Ultralente insulin

Ultralente insulin was a long-acting form of insulin. It has an onset of 4 to 6 hours, a peak of 14 to 24 hours, and a duration of 28 to 36 hours.[1] Ultralente insulin, along with lente insulin, were discontinued in the US by manufacturers in the mid-2000s. One of the reasons for discontinuation was declining use in favor of NPH insulin and other newer insulin products.[2] The FDA withdrew approval for ultralente insulin products by 2011.[3]

History
See also: Insulin (medication) § history

Insulin which was extracted from animal sources was used as a medicine as early as 1922.[4] These early insulin preparations required multiple daily injections due to the short duration of action and quick degradation of the insulin protein. For this reason, researchers began studying how to prolong the effects of injected insulin. In 1952, a team at Novo Terapeutisk led by K. Hallas-Møller discovered that crystals of various sizes would form when zinc was added to insulin suspensions.[5] Larger insulin crystals take longer to dissolve into the bloodstream when injected into the body, and as such have a much longer duration of action than amorphous or small insulin crystals. Ultralente insulin was considered to be a "long-acting" insulin that could be used once per day to provide a basal level of insulin, similar to some protamine-containing preparations.[6]

While originally isolated from bovine or porcine sources, the advent of recombinant DNA technology in the 1980s allowed human insulin to be mass produced in yeast or bacteria.[7] By the mid 1990s, ultralente insulin was being prepared from recombinant human insulin, instead of insulin extracted from animals.[8] The advent of insulin analogues and continued use of NPH insulin led to the discontinuation of ultralente insulin products in the mid-2000s, and FDA approval to be marketed in the US was withdrawn by 2011.[2][9][10]

Lente insulin was a combination of ultralente insulin and amorphous, or plain, insulin in a fixed percentage combination. Ultralente insulin comprises 65% of the lente insulin preparation Vetsulin®/Caninsulin® which is produced by Merck Animal Health for veterinary use.[11]

Adverse effects

Hypoglycemia
Main article: Hypoglycemia

The primary adverse effect of any insulin product is hypoglycemia, or low blood sugar. Hypoglycemia can manifest as dizziness, disorientation, trouble speaking, and changes in mental status. In severe cases, hypoglycemia can lead to loss of consciousness if not treated.[12] As lente insulin continues to be absorbed in the body for hours after use, these signs and symptoms may be delayed from the time of administration and begin with little or no warning.

Hypersensitivity

Lente insulin is a combination of porcine and bovine insulin products which are filtered and combined with zinc to form the suspension. Even product that is filtered very well is still of animal origin, and there is a chance the body may recognize the foreign protein as such and form antibodies against it. These reactions are slightly more likely with lente insulin than with insulin derived from a single source as lente insulin contains bovine insulin which is more immunogenic than porcine insulin.[13]

Society and culture

Historical brand names of ultralente insulin, all of which are now discontinued, included Ultratard HM,[14] Humulin U, and Novolin U.

References
  1. Gomella LG, Haist SA. Chapter 22. Commonly Used Medications. In: Gomella LG, Haist SA, eds. Clinician's Pocket Reference: The Scut Monkey. 11th ed. New York: McGraw-Hill; 2007. http://www.accessmedicine.com/content.aspx?aID=2696124. Accessed February 4, 2012
  2. Discontinuation of Humulin®U ULTRALENTE at the Wayback Machine (archived 1 December 2011)
  3. "List of Withdrawn Applications for Biological Products That Were Removed From FDA's Orange Book on March 23, 2020". fda.gov. US Food and Drug Administration. Retrieved 18 May 2020.
  4. Quianzon, Celeste C.; Cheikh, Issam (16 July 2012). "History of insulin". Journal of Community Hospital Internal Medicine Perspectives. 2 (2): 18701. doi:10.3402/jchimp.v2i2.18701. PMC 3714061. PMID 23882369.
  5. Hallas-Moller, K.; Petersen, K.; Schlichtkrull, J. (10 October 1952). "Crystalline and Amorphous Insulin-Zinc Compounds with Prolonged Action". Science. 116 (3015): 394–398. Bibcode:1952Sci...116..394H. doi:10.1126/science.116.3015.394. PMID 12984132.
  6. Hallas-Mo, K. (1 January 1956). "The Lente Insulins". Diabetes. 5 (1): 7–14. doi:10.2337/diab.5.1.7. PMID 13294001. S2CID 84960159.
  7. Ladisch, Michael R.; Kohlmann, Karen L. (November 1992). "Recombinant human insulin". Biotechnology Progress. 8 (6): 469–478. doi:10.1021/bp00018a001. PMID 1369033. S2CID 11674368.
  8. Riccio, A.; Avogaro, A.; Valerio, A.; Zappella, A.; Tiengo, A.; Prato, S. D. (1 June 1994). "Improvement of Basal Hepatic Glucose Production ana Fasting Hyperglycemia of Type I Diabetic Patients Treated With Human Recombinant Ultralente Insulin". Diabetes Care. 17 (6): 535–540. doi:10.2337/diacare.17.6.535. PMID 8082521. S2CID 39297137.
  9. Federal Register Doc. E9-2901
  10. Federal Register Doc. 2011-14164
  11. "Vetsulin Insulin for Pets". www.merck-animal-health-usa.com. Merck Animal Health USA. Retrieved 18 May 2020.
  12. "Hypoglycemia". National Institute of Diabetes and Digestive and Kidney Diseases. October 2008. Archived from the original on 1 July 2015.
  13. Deckert, T. (1 September 1980). "Intermediate-acting Insulin Preparations: NPH and Lente". Diabetes Care. 3 (5): 623–626. doi:10.2337/diacare.3.5.623. PMID 7192205. S2CID 22310080.
  14. Holman, R R; Steemson, J; Darling, P; Reeves, W G; Turner, R C (3 March 1984). "Human ultralente insulin". BMJ. 288 (6418): 665–668. doi:10.1136/bmj.288.6418.665. PMC 1444374. PMID 6421424.
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