Insulin

Development of Insulin – Timeline¹

• 1921: discovery of insulin
• 1942: long-acting protamine/insulin zinc suspension known as Neutral Protamine Hagedorn, or NPH, insulin, with a duration of action of 12-18 hours but with a pronounced peak effect (which risks nocturnal hypoglycaemia)
• 1970s: mono-component insulin
  • Unit 100 (100 U / mL) standard
• 1980s: recombinant (human) insulin
  • insulin pens
  • insulin pump
• 1990s: insulin analogues
  • 1992: Glargine
  • 1996: Detemir
• 2000s: a plethora of insulins
  • 2010: Degludec; Pegylated lispro
  • 2011: Glargine (U-300)

There has been considerable Pharma research and development of various short- and long-acting insulins over the last two decades, because the older insulins did not cover a full 24 hours (long-acting) or nicely match nutrient input (short-acting took 45 minutes to start working and peaked at 2 hours, much slower than the natural surge in portal-vein insulin levels in response to a meal and, therefore, somewhat ungainly, even when injected 30 minutes prior to eating).² Even the ultra-rapid insulins, as fast-acting as they are, still can’t obviously quite match the responsiveness of endogenous pancreatic portal secretion of insulin, shown in light blue in the image below.

As groundbreaking as insulin discovery and early developments were, the newer agents are far superior in terms of profile of insulin action. Newer, soluble long-acting insulins have a considerably longer duration than NPH insulin (and other traditional crystalline preparations in which the crystals slowly dissolve, gradually releasing the insulin) and with a more consistent action.²

As the graph below shows (© Focus Information Technologies Inc.), detemir- and glargine-insulins go closer to achieving a 24-hour duration of action from a single dose.

Action Profiles of Various Insulins 

Normal pancreatic insulin secretion

The pancreas secretes a regular basal output of insulin at a rate of 0.5 – 1 unit per hour, easing somewhat overnight and inclining slightly in the morning. Mealtime surges by a factor of ten (i.e. 5 – 10 units) of insulin are released by the pancreas directly into the portal circulation in response to ingestion of nutrients from the taking of a meal.

The natural history of disease of Type 2 diabetes is gradual reduction in insulin secretion and increasing insulin resistance such that most if not all patients will eventually require insulin replacement therapy. The timing for introducing insulin therapy in Type 2 Diabetes is a matter of debate because while the later the better might seem an obvious choice, introduction of insulin therapy, although associated with weight gain and risk of hypoglycaemia (and the obvious inconvenience of injections), provides better glycaemic control—and thereby reduces end-organ damage and macrovascular events—and may restore some β-cell function, ultimately enhancing quality of life. (Bailey et al, 2016).

 

 

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Initial Insulin Dosing (Faradji et al, 2019)

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Reference

1. Singh, Awadhesh Kumar and Gangopadhyay, Kalyan Kumar. “Modern basal insulin analogs: An incomplete story.” Indian Journal of Endocrinology and Metabolism 18 (6). Nov-Dec 2014: 784-793.
2. Phillips, Pat. “Insulins in 2002.” Aust Prescr 25(2): 104-7. 1 March 2002. DOI: 10.18773/austprescr.2002.032.
3. Wong, Jencia and Tabet, Eddy. “The introduction of insulin in type 2
   diabetes mellitus.” AFP 44(5); MAY 2015: 278-283.
4. Faradji R.N., Barriga-Menchaca A.P.D., Sainz de la Maza Viadero M.E. “Use of Insulin in Outpatient Diabetes Management.” In: Rodriguez-Saldana J. (eds) The Diabetes Textbook. Springer, Cham. https://doi.org/10.1007/978-3-030-11815-0_35
5. Evans, M., Wilkinson, M., and Giannpolou, A. “Fast-Acting Insulin Aspart: The Rationale for a New Mealtime Insulin.” Diabetes Ther 10; 2019: 1793–1800. https://doi.org/10.1007/s13300-019-00685-0.
6. Bailey, Clifford; Heise, Tim; Hood, Robert C. “Novel Concentrated Insulins: what benefits and for which patients?” Medscape Education. https://www.medscape.org/viewarticle/857504.