entry recommending that the prescriber order a consult with endocrinology and requiring the prescriber to provide the patient's home insulin measuring device and the source of the patient's reported home dose. In order verification, a customized alert fired directing the pharmacist to contact the patient or patient's nurse and validate the information provided by the prescriber. Phase 2 involved transitioning dispensing of patient-specific doses from tuberculin syringes to U-500 insulin syringes. Phase 3 transitioned to use of U-500 insulin pens and included automatic dose rounding of ordered doses down to the nearest 5 units, and an additional customized pharmacist alert intended for cost conservation was added to fire if the patient had a recent administration of U-500 insulin documented, directing the pharmacist to determine whether the nurse needed a new pen dispensed. Cleveland Clinic successfully implemented customized tools and processes within the EHR pertaining to the prescribing, verification, dispensing, and administration of U-500 insulin.

Impact of OMNIPOD® on the quality of life of adolescents with type 1 diabetes

IntroductionSeveral pediatric studies have demonstrated that therapy using a conventional insulin pump improves glycemic control and quality of life. At the beginning of this study, a new tubeless insulin pump, Omnipod®, had recently been marketed in France. ObjectivesAnalyze the response of adolescents treated with multiple injections to the proposal to use this new medical device and compare both the quality of life and the glycemic control of adolescents according to their choice. Material and MethodsThis was a prospective, observational study of adolescents aged 10–17 years who had type 1 diabetes for more than 1 year, all treated with multi-injection insulin delivery according to a basal-bolus regimen. They were separated into three groups: group A choosing to use the Omnipod® system, group B taking the time to think before making a decision, and group C choosing to keep their multi-injection therapy. The three groups were compared according to their quality of life with validated tools and glycemic control. ResultsGroups were formed with 30 (25%) patients in group A, 55 patients (45%) in group B, and 36 patients (30%) in group C. As to the WHO Well-Being Index, no significant difference appeared in the study for the patients in the three groups. An increased treatment satisfaction score was found, evolving from 3.79 ± 0.68 to 4.36 ± 0.56, p = 0.002 (group A) and from 3.87 ± 0.7 to 4.16 ± 0.7, p = 0.032 (group B), with no significant change for group C (from 4.39 ± 0.6 to 4.31 ± 0.62, p = 0.582). The wish to change treatment score improved for group A (from 4.14 ± 0.88 to 1.68 ± 0.9; p < 0.001) and group B (from 3.51 ± 1.05 to 1.84 ± 1; p < 0.001), with no significant change for group C (from 1.81 ± 0 0.98 to 1.61 ± 0.8; p = 0.432). There was no significant difference regarding HbA1c rates in the three groups. ConclusionThere was no significant difference in quality-of-life scores between adolescents who chose to switch from multiple injection to the tubeless patch pump and those who retained multi-injection treatment, but increased satisfaction was observed in the former group.

Tetrahedral Framework Nucleic Acids Reverse New-Onset Type 1 Diabetes.

Type 1 diabetes (T1D) is caused by breakdowns of central and peripheral immune tolerance and destructions of insulin-producing β-cells. Conventional insulin injection cannot cure the disease. Regulatory immune cells, including regulatory T-cells (Tregs) and regulatory B-cells (Bregs), play critical roles in immune tolerance. Inducing regulatory immune cells to halt the progress of T1D and restore immune tolerance is the promising approach in T1D immunotherapy. Here, tetrahedral framework nucleic acids (tFNAs) were utilized to treat T1D in non-obese diabetic (NOD) mice. 250 nM tFNA treatment was adopted in the experiment to reverse hyperglycemia and protect insulin-secreting β-cells in diabetic NOD mice. In addition, 250 nM tFNA treatment could induce Tregs and Bregs and suppress helper T (Th)-cells in the pancreas. In the pancreas, cytokines, as a significant signal during CD4+ T-cell differentiation, directly direct the differentiation programs. Apart from cytokines directing the differentiation of T-cells, the signal transducer and activator of transcription (STAT) signal is strongly associated with T-cell differentiation and T1D progression. We demonstrated tFNA treatment inducing regulatory immune cells probably by increasing TGF-β levels and the STAT signal. To sum up, 250 nM tFNA treatment could protect the diabetic NOD mice from hyperglycemia and preserve the functions of β-cells by restoring peripheral immune tolerance. The possible mechanism of inducing immune tolerance was related to the STAT signal and cytokine changes in the pancreas. Moreover, immunoregulation capabilities of tFNAs were demonstrated in the experiment, which set the foundation of tFNAs participating in further antigen-specific immunotherapies.

A prospectively randomized controlled study of the effects of intensive insulin therapy combined with glutamine on nutritional metabolism, inflammatory response, and hemodynamics in severe burn patients

Objective: To observe the effects of intensive insulin therapy combined with glutamine on nutritional metabolism, inflammatory response, and hemodynamics in severe burn patients. Methods: Thirty-two severe burn patients who met the inclusion criteria and hospitalized in the Affiliated Huaihai Hospital of Xuzhou Medical University from June 2017 to January 2019 were recruited into a prospectively randomized controlled study. According to the random number table, the patients were divided into conventional insulin therapy alone group, conventional insulin therapy+glutamine group, intensive insulin therapy alone group, and intensive insulin therapy+glutamine group, with 8 patients in each group, with genders of 5 males and 3 females, 4 males and 4 females, 3 males and 5 females, 4 males and 4 females, and ages of (35±7), (36±9), (33±11), and (38±7) years, respectively. Patients in conventional insulin therapy alone group were treated with conventional insulin therapy on the basis of routine treatment to control the blood glucose. Patients in conventional insulin therapy+glutamine group were supplemented with alanyl-glutamine for more than 14 days in addition to the treatment in conventional insulin therapy alone group. Patients in intensive insulin therapy alone group were treated with intensive insulin therapy on the basis of routine treatment to control the blood glucose. Patients in intensive insulin therapy+glutamine group were supplemented with alanyl-glutamine in addition to the treatment in intensive insulin therapy alone group. On treatment day (TD) 1, 3, 7, and 14, the blood glucose, albumin, prealbumin, white blood cell count, procalcitonin (PCT), and C-reactive protein (CRP) of patients in the 4 groups were detected. The cardiac index (CI), stroke volume index (SVI), global end-diastolic volume index (GEDVI), systemic vascular resistance index (SVRI), extravascular lung water index (EVLWI), and pulmonary vascular permeability index (PVPI) of patients in the 4 groups on TD 1, 3, and 7 were measured. Data were statistically analyzed with Fisher's exact probability test, one-way analysis of variance, analysis of variance for repeated measurement, and Bonferroni method. Results: All patients in the 4 groups successfully completed the study, and there were no withdrawal cases. On TD 3, 7, and 14, the blood glucose of patients in intensive insulin therapy alone group ((5.9±1.3), (5.8±0.6), (5.5±0.5) mmol/L) and intensive insulin therapy+glutamine group ((5.9±1.1), (5.6±1.1), (5.2±0.8) mmol/L) were significantly lower than those in conventional insulin therapy alone group ((9.1±0.5), (8.4±0.9), (7.4±1.1) mmol/L, P<0.05). Compared with those in conventional insulin therapy alone group, the levels of albumin of patients in conventional insulin therapy+glutamine group, intensive insulin therapy alone group, and intensive insulin therapy+glutamine group were significantly increased on TD 7 and 14 (P<0.05). Compared with the level of albumin of patients in intensive insulin therapy+glutamine group, the levels of albumin of patients in conventional insulin therapy+glutamine group and intensive insulin therapy alone group were significantly decreased on TD 14 (P<0.05). Compared with those in conventional insulin therapy alone group, the levels of prealbumin of patients in conventional insulin therapy+glutamine group and intensive insulin therapy alone group were significantly increased on TD 7 and 14 (P<0.05). Compared with those in intensive insulin therapy+glutamine group, the levels of prealbumin of patients in intensive insulin therapy alone group and conventional insulin therapy+glutamine group were significantly decreased on TD 1, 7, and 14 (P<0.05). There were no statistically significant differences in the white blood cell count, PCT, and CRP of patients in the 4 groups in pairwise comparison between groups on TD 1, 3, 7, and 14 (P>0.05). On TD 3 and 7, the levels of cardiac index, SVI, GEDVI, and SVRI of patients in intensive insulin therapy+glutamine group were significantly higher than those in conventional insulin therapy alone group (P<0.05), while the levels of EVLWI and PVPI were significantly lower than those in conventional insulin therapy alone group (P<0.05). Conclusions: Glutamine combined with intensive insulin therapy can improve the hypermetabolism in patients after severe burns, reduce the decomposition and consumption of endogenous nutrient substrates, and at the same time help the recovery of cardiac function and maintenance of hemodynamic stability.

Efficacy and Safety of Insulin Degludec/Insulin Aspart Compared with a Conventional Premixed Insulin or Basal Insulin: A Meta-Analysis.

Insulin degludec/insulin aspart (IDegAsp) is a novel co-formulation of 70% insulin degludec and 30% insulin aspart. The present meta-analysis was conducted to assess the efficacy and safety of IDegAsp compared with a conventional premixed insulin or basal insulin. We extracted data from citation databases, including PubMed, EMBASE, and the Cochrane Library, since inception to 2021. We calculated the mean differences for hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), self-measured mean glucose, and postprandial glucose (PPG) and odds ratios for confirmed hypoglycemia events. Compared with twice-daily conventional premixed insulin, twice-daily IDegAsp showed a similar effect on changes in HbA1c, but it significantly reduced FPG and self-measured mean glucose levels. Furthermore, compared to once-daily basal insulin, once-daily IDegAsp had a similar effect on changes in HbA1c, but it significantly reduced self-measured mean glucose and PPG levels. The risk of overall confirmed hypoglycemia was similar between treatments; however, the risk of nocturnal hypoglycemia events was significantly lower with IDegAsp than with conventional premixed insulin and basal insulin. Thus, IDegAsp was more effective than conventional premixed insulin and basal insulin at reducing blood glucose with fewer nocturnal hypoglycemia events.

A Comprehensive Review of Intranasal Insulin and Its Effect on the Cognitive Function of Diabetics.

Diabetes mellitus continues to be a disease that affects a good percentage of our population. The majority affected need insulin on a day-to-day basis. Before the invention of the first manufactured insulin in 1978, dealing with diabetes took a significant toll on patient's lives. As technology and human innovation prevail, significant advancements have taken place in managing this chronic disease. Patients have an option to decide their mode of insulin delivery. Intranasal insulin, one such form, has a rapid mode of action while effectively controlling postprandial hyperglycemia. It has also been proven to reduce hypoglycemia and insulin resistance problems, which seem to be the main adverse effects of using conventional insulin regularly. However, due to the large dosages needed and high incurring costs, Intranasal Insulin is currently being used as adjunctive therapy along with conventional insulin. We conducted a literature search in PubMed indexed journals using the medical terms "Intranasal insulin," "diabetes," and "cognitive impairment" to provide an overview of the mechanism of action of Intranasal Insulin, its distinctive cognitive benefits, and how it can be compared to the standard parenteral insulin therapy. One unique feature of intranasal insulin is its ability to directly affect the central nervous system, bypassing the blood-brain barrier. Not only does this help in reducing the peripheral side effects of insulin, but it has also proven to play a role in improving the cognitive function of diabetics, especially those who have Alzheimer's or mild cognitive impairment, as decreased levels of insulin in the brain has been shown to impact cognitive function negatively. However, it does come with its limitations of poor absorption through the nasal mucosa due to mucociliary clearance and proteolytic enzymes, our body's natural defence mechanisms. This review focuses on the efficacy of intranasal insulin, its potential benefits, limitations, and role in cognitive improvement in people with diabetes with pre-existing cognitive impairment.

Dual-hormone artificial pancreas for management of type 1 diabetes: Recent progress and future directions.

Over the last few years, technological advances have led to tremendous improvement in the management of type 1 diabetes (T1D). Artificial pancreas systems have been shown to improve glucose control compared with conventional insulin pump therapy. However, clinically significant hypoglycemic and hyperglycemic episodes still occur with the artificial pancreas. Postprandial glucose excursions and exercise-induced hypoglycemia represent major hurdles in improving glucose control and glucose variability in many patients with T1D. In this regard, dual-hormone artificial pancreas systems delivering other hormones in addition to insulin (glucagon or amylin) may better reproduce the physiology of the endocrine pancreas and have been suggested as an alternative tool to overcome these limitations in clinical practice. In addition, novel ultra-rapid-acting insulin analogs with a more physiological time-action profile are currently under investigation for use in artificial pancreas devices, aiming to address the unmet need for further improvements in postprandial glucose control. This review article aims to discuss the current progress and future outlook in the development of novel ultra-rapid insulin analogs and dual-hormone closed-loop systems, which offer the next steps to fully closing the loop in the artificial pancreas.

The effects of exercise training versus intensive insulin treatment on skeletal muscle fibre content in type 1 diabetes mellitus rodents

BackgroundIntensive-insulin treatment (IIT) strategy for patients with type 1 diabetes mellitus (T1DM) has been associated with sedentary behaviour and the development of insulin resistance. Exercising patients with T1DM often utilize a conventional insulin treatment (CIT) strategy leading to increased insulin sensitivity through improved intramyocellular lipid (IMCL) content. It is unclear how these exercise-related metabolic adaptations in response to exercise training relate to individual fibre-type transitions, and whether these alterations are evident between different insulin strategies (CIT vs. IIT). Purpose: This study examined glycogen and fat content in skeletal muscle fibres of diabetic rats following exercise-training.MethodsMale Sprague-Dawley rats were divided into four groups: Control-Sedentary, CIT- and IIT-treated diabetic sedentary, and CIT-exercised trained (aerobic/resistance; DARE). After 12 weeks, muscle-fibre lipids and glycogen were compared through immunohistochemical analysis.ResultsThe primary findings were that both IIT and DARE led to significant increases in type I fibres when compared to CIT, while DARE led to significantly increased lipid content in type I fibres compared to IIT.ConclusionsThese findings indicate that alterations in lipid content with insulin treatment and DARE are primarily evident in type I fibres, suggesting that muscle lipotoxicity in type 1 diabetes is muscle fibre-type dependant.