Ultralente insulin

History

Insulin which was extracted from animal sources was used as a medicine as early as 1922. 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. 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.

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. By the mid-1990s, ultralente insulin was being prepared from recombinant human insulin, instead of insulin extracted from animals. The biggest supplier of human Ultralente was Eli Lilly, under the brand Humulin U.

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.

The advent of insulin analogs 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to the discontinuation of ultralente insulin products in the mid-2000s, and FDA approval to be marketed in the US was withdrawn by 2011.

Adverse effects

Hypoglycemia

Main article: Hypoglycemia

The primary adverse effect of any insulin product is hypoglycemia, or low blood sugar. 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

Prior to the advent of the "human" lente insulins, the lente insulins (semi-lente, lente, and ultra-lente) were a combination of porcine and bovine insulin products that were filtered and combined with zinc to form the suspension. Even with product filtering, due to the animal origin, the human body might recognize the foreign protein as such and form antibodies against it. These reactions were slightly more likely with lente insulins than insulins derived from a solely porcine source, as bovine insulin was more immunogenic than porcine insulin.

Society and culture

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

References

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".
3. "List of Withdrawn Applications for Biological Products That Were Removed From FDA's Orange Book on March 23, 2020". US Food and Drug Administration.
4. (16 July 2012). "History of insulin". Journal of Community Hospital Internal Medicine Perspectives.
5. (10 October 1952). "Crystalline and Amorphous Insulin-Zinc Compounds with Prolonged Action". Science.
6. (1 January 1956). "The Lente Insulins". Diabetes.
7. (November 1992). "Recombinant human insulin". Biotechnology Progress.
8. (15 April 2003). "Patient Information Page: HUMULIN® U ULTRALENTE® – HUMAN INSULIN (rDNA ORIGIN) –EXTENDED ZINC SUSPENSION". FDA.
9. (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.
10. "Vetsulin Insulin for Pets". Merck Animal Health USA.
11. Federal Register Doc. [https://www.federalregister.gov/a/E9-2901 E9-2901]
12. Federal Register Doc. [https://www.federalregister.gov/a/2011-14164 2011-14164]
13. (October 2008). "Hypoglycemia".
14. (1 September 1980). "Intermediate-acting Insulin Preparations: NPH and Lente". Diabetes Care.
15. (3 March 1984). "Human ultralente insulin.". BMJ.