Neutral Protamine Hagedorn (NPH) insulin, also known as isophane insulin, is an intermediate-acting insulin given to help control blood sugar levels 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 ...

. 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 Regular insulin, also known as neutral insulin and soluble insulin, is a type of short-acting medical insulin. It is used to treat type 1 diabetes, type 2 diabetes, gestational diabetes, and complications of diabetes such as diabetic ketoacid ...

. The common side effect is

low blood sugar Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

. Other side effects may include pain or skin changes at the sites of injection,

low blood potassium Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abnor ...

, and

allergic reactions Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...

. Use during

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

is relatively safe for the baby. NPH insulin is made by mixing regular insulin and

protamine Protamines are small, arginine-rich, nuclear proteins that replace histones late in the haploid phase of spermatogenesis and are believed essential for sperm head condensation and DNA stabilization. They may allow for denser packaging of DNA in t ...

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 ...

such that a neutral-pH is maintained and

crystals A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macros ...

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 The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. 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 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 Kingd ...

or detemir). A recent Cochrane systematic review compared the effects of NPH insulin to other insulin analogues (

insulin 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. C ...

, insulin glargine,

insulin degludec Insulin degludec ( INN/USAN) is an ultralong-acting basal insulin analogue that was developed by Novo Nordisk under the brand name Tresiba. It is administered via subcutaneous injection once daily to help control the blood sugar level of those ...

) 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 ...

. 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 (1888–1971) and August Krogh (1874–1949) obtained the rights for insulin from Banting and Best in

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 anch ...

, 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

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. Sem ...

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 university, public research university in Toronto, Ontario, Canada, located on the grounds that surround Queen's Park (Toronto), Queen's Park. It was founded by royal charter in 1827 ...

Canada Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...

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 * 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