Pramlintide (trade name Symlin) is an injectable amylin analogue drug for diabetes (both type 1 and 2), developed by Amylin Pharmaceuticals (now a wholly owned subsidiary of AstraZeneca).[1] Pramlintide is sold as an acetate salt.
Pramlintide is an analogue of amylin, a small peptide hormone that is released into the bloodstream by the β cells of the pancreas along with insulin after a meal.[2] Like insulin, amylin is completely absent in individuals with Type I diabetes.[3]
In synergy with endogenous amylin, pramlintide aids in the regulation of blood glucose by slowing gastric emptying, promoting satiety via hypothalamic receptors (different receptors than for GLP-1), and inhibiting inappropriate secretion of glucagon, a catabolic hormone that opposes the effects of insulin and amylin. Pramlintide also has effects in raising the acute first-phase insulin response threshold following a meal.[citation needed]
Both a reduction in glycated hemoglobin and weight loss have been shown in insulin-treated patients with type 2 diabetes taking pramlintide as an adjunctive therapy.[4]
Research Applications
In the research field, pramlintide has been experimented with and used as a potential treatment drug. Pramlintide has demonstrated its ability to decrease amyloid beta plaques in Alzheimer's disease mouse models.[5]
Approval
Pramlintide has been approved on 3/16/2005 by the FDA, for use by type 1 and type 2 diabetic patients who use insulin.[6](subscription required) Pramlintide allows patients to use less insulin, lowers average blood sugar levels, and substantially reduces what otherwise would be a large unhealthy rise in blood sugar that occurs in diabetics right after eating.
Apart from insulin analogs, pramlintide is the only drug approved by the FDA to lower blood sugar in type 1 diabetics since insulin in the early 1920s.[citation needed][7]
Since native human amylin is highly amyloidogenic and potentially toxic, the strategy for designing pramlintide was to substitute residues from rat amylin, which is less amyloidogenic[8][9] but presumably retains clinical activity. Proline residues are known to be structure-breaking[clarification needed] residues, so these were directly grafted into the human sequence. Despite its enhanced stability compared to human amylin, however, pramlintide is still able to organize into amyloid material.[10]
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.
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.
Beta cells (β-cells), are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vital role in maintaining blood glucose levels. Problems with beta cells can lead to disorders such as diabetes.
The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of the pancreas volume and receive 10–15% of its blood flow. The pancreatic islets are arranged in density routes throughout the human pancreas, and are important in the metabolism of glucose.
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.
Drugs used in diabetes treat diabetes mellitus by decreasing 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 hypoglycemic drugs, and their selection depends on the nature of diabetes, age, and situation of the person, as well as other factors.
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 type2 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.
Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for energy and it helps regulate glucose levels in the bloodstream. Before treatment this results in high blood sugar levels in the body. The common symptoms of this elevated blood sugar are frequent urination, increased thirst, increased hunger, weight loss, and other serious complications. Additional symptoms may include blurry vision, tiredness, and slow wound healing. Symptoms typically develop over a short period of time, often a matter of weeks if not months.
The term diabetes includes several different metabolic disorders that all, if left untreated, result in abnormally high concentrations of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces significant amounts of the hormone insulin, usually owing to the autoimmune destruction of the insulin-producing beta cells of the pancreas. Diabetes mellitus type 2, in contrast, is now thought to result from autoimmune attacks on the pancreas and/or insulin resistance. The pancreas of a person with type 2 diabetes may be producing normal or even abnormally large amounts of insulin. Other forms of diabetes mellitus, such as the various forms of maturity-onset diabetes of the young, may represent some combination of insufficient insulin production and insulin resistance. Some degree of insulin resistance may also be present in a person with type 1 diabetes.
Exenatide, sold under the brand name Byetta and Bydureon among others, is a medication used to treat diabetes mellitus type 2. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after metformin and sulfonylureas. It is given by injection under the skin twice daily or once weekly.
Streptozotocin or streptozocin (STZ) is a naturally occurring alkylating antineoplastic agent that is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. It is used in medicine for treating certain cancers of the islets of Langerhans and used in medical research to produce an animal model for hyperglycemia and Alzheimer's in a large dose, as well as type 2 diabetes or type 1 diabetes with multiple low doses.
Automated insulin delivery systems are automated systems designed to assist people with insulin-requiring diabetes, by automatically adjusting insulin delivery in response to blood glucose levels. Currently available systems can only deliver a single hormone—insulin. Other systems currently in development aim to improve on current systems by adding one or more additional hormones that can be delivered as needed, providing something closer to the endocrine functionality of the pancreas.
Saxagliptin, sold under the brand name Onglyza, is an oral hypoglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Early development was solely by Bristol-Myers Squibb; in 2007 AstraZeneca joined with Bristol-Myers Squibb to co-develop the final compound and collaborate on the marketing of the drug.
Amylin Pharmaceuticals is a biopharmaceutical founded in 1987 that was based in San Diego, California. The company was engaged in the discovery, development, and commercialization of drug candidates for the treatment of diabetes, obesity, and other diseases. Amylin produced three drugs: Symlin, Byetta (exenatide) and Bydureon.
Free fatty acid receptor 1 (FFAR1), also known as G-protein coupled receptor 40 (GPR40), is a rhodopsin-like G-protein coupled receptor that is coded by the FFAR1 gene. This gene is located on the short arm of chromosome 19 at position 13.12. G protein-coupled receptors reside on their parent cells' surface membranes, bind any one of the specific set of ligands that they recognize, and thereby are activated to trigger certain responses in their parent cells. FFAR1 is a member of a small family of structurally and functionally related GPRs termed free fatty acid receptors (FFARs). This family includes at least three other FFARs viz., FFAR2, FFAR3, and FFAR4. FFARs bind and thereby are activated by certain fatty acids.
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 1million prescriptions.
Complications of diabetes are secondary diseases that are a result of elevated blood glucose levels that occur in diabetic patients. These complications can be divided into two types: acute and chronic. Acute complications are complications that develop rapidly and can be exemplified as diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS), lactic acidosis (LA), and hypoglycemia. Chronic complications develop over time and are generally classified in two categories: microvascular and macrovascular. Microvascular complications include neuropathy, nephropathy, and retinopathy; while cardiovascular disease, stroke, and peripheral vascular disease are included in the macrovascular complications.
Type 3 diabetes is a proposed pathological linkage between Alzheimer's disease and certain features of type 1 and type 2 diabetes. Specifically, the term refers to a set of common biochemical and metabolic features seen in the brain in Alzheimer's disease, and in other tissues in diabetes; it may thus be considered a "brain-specific type of diabetes." It was recognized at least as early as 2005 that some features of brain function in Alzheimer's disease mimic those that underlie diabetes. However, the concept of type 3 diabetes is controversial, and as of 2021 it was not an officially recognized diagnosis.
Lixisenatide is a once-daily injectable GLP-1 receptor agonist for the treatment of type 2 diabetes.
↑ Ryan GJ, Jobe LJ, Martin R (October 2005). "Pramlintide in the treatment of type 1 and type 2 diabetes mellitus". Clinical Therapeutics. 27 (10): 1500–1512. doi:10.1016/j.clinthera.2005.10.009. PMID16330288.
↑ Palmieri LC, Melo-Ferreira B, Braga CA, Fontes GN, Mattos LJ, Lima LM (2013). "Stepwise oligomerization of murine amylin and assembly of amyloid fibrils". Biophysical Chemistry. 180–181: 135–144. doi:10.1016/j.bpc.2013.07.013. PMID23974296.
↑ Erthal LC, Marques AF, Almeida FC, Melo GL, Carvalho CM, Palmieri LC, etal. (November 2016). "Regulation of the assembly and amyloid aggregation of murine amylin by zinc". Biophysical Chemistry. 218: 58–70. doi:10.1016/j.bpc.2016.09.008. PMID27693831.
↑ da Silva DC, Fontes GN, Erthal LC, Lima LM (December 2016). "Amyloidogenesis of the amylin analogue pramlintide". Biophysical Chemistry. 219: 1–8. doi:10.1016/j.bpc.2016.09.007. PMID27665170.
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