Symposium: New horizons in the treatment of type 1 diabetes mellitus. New insulins. Smart insulin

Abstract

In 1921, Dr. Banting's impressive intuition led to discovery and subsequent crystallization of insulin in Toronto University. Its administration to the patient Leonard Thompson marked a historic milestone in humanity and immediately determined a scientific success which translated into therapeutic benefits for millions of patients diagnosed with diabetes.

However, transformation of this molecule into a safe drug that would solve the need for an adequate physiological replacement for endogenous insulin is still a long ongoing process.

In 1936, Hagerdon and Jensen discovered that adding protamine, a protein obtained from river trout semen, could extend insulin median lifespan. In 1946, an intermediate acting insulin (NPH), which includes insulin and protamine crystals, was developed at Novo Nordisk Lab. In 1959, due to a high level of allergic reactions to bovine derived insulin, Yalow and Salomon thought "humanized" insulin should be used. Moreover, there was an issue with the amount of bovine and porcine pancreas supply as raw material not being enough. Towards 1973, early "monocomponent" purified animal insulins were manufactured.

In 1980, a big leap forward was given by Genentech company, after Goeddel’s and Riggs' publication, while obtaining human insulin protein via recombinant DNA in Escherichia Coli culture technology. In 1982, the first insulin human obtained from recombinant DNA at a big scale was produced by Lilly Lab. Subsequently, Novo Nordisk achieved the same result by using Saccharomyces Cerevisiae cultures. (1-2)

In 1996, faster acting analog insulin with a L-lysine and L-proline switched position in its B chain was developed by Lilly. Also, fast-acting insulin with L-proline replaced by aspart at position B 28 was developed by Novo Nordisk. Later, Sanofi Lab obtained a fast analog with a switched position of amino-acids at position B 3 of L-asparagine for lysine and lysine at position B 29 for glutamine.

As regards long-acting analog insulins, Sanofi Lab achieved a long-acting analog by replacing asparaginase for glycine on the α chain and adding arginine residues on the β chain. L-arginine changes the isoelectric point of a molecule, going from a 5,4 pH to 6,7, making it more soluble at acid pH and less at physiological ph. In 2005, a long-acting analog was developed by Novo Nordisk, which is called insulin Detemir. It was created by adding a 14-carbon fatty acid (myristic acid) at position B 29 and suppressing L-threonine at position 30.  This determines insulin bonding to albumin in a reversible manner^1-2.

By the end of this decade, long-acting insulin analogs of a second generation finally appeared, such as insulin Degludec, in which threonine at position B 30 was removed and a 16-carbon fatty acid was added to lysine at position B 29 via a spacer glutamic acid, which allowed a prolonged action up to almost 42 h³. Subsequently, Sanofi developed concentrated insulin Toujeo in 300 U, which facilitated its diffusion process at a lower injection volume. Last year, concentrated insulin Degludec in 200 U was manufactured⁴.

Since 2017, new ultra-rapid-acting insulin alternative trials started to be available: insulin Fiasp^5,6,7 and ultra-rapid-acting insulin lispro⁸. In the first case, niacinamide was added to the insulin molecule, modifying absorption rate and also arginine was added, acting like a molecule stabilizer. By performing these modifications, more exposure to insulin in the area under the curve in the first 30 minutes, as compared to faster insulin aspart, was achieved twice. A similar situation occurred with ultra-rapid-acting insulin lispro (insulin lispro –aabc), using Treprostinil (a vasodilator) and citrate, which increases vascular permeability accelerating the apparition of insulin in blood by 8 minutes. In patients diagnosed with T1D, ultra-rapid-acting insulin lispro reduces postprandial glycemic excursion by 30-40% compared to insulin lispro.

However, one of the most promising changes lately was obtaining long-duration insulins that can be used weekly. One of the companies involved was Lilly by using insulin joined to an immunoglobulin Fc fragment (IgF2 FC). Other studies involved insulin PEGylated and finally, insulin icodec was developed by Novo Nordisk. It featured a threonine terminal remotion at position 29 in chain B and replacement of 3 amino acids (A14E,B16H,yB25H), joined via a spacer or hydrophilic linker to a 20-carbon fatty diacid. After injection, insulin hexamers dissociate in monomers and join albumin to create an inactive deposit strongly tied, reducing enzymatic degradation and mitigating a bond to receptor and insulin clearance. Afterwards, the molecule begins to slowly release monomers and after 3 to 4 weekly injections, equilibrium is achieved by a frequent release of insulin icodec of albumin.