Neutral Protamine Hagedorn (NPH) insulin, also known as isophane insulin, is an

intermediate-acting insulin As a medication, insulin is any pharmaceutical preparation of the protein hormone insulin that is used to treat high blood glucose. Such conditions include type 1 diabetes, type 2 diabetes, gestational diabetes, and complications of diabetes s ...

given to help control

blood sugar level Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the blo ...

s in people with

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

. It is used by injection under the skin once to twice a day. Onset of effects is typically in 90 minutes and they last for 24 hours. Versions are available that come premixed with a short-acting insulin, such as regular insulin. The common side effect is low blood sugar. Other side effects may include pain or skin changes at the sites of injection, low blood potassium, and allergic reactions. Use during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...

is relatively safe for the baby. NPH insulin is made by mixing regular insulin and protamine in exact proportions with

zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...

and

phenol Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it req ...

such that a neutral-pH is maintained and crystals form. There are human and pig insulin based versions. Protamine insulin was first created in 1936 and NPH insulin in 1946. It is on the World Health Organization's List of Essential Medicines. NPH is an abbreviation for "neutral protamine Hagedorn". In 2020, insulin isophane was the 221st most commonly prescribed medication in the United States, with more than 2million prescriptions. In 2020, the combination of human insulin with insulin isophane was the 246th most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

NPH insulin is cloudy and has an onset of 1–3 hours. Its peak is 6–8 hours and its duration is up to 24 hours. It has an intermediate duration of action, meaning longer than that of regular and rapid-acting insulin, and shorter than long acting insulins ( ultralente, glargine or

detemir Insulin detemir, sold under the brand name Levemir among others, is a long-acting modified form of medical insulin used to treat both type 1 and type 2 diabetes. It is used by injection under the skin. It is effective for up to 24 hours. ...

). A recent Cochrane systematic review compared the effects of NPH insulin to other

insulin analog An insulin analog ( also called an insulin analogue) is any of several types of medical insulin that are altered forms of the hormone insulin, different from any occurring in nature, but still available to the human body for performing the same a ...

ues ( insulin detemir,

insulin glargine Insulin glargine, sold under the brand name Lantus among others, is a long-acting modified form of medical insulin, used in the management of type I and type II diabetes. It is typically the recommended long acting insulin in the United King ...

, insulin degludec) in both children and adults with

Type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

. Insulin detemir appeared provide a lower risk of severe hyperglycemia compared to NPH insulin, however this finding was inconsistent across included studies. In the same review no other clinically significant differences were found between different insulin analogues in either adults nor children.

History

Hans Christian Hagedorn Hans Christian Hagedorn (6 March 1888 – 6 October 1971) was the creator of NPH insulin and the founder of Nordisk Insulinlaboratorium, which is known today as Novo Nordisk. Biography Hagedorn and August Krogh (1874–1949) obtained the rights fo ...

(1888–1971) and

August Krogh Schack August Steenberg Krogh (15 November 1874 – 13 September 1949) was a Danish professor at the department of zoophysiology at the University of Copenhagen from 1916 to 1945. He contributed a number of fundamental discoveries within several ...

(1874–1949) obtained the rights for

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

from

Banting Banting is a town and the seat of Kuala Langat District, Selangor, Malaysia. Banting has a population of 93,497. The postal code for Banting is 42700 and is administered by the Zone of 15 and 19 of the Kuala Langat Municipal Council. It is situa ...

and

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Toronto Toronto ( ; or ) is the capital city of the Canadian province of Ontario. With a recorded population of 2,794,356 in 2021, it is the most populous city in Canada and the fourth most populous city in North America. The city is the ancho ...

, Canada. In 1923 they formed Nordisk Insulin laboratorium, and in 1926 with August Kongsted he obtained a Danish Royal Charter as a non-profit foundation. In 1936, Hagedorn and B. Norman Jensen discovered that the effects of injected insulin could be prolonged by the addition of protamine obtained from the "milt" or

semen Semen, also known as seminal fluid, is an organic bodily fluid created to contain spermatozoa. It is secreted by the gonads (sexual glands) and other sexual organs of male or hermaphroditic animals and can fertilize the female ovum. Semen i ...

of river trout. The insulin would be added to the protamine, but the solution would have to be brought to pH 7 for injection.

University of Toronto The University of Toronto (UToronto or U of T) is a public research university in Toronto, Ontario, Canada, located on the grounds that surround Queen's Park. It was founded by royal charter in 1827 as King's College, the first institution ...

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later licensed protamine zinc insulin (PZI), to several manufacturers. This mixture only needs to be shaken before injection. The effects of PZI lasted for 24–36 h. In 1946, Nordisk was able to form crystals of protamine and insulin and marketed it in 1950, as neutral protamine Hagedorn (NPH) insulin. NPH insulin has the advantage that it can be mixed with an insulin that has a faster onset to complement its longer lasting action. Eventually all animal insulins made by Novo Nordisk were replaced by synthetic, recombinant 'human' insulin. Synthetic 'human' insulin is also complexed with protamine to form NPH.

Timeline

The timeline is as follows: * 1926 Nordisk receives Danish charter to produce insulin * 1936 Hagedorn discovers that adding protamine to insulin prolongs the effect of insulin * 1936 Canadians D.M. Scott and A.M. Fisher formulate zinc insulin mixture and license to

Novo ''Novo'' is a 2002 French romantic comedy film directed by Jean-Pierre Limosin and starring Eduardo Noriega. The film tells the story of a man who suffers from amnesia. It screened at the Locarno Film Festival. Plot Graham suffers from severe am ...

* 1946 Nordisk crystallizes a protamine and insulin mixture * 1950 Nordisk markets NPH insulin * 1953 Nordisk markets "Lente" zinc insulin mixtures.

Society and culture

Names

NPH stands for neutral protamine Hagedorn, and the words refer to neutral pH (pH = 7), protamine (a protein), and Hans Christian Hagedorn (an insulin researcher).Brand names include Humulin N, Novolin N, Novolin NPH, Gensulin N, SciLin N, Insulatard, and NPH Iletin II.

References