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

blood sugar level The blood sugar level, blood sugar concentration, blood glucose level, or glycemia is the measure of glucose concentrated in the blood. The body tightly regulates blood glucose levels as a part of metabolic homeostasis. For a 70 kg (1 ...

s in people with

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

. The words refer to neutral pH (pH = 7),

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 ...

a protein, and Hans Christian Hagedorn, the insulin researcher who invented this formulation. It is designed to improve the delivery of insulin, and is one of the earliest examples of engineered drug delivery. 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 Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes 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 tria ...

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

allergic reactions Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, alle ...

. Use during

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

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

in exact proportions with

zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It 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 periodic tabl ...

and

phenol Phenol (also known as carbolic acid, phenolic acid, or benzenol) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile and can catch fire. The molecule consists of a phenyl group () ...

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, macrosc ...

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 or detemir). A recent Cochrane systematic review compared the effects of NPH insulin to other insulin analogues ( 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 1 and type 2 diabetes. It is injected just under the skin. Effects generally begin an hour af ...

, 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 occurs when the body's immune system destroys pancreatic cells (beta cells). In healthy persons, beta cells produce insulin. Insulin is a hormone require ...

. 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 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 seve ...

(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 insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

from

Frederick Banting Sir Frederick Grant Banting (November 14, 1891 – February 21, 1941) was a Canadian pharmacologist, orthopedist, and field surgeon. For his co-discovery of insulin and its therapeutic potential, Banting was awarded the Nobel Prize in Physi ...

and Charles Best in

Toronto Toronto ( , locally pronounced or ) is the List of the largest municipalities in Canada by population, most populous city in Canada. It is the capital city of the Provinces and territories of Canada, Canadian province of Ontario. With a p ...

, 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 a bodily fluid that contains spermatozoon, spermatozoa which is secreted by the male gonads (sexual glands) and other sexual organs of male or hermaphrodite, hermaphroditic animals. In humans and placen ...

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 whose main campus is located on the grounds that surround Queen's Park (Toronto), Queen's Park in Toronto, Ontario, Canada. It was founded by ...

Canada Canada is a country in North America. Its Provinces and territories of Canada, ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, making it the world's List of coun ...

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

Brand names include Humulin N, Novolin N, Novolin NPH, Gensulin N, SciLin N, Insulatard, and NPH Iletin II.

References