JOTHYDEV KESAVADEV, MD
JOTHYDEV’S DIABETES RESEARCH CENTER, TRIVANDRUM
www.jothydev.net
jothydev@gmail.com

Why do we require new generation Insulins?
The human Insulins though were excellent enough to reduce the blood sugars, had some serious drawbacks. Hence newer designer insulins are becoming popular nowadays. Insulin was discovered by Dr Frederick Banting and Dr Charles Best in 1921 and were awarded Nobel Prize for this priceless discovery in 1922. In January 1922, bovine insulin was first given to humans by injection. It was still so impure that as a result of the first insulin injection to the type 1 kid, Leonard Thompson, a 7.5 cm callus developed at the injection site on his left buttock. The co-discoverers, in particular James Collip, continued their work to purify the insulin extract to make it safer and more effective. Nevertheless, the quality of the insulin administered at that time was far from the quality of today’s   products. Since its discovery, insulin has become one of the most thoroughly studied molecules in scientific history. 

Evolution of Insulins
Animal Insulin
​During the initial few decades, the only available insulin was of animal origin.Some patients had religious concerns using pork and beef Insulins. In 1974, chromatographic purification techniques allowed the production of highly purified animal insulin. Before this development, porcine and bovine insulin at times caused antibody allergies, lipohypertrophy and lipoatrophy at injection sites. 

Human Insulin 
​After several years of laboratory work during the years 1963–1966 human insulin was chemically synthesized. In 1978, scientists succeeded in producing insulin with the same amino sequence as seen in humans. In 1980, recombinant DNA  human insulin was first tested followed by its FDA approval in 1982. The human Insulins whether they are regular Insulins or long acting or ultra-long acting need to be injected 30 minutes or more before the intake of food. Practically for almost all diabetes patients this timing of Insulin related to food intake is a major challenge. Due to the impending fear of low sugar or hypoglycaemia many patients were advised to inject human Insulin after the intake of food. This could be one of the reasons for unacceptably high HbA1c, fasting sugars and post prandial sugars which prevails in the general diabetes population.

Insulin Analogues
​Insulin analogues were developed in an attempt to overcome the problems associated with human insulin. Insulin analogue is a type of insulin that has been chemically modified to either act faster or slower than the type of insulin naturally made by the body to more quickly cover for meals or to make the insulin last longer thereby taking fewer injections. Analogues have been available for use by people with diabetes since the introduction of the first rapid-acting analogue, insulin Lispro, in the mid1990s. Analogue insulin is available in two main forms, rapid acting and long acting, as well as premixed combinations.Since 1996, different insulin analogues have been introduced worldwide.  A large number of additional analogue insulin formulas are currently being tested. Luckily in India we have all analogue insulins freely available in the market.

Long acting analogue Insulins
The long acting analogue Insulins replaces the earlier NPH insulin. Unlike human Insulin the long acting analogue Insulins like glargine (Lantus), detemir (Levemir) and the upcoming degludec (Tresiba) are all sufficiently long acting but still don’t have a significant peak. And due to this advantage, these injections are not related to meal timing of the patient and can either be taken before or after food. The only requirement is that it should be injected almost at the same time every day either at the morning or at the evening as per the directions of the treating diabetes team. When compared to NPH the absence of a peak also helps reduce the occurrence of hypoglycaemia. At the same time these long acting Insulins are capable of replacing the basal Insulin requirements in insulin requiring Type 1 and Type 2 diabetes subjects. The basal Insulins are now used for initiating insulins. The rapid acting insulins can be used in addition to basal insulins in a basal plus or a basal bolus regimen. Unlike the human basal insulin NPH, the analogue basal Insulins are clear solutions and does not require any mixing.

Rapid acting analogue Insulins
​The analogue rapid acting Insulins are gradually replacing the fast acting human Insulins. The commonly available once are Lispro(Humalog), Aspart (Novorapid),  Glulisine(Apidra).The major advantage of the rapid acting Insulins are its early peaking and shorter duration of action. When compared to human fast acting Insulins like Huminsulin R or Actrapid they need not be injected half an hour before food but only 10 or 15 minutes before food.In small children when the parents are not sure of the amount of calorie intake the injection can be taken even immediately after the intake of food.

        These rapid acting analogues are now preferred for use in insulin pumps as well and when used in the pump the rapid acting Insulins could be continuously and slowly delivered subcutaneously so that the same insulin will fulfil both bolus and basal requirements of the subject. Of the three Insulins available in the market, Aspart is the preferred rapid acting insulin in the pumps due to the least incidence of occlusion in the pump infusion set and also of its capability to withstand physical conditions like when the pump is in the vibratory mode.

Analogue Pre mix
​Similar to the human premix Insulins, Mixtard and Huminsulin, the analogue Insulins are also available in the premix form Eg.Novomix 30/70, 50/50. Here the 30percent will be rapid acting aspart and the long acting component will be the Protaminated Aspart with a longer duration of action. With the help of self-monitoring of blood glucose, and if required Continuous Glucose Monitoring, the analogue Insulins can be used in subjects at the required frequency to help avoid both hypoglycaemia and unwanted hyperglycaemias. Due to the rapidity of action and shorter duration of action, the rapid acting analogue insulins act as pre-dinner Insulin avoiding the occurrence of nocturnal hypoglycaemia. 

       Analogue Insulins are available in the Indian market for more than 10 years now. Though they have several advantages, the human Insulins are still popular in the global market due to the higher cost of analogue Insulins. Apart from the convenience in the timing of insulin shots, the analogue insulins have an edge over the human insulins in patients with Coronary Artery Disease, Peripheral Vascular Disease and Chronic Kidney Disease. These may be explained by the pleotropic actions of Insulin which include its anti-inflammatory properties.  Human Insulins like Mixtard 30/70, Insugens 30/70, Insuman 25/75 are all relatively cheap, highly purified and widely available. For the majority of patients and those with cost concerns human insulins should remain the insulin of first choice.