What is Human Recombinant Insulin?

Keywords

Insulin, recombinant human insulin, manufacturing process, bioequivalence, clinical studies, Insuman formulations, NPH insulin, premix insulin, review.

Introduction

Recombinant human insulin was one of the first products of biotechnology. Insulin replacement therapy is the early standard of care for patients with type 1 and type 2 diabetes mellitus. Recombinant human insulin replaced the animal insulins and semisynthetic insulins obtained by modification of animal insulins.

With the development of recombinant DNA technology, recombinant (biosynthetic) human insulin became available in large amounts by biosynthesis in microorganisms (Escherichia coli, yeast) providing reliable supplies of the hormone worldwide at affordable costs. Insulin, recombinant human (rHu) is identical in function and structure to the native human sequence. A hormone consisting of two polypeptide chains, rHu Insulin′s A-chain (21 amino acids) and B-chain (30 amino acids) are covalently linked by disulfide bonds between cysteine residues.

Three recombinant insulins (Insuman®, Humulin®, Novolin®) were independently established. Bioequivalence studies were required for regulatory approval. Human insulin for Humulin and Insuman are produced by fermentation in bacteria (Escherichia coli) and for Novolin in yeast (Saccharomyces cerevisiae) for therapeutic use in humans.

Transgenic plants are also used to produce insulin in large quantities for therapeutic use in humans. The rapid increase in the number of diabetic patients globally and current manufacturing technologies escalate the demand for recombinant insulin in near future and its use in therapy.

Clinical Studies with Recombinant Human Insulins

The initial clinical studies with recombinant human insulins (Humulin, Novolin®, Insuman) explored the change from animal insulin to semisynthetic insulin and to recombinant human insulin formulations. Clinical studies in patients with type 1 or type 2 diabetes included pediatric and pregnant subjects.

Safety aspects comprised the incidence of hypoglycemia, the decreasing glucose levels and the level of hypersensitivity reactions, injection-site reactions, and adverse events. Glycemic targets (glycated hemoglobin [HbA1c], fasting blood glucose [FBG]) were usually taken into consideration. Insulin dose titration did not yet follow a fasting treat-to-target concept at that time.

Humulin and Novolin

The pharmaceutical formulations of recombinant human insulins provided by the key manufacturers include soluble regular insulin, crystalline NPH insulin and premixed formulations (soluble insulin and NPH insulin in fixed ratios).

The formulations were found to be bioequivalent and similar in efficacy and safety to those of semisynthetic insulin. Clinical studies with semisynthetic and recombinant insulin derived from baker’s yeast (Novolin) showed similar profiles in efficacy and safety and established that patients with diabetes can be safely and effectively transferred from semisynthetic human insulin to recombinant human insulin with no change expected in the insulin dose.

Clinical pharmacology studies with recombinant human insulin produced by fermentation in E. coli (Humulin) established bioequivalence of semisynthetic and recombinant Humulin formulations. Extensive clinical studies were performed in patients with type 1 and type 2 diabetes to confirm consistent clinical efficacy when transferring patients to the recombinant formulations.

Insuman

Recombinant Insuman was approved in Europe in 1997 and launched in 1999. The formulations comprise regular soluble insulin (Insuman Rapid), an intermediate-acting insulin suspension that contains isophane insulin (Insuman Basal), and premixed combinations of regular insulin and intermediate-acting insulin (Insuman Comb).

When clinical studies with recombinant Insuman were conducted in patients with type 1 and type 2 diabetes investigating the efficacy and safety of the change from semisynthetic insulin to recombinant Insuman, and in comparison, with recombinant insulin formulations of Huminsulin®. Both recombinant and semisynthetic human insulin achieved a similar decrease of HbA1c and FBG.

There has been no difference of hypoglycemia in patients previously treated with animal insulins after changing to semisynthetic or recombinant human insulins. This proves that there is improvement in glycemic control and good tolerability with Insuman in type 1 and type 2 diabetes patients comparable to comparator treatment.

In addition, no difference in immunogenicity between Insuman and Huminsulin or semisynthetic insulin was found, an important characteristic of recombinant insulin formulations.

Clinical Use of Recombinant Human Insulin Formulations

Recombinant rDNA technology has enabled a worldwide human insulin supply of consistent high quality. Recombinant human insulin has proved effective and safe in the long term. Hypoglycemia associated with insulin treatment remains one of the major challenges during therapy to minimize the risk. Self-monitoring of fasting and post-prandial blood glucose are helpful tools to avoid or reduce hypoglycemia and to maintain blood glucose values in the target range. Therefore, patient education and guidance are a general task of insulin therapy to ensure a continued adherence to therapy and good metabolic control.

Applications

Insulin is essential for the growth of cell lines. When insulin is absent, cells may exhibit disturbances in morphology and growth rate. Recombinant human insulin has been used for induction of mesenchymal stem cells.

Use in Pregnancy and Gestational Diabetes

Human insulin is the standard of care in pregnant women. The condition of gestational diabetes has received much attention because there are established treatment options with insulin during pregnancy.

Consistent glucose monitoring and dose adaptation is important throughout pregnancy and counselling needs to be established within the program of pregnancy care for mothers with diabetes. The use of human insulin and Insuman formulations during pregnancy has been monitored and found to be safe. Gestational diabetes develops during pregnancy and may disappear after delivery.

Pediatrics

The change from animal insulin to recombinant human insulin has an advantage in pediatric population because the decrease in manifestations of antigenicity is particularly relevant in children. Consistent glucose monitoring is required because of the widely varying dose requirement and distinct changes in insulin requirement during the growth period of children.

Recombinant Human Insulin in Diabetes Therapy

Human insulin formulations have advantages in the therapy of type 1 and type 2 diabetes. The need for action is particularly urgent in type 2 diabetes. The use of insulin has certain advantages in reducing hypoglycemic episodes. The essential conditions for improving therapy are glucose monitoring, its frequent implementation, and continuing patient education about insulin injection technique. Considering worldwide awareness that early implementation of insulin therapy can prevent or delay diabetes complications, access to affordable insulin therapy is the predominant factor when considering recombinant human insulin formulations.

Conclusion

Insulin is a scarce commodity, with global demands projected to rise due to increasing prevalence of diabetes. Insulin regulates the cellular uptake, utilization, and storage of glucose, amino acids, and fatty acids and inhibits the breakdown of glycogen, protein, and fat. The chronic nature of diabetes means that patients require long-term insulin treatment.

Continuing patient education support programs on disease management and correct use of human insulins are essential for a key role of recombinant human insulins in diabetes treatment. Recombinant human insulin has been the standard of care and effective alternatives to insulin analogues in countries with limited healthcare systems and limited resources.

Efficacy of diabetes therapy with recombinant human insulin formulations is well established, this is the predominant concern for diabetes therapy in countries where affordability remains an important selection factor.