over the past few decades continuous progress has been made in the development of insulin therapy . the need for basal insulin was felt around 60 years ago , and so longer - acting insulins like lectin and neutral protamine hagedorn ( nph ) were developed . studies have also shown that missing two basal insulin injections per week can lead to a 0.20.3% increase in glycated hemoglobin ( hba1c ) . at the same time , existing basal insulins were found to have limitations . in order to counter these limitations , insulin analogues were developed . there are three kinds of insulin analogues : rapid - acting insulin analogues , biphasic insulin analogues , and basal insulin analogs . the primary structure of insulin is based on a specific sequence of amino acids in the protein . the same structure slight changes were made in this insulin structure to produce different analogs with desired pharmacokinetic properties . the need of insulin analogues arises from the fact that the human insulin injections have a lag period of around 1/2 h between administration and onset of action . as a result , endogenous insulin , after secretion from the pancreas , enters the portal circulation , after which it reaches the systemic circulation . on the other hand , exogenous human insulin , after injection into sub - cutaneous tissue , enters the systemic circulation , and then about 10% of the originally administered insulin reaches the portal circulation . thus , the portal and systemic gradient of insulin is inverted in the case of exogenous insulin . it is because of this reason that exogenous human insulin is not the best physiological way of using insulin therapy . rapid - acting insulin analogs overcome this by being more in tune with the physiological rise and fall of glucose values after each meal . the basal human insulin that is available is nph , which lacks the desired 24 h effect . this limitation highlights the need for the development of basal insulin analogues including insulin detemir , insulin glargine and insulin degludec with duration of action of at least a day . in addition , a research study has established that insulin detemir has better glycaemic control with fewer hypoglycaemic epsiodes in children when compared to nph insulin . longer duration of action , a flat time - action profile , low day - to - day glycemic variability , and the potential for flexible dosing . hypoglycemia in children and adults is still a concern , but with the advent of better devices , it is easier to detect and manage hypoglycemia . the physicians thus aim to achieve tighter glucose control , as a result of which the hba1c targets are improved . insulindetemir , for instance , produce better hba1c control with less hypoglycemia than nph insulin . research studies have shown that in children / adolescents , an intramuscular instead of subcutaneous injection of insulin therapy leads to faster absorption and action , and also shorter duration of action . it has also been found that the rigidity of the insulin regimen interferes with the patient 's lifestyle ( diet / exercise ) , which is an integral part of any child or adolescent 's life . all the basal insulin analogues have a similar onset of action ( between 1 and 2 h ) but the duration of action varies ( glargine : 20 - 30 h , detemir : 24 h and degludec : 42 h ) . both detemir and degludec have a 50 amino acid chain while glargine has a 53 amino acid chain . in glargine , there is the addition of two , and substitution of one amino acid . in detemir , there is a lack of b30 amino acid and an addition of acylated fatty acid side chain at b29 position . in degludec , there is a lack of b30 ; addition of glutamic acid spacer and diacylated fatty acid side chain at b29 . the mechanism of prolongation of action of glargine involves precipitation at acidic ph , while the mechanism of prolongation of action of detemir and degludec involves binding to albumin and multi - hexamer formation respectively . both glargine and degludec have been classified as pregnancy category c molecules while detemir is classified as pregnancy category b. glargine is a pro - drug that requires conversion from its monomeric soluble form to a microcrystalline precipitate in the subcutaneous tissue to obtain its long - acting pharmacokinetics . this process may be disturbed by its rapid access to the circulation after intramuscular injection , leading to hypoglycemia . a study has shown that accidental intramuscular injection of glargine can happen in 30% of children with type 1 diabetes mellitus ( t1 dm ) . the definition of hypoglycemia is debatable . according to the 2009 and 2014 ispad guidelines , < 3.6 mmol / l ( 65 mg / dl ) has been used most often for clinical definition , and ( 70 mg / dl ) is the recommended lower target for blood glucose , whereas the ada working group suggests 70 mg / dl as hypoglycemia . the who guidelines for neonatal hypoglycemia suggest that the newborn / infant / child with  signs of illness would be diagnosed with hypoglycemia if blood glucose is < 2.5 mmol / l or 45 mg / dl ; for healthy term / pre - term newborn   feeding well , the hypoglycemia cut - off value is < 1.1 mmol / l or 19.8 mg / dl , and for an infant / child with severe malnutrition the value is < 3.0 mmol / l or 54 mg / dl . insulin degludec is neutral , soluble ultra - long - acting insulin that forms large multi - hexamer assemblies at physiological ph following subcutaneous injection . its molecular structure is similar to the human insulin amino acid sequence , apart from deletion of threonine at position b30 and the addition of a 16-carbon fatty acid chain attached to lysine at position b29 via a glutamic acid spacer . these subsequently release monomers that are absorbed at a slow and steady rate into the circulation . pharmacokinetic / pharmacodynamic studies show that insulin degludec has a very long duration of action of 42 h , with a half - life exceeding 25 h , and variability of 25% with respect to glargine . a study was recently conducted which investigated once - daily insulin degludec versus insulin detemir , both in combination with bolus insulin aspart in a 26 week trial , followed by another 26 week extension , in children and adolescents with t1 dm . this trial ( n = 350 ) was the first to look into the long - term safety of insulin degludec in children and adolescents ( age : 118 years ) . the results showed that at 26 weeks , insulin degludec in combination with insulin aspart was noninferior to insulin detemir in combination with insulin aspart . the mean basal insulin doses at the end of treatment were reduced by 31% in the insulin degludec group . in the 26-week extension , a lower insulin dose and a significantly greater reduction in fasting plasma glucose versus insulin detemir both regimens had similar rates of overall and nocturnal hypoglycemia , the rate of severe hypoglycemia was numerically higher with insulin degludec plus insulin aspart . of note , patients on insulin degludec had significantly lower rates ( 59% less ) of hyperglycemia with ketosis . insulin degludec , however , is currently not approved in patients below the age of 18 years . new formulations of basal insulin that are under development are u300 glargine , which has completed phase iii and pegylated insulin lispro , which is in phase iii , insulin degludec / insulin aspart ( idegasp ) , which is a soluble co - formulation of insulin degludec and insulin aspart , and ideglira , which is a fixed - ratio combination of insulin degludec and liraglutide for t2 dm .
over the past few decades , continuous progress has been made in the development of insulin therapy . 
 basal insulins were developed around 60 years ago . however , existing basal insulins were found to have limitations . 
 an ideal basal insulin should have the following properties viz . 
 longer duration of action , a flat time - action profile , low day - to - day glycaemic variability , and the potential for flexible dosing . 
 basal insulins have advanced over the years , from lectin and neutral protamine hagedorn to the currently available insulin degludec . currently , the focus is on developing a basal insulin that can give coverage for the entire day , with lesser variability and flexible administration . 
 insulin degludec has been a significant leap in that direction . 
 in addition , u300 insulin glargine and pegylated lispro represent further developments in basal insulin pharmacotherapeutics .