Lente insulin

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An insulin zinc hexamer

Lente insulin (from Italian lento, "slow"; also called insulin zinc suspension) was an intermediate duration insulin that is no longer used in humans. [1] The onset of lente insulin is one to two hours after the dose is administered, and the peak effect is approximately 8 to 12 hours after administration, with some effects lasting over 24 hours. [2]

Contents

Lente insulin products, along with other insulin analogs in the same family, were discontinued by their manufacturers in the mid-2000s, and are no longer permitted to be marketed for use in humans in the US. [3] [4] This was in part because health care providers began to favor more predictable forms of insulin, such as recombinant NPH insulin. [5]

History

Lente insulin arose from research into ways to alter the pharmacokinetics of bovine or porcine insulin products. Prior to the late 1940s, insulin products were derived from pork or beef sources, and then used virtually unaltered as "short-acting" insulin products. It was known by 1950 that the addition of protamine or zinc could alter the duration of action of these insulin products, and in 1952, K. Hallas-Møller at Novo Nordisk produced the first commercial insulin zinc suspension for use in humans. [6] For decades, lente insulin was used as a basal insulin, designed to mimic the body's continual slow release of insulin throughout the day. Compared to NPH insulin, lente insulin has a similar but more protracted loss of action after a dose is administered. [7]

In the 1990s, recombinant DNA technology allowed for the mass production of the human insulin protein in yeast or bacteria. This led to formulations of recombinant lente human insulin products by the early 2000s. [8] However, lente insulin began to fall out of favor with doctors in the mid-2000s, when insulin analogues such as glargine began to be approved. Insulin analogues made by recombinant DNA production methods have less variation in their strength and purity between doses and batches. Furthermore, while lente insulin (and NPH) have a definitive peak in effect, insulin analogs have a much less pronounced peak, making for more predictable effects and less risk of hypoglycemia. [9]

Veterinary use

After the discontinuation of lente insulin for human use, the FDA approved a veterinary porcine-derived lente insulin (Vetsulin®, [10] Merck Animal Health) for daily use in dogs or twice daily use in cats. Insulin analogs used in humans after the discontinuation of lente insulin have not yet been proven to provide the same benefits and predictability as lente insulin in cats and dogs. [11] For this and other reasons, lente insulin is still commonly used in both dogs and cats. [11]

Adverse effects

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.[ citation needed ]

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. [7]

Pharmacology

Mechanism of action

Insulin is a protein normally produced in the pancreas which regulates metabolic processes throughout the body. The primary role of insulin is to increase the metabolism of glucose, storage of energy in adipose tissue, and decrease the body's own production of glucose. [13]

Pharmacokinetics

The half life of endogenous insulin once it enters the bloodstream is 4 to 6 minutes. [14] This allows the endocrine system to rapidly adapt to changing conditions within the body. Exogenous insulin, however, would not be effective with a short half life, as it would require continuous injection or infusion to have the desired effect. While it is difficult to change the rate at which the protein is metabolized in the bloodstream, it is possible to alter how fast the protein is absorbed from the site of injection in various ways. [7]

Lente insulin was formulated by the addition of zinc to the crude porcine and bovine insulin extracts, which causes the insulin protein to form larger crystals which dissolve into the body slower upon injection. [7] This means that while the insulin in the bloodstream is still metabolized in 4–6 minutes, more insulin is continually being absorbed from the dose injected for hours after administration. Compared to NPH insulin, another intermediate acting insulin, up to 40% of the dose of lente insulin may remain unabsorbed for over 24 hours after administration. The variation in absorption between doses in the same patient of lente insulin is comparable to that of insulin NPH. [7]

The distribution of insulin is not well understood, but it is known that it is heavily bound to receptors throughout the body (approximately 80% to receptors on liver cells) and metabolized in large part by phase one processes in the liver. Of the approximately 71-minute estimated lifetime of an insulin molecule, over 60 minutes is spent attached to a liver receptor. In addition, circulating unbound insulin is excreted and reabsorbed by the kidneys and broken down in the lysosomes. The remainder of metabolism of insulin molecules is via intracellular proteolysis via insulysin and related enzymes. [14]

Manufacturing

Commercial preparations of lente insulin are standardized to 30% semilente (amorphous precipitates of insulin), and 70% ultralente (crystallized insulin). [15] In early versions, the semilente insulin was extracted from pigs, and the ultralente insulin was extracted from cows. [15]

Society and culture

Brand names of lente insulin that have been discontinued include Iletin (animal), and HumulinL/NovolinL (human). As of 2023, Lente insulin is produced under the brand name Vetsulin for veterinary use in dogs and cats with diabetes. [10]

Related Research Articles

<span class="mw-page-title-main">Hypoglycemia</span> Health condition

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 below 70 mg/dL (3.9 mmol/L), symptoms associated with hypoglycemia, and resolution of symptoms when blood sugar returns to normal. Hypoglycemia may result in headache, tiredness, clumsiness, trouble talking, confusion, fast heart rate, sweating, shakiness, nervousness, hunger, loss of consciousness, seizures, or death. Symptoms typically come on quickly.

<span class="mw-page-title-main">Insulin</span> Peptide hormone

Insulin is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (INS) gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of glucose from the blood into liver, fat and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat.

<span class="mw-page-title-main">Glimepiride</span> Group of stereoisomers

Glimepiride is an antidiabetic medication within the sulfonylurea class, primarily prescribed for the management of type 2 diabetes. It is regarded as a second-line option compared to metformin, due to metformin's well-established safety and efficacy. Use of glimepiride is recommended in conjunction with lifestyle modifications such as diet and exercise. It is taken by mouth, reaching a peak effect within three hours and lasting for about a day.

Drugs used in diabetes treat diabetes mellitus by altering the glucose level in the blood. With the exception of insulin, most GLP receptor agonists, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of anti-diabetic drugs, and their selection depends on the nature of diabetes, age, and situation of the person, as well as other factors.

<span class="mw-page-title-main">Bovine somatotropin</span> Peptide hormone produced by cows pituitary glands

Bovine somatotropin or bovine somatotrophin, or bovine growth hormone (BGH), is a peptide hormone produced by cows' pituitary glands.

Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin.

Diabetes is a chronic disease in cats whereby either insufficient insulin response or insulin resistance leads to persistently high blood glucose concentrations. Diabetes affects up to 1 in 230 cats, and may be becoming increasingly common. Diabetes is less common in cats than in dogs. The condition is treatable, and if treated properly the cat can experience a normal life expectancy. In cats with type 2 diabetes, prompt effective treatment may lead to diabetic remission, in which the cat no longer needs injected insulin. Untreated, the condition leads to increasingly weak legs in cats and eventually to malnutrition, ketoacidosis and/or dehydration, and death.

<span class="mw-page-title-main">Reactive hypoglycemia</span> Medical condition

Reactive hypoglycemia, postprandial hypoglycemia, or sugar crash is a term describing recurrent episodes of symptomatic hypoglycemia occurring within four hours after a high carbohydrate meal in people with and without diabetes. The term is not necessarily a diagnosis since it requires an evaluation to determine the cause of the hypoglycemia.

An insulin analog 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 action as human insulin in terms of controlling blood glucose levels in diabetes. Through genetic engineering of the underlying DNA, the amino acid sequence of insulin can be changed to alter its ADME characteristics. Officially, the U.S. Food and Drug Administration (FDA) refers to these agents as insulin receptor ligands, although they are usually just referred to as insulin analogs or even just insulin.

<span class="mw-page-title-main">NPH insulin</span> Intermediate acting insulin formulation

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. 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.

<span class="mw-page-title-main">Glucagon rescue</span>

Glucagon rescue is the emergency injection of glucagon in case of severe diabetic hypoglycemia. It is needed during seizures and/or unconsciousness by an insulin user who is unable at that point to help themselves. Glucagon will facilitate the release of stored glucose back into the bloodstream, raising the blood glucose level.

Chronic Somogyi rebound is a contested explanation of phenomena of elevated blood sugars experienced by diabetics in the morning. Also called the Somogyi effect and posthypoglycemic hyperglycemia, it is a rebounding high blood sugar that is a response to low blood sugar. When managing the blood glucose level with insulin injections, this effect is counter-intuitive to people who experience high blood sugar in the morning as a result of an overabundance of insulin at night.

<span class="mw-page-title-main">Insulin aspart</span> Rapid-acting man-made insulin

Insulin aspart, sold under the brand name NovoLog, among others, is a modified type of medical insulin used to treat type 1 and type 2 diabetes. It is generally used by injection under the skin but may also be used by injection into a vein. Maximum effect occurs after about 1–3 hours and lasts for 3–5 hours. Generally a longer-acting insulin like insulin NPH is also needed.

<span class="mw-page-title-main">Regular insulin</span> Short-acting insulin formulation

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 ketoacidosis and hyperosmolar hyperglycemic states. It is also used along with glucose to treat high blood potassium levels. Typically it is given by injection under the skin, but may also be used by injection into a vein or muscle. Onset of effect is typically in 30 minutes and it typically lasts for 8 hours.

<span class="mw-page-title-main">Insulin (medication)</span> Use of insulin protein and analogs as medical treatment

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 such as diabetic ketoacidosis and hyperosmolar hyperglycemic states. Insulin is also used along with glucose to treat hyperkalemia. Typically it is given by injection under the skin, but some forms may also be used by injection into a vein or muscle. There are various types of insulin, suitable for various time spans. The types are often all called insulin in the broad sense, although in a more precise sense, insulin is identical to the naturally occurring molecule whereas insulin analogues have slightly different molecules that allow for modified time of action. It is on the World Health Organization's List of Essential Medicines. In 2020, regular human insulin was the 307th most commonly prescribed medication in the United States, with more than 1 million prescriptions.

<span class="mw-page-title-main">Diabetes in dogs</span>

Diabetes mellitus is a disease in which the beta cells of the endocrine pancreas either stop producing insulin or can no longer produce it in enough quantity for the body's needs. The disease can affect humans as well as animals such as dogs.

<span class="mw-page-title-main">Insulin degludec</span> Ultralong-acting basal insulin analogue

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 with diabetes. It has a duration of action that lasts up to 42 hours, making it a once-daily basal insulin, that is one that provides a base insulin level, as opposed to the fast- and short-acting bolus insulins.

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. 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. The FDA withdrew approval for ultralente insulin products by 2011.

Chromium is claimed to be an essential element involved in the regulation of blood glucose levels within the body. More recent reviews have questioned this, however.

References

  1. ↑ Holmberg, Monica (1 October 2006). "An Overview of Insulin Breakthroughs". Pharmacy Times. Vol. 2006, no. 10. Pharmacy & Healthcare Communications. Retrieved 11 May 2020.
  2. ↑ Owens, David R. (June 2011). "Insulin Preparations with Prolonged Effect". Diabetes Technology & Therapeutics. 13 (S1): S-5–S-14. doi: 10.1089/dia.2011.0068 . PMID   21668337.
  3. ↑ Federal Register Doc. E9-2901
  4. ↑ Federal Register Doc. 2011-14164
  5. ↑ "Discontinuation of Humulin®U ULTRALENTE" (PDF). Food and Drug Administration . Archived from the original on 1 December 2011. Retrieved 11 May 2020.{{cite web}}: CS1 maint: bot: original URL status unknown (link)
  6. ↑ Hallas-Møller, K.; Petersen, K.; Schlichtkrull, J. (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. ISSN   0036-8075. JSTOR   1680777. PMID   12984132.
  7. 1 2 3 4 5 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.
  8. ↑ Landgraf, Wolfgang; Sandow, Juergen (2016). "Recombinant Human Insulins – Clinical Efficacy and Safety in Diabetes Therapy". European Endocrinology. 12 (1): 12–17. doi:10.17925/EE.2016.12.01.12. PMC   5813452 . PMID   29632581.
  9. ↑ Horvath, Karl; Jeitler, Klaus; Berghold, Andrea; Ebrahim, Susanne H; Gratzer, Thomas W; Plank, Johannes; Kaiser, Thomas; Pieber, Thomas R; Siebenhofer, Andrea (18 April 2007). "Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus". Cochrane Database of Systematic Reviews (2): CD005613. doi:10.1002/14651858.CD005613.pub3. PMID   17443605.
  10. 1 2 "Compendium of Veterinary Products". merckusa.cvpservice.com.
  11. 1 2 Behrend, Ellen; Holford, Amy; Lathan, Patty; Rucinsky, Renee; Schulman, Rhonda (January 2018). "2018 AAHA Diabetes Management Guidelines for Dogs and Cats". Journal of the American Animal Hospital Association . 54 (1): 4–6. doi:10.5326/JAAHA-MS-6822. PMID   29314873. S2CID   43327430.
  12. ↑ "Hypoglycemia". National Institute of Diabetes and Digestive and Kidney Diseases. October 2008. Archived from the original on 1 July 2015.
  13. ↑ Dimitriadis, George; Mitrou, Panayota; Lambadiari, Vaia; Maratou, Eirini; Raptis, Sotirios A. (August 2011). "Insulin effects in muscle and adipose tissue". Diabetes Research and Clinical Practice. 93: S52–S59. doi:10.1016/S0168-8227(11)70014-6. PMID   21864752.
  14. 1 2 Duckworth, William C.; Bennett, Robert G.; Hamel, Frederick G. (1 October 1998). "Insulin Degradation: Progress and Potential*". Endocrine Reviews. 19 (5): 608–624. doi: 10.1210/edrv.19.5.0349 . PMID   9793760.
  15. 1 2 Wittlin, Steven D.; Woehrle, Hans J.; Gerich, John E. (2002). "Insulin Pharrmacokinetics". In Leahy, Jack L.; Cefalu, William T. (eds.). Insulin therapy. New York: CRC Press. pp. 78–79. ISBN   0-8247-4462-4. OCLC   52707816.
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