Prolonged control of insulin-dependent diabetes via intramuscular expression of plasmid-encoded single-strand insulin analogue

Daily insulin injection is necessary for the treatment of the insulin-dependent diabetes. However, the process is painful and inconvenient. Accordingly, we have made exploratory efforts to establish an alternative method for continuous insulin supply via intramuscular injection of a designed plasmid encoding the single-strand insulin analogue (SIA), which provides safe, effective and prolonged control of insulin-dependent diabetes. To generate a SIA, a short flexible peptide was alternatively introduced into the natural proinsulin to replace its original long and rigid C-peptide. Then, the synthetic promoter SP301 was used to drive potent and specific expression of SIA in skeletal muscle cells. By combining the Pluronic L64 and low-voltage electropulse (L/E), the specialized gene delivery technique was applied to efficiently transfer the constructed plasmid into skeletal muscle cells via intramuscular injection. Through these efforts, a plasmid-based intramuscular gene expression system was established and improved, making it applicable for gene therapy. The plasmid-expressed SIA showed biological functions that were similar to that of natural insulin. A single L/E-pSP301-SIA administration provided sustained SIA expression in vivo for about 1.5 months. In addition, the diabetic mice treated with L/E-pSP301-SIA were much healthier than those with other treatments. This plasmid-based system was safe for the treatment of diabetes and did not cause immune responses or pathological damage. The results confirmed that, in a mouse model, long-term positive effects were achieved by a single intramuscular L/E-pSP301-SIA injection, which consequently provided reliable experimental basis for its clinical application for the treatment of diabetes mellitus with promising prospects.

Glycated haemoglobin reduction and fixed ratio combinations of analogue basal insulin and glucagon-like peptide-1 receptor agonists:A systematic review

BACKGROUND Fixed ratio combinations(FRCs)of analogue basal insulin and glucagon-like peptide-1 receptor agonists are a newer addition to the therapeutic armamentarium for the management of type 2 diabetes mellitus.They reduce treatment complexity by combining two injectables in a single daily injectable,thus potentially improving adherence and persistence.Clinicians wanting to use FRCs would need to choose between members of the class.AIM To describe and contrast the glycated haemoglobin reduction of two FRCs of analogue basal insulin and glucagon like peptide-1 receptor agonist in adults with type 2 diabetes mellitus.METHODS The following Population,Intervention,Comparison,Outcome question was used for the primary analysis:Among adult patients with type 2 diabetes mellitus[P],what is the effect of iGlarLixi[I]compared to IDegLira[C]for bringing about glycaemic control(as measured by reduction in glycosylated haemoglobin)[O]?The Prisma Statement was used as a guideline for framing this systematic review.We searched PubMed,EMBASE and Cochrane library databases and Clinicaltrials.gov using various keywords and medical search headings related to type 2 diabetes mellitus,iGlarlixi,IDegLira and glycated haemoglobin A1c.RESULTS All 14 studies identified by the systematic search met the primary efficacy endpoint of reduction in glycated haemoglobin.There were no head-to-head studies between the FRCs of iGlarlixi and IDegLira,and we therefore did an indirect comparison based on a common comparator of insulin glargine U100.Both iGlarLixi and IDegLira effectively reduce glycated haemoglobin when compared to insulin glargine U100.However,using indirect comparisons,IDegLira had a greater haemoglobin A1c reducing ability(0.6%vs 0.3%).The indirect comparison is limited by the differences between the studies;the fasting blood glucose targets were slightly higher for iGlarLixi studies when compared to the IDegLira studies(4.0-5.0 mmol/L and 4.4-5.6 mmol/L),and the IDegLira study used a greater average dose of insulin glargine when compared to the iGlarLixi studies(66 U/d vs 40 U/d).CONCLUSION Both iGlarLixi and IDegLira effectively reduce glycated haemoglobin.Indirect comparisons,using insulin glargine as the common comparator,suggest that IDegLira reduces glycated haemoglobin to a greater extent than iGlarLixi.However,given the limitations of indirect comparisons,robust head to head studies and real-world data would better inform clinician choice and clinical practice guidelines.

A 2-way cross-over,open-labeled trial to compare efficacy and safety of insulin Aspart and Novolin R delivered with CSII in 21 Chinese diabetic patients

Background Subcutaneous absorption is accelerated by the monomeric conformation of insulin Aspart, which provides good glycemic control with a lower risk of hypoglycemia and less body weight increase. In the present study we investigated the efficacy and safety of a rapid-acting human insulin analogue （insulin Aspart） delivered with continuous subcutaneous insulin infusion （CSII） into Chinese diabetic patients. Methods A total of 21 patients with type 1 or type 2 diabetes were recruited for the 2-way cross-over, open-labeled trial, and then randomized to Group A （n=-10, treated with insulin Aspart） or Group B （n=11, treated with Novolin R）. Insulin Aspart and Novolin R were administered by CSII. Capillary glucose concentrations were measured at 8 time points, pre-prandial and postprandial, bedtime （10 pm）, midnight （2 am） every day during the treatment. Results The average capillary glucose profiles for the day were much better controlled in Group A than in Group B （P〈0.01）. The blood glucose levels were particularly better controlled in Group A than in Group B at pre-breakfast （（6.72±1.24） mmol/L vs （7.84±1.58） mmol/L, P=0.014）, post-breakfast （（8.96±2.41） mmol/L vs （11.70±3.11） mmol/L, P=0.0028）, post-supper （（8.15±2.10） mmol/L vs （10.07±2.36） mmol/L, P=0.008）, bed time （（7.73±1.72） mmol/L vs （9.39±.2.05） mmol/L, P=0.007） and midnight （（6.32±1.16） mmol/L vs （7.48±1.36） mmol/L, P=0.0049）. There was no significant difference in the frequency of hypoglycemic episodes between the two groups. Conclusion Insulin Aspart results in better control of blood glucose levels than regular human insulin （Novolin R） in diabetic patients during delivery by CSII.