Insulin
Insulin crystals
Genetic data
Locus:	Chr. 11 p15.5
Gene code:	HUGO/INS
Gene type:	Protein codingp
Protein Structure/Function
Molecular Weight:	5808 (Da)
Structure:	Solution Structure of Human pro-Insulin Polypeptide
Protein type:	insulin family
Functions:	glucose regulation
Domains:	INS domain
Motifs:	SP motif
Other
Taxa expressing:	Homo sapiens; homologs: in metazoan taxa from invertebrates to mammals
Cell types:	pancreas: beta cells of the Islets of Langerhans
Subcellular localization:	extracellular fluids
Covalent modifications:	glycation, proteolytic cleavage
Pathway(s):	Insulin signaling pathway (KEGG); Type II diabetes mellitus (KEGG); Type I diabetes mellitus (KEGG); Maturity onset diabetes of the young (KEGG); Regulation of actin cytoskeleton (KEGG)
Receptor/Ligand data
Antagonists:	glucagon, steroids, most stress hormomes
Medical/Biotechnological data
Diseases:	familial hyperproinsulinemia, Diabetes mellitus
Pharmaceuticals:	insulin (Humulin Novolin), insulin lispro (Humalog), insulin aspart (NovoLog), insulin detemir (Levemir), insulin glargine (Lantus), etc
Database Links
Codes:	EntrezGene 3630; Online 'Mendelian Inheritance in Man' (OMIM) 176730; UniProt P01308; RefSeq NM_000207

Insulin is a hormone with extensive effects on both metabolism and several other body systems (eg, vascular compliance). Genetics (from Ancient Greek grc-Latn genetikos, “genitive” and that from grc-Latn genesis, “origin” a discipline of Biology, is In the fields of Genetics and Evolutionary computation, a locus (plural loci) is a fixed position on a Chromosome such as the position of a Chromosome 11 is one of the 23 pairs of Chromosomes in Humans People normally have two copies of this chromosome Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl The unified atomic mass unit ( u) or Dalton ( Da) or sometimes universal mass unit, is an unit of Mass used to express Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Glucose (Glc a Monosaccharide (or simple Sugar) also known as grape sugar, is an important Carbohydrate in Biology. A protein domain is a part of protein sequence and structure that can evolve, function and exist independently of the rest of the protein chain In an unbranched chain-like biological Molecule, such as a Protein or a strand of RNA, a structural motif is a three-dimensional structural A taxon (plural taxa) or taxonomic unit, is a name designating an organism or a group of Organisms In Biological nomenclature according to Human beings, humans or man (Origin 1590–1600 L homō man OL hemō the earthly one (see Humus A taxon (plural taxa) or taxonomic unit, is a name designating an organism or a group of Organisms In Biological nomenclature according to There are about 210 known distinct human Cell types. Keratinizing epithelial cells Epidermal Keratinocyte (differentiating The pancreas is a Gland organ in the digestive and Endocrine system of Vertebrates. Islets of Langerhans is the area in which the Endocrine (ie hormone-producing cells of the Pancreas are grouped In Cell biology, Molecular biology and related fields the word extracellular (or sometimes extracellular space) means "outside the cell Glycation (sometimes called non-enzymatic Glycosylation) is the result of a sugar molecule such as Fructose or Glucose, bonding to a Protein A protease is any Enzyme that conducts Proteolysis, that is begins protein Catabolism by Hydrolysis of the Peptide bonds that link Cell signaling is part of a Complex system of Communication that governs basic cellular activities and coordinates cell actions Diabetes mellitus type 2 or Type 2 Diabetes (formerly called non - Insulin -dependent Diabetes mellitus (NIDDM or adult-onset diabetes is a metabolic Diabetes mellitus type 1 (Type 1 diabetes Type I diabetes T1D T1DM IDDM juvenile diabetes is a form of Diabetes mellitus. Maturity onset diabetes of the young ( MODY) refers to any of several hereditary forms of diabetes caused by mutations in an autosomal dominant gene Actin is a globular roughly 42-kDa Protein found in all eukaryotic cells (except for Nematode sperm where it may be present at concentrations of cytoskeleton (also CSK is a cellular " Scaffolding " or " Skeleton " contained within the Cytoplasm. A receptor antagonist is a type of receptor ligand or Drug that does not provoke a biological response itself upon binding to a receptor, but blocks Glucagon is an important Hormone involved in Carbohydrate metabolism. A steroid is a Terpenoid Lipid characterized by a Carbon skeleton with four fused rings generally arranged in a 6-6-6-5 fashion A disease is an abnormal condition of an organism that impairs bodily functions and can be deadly Hyperproinsulinemia is a disease where Insulin is not sufficiently processed before Secretion and immature forms of insulin make up the majority of circulating insulin Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc A drug, broadly speaking is any chemical substance that when absorbed into the body Humilin is the Brand name for a Human Insulin, which was developed by Genentech in 1978 (Generic name insulin isophane Insulin lispro (marketed by Lilly as "Humalog" is a fast acting Insulin analogue; it was the first insulin analogue Insulin aspart (marketed by Novo Nordisk as "NovoLog/NovoRapid" is a fast acting Insulin analogue. Insulin detemir is a long-acting human Insulin analogue for maintaining the basal level of insulin Insulin glargine, marketed by Sanofi-Aventis under the name Lantus, is a long-acting basal Insulin analogue, usually given once or twice daily to help control The Entrez Global Query Cross-Database Search System is a powerful Federated search engine or Web portal that allows users to search many discrete Health sciences The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them Swiss-Prot is a manually curated Biological database of Protein sequences The National Center for Biotechnology Information ( NCBI) is part of the United States National Library of Medicine (NLM a branch of the National Institutes Hormones (from Greek ὁρμή - "impetus" are chemicals released by cells that affect cells in other parts of the body When present, it causes most of the body's cells to take up glucose from the blood (including liver, muscle, and fat tissue cells), storing it as glycogen in the liver and muscle, and stops use of fat as an energy source. Glucose (Glc a Monosaccharide (or simple Sugar) also known as grape sugar, is an important Carbohydrate in Biology. Blood is a specialized Bodily fluid that delivers necessary substances to the body's cells ��such as nutrients and oxygen—and transports Waste products The liver is a vital organ in the human body and is present in Vertebrates and some other animals Muscle (from Latin musculus, diminutive of mus "mouse" is contractile tissue of the body and is derived from the Adipocytes are the cells that primarily compose Adipose tissue, specialized in storing energy as Fat. Glycogen is a Polysaccharide of Glucose (Glc which functions as the secondary short term energy storage in Animal cells When insulin is absent (or low), glucose is not taken up by most body cells and the body begins to use fat as an energy source (ie, transfer of lipids from adipose tissue to the liver for mobilization as an energy source). As its level is a central metabolic control mechanism, its status is also used as a control signal to other body systems (such as amino acid uptake by body cells). In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this It has several other anabolic effects throughout the body. Anabolism is the set of Metabolic pathways that construct molecules from smaller units When control of insulin levels fail, diabetes mellitus results. Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc

Insulin is used medically to treat some forms of diabetes mellitus. Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc Patients with Type 1 diabetes mellitus depend on external insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer produced internally. Diabetes mellitus type 1 (Type 1 diabetes Type I diabetes T1D T1DM IDDM juvenile diabetes is a form of Diabetes mellitus. An injection is an infusion method of putting Liquid into the Body, usually with a hollow needle and a Syringe which is pierced through Patients with Type 2 diabetes mellitus are insulin resistant, have relatively low insulin production, or both; some patients with Type 2 diabetes may eventually require insulin when other medications fail to control blood glucose levels adequately. Diabetes mellitus type 2 or Type 2 Diabetes (formerly called non - Insulin -dependent Diabetes mellitus (NIDDM or adult-onset diabetes is a metabolic Insulin resistance is the condition in which normal amounts of Insulin are inadequate to produce a normal Insulin response from Fat, Muscle

Insulin is a peptide hormone composed of 51 amino acid residues and has a molecular weight of 5808 Da. Peptide hormones are a class of peptides that are secreted into the blood stream and have Endocrine functions in living animals In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one The unified atomic mass unit ( u) or Dalton ( Da) or sometimes universal mass unit, is an unit of Mass used to express It is produced in the Islets of Langerhans in the pancreas. Islets of Langerhans is the area in which the Endocrine (ie hormone-producing cells of the Pancreas are grouped The pancreas is a Gland organ in the digestive and Endocrine system of Vertebrates. The name comes from the Latin insula for "island". Latin ( lingua Latīna, laˈtiːna is an Italic language, historically spoken in Latium and Ancient Rome.

Insulin's structure varies slightly between species of animal. In Biology, a species is one of the basic units of Biological classification and a Taxonomic rank. Insulin from animal sources differs somewhat in 'strength' (i. e. , in carbohydrate metabolism control effects) in humans because of those variations. Carbohydrate metabolism denotes the various biochemical processes responsible for the formation, breakdown and interconversion of Carbohydrates Porcine (pig) insulin is especially close to the human version. Pigs, also called hogs or' swine', are Ungulates which have been domesticated as sources of food leather and similar products since ancient times Human beings, humans or man (Origin 1590–1600 L homō man OL hemō the earthly one (see Humus

Structure

Within vertebrates, the similarity of insulins is extremely close. Bovine insulin differs from human in only three amino acid residues, and porcine insulin in one. Cattle, colloquially referred to as cows, are domesticated Ungulates a member of the Subfamily Bovinae of the family In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this Pigs, also called hogs or' swine', are Ungulates which have been domesticated as sources of food leather and similar products since ancient times Even insulin from some species of fish is similar enough to human to be clinically effective in humans. Insulin in some invertebrates (eg, the c elegans nematode) is quite close to human insulin, has similar effects inside cells, and is produced very similarly. Insulin has been strongly preserved over evolutionary time, suggesting its centrality in animal metabolic control. The C-peptide of proinsulin (discussed later), however, differs much more amongst species; it is also a hormone, but a secondary one.

Mechanism

Insulin is produced in the pancreas, and released when any of several stimuli are detected. The pancreas is a Gland organ in the digestive and Endocrine system of Vertebrates. These include protein ingestion, and glucose in the blood (from food which produces glucose when digested -- characteristically this is carbohydrate, though not all types produce glucose and so an increase in blood glucose levels). Carbohydrates (from ' Hydrates of Carbon ' or saccharides ( Greek σάκχαρον meaning " Sugar " are the most In target cells, they initiate a signal transduction which has the effect of increasing glucose uptake and storage. In Biology, signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another Glucose (Glc a Monosaccharide (or simple Sugar) also known as grape sugar, is an important Carbohydrate in Biology. Finally, insulin is degraded, terminating the response.

Production

Insulin undergoes extensive posttranslational modification along the production pathway. Production and secretion are largely independent; prepared insulin is stored awaiting secretion. Both C-peptide and mature insulin are biologically active. Cell components and proteins in this image are not to scale.

In mammals, insulin is synthesized in the pancreas within the beta cells (β-cells) of the islets of Langerhans. The pancreas is a Gland organ in the digestive and Endocrine system of Vertebrates. Beta cells ( beta-cells, β-cells) are a type of cell in the Pancreas in areas called the Islets of Langerhans. Islets of Langerhans is the area in which the Endocrine (ie hormone-producing cells of the Pancreas are grouped One million to three million islets of Langerhans (pancreatic islets) form the endocrine part of the pancreas, which is primarily an exocrine gland. The endocrine system is an integrated system of small organs that involve the release of extracellular signaling molecules known as Hormones The endocrine system is instrumental Exocrine glands are Glands that secrete their products ( Enzymes into ducts (duct glands A gland is an organ in an animal's body that synthesizes a substance for release such as Hormones or Breast milk, often into the Bloodstream The endocrine portion only accounts for 2% of the total mass of the pancreas. Within the islets of Langerhans, beta cells constitute 60–80% of all the cells.

In beta cells, insulin is synthesized from the proinsulin precursor molecule by the action of proteolytic enzymes, known as prohormone convertases (PC1 and PC2), as well as the exoprotease carboxypeptidase E. Carboxypeptidase ( EC number 3416 - 3418 is an enzyme that hydrolyzes the carboxy-terminal (C-terminal end of a peptide bond These modifications of proinsulin remove the center portion of the molecule (ie, C-peptide), from the C- and N- terminal ends of proinsulin. C-peptide is a Peptide which is made when Proinsulin is split into Insulin and C-peptide The remaining polypeptides (51 amino acids in total), the B- and A- chains, are bound together by disulfide bonds/disulphide bonds. In Chemistry, a disulfide bond is a single Covalent bond derived from the coupling of Thiol groups Confusingly, the primary sequence of proinsulin goes in the order "B-C-A", since B and A chains were identified on the basis of mass, and the C peptide was discovered after the others.

Regulation of production

Further information: Insulin gene

The endogenous production of insulin is regulated in several steps along the synthesis pathway:

• At transcription from the insulin gene
• In mRNA stability
• At the mRNA translation
• In the posttranslational modifications

Release

See also: Blood glucose regulation

Beta cells in the islets of Langerhans release insulin mostly in response to increased blood glucose levels through the following mechanism (see figure to the right):

• Glucose enters the beta cells through the glucose transporter GLUT2
• Glucose goes into the glycolysis and the respiratory cycle where multiple high-energy ATP molecules are produced by oxidation
• Dependent on ATP levels, and hence blood glucose levels, the ATP-controlled potassium channels (K⁺) close and the cell membrane depolarizes
• On depolarization, voltage controlled calcium channels (Ca²⁺) open and calcium flows into the cells
• An increased calcium level causes activation of phospholipase C, which cleaves the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate into inositol 1,4,5-triphosphate and diacylglycerol. The insulin gene (abbreviated INS is the Gene coding for the Hormone Insulin. Transcription is the synthesis of RNA under the direction of DNA The insulin gene (abbreviated INS is the Gene coding for the Hormone Insulin. Messenger ribonucleic acid ( mRNA) is a molecule of RNA encoding a chemical "blueprint" for a Protein product Translation is the first stage of Protein biosynthesis (part of the overall process of Gene expression) Posttranslational modification (PTM is the chemical modification of a Protein after its translation. Blood sugar, used in a physiological context is a misnomer and misleading Blood sugar, used in a physiological context is a misnomer and misleading Beta cells ( beta-cells, β-cells) are a type of cell in the Pancreas in areas called the Islets of Langerhans. Glucose transporters (GLUT or SLC2A family are a family of Membrane proteins found in most mammalian cells Function Glucose is an essential GLUT 2 is a transmembrane carrier Protein and gene which is involved in passive glucose transport, especially the Renal glucose reabsorption. See also Gluconeogenesis, which carries out a process wherein glucose is synthesized rather than catabolized Adenosine-5'-triphosphate ( ATP) is a multifunctional Nucleotide that is most important as a " molecular currency" of intracellular Energy In the field of Cell biology, potassium channels are the most widely distributed type of Ion channel and are found in virtually all living organisms In biology depolarization is a decrease in the Absolute value of a cell's Membrane potential. A Calcium channel is an Ion channel which displays selective permeabiltiy to Calcium ions A phospholipase is an enzyme that converts Phospholipids into Fatty acids and other Lipophilic substances Phosphatidylinositol (45-bisphosphate (PtdIns(45 P 2 is a minor Phospholipid component of cell membranes Inositol trisphosphate or inositol 145-trisphosphate (also commonly known as triphosphoinositol; abbreviated InsP3 or IP3 A diglyceride, or a diacylglycerol (DAG is a Glyceride consisting of two Fatty acid chains covalently bonded to a Glycerol
• Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the membrane of endoplasmic reticulum (ER). The endoplasmic reticulum (Greek endo = "within" (prefix plásma = "formed entity" Latin reticulum = "little net" or ER, is an Organelle This allows the release of Ca²⁺ from the ER via IP3 gated channels, and further raises the cell concentration of calcium.
• Significantly increased amounts of calcium in the cells causes release of previously synthesised insulin, which has been stored in secretory vesicles

This is the main mechanism for release of insulin and regulation of insulin synthesis. Secretion is the process of segregating elaborating and releasing chemicals from a cell, or a secreted Chemical substance or amount of substance A vesicle is a small bubble of liquid within a cell A more formal definition in Cell biology, would be that a vesicle is a relatively small intracellular membrane-enclosed In addition some insulin synthesis and release takes place generally at food intake, not just glucose or carbohydrate intake, and the beta cells are also somewhat influenced by the autonomic nervous system. Carbohydrates (from ' Hydrates of Carbon ' or saccharides ( Greek σάκχαρον meaning " Sugar " are the most &trade The autonomic nervous system ( ANS) (or visceral nervous system) is the part of the Peripheral nervous system that acts as a Control The signalling mechanisms controlling these linkages are not fully understood.

Other substances known to stimulate insulin release include amino acids from ingested proteins, acetylcholine, released from vagus nerve endings (parasympathetic nervous system), cholecystokinin[citation needed], released by enteroendocrine cells of intestinal mucosa and glucose-dependent insulinotropic peptide (GIP). The parasympathetic Nervous system ( PSNS) is a division of the Autonomic nervous system (ANS along with the Sympathetic nervous system Cholecystokinin ( CCK; from Greek chole, "bile" cysto, "sac" kinin, "move" hence move the bile-sac Enteroendocrine cells are specialized Endocrine cells of the Gastrointestinal tract. Gastric inhibitory polypeptide ( GIP) also known as the glucose-dependent insulinotropic peptide is a member of the secretin family of Hormones Three amino acids (alanine, glycine and arginine) act similarly to glucose by altering the beta cell's membrane potential. Acetylcholine triggers insulin release through phospholipase C, while the last acts through the mechanism of adenylate cyclase. Adenylate cyclase ( also known as adenylyl cyclase or AC) is a Lyase Enzyme.

The sympathetic nervous system (via Alpha2-adrenergic stimulation as demonstrated by the agonists clonidine or methyldopa) inhibit the release of insulin. The Sympathetic Nervous System ( SNS) is a branch of the Autonomic nervous system along with the Enteric nervous system and Parasympathetic nervous Clonidine is a direct-acting α2 Adrenergic agonist prescribed historically as an Antihypertensive agent Methyldopa or alpha-methyldopa (brand names Aldomet, Apo-Methyldopa, Dopamet, Novomedopa) is a centrally-acting adrenergic Antihypertensive However, it is worth noting that circulating epinephrine will activate Beta₂-Receptors on the Beta cells in the pancreatic Islets to promote insulin release. This is important since muscle cannot benefit from the raised blood sugar resulting from adrenergic stimulation (increased gluconeogenesis and glycogenolysis from the low blood insulin: glucagon state) unless insulin in present to allow for GLUT-4 translocation in the tissue. GLUT4 is the Insulin -regulated Glucose transporter found in Adipose tissues and Striated muscle (skeletal and cardiac that is responsible for So in summary, first through direct innervation, NE inhibits insulin release via alpha₂-receptors, then later, circulating Epi from the adrenal medulla will stimulate beta₂-receptors thereby promoting insulin release. The adrenal medulla is part of the Adrenal gland. It is located at the center of the gland being surrounded by the Adrenal cortex.

When the glucose level comes down to the usual physiologic value, insulin release from the beta cells slows or stops. If blood glucose levels drop lower than this, especially to dangerously low levels, release of hyperglycemic hormones (most prominently glucagon from Islet of Langerhans' alpha cells) forces release of glucose into the blood from cellular stores, primarily liver cell stores of glycogen. Glucagon is an important Hormone involved in Carbohydrate metabolism. By increasing blood glucose, the hyperglycemic hormones correct life-threatening hypoglycemia. Release of insulin is strongly inhibited by the stress hormone norepinephrine (noradrenaline), which leads to increased blood glucose levels during stress. Stress hormones such as Cortisol and Norepinephrine are released at periods of high stress Norepinephrine ( INN) (abbreviated norepi or NE) or noradrenaline ( BAN) (abbreviated NA or NAd) is a

Oscillations

Main article: Insulin release oscillations

Insulin release from pancreas oscillates with a period of 3–6 minutes. The insulin concentration in blood increases after meals and gradually returns to basal levels during 1-2 hours ^[1]

Even during digestion, generally one or two hours following a meal, insulin release from pancreas is not continuous, but oscillates with a period of 3–6 minutes, changing from generating a blood insulin concentration more than ~800 pmol/l to less than 100 pmol/l. Oscillation is the repetitive variation typically in Time, of some measure about a central value (often a point of Equilibrium) or between two or more different states pico- (symbol p) is a prefix denoting a factor of 10-12 in the International System of Units (SI The mole (symbol mol) is a unit of Amount of substance: it is an SI base unit, and almost the only unit to be used to measure this ^[1] This is thought to avoid downregulation of insulin receptors in target cells and to assist the liver in extracting insulin from the blood. In Biochemistry, a receptor is a Protein molecule embedded in either the Plasma membrane or Cytoplasm of a cell to which a mobile signaling In Molecular biology, the insulin receptor is a transmembrane receptor that is activated by Insulin. ^[1] This oscillation is important to consider when administering insulin-stimulating medication, since it is the oscillating blood concentration of insulin release which should, ideally, be achieved, not a constant high concentration. ^[1] This may be achieved by delivering insulin rhythmically to the portal vein or by islet cell transplantation to the liver. Islet transplantation is the transplantation of isolated islets from a donor Pancreas and into another person ^[1]Future insulin pumps may include this characteristic.

Signal transduction

There are special transporter proteins in cell membranes through which glucose from the blood can enter a cell. The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer Glucose (Glc a Monosaccharide (or simple Sugar) also known as grape sugar, is an important Carbohydrate in Biology. These transporters are, indirectly, under blood insulin's control in certain body cell types (e. g. , muscle cells). Low levels of circulating insulin, or its absence, will prevent glucose from entering those cells (e. g. , in Type 1 diabetes). However, more commonly there is a decrease in the sensitivity of cells to insulin (e. g. , the reduced insulin sensitivity characteristic of Type 2 diabetes), resulting in decreased glucose absorption. In either case, there is 'cell starvation', weight loss, sometimes extreme. In a few cases, there is a defect in the release of insulin from the pancreas. Either way, the effect is, characteristically, the same: elevated blood glucose levels.

Activation of insulin receptors leads to internal cellular mechanisms that directly affect glucose uptake by regulating the number and operation of protein molecules in the cell membrane that transport glucose into the cell. In Molecular biology, the insulin receptor is a transmembrane receptor that is activated by Insulin. The genes that specify the proteins that make up the insulin receptor in cell membranes have been identified and the structure of the interior, cell membrane section, and now, finally after more than a decade, the extra-membrane structure of receptor (Australian researchers announced the work 2Q 2006).

Two types of tissues are most strongly influenced by insulin, as far as the stimulation of glucose uptake is concerned: muscle cells (myocytes) and fat cells (adipocytes). A myocyte (also known as a myocardial cell is the type of cell found in heart muscles. Adipocytes are the cells that primarily compose Adipose tissue, specialized in storing energy as Fat. The former are important because of their central role in movement, breathing, circulation, etc, and the latter because they accumulate excess food energy against future needs. Food energy is the amount of Energy in food that is available through Digestion. Together, they account for about two-thirds of all cells in a typical human body.

Effects

Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6). The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer Glycogen is a Polysaccharide of Glucose (Glc which functions as the secondary short term energy storage in Animal cells See also Gluconeogenesis, which carries out a process wherein glucose is synthesized rather than catabolized In Chemistry, especially Biochemistry, a fatty acid is a Carboxylic acid often with a long unbranched Aliphatic tail ( chain) which

The actions of insulin on the global human metabolism level include:

• Control of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about ⅔ of body cells). Glucose (Glc a Monosaccharide (or simple Sugar) also known as grape sugar, is an important Carbohydrate in Biology. "Adipose" redirects here For the Doctor Who monster see " Partners in Crime "
• Increase of DNA replication and protein synthesis via control of amino acid uptake. DNA replication is the process of copying a double-stranded DNA molecule to form two double-stranded molecules Protein synthesis is the creation of proteins using DNA and' RNA'.
• Modification of the activity of numerous enzymes. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins

The actions of insulin on cells include:

• Increased glycogen synthesis – insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. Glycogen is a Polysaccharide of Glucose (Glc which functions as the secondary short term energy storage in Animal cells This is the clinical action of insulin which is directly useful in reducing high blood glucose levels as in diabetes.
• Increased fatty acid synthesis – insulin forces fat cells to take in blood lipids which are converted to triglycerides; lack of insulin causes the reverse. In Chemistry, especially Biochemistry, a fatty acid is a Carboxylic acid often with a long unbranched Aliphatic tail ( chain) which (more properly known as, TAG or triacylglyceride) is Glyceride in which the Glycerol is Esterified with three Fatty acids It is the
• Increased esterification of fatty acids – forces adipose tissue to make fats (i. Esterification is the general name for a Chemical reaction in which two reactants (typically an alcohol and an acid form an Ester as the reaction product "Adipose" redirects here For the Doctor Who monster see " Partners in Crime " e. , triglycerides) from fatty acid esters; lack of insulin causes the reverse.
• Decreased proteolysis – decreasing the breakdown of protein. Proteolysis is the directed degradation ( digestion) of Proteins by cellular Enzymes called Proteases or by intramolecular digestion
• Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse. Lipolysis is the breakdown of fat stored in fat cells During this process Free fatty acids are released into the bloodstream and circulate throughout the body
• Decreased gluconeogenesis – decreases production of glucose from non-sugar substrates, primarily in the liver (remember, the vast majority of endogenous insulin arriving at the liver never leaves the liver) ; lack of insulin causes glucose production from assorted substrates in the liver and elsewhere. Gluconeogenesis (abreviated GNG) is a Metabolic pathway that results in the generation of Glucose from non- Carbohydrate carbon substrates such
• Increased amino acid uptake – forces cells to absorb circulating amino acids; lack of insulin inhibits absorption.
• Increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption. Thus lowers potassium levels in blood.
• Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in micro arteries; lack of insulin reduces flow by allowing these muscles to contract.

Degradation

Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment or it may be degraded by the cell. Degradation normally involves endocytosis of the insulin-receptor complex followed by the action of insulin degrading enzyme. Endocytosis is a process where cells absorb material ( Molecules such as proteins from the outside by engulfing it with their Cell membrane. Insulin-degrading enzyme, also known as IDE, is a human Gene. Most insulin molecules are degraded by liver cells. The liver is a vital organ in the human body and is present in Vertebrates and some other animals It has been estimated that a typical insulin molecule that is produced endogenously by the pancreatic beta cells is finally degraded about 71 minutes after its initial release into circulation. ^[2]

Hypoglycemia

Main article: Hypoglycemia

Although other cells can use other fuels for a while (most prominently fatty acids), neurons depend on glucose as a source of energy in the non-starving human. Hypoglycemia or hypoglycaemia is the medical term for a pathologic state produced by a lower than normal level of Glucose ( sugar) in the blood Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information They do not require insulin to absorb glucose, unlike muscle and adipose tissue, and they have very small internal stores of glycogen. Glycogen stored in liver cells (unlike glycogen stored in muscle cells) can be converted to glucose, and released into the blood, when glucose from digestion is low or absent, and the glycerol backbone in triglycerides can also be used to produce blood glucose. Glycogen is a Polysaccharide of Glucose (Glc which functions as the secondary short term energy storage in Animal cells (more properly known as, TAG or triacylglyceride) is Glyceride in which the Glycerol is Esterified with three Fatty acids It is the

Sufficient lack of glucose and scarcity of these sources of glucose can dramatically make itself manifest in the impaired functioning of the central nervous system; dizziness, speech problems, and even loss of consciousness, can occur. In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. Low glucose is known as hypoglycemia or, in cases producing unconsciousness, "hypoglycemic coma" (sometimes termed "insulin shock" from the most common causative agent). Hypoglycemia or hypoglycaemia is the medical term for a pathologic state produced by a lower than normal level of Glucose ( sugar) in the blood Endogenous causes of insulin excess (such as an insulinoma) are very rare, and the overwhelming majority of insulin-excess induced hypoglycemia cases are iatrogenic and usually accidental. An insulinoma is a Tumour of the Pancreas derived from the Beta cells which while retaining the ability to synthesize and secrete Insulin is autonomous The terms iatrogenesis and iatrogenic artifact refer to adverse effects or complications caused by or resulting from medical treatment or advice There have been a few reported cases of murder, attempted murder, or suicide using insulin overdoses, but most insulin shocks appear to be due to errors in dosage of insulin (e. g. , 20 units of insulin instead of 2) or other unanticipated factors (didn't eat as much as anticipated, or exercised more than expected, or unpredicted kinetics of the subcutaneously injected insulin itself).

Possible causes of hypoglycemia include:

• External insulin (usually injected subcutaneously).
• Oral hypoglycemic agents (e. g. , any of the sulfonylureas, or similar drugs, which increase insulin release from beta cells in response to a particular blood glucose level).
• Ingestion of low-carbohydrate sugar substitutes (animal studies show these can trigger insulin release (albeit in much smaller quantities than sugar) according to a report in Discover magazine, August 2004, p18). Note that this can never be a cause of hypoglycemia in type 1 diabetes mellitus, as endogenous insulin production no longer exists. Diabetes mellitus type 1 (Type 1 diabetes Type I diabetes T1D T1DM IDDM juvenile diabetes is a form of Diabetes mellitus.

Diseases and syndromes

There are several conditions in which insulin disturbance is pathologic:

• Diabetes mellitus – general term referring to all states characterized by hyperglycemia. Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc
  • Type 1 – autoimmune-mediated destruction of insulin producing beta cells in the pancreas resulting in absolute insulin deficiency. Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc
  • Type 2 – multifactoral syndrome with combined influence of genetic susceptibility and influence of environmental factors, the best known being obesity, age, and physical inactivity, resulting in insulin resistance in cells requiring insulin for glucose absorption. Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc Obesity is a condition in which excess Body fat has accumulated to such an extent that health may be negatively affected Insulin resistance is the condition in which normal amounts of Insulin are inadequate to produce a normal Insulin response from Fat, Muscle This form of diabetes is strongly inherited.
  • Other types of impaired glucose tolerance (see the diabetes article). Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc
• Insulinoma - a tumor of pancreatic beta cells producing excess of insulin or reactive hypoglycemia. An insulinoma is a Tumour of the Pancreas derived from the Beta cells which while retaining the ability to synthesize and secrete Insulin is autonomous Reactive hypoglycemia is a medical term describing recurrent episodes of symptomatic Hypoglycemia occurring 2-4 hours after a high Carbohydrate meal (or oral
• Metabolic syndrome – a poorly understood condition first called Syndrome X by Gerald Reaven, Reaven's Syndrome after Reaven, CHAOS in Australia (from the signs which seem to travel together), and sometimes prediabetes. Metabolic syndrome is a combination of medical disorders that increase the risk of developing Cardiovascular disease and diabetes. The terms Syndrome X or Metabolic syndrome X may also be referring to Metabolic syndrome. Gerald M "Jerry" Reaven is an American endocrinologist and professor emeritus in medicine at the Stanford University School of Medicine in Prediabetes is the state in which Blood glucose levels are above normal but have not reached that of Diabetes. It is currently not clear whether these signs have a single, treatable cause, or are the result of body changes leading to type 2 diabetes. It is characterized by elevated blood pressure, dyslipidemia (disturbances in blood cholesterol forms and other blood lipids), and increased waist circumference (at least in populations in much of the developed world). The basic underlying cause may be the insulin resistance of type 2 diabetes which is a diminished capacity for insulin response in some tissues (e. g. , muscle, fat) to respond to insulin. Commonly, morbidities such as essential hypertension, obesity, Type 2 diabetes, and cardiovascular disease (CVD) develop. Hypertension, also referred to as high blood pressure, HTN or HPN, is a medical condition in which the Blood pressure is chronically elevated Obesity is a condition in which excess Body fat has accumulated to such an extent that health may be negatively affected Cardiovascular disease or cardiovascular diseases refers to the class of diseases that involve the Heart or Blood vessels ( arteries and
• Polycystic ovary syndrome – a complex syndrome in women in the reproductive years where there is anovulation and androgen excess commonly displayed as hirsutism. Polycystic ovary syndrome abbreviated PCOS or PCO (also known clinically as Stein-Leventhal syndrome, Sclerocystic ovary syndrome, Hyperthecosis An anovulatory cycle is a cycle during which the ovaries fail to release an oocyte Androgen is the generic term for any natural or synthetic compound usually a Steroid Hormone, that stimulates or controls the development and maintenance of masculine Hirsutism (from Latin hirsutus = shaggy hairy is defined as excessive and increased Hair growth in women in locations where the occurrence of Terminal In many cases of PCOS insulin resistance is present. Insulin resistance is the condition in which normal amounts of Insulin are inadequate to produce a normal Insulin response from Fat, Muscle

As a medication

Principles

Insulin is required for all animal life (excluding insects). Its mechanism of action is almost identical in nematode worms (e. g. C. elegans), fish, and mammals, and it is a protein that has been highly conserved across evolutionary time. Caenorhabditis elegans (ˌsiːnoʊræbˈdaɪtɪs ˈɛlɪgænz is a free-living Nematode (roundworm about 1  mm in length which In humans, insulin deprivation due to the removal or destruction of the pancreas leads to death in days or, at most, weeks. Insulin must be administered to patients who experience such a deprivation. Clinically, this condition is called diabetes mellitus type 1. Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc

The initial sources of insulin for clinical use in humans were cow, horse, pig or fish pancreases. Cattle, colloquially referred to as cows, are domesticated Ungulates a member of the Subfamily Bovinae of the family The horse ( Equus caballus) is a hoofed ( Ungulate) Mammal, one of eight living species of the family Equidae. Pigs, also called hogs or' swine', are Ungulates which have been domesticated as sources of food leather and similar products since ancient times Fish are aquatic Vertebrate animals that are typically ectothermic (previously Cold-blooded) covered with scales, and equipped with two Insulin from these sources is effective in humans as it is nearly identical to human insulin (three amino acid difference in bovine insulin, one amino acid difference in porcine). Differences in suitability of beef, pork, or fish derived insulin for individual patients have historically been due to lower preparation purity resulting in allergic reactions to the presence of non-insulin substances. Though purity has improved steadily since the 1920s ultimately reaching purity of 99% by the mid-1970s thanks to high-pressure liquid chromatography (HPLC) methods, but minor allergic reactions still occur occasionally, although the same types of allergic reactions have also been known to occur in response to synthetic "human" insulin varieties. High-performance liquid chromatography (or High pressure liquid chromatography, HPLC) is a form of Column chromatography used frequently in Biochemistry Insulin production from animal pancreases was widespread for decades, but very few patients today rely on insulin from animal sources, largely because few pharmaceutical companies sell it anymore.

Synthetic "human" insulin is now manufactured for widespread clinical use using genetic engineering techniques using recombinant DNA technology, which the manufacturers claim reduces the presence of many impurities. Recombinant DNA is a form of synthetic DNA that is engineered through the combination or insertion of one or more DNA strands thereby combining DNA sequences Eli Lilly marketed the first such insulin, Humulin, in 1982. Eli Lilly and Company ( is a global Pharmaceutical company and one of the world's largest corporations Humulin was the first medication produced using modern genetic engineering techniques in which actual human DNA is inserted into a host cell (E. coli in this case). The host cells are then allowed to grow and reproduce normally, and due to the inserted human DNA, they produce a synthetic version of human insulin. However, the clinical preparations prepared from such insulins differ from endogenous human insulin in several important respects; an example is the absence of C-peptide which has in recent years been shown to have systemic effects itself. C-peptide is a Peptide which is made when Proinsulin is split into Insulin and C-peptide

Genentech developed the technique Lilly used to produce Humulin, although the company never commercially marketed the product themselves. Genentech Inc ( a composite of Genetic Engineering Technology Inc Novo Nordisk has also developed a genetically engineered insulin independently. Novo Nordisk () manufactures and markets Pharmaceutical products and services According to a survey that the International Diabetes Federation conducted in 2002 on the access to and availability of insulin in its member countries, approximately 70% of the insulin that is currently sold in the world is recombinant, biosynthetic 'human' insulin^[3]. A majority of insulin used clinically today is produced this way, although the clinical evidence has provided conflicting evidence on whether these insulins are any less likely to produce an allergic reaction. Also, the International Diabetes Federation's position statement is very clear in stating that "there is NO overwhelming evidence to prefer one species of insulin over another" and "[modern, highly-purified] animal insulins remain a perfectly acceptable alternative. "^[4]

Since January 2006, all insulins distributed in the U. S. and some other countries are synthetic "human" insulins or their analogs. A special FDA importation process is required to obtain bovine or porcine derived insulin for use in the U. S. , although there may be some remaining stocks of porcine insulin made by Lilly in 2005 or earlier.

There are several problems with insulin as a clinical treatment for diabetes:

• Mode of administration.
• Selecting the 'right' dose and timing.
• Selecting an appropriate insulin preparation (typically on 'speed of onset and duration of action' grounds).
• Adjusting dosage and timing to fit food intake timing, amounts, and types.
• Adjusting dosage and timing to fit exercise undertaken.
• Adjusting dosage, type, and timing to fit other conditions, for instance the increased stress of illness.
• The dosage is non-physiological in that a subcutaneous bolus dose of insulin alone is administered instead of combination of insulin and C-peptide being released gradually and directly into the portal vein. In medicine a bolus (from Latin bolus, ball is the administration of a Medication, Drug or other compound that is given to raise C-peptide is a Peptide which is made when Proinsulin is split into Insulin and C-peptide
• It is simply a nuisance for patients to inject whenever they eat carbohydrate or have a high blood glucose reading.
• It is dangerous in case of mistake (most especially 'too much' insulin).

Types

Medical preparations of insulin (from the major suppliers – Eli Lilly, Novo Nordisk, and Sanofi Aventis – or from any other) are never just 'insulin in water'. Eli Lilly and Company ( is a global Pharmaceutical company and one of the world's largest corporations Novo Nordisk () manufactures and markets Pharmaceutical products and services Sanofi-Aventis () headquartered in Paris, France, is a multinational pharmaceutical company Clinical insulins are specially prepared mixtures of insulin plus other substances. These delay absorption of the insulin, adjust the pH of the solution to reduce reactions at the injection site, and so on.

Slight variations of the human insulin molecule are called insulin analogs, so named because they are not technically insulin, rather they are analogs which retain the hormone's glucose management functionality. An insulin analog is an altered form of Insulin, different from any occurring in nature but still available to the human body for performing the same action as human insulin They have absorption and activity characteristics not currently possible with subcutaneously injected insulin proper. They are either absorbed rapidly in an attempt to mimic real beta cell insulin (as with Lilly's lispro, Novo Nordisk's aspart and Sanofi Aventis' glulisine), or steadily absorbed after injection instead of having a 'peak' followed by a more or less rapid decline in insulin action (as with Novo Nordisk's version Insulin detemir and Sanofi Aventis's Insulin glargine), all while retaining insulin action in the human body. Novo Nordisk () manufactures and markets Pharmaceutical products and services Sanofi-Aventis () headquartered in Paris, France, is a multinational pharmaceutical company However, a number of meta-analyses, including those done by the Cochrane Collaboration in the United Kingdom in 2002^[5], Germany's Institute for Quality and Cost Effectiveness in the Health Care Sector [IQWiG] released in 2007^[6], and the Canadian Agency for Drugs and Technology in Health (CADTH)^[7], also released in 2007 have proven unequivocally that any claims of superiority for insulin analogs over regular insulin are unsupported by clinical evidence. In Statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses The Cochrane Collaboration is a group of over 11500 volunteers in more than 90 countries who apply a rigorous systematic process to review the effects of interventions tested in biomedical

Choosing insulin type and dosage/timing should be done by an experienced medical professional working with the diabetic patient.

The commonly used types of insulin are:

• Rapid-acting, are presently insulin analogs, such as the insulin analog aspart or lispro – begins to work within 5 to 15 minutes and is active for 3 to 4 hours. Newer varieties are in now in Phase II clinical trials which are designed to work rapidly, but retain the same genetic structure as regular human insulin^[8].

• Short-acting, such as regular insulin – starts working within 30 minutes and is active about 5 to 8 hours.
• Intermediate-acting, such as NPH, or lente insulin – starts working in 1 to 3 hours and is active 16 to 24 hours. Neutral Protamine Hagedorn was created in 1936 when Nordisk formulated "isophane" porcine Insulin by adding Neutral Protamine to regular
• Long-acting, such as ultralente insulin – starts working in 4 to 6 hours, and is active 24 to 28 hours.
• Insulin glargine and Insulin detemir – both insulin analogs which start working within 1 to 2 hours and continue to be active, without major peaks or dips, for about 24 hours, although this varies in many individuals.
• A mixture of NPH and regular insulin – starts working in 30 minutes and is active 16 to 24 hours. There are several variations with different proportions of the mixed insulins.

Yeast-based

In late 2003, Wockhardt commenced manufacture of a yeast-based insulin costing $3. Yeasts are a growth form of eukaryotic Microorganisms classified in the kingdom Fungi, with about 1500 Species currently described 25 in India claiming it eliminates the risk of contracting diseases such as BSE and CJD associated with insulin derived from pigs and cattle. Bovine Spongiform Encephalopathy ( BSE) commonly known as Mad-Cow Disease ( MCD) is a fatal Neurodegenerative disease in Cattle Creutzfeldt-Jakob disease ( CJD) is a very rare and incurable degenerative neurological disorder ( Brain Disease) that is ultimately ^[9]

Modes of administration

Unlike many medicines, insulin cannot be taken orally. Like nearly all other proteins introduced into the gastrointestinal tract, it is reduced to fragments (even single amino acid components), whereupon all 'insulin activity' is lost.

Subcutaneous

Insulin is usually taken as subcutaneous injections by single-use syringes with needles, an insulin pump, or by repeated-use insulin pens with needles. The subcutaneous tissue or subcutis is the layer of Loose connective tissue directly underlying the Dermis. An injection is an infusion method of putting Liquid into the Body, usually with a hollow needle and a Syringe which is pierced through A syringe is a simple piston Pump consisting of a plunger that fits tightly in a tube A hypodermic needle is a hollow needle commonly used with a Syringe to inject substances into the body An insulin pump is a medical device used for the administration of Insulin in the treatment of Diabetes mellitus, also known as continuous subcutaneous An insulin pen is an Insulin injection system for the treatment of Diabetes.

Administration schedules attempt to mimic the physiologic secretion of insulin by the pancreas. Hence, both a long-acting insulin and a short-acting insulin are typically used.

Insulin pump

Main article: Insulin pump

Insulin pumps are a reasonable solution for some. An insulin pump is a medical device used for the administration of Insulin in the treatment of Diabetes mellitus, also known as continuous subcutaneous An insulin pump is a medical device used for the administration of Insulin in the treatment of Diabetes mellitus, also known as continuous subcutaneous Advantages to the patient are better control over background or 'basal' insulin dosage, bolus doses calculated to fractions of a unit, and calculators in the pump that may help with determining 'bolus' infusion doages. The limitations are cost, the potential for hypoglycemic and hyperglycemic episodes, catheter problems, and no "closed loop" means of controlling insulin delivery based on current blood glucose levels.

Insulin pumps may be like 'electrical injectors' attached to a temporarily implanted catheter or cannula. In Medicine a catheter is a tube that can be inserted into a body cavity duct or vessel A cannula (from Latin "little reed" plural cannulae) or canula is a tube which can be inserted into the body often for the delivery or removal Some who cannot achieve adequate glucose control by conventional (or jet) injection are able to do so with the appropriate pump.

As with injections, if too much insulin is delivered or the patient eats less than he or she dosed for, there will be hypoglycemia. On the other hand, if too little insulin is delivered, there will be hyperglycemia. Both can be life-threatening. In addition, indwelling catheters pose the risk of infection and ulceration, and some patients may also develop lipodystrophy due to the infusion sets. Lipodystrophy is a medical condition characterized by abnormal or degenerative conditions of the body's Adipose tissue These risks can often be minimized by keeping infusion sites clean. Insulin pumps require care and effort to use correctly. However, some patients with diabetes are capable of keeping their glucose in reasonable control only with an insulin pump.

Inhalation

Main article: Inhalable insulin

In 2006 the U. Inhalable insulin was available from September 2006 to October 2007 in the United States as a new method of delivering Insulin, a drug used in the treatment of diabetes S. Food and Drug Administration approved the use of Exubera, the first inhalable insulin. Inhalable insulin was available from September 2006 to October 2007 in the United States as a new method of delivering Insulin, a drug used in the treatment of diabetes ^[10] It has been withdrawn from the market by its maker as of 3Q 2007, due to lack of acceptance.

Inhaled insulin has similar efficacy to injected insulin, both in terms of controlling glucose levels and blood half-life. Currently, inhaled insulin is short acting and is typically taken before meals; an injection of long-acting insulin at night is often still required. ^[11] When patients were switched from injected to inhaled insulin, no significant difference was found in Hb_A1c levels over three months. Accurate dosing is still a problem, although patients showed no significant weight gain or pulmonary function decline over the length of the trial, when compared to the baseline. ^[12] Following its commercial launch in 2005 in the UK, it was not (as of July 2006) recommended by National Institute for Health and Clinical Excellence for routine use, except in cases where there is "proven injection phobia diagnosed by a psychiatrist or psychologist". ^[11]

In January 2008, the world's largest insulin manufacturer, Novo Nordisk A/S, also announced that the company was discontinuing all further development of the company's own version of inhalable insulin, known as the AERx iDMS inhaled insulin system^[13]. Novo Nordisk () manufactures and markets Pharmaceutical products and services Similarly, Eli Lilly and Company ended its efforts to develop its Air inhaled insulin in March 2008^[14]. Eli Lilly and Company ( is a global Pharmaceutical company and one of the world's largest corporations MannKind Corp. (whose majority owner, Alfred E. Mann, remained unusually bullish on the concept in spite of Pfizer's costly failure^[15]

Transdermal

There are several methods for transdermal delivery of insulin. Alfred E Mann (born 1925 Portland OR) who is also known as Al Mann is an American Entrepreneur and philanthropist Pulsatile insulin uses microjets to pulse insulin into the patient, mimicking the physiological secretions of insulin by the pancreas. Pulsatile insulin, sometimes called metabolic activation therapy, describes in a literal sense the injection of Insulin in pulses versus continuous infusions ^[16] Jet injection had different insulin delivery peaks and durations as compared to needle injection. jet injector is a type of medical injecting Syringe that uses a high- Pressure narrow jet of the injection liquid instead of a Hypodermic needle Some diabetics find control possible with jet injectors, but not with hypodermic injection.

Both electricity using iontophoresis^[17] and ultrasound have been found to make the skin temporarily porous. Iontophoresis is a non-invasive method of propelling high concentrations of a charged substance normally medication or bioactive agents transdermally by repulsive electromotive force The insulin administration aspect remains experimental, but the blood glucose test aspect of 'wrist appliances' is commercially available.

Researchers have produced a watch-like device that tests for blood glucose levels through the skin and administers corrective doses of insulin through pores in the skin. The sebaceous glands are Glands found in the Skin of Mammals Locations and morphology A branched type of Acinar gland, these

Intranasal insulin

Intranasal insulin is being investigated. ^[18]

Oral insulin

The basic appeal of oral hypoglycemic agents is that most people would prefer a pill to an injection. However, insulin is a protein, which are digested in the stomach and gut and in order to be effective at controlling blood sugar, can not be taken orally. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Digestion is the breaking down of chemicals in the body into a form that can be absorbed In Human anatomy, the stomach is a J-shaped hollow muscular organ of the Gastrointestinal tract involved in the second phase of Digestion, following

The potential market for an oral form of insulin is assumed to be enormous, thus many laboratories have attempted to devise ways of moving enough intact insulin from the gut to the portal vein to have a measurable effect on blood sugar. As of 2004, no products appear to be successful enough yet to bring to market. ^[19]

A Connecticut-based biopharmaceutical company called Biodel, Inc. is developing what it calls VIAtab, an oral formulation of insulin designed to be administered sublingually. This therapy is a tablet that dissolves in minutes when placed under the tongue. In a Phase I study, VIAtab delivered insulin to the blood stream quickly and resembled the first-phase insulin release spike found in healthy individuals. The company claims that an oral insulin therapy would be more convenient than currently available injectable or inhalable therapies, and they expect that convenience to result in increased insulin usage among the currently underserved early-stage patients with Type 2 diabetes, thus helping to create better long-term outcomes for that patient population^[20].

An Israeli pharmaceutical company, Oramed Pharmaceuticals, is currently conducting Phase 2A studies on an oral insulin pill^[21].

Australian biopharmaceutical company, Apollo Life Sciences, plans to enter the Phase I trial of its oral insulin tablet in mid-2008. For a topic outline on this subject see List of basic Australia topics. ^[22]

Pancreatic transplantation

Main article: Islet cell transplantation

Another improvement would be a transplantation of the pancreas or beta cell to avoid periodic insulin administration. Islet transplantation is the transplantation of isolated islets from a donor Pancreas and into another person This would result in a self-regulating insulin source. Transplantation of an entire pancreas (as an individual organ) is difficult and relatively uncommon. In Biology, an organ ( Latin: organum, "instrument tool" from Greek όργανον - organon "organ instrument It is often performed in conjunction with liver or kidney transplant, although it can be done by itself. The liver is a vital organ in the human body and is present in Vertebrates and some other animals The kidneys are complicated organs that have numerous biological roles It is also possible to do a transplantation of only the pancreatic beta cells. However, islet transplants had been highly experimental (for which read 'prone to failure') for many years, but some researchers in Alberta, Canada, have developed techniques with a high initial success rate (about 90% in one group). Alberta (ælˈbɝtə is one of Canada's prairie provinces. It became a province on September 1 1905 Nearly half of those who got an islet cell transplant were insulin-free one year after the operation; by the end of the second year that number drops to about one in seven. Beta cell transplant may become practical in the near future. Additionally, some researchers have explored the possibility of transplanting genetically engineered non-beta cells to secrete insulin. Genetic engineering, Recombinant DNA technology, genetic modification/manipulation (GM and gene splicing are terms that apply to the direct ^[23] Clinically testable results are far from realization at this time. Several other non-transplant methods of automatic insulin delivery are being developed in research labs, but none is close to clinical approval.

Artificial pancreas

Main article: artificial pancreas

Dosage and timing

The central problem for those requiring external insulin is picking the right dose of insulin and the right timing. The artificial pancreas is a technology in development to help people with Diabetes automatically control their Blood glucose level by providing the substitute

Physiological regulation of blood glucose, as in the non-diabetic, would be best. Increased blood glucose levels after a meal is a stimulus for prompt release of insulin from the pancreas. The increased insulin level causes glucose absorption and storage in cells, reducing glycogen to glucose conversion, reducing blood glucose levels, and so reducing insulin release. The result is that the blood glucose level rises somewhat after eating, and within an hour or so, returns to the normal 'fasting' level. Even the best diabetic treatment with synthetic human insulin or even insulin analogs, however administered, falls far short of normal glucose control in the non-diabetic.

Complicating matters is that the composition of the food eaten (see glycemic index) affects intestinal absorption rates. The Glycemic index (also glycaemic index) or GI is a measure of the effects of Carbohydrates on Blood glucose levels Glucose from some foods is absorbed more (or less) rapidly than the same amount of glucose in other foods. Fats and proteins cause delays in absorption of glucose from carbohydrate eaten at the same time. As well, exercise reduces the need for insulin even when all other factors remain the same, since working muscle has some ability to take up glucose without the help of insulin.

It is, in principle, impossible to know for certain how much insulin (and which type) is needed to 'cover' a particular meal to achieve a reasonable blood glucose level within an hour or two after eating. Non-diabetics' beta cells routinely and automatically manage this by continual glucose level monitoring and insulin release. All such decisions by a diabetic must be based on experience and training (i. e. , at the direction of a physician, PA, or in some places a specialist diabetic educator) and, further, specifically based on the individual experience of the patient. But it is not straightforward and should never be done by habit or routine. With some care however, it can be done reasonably well in clinical practice.

For example, some patients with diabetes require more insulin after drinking skim milk than they do after taking an equivalent amount of fat, protein, carbohydrate, and fluid in some other form. Milk is an opaque white liquid produced by the Mammary glands of female Mammals (including Monotremes. Their particular reaction to skimmed milk is different from other people with diabetes, but the same amount of whole milk is likely to cause a still different reaction even in that person. Whole milk contains considerable fat while skimmed milk has much less. It is a continual balancing act for all people with diabetes, especially for those taking insulin.

Patients with insulin-dependent diabetes require some base level of insulin (basal insulin), as well as short-acting insulin to cover meals (bolus insulin). Maintaining the basal rate and the bolus rate is a continuous balancing act that people with insulin-dependent diabetes must manage each day. This is normally achieved through regular blood tests, although continuous blood sugar testing equipment (Continuous Glucose Monitors or CGMs) are now becoming available.

Strategies

A long-acting insulin is used to approximate the basal secretion of insulin by the pancreas. NPH/isophane, lente, ultralente, glargine, and detemir may be used for this purpose. The advantage of NPH is its low cost and the fact that you can mix it with short-acting forms of insulin, thereby minimizing the number of injections that must be administered. The disadvantage is that the activity of NPH is less steady and will peak 4–6 hours after administration, and this peak has the potential of causing hypoglycemia. NPH and regular insulin in combination are available as premixed solutions, which can sometimes simplify administration. The theoretical advantage of glargine and detemir is that they only need to be administered once a day, and they also have steady activity, generally without peaks, although in practice, many patients find that neither lasts a full 24 hours. Glargine and detemir are also signifincantly more expensive, and they cannot be mixed with other forms of insulin.

A short-acting insulin is used to simulate the endogenous insulin surge produced in anticipation of eating. Regular insulin, lispro, aspart and glulisine can be used for this purpose. Regular insulin should be given with about a 30 minute lead-time prior to the meal to be maximally effective and to minimize the possibility of hypoglycemia. Lispro, aspart and glulisine can be given with the first bite of the meal, and may even be effective if given after completing the meal.

The short-acting insulin is also used to correct hyperglycemia.

The usual schedule for checking fingerstick blood glucose and administering insulin is before all meals and sometimes also at bedtime. More recent guidelines also call for a check 2 hours after a meal to ensure the meal has been 'covered' effectively. When insulin glargine or insulin detemir is used, it can be administered at any time during the day, provided that it is given at the same time every day.

Sliding scales

Insulin prescriptions generally specify fixed amounts of long-acting insulin to be given routinely, and fixed amounts of short-acting insulin prior to every meal (the 'sliding scale' approach). However, the amount of short-acting insulin may be varied depending on the patient's preprandial fingerstick glucose, in order to correct pre-existing hyperglycemia. The so-called "sliding-scale" is still widely taught, although it is controversial. ^[24]

Sample regimen using insulin NPH and regular insulin

Sample regimen using insulin glargine and insulin lispro
insulin glargine 20 units at bedtime
insulin lispro to be given as follows:

Carb counting and DAFNE

A more complicated method that allows greater freedom with meal times and snacks is "carb counting. " This approach is taught to diabetic patients in Europe as Dose Adjustment for Normal Eating, or DAFNE. The patient can use his or her total daily dose (TDD) of insulin to estimate how many grams of carbohydrates will be "covered" by 1 unit of insulin, and using this result, the patient can estimate how many units of insulin should be administered depending on the carbohydrate concentration of their meal. For example, if the patient determines that 1 unit of insulin will cover 15 grams of carbohydrates, then they must administer 5 units of insulin before consuming a meal that contains 75 grams of carbohydrates. Some alternative methods also consider the protein content of the meal (since excess dietary protein can be converted to glucose via gluconeogenesis). Gluconeogenesis (abreviated GNG) is a Metabolic pathway that results in the generation of Glucose from non- Carbohydrate carbon substrates such However, all dosages involve a fair degree of guesswork, and will seldom work consistently from one dosage to the next.

Abuse

There are reports that some patients abuse insulin by injecting large doses that lead to hypoglycemic states. This is extremely dangerous. Severe acute or prolonged hypoglycemia can result in brain damage or death.

On July 23, 2004, news reports claimed that a former spouse of a prominent international track athlete said that the ex-spouse had used insulin as a way of 'energizing' the body. Events 1632 - Three hundred colonists bound for New France depart from Dieppe France. "MMIV" redirects here For the Modest Mouse album see " Baron von Bullshit Rides Again " There is no evidence to suggest it should act as a performance enhancer in non-diabetics. Poorly controlled diabetics are more prone than others to exhaustion and tiredness, and properly-administered insulin can relieve such symptoms.

"Game of Shadows," by reporters Mark Fainaru-Wada and Lance Williams, includes allegations that Barry Bonds used insulin in the apparent belief that it would increase the effectiveness of the growth hormone he was (also alleged to be) taking. Game of Shadows is a bestselling non-fiction book published on March 23, 2006 and written by Mark Fainaru-Wada and Lance Williams, reporters Barry Lamar Bonds (born July 24 1964 is a Major League Baseball Outfielder who is currently a Free agent. On top of this, non-prescribed insulin is a banned drug at the Olympics and other global competitions.

The use and abuse of exogenous insulin is reportedly widespread amongst the bodybuilding community. Both insulin, human growth hormone (HGH) and insulin-like growth factor 1 (IGF-1) are self-administered by those looking to increase muscle mass beyond the scope offered by anabolic steroids alone. Their rationale is this: Since insulin and HGH act synergistically to promote growth, and since IGF-1 is the primary mediator of the musculoskeletal effects of growth hormone, the 'stacking' of insulin, HGH and IGF-1 should offer a synergistic growth effect on skeletal muscle. This theory has been borne out in recent years by the creation of top-level bodybuilders whose competition weight is in excess of 50 lb (23 kg) of muscle greater than the professionals of the past, yet with even lower levels of body fat. Indeed, the use of insulin, combined with HGH and/or IGF-1 has resulted in the development of such massively muscled physiques, that there has been a backlash amongst fans of the sport, with a professed disgust at the 'freakish' appearance of top-level professionals.

Bodybuilders will inject up to 10 i.u. of quick-acting synthetic insulin following meals containing starchy carbohydrates and protein, but little fat, in an attempt to 'force feed' nutrients necessary for growth into skeletal muscle, whilst preventing growth of adipocytes. In Pharmacology, the International Unit is a unit of measurement for the amount of a substance based on measured Biological activity or effect This may be done up to four times each day, following meals, for a total usage of 40iu of synthetic insulin per day. However there have been reports of substantially heavier usage, amongst even 'recreational' bodybuilders.

The abuse of exogenous insulin carries with it an attendant risk of hypoglycemic coma and death. Long-term risks may include development of type 2 diabetes, and potentially a lifetime dependency on exogenous insulin.

History

Discovery and characterization

In 1869 Paul Langerhans, a medical student in Berlin, was studying the structure of the pancreas under a microscope when he identified some previously un-noticed tissue clumps scattered throughout the bulk of the pancreas. Paul Langerhans ( July 25 1847 - July 20 1888) was a German pathologist, physiologist biologist. Berlin is the capital city and one of sixteen states of Germany. The pancreas is a Gland organ in the digestive and Endocrine system of Vertebrates. A microscope ( Greek: ( micron) = small + ( skopein) = to look or see is an instrument for viewing objects that are The function of the "little heaps of cells," later known as the Islets of Langerhans, was unknown, but Edouard Laguesse later suggested that they might produce secretions that play a regulatory role in digestion. Islets of Langerhans is the area in which the Endocrine (ie hormone-producing cells of the Pancreas are grouped Gustave-Edouard Laguesse (1861-1927 was a French Pathologist and Histologist who was a native of Dijon. Paul Langerhans' son, Archibald, also helped to understand this regulatory role.

In 1889, the Polish-German physician Oscar Minkowski in collaboration with Joseph von Mering removed the pancreas from a healthy dog to test its assumed role in digestion. Germany, officially the Federal Republic of Germany ( ˈbʊndəsʁepuˌbliːk ˈdɔʏtʃlant is a Country in Central Europe. Oskar Minkowski ( January 13 1858, Kaunas, Lithuania - July 18 1931, Sanatorium Fürstenburg an der Havel Mecklenburg-Strelitz Josef Baron von Mering (born February 28, 1849, in Cologne - died January 5, 1908, at Halle an der Saale, Germany The pancreas is a Gland organ in the digestive and Endocrine system of Vertebrates. Several days after the dog's pancreas was removed, Minkowski's animal keeper noticed a swarm of flies feeding on the dog's urine. On testing the urine they found that there was sugar in the dog's urine, establishing for the first time a relationship between the pancreas and diabetes. In 1901, another major step was taken by Eugene Opie, when he clearly established the link between the Islets of Langerhans and diabetes: Diabetes mellitus … is caused by destruction of the islets of Langerhans and occurs only when these bodies are in part or wholly destroyed. Before his work, the link between the pancreas and diabetes was clear, but not the specific role of the islets.

The structure of insulin. The left side is a space-filling model of the insulin monomer, believed to be biologically active. Carbon is green, hydrogen white, oxygen red, and nitrogen blue. Carbon (kɑɹbən is a Chemical element with the symbol C and its Atomic number is 6 Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the Nitrogen (ˈnaɪtɹəʤɪn is a Chemical element that has the symbol N and Atomic number 7 and Atomic weight 14 On the right side is a cartoon of the insulin hexamer, believed to be the stored form. A monomer unit is highlighted with the A chain in blue and the B chain in cyan. Yellow denotes disulfide bonds, and magenta spheres are zinc ions.

Over the next two decades, several attempts were made to isolate whatever it was the islets produced as a potential treatment. In 1906 George Ludwig Zuelzer was partially successful treating dogs with pancreatic extract but was unable to continue his work. George Ludwig Zuelzer (German spelling- Georg Ludwig Zülzer) ( April 10, 1870 - October 16, 1949) was a German physician who was a Between 1911 and 1912, E. L. Scott at the University of Chicago used aqueous pancreatic extracts and noted a slight diminution of glycosuria but was unable to convince his director of his work's value; it was shut down. The University of Chicago is a Private university located principally in the Hyde Park neighborhood of Chicago. Israel Kleiner demonstrated similar effects at Rockefeller University in 1919, but his work was interrupted by World War I and he did not return to it. Professor Israel Simon Kleiner (born April 8, 1885, died June 15, 1966) was a biochemist whose work helped lead to the discovery of Insulin The Rockefeller University is a private University which focuses primarily on basic research in the biomedical fields and offers graduate and postgraduate education World War I (abbreviated WWI; also known as the First World War, the Great War, and the War to End All Nicolae Paulescu, a professor of physiology at the University of Medicine and Pharmacy in Bucharest was the first one to isolate insulin, which he called at that time pancrein, and published his work in 1921 that had been carried out in Bucharest. Nicolae Paulescu ( October 30, 1869 &ndash July 17, 1931) was a Romanian physiologist, professor of medicine and the Carol Davila University of Medicine and Pharmacy is a state-run Health sciences university in Bucharest, Romania. Use of his techniques was patented in Romania, though no clinical use resulted. Romania ( dated: Rumania, Roumania ^[25]

In October 1920 Canadian Frederick Banting was reading one of Minkowski's papers and concluded that it is the very digestive secretions that Minkowski had originally studied that were breaking down the islet secretion(s), thereby making it impossible to extract successfully. Frederick Grant Banting KBE MC FRSC ( November 14, 1891 &ndash February 21, 1941) was a He jotted a note to himself Ligate pancreatic ducts of the dog. Keep dogs alive till acini degenerate leaving islets. Try to isolate internal secretion of these and relieve glycosurea.

The idea was that the pancreas's internal secretion, which supposedly regulates sugar in the bloodstream, might hold the key to the treatment of diabetes.

He travelled to Toronto to meet with J.J.R. Macleod, who was not entirely impressed with his idea – so many before him had tried and failed. Toronto (təˈrɒntoʊ colloquially pronounced or) is the largest city in Canada and is the provincial capital of Ontario John James Richard Macleod ( September 6, 1876 &ndash March 16, 1935) was a Scottish physician physiologist and recipient of Nevertheless, he supplied Banting with a lab at the University of Toronto, an assistant (medical student Charles Best), and 10 dogs, then left on vacation during the summer of 1921. This article is about the University of Toronto's St George Campus Dr Charles Herbert Best, CC ( February 27, 1899 &ndash March 31, 1978) was a medical scientist Their method was tying a ligature (string) around the pancreatic duct, and, when examined several weeks later, the pancreatic digestive cells had died and been absorbed by the immune system, leaving thousands of islets. They then isolated an extract from these islets, producing what they called isletin (what we now know as insulin), and tested this extract on the dogs. Banting and Best were then able to keep a pancreatectomized dog alive all summer because the extract lowered the level of sugar in the blood.

Computer-generated image of insulin hexamers highlighting the threefold symmetry, the zinc ions holding it together, and the histidine residues involved in zinc binding. Symmetry generally conveys two primary meanings The first is an imprecise sense of harmonious or aesthetically-pleasing proportionality and balance such that it reflects beauty or Zinc (ˈzɪŋk from Zink is a Metallic Chemical element with the symbol Zn and Atomic number 30 Histidine (abbreviated as His or H) is one of the 20 standard Amino acids present in Proteins In the Nutritional sense in

Macleod saw the value of the research on his return but demanded a re-run to prove the method actually worked. Several weeks later it was clear the second run was also a success, and he helped publish their results privately in Toronto, ON that November. Toronto (təˈrɒntoʊ colloquially pronounced or) is the largest city in Canada and is the provincial capital of Ontario However, they needed six weeks to extract the isletin, which forced considerable delays. Banting suggested that they try to use fetal calf pancreas, which had not yet developed digestive glands; he was relieved to find that this method worked well. With the supply problem solved, the next major effort was to purify the extract. In December 1921, Macleod invited the biochemist James Collip, to help with this task, and, within a month, the team felt ready for a clinical test. Typical biochemists study chemical processes and chemical transformations in living organisms James Bertram Collip ( November 20, 1892 &ndash June 19, 1965) was part of the Toronto group which isolated Insulin.

On January 11, 1922, Leonard Thompson, a 14-year-old diabetic who lay dying at the Toronto General Hospital, was given the first injection of insulin. Events 1055 - Theodora is crowned Empress of the Byzantine Empire. Year 1922 ( MCMXXII) was a Common year starting on Sunday of the Gregorian calendar. Leonard Thompson (1908 - 1935 is regarded as the very first person to have received injection of Insulin as a treatment for Diabetes. The Toronto General Hospital (TGH is a part of the University Health Network, and a major teaching hospital in downtown Toronto, Ontario. However, the extract was so impure that Thompson suffered a severe allergic reaction, and further injections were canceled. Anaphylaxis is an acute systemic (multi-system and severe Type I Hypersensitivity allergic reaction in humans and other Mammals Over the next 12 days, Collip worked day and night to improve the ox-pancreas extract, and a second dose was injected on the 23rd. This was completely successful, not only in having no obvious side-effects, but in completely eliminating the glycosuria sign of diabetes.

Children dying from diabetic keto-acidosis were kept in large wards, often with 50 or more patients in a ward, mostly comatose. Grieving family members were often in attendance, awaiting the (until then, inevitable) death. In one of medicine's more dramatic moments Banting, Best and Collip went from bed to bed, injecting an entire ward with the new purified extract. Before they had reached the last dying child, the first few were awakening from their coma, to the joyous exclamations of their families.

However, Banting and Best never worked well with Collip, regarding him as something of an interloper, and Collip left the project soon after.

Over the spring of 1922, Best managed to improve his techniques to the point where large quantities of insulin could be extracted on demand, but the preparation remained impure. The drug firm Eli Lilly and Company had offered assistance not long after the first publications in 1921, and they took Lilly up on the offer in April. Eli Lilly and Company ( is a global Pharmaceutical company and one of the world's largest corporations In November, Lilly made a major breakthrough, and were able to produce large quantities of highly refined, 'pure' insulin. Insulin was offered for sale shortly thereafter.

Nobel Prizes

The Nobel Prize committee in 1923 credited the practical extraction of insulin to a team at the University of Toronto and awarded the Nobel Prize to two men; Frederick Banting and J.J.R. Macleod. The Nobel Prize (Nobelpriset (Nobelprisen is a Swedish prize established in the 1895 will of Swedish chemist Alfred Nobel; it was first awarded in Peace, Literature This article is about the University of Toronto's St George Campus Frederick Grant Banting KBE MC FRSC ( November 14, 1891 &ndash February 21, 1941) was a John James Richard Macleod ( September 6, 1876 &ndash March 16, 1935) was a Scottish physician physiologist and recipient of They were awarded the Nobel Prize in Physiology or Medicine in 1923 for the discovery of insulin. The Nobel Prize in Physiology or Medicine (Nobelpriset i fysiologi eller medicin is awarded once a year by the Swedish Karolinska Institute. Banting, insulted that Best was not mentioned, shared his prize with Best, and Macleod immediately shared his with Collip. The patent for insulin was sold to the University of Toronto for one dollar. This article is about the University of Toronto's St George Campus

Surprisingly, Banting and Macleod received the 1923 Nobel Prize in Physiology or Medicine for the discovery of insulin, while Paulescu's pioneering work was being completely ignored by the scientific and medical community. Nicolae Paulescu ( October 30, 1869 &ndash July 17, 1931) was a Romanian physiologist, professor of medicine and the International recognition for Paulescu's merits as the true discoverer of insulin came only 50 years later.

The primary structure of insulin was determined by British molecular biologist Frederick Sanger. In Biochemistry, the primary structure of a biological molecule is the exact specification of its atomic composition and the chemical bonds connecting those atoms (including Frederick Sanger, OM, CH, CBE, FRS (born 13 August 1918) is an English biochemist and twice It was the first protein to have its sequence be determined. He was awarded the 1958 Nobel Prize in Chemistry for this work. The Nobel Prize in Chemistry (Nobelpriset i kemi is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of Chemistry.

In 1969, after decades of work, Dorothy Crowfoot Hodgkin determined the spatial conformation of the molecule, the so-called tertiary structure, by means of X-ray diffraction studies. Dorothy Crowfoot Hodgkin, born Dorothy Mary Crowfoot OM, FRS ( 12 May 1910 &ndash 29 July 1994) was a British In Biochemistry and Chemistry, the tertiary structure of a Protein or any other Macromolecule is its three-dimensional structure as defined X-ray scattering techniques are a family of non-destructive analytical techniques which reveal information about the crystallographic structure chemical composition She had been awarded a Nobel Prize in Chemistry in 1964 for the development of crystallography. Crystallography is the experimental science of determining the arrangement of Atoms in Solids In older usage it is the scientific study of Crystals The

Rosalyn Sussman Yalow received the 1977 Nobel Prize in Medicine for the development of the radioimmunoassay for insulin. Rosalyn Sussman Yalow (born July 19, 1921) is an American medical physicist, and a co-winner of the 1977 Nobel Prize in Physiology Radioimmunoassay (RIA is a Scientific method used to test Antigens (for example Hormone levels in the Blood) without the need to use a

Timeline of insulin research

• 1922 Banting, Best, Collip use bovine insulin extract in human
• 1923 Eli Lilly produces commercial quantities of much purer bovine insulin than Banting et al had used
• 1923 Farbwerke Hoechst, one of the forerunner's of today's Sanofi Aventis, produces commercial quantities of bovine insulin in Germany
• 1923 Hagedorn founds the Nordisk Insulinlaboratorium in Denmark – forerunner of today's Novo Nordisk
• 1926 Nordisk receives a Danish charter to produce insulin as a non-profit
• 1936 Canadians D. Eli Lilly and Company ( is a global Pharmaceutical company and one of the world's largest corporations Sanofi-Aventis () headquartered in Paris, France, is a multinational pharmaceutical company Novo Nordisk () manufactures and markets Pharmaceutical products and services Novo Nordisk () manufactures and markets Pharmaceutical products and services M. Scott, A. M. Fisher formulate a zinc insulin mixture and license it to Novo
• 1936 Hagedorn discovers that adding protamine to insulin prolongs the duration of action of insulin
• 1946 Nordisk formulates Isophane porcine insulin aka Neutral Protamine Hagedorn or NPH insulin
• 1946 Nordisk crystallizes a protamine and insulin mixture
• 1950 Nordisk markets NPH insulin
• 1953 Novo formulates Lente porcine and bovine insulins by adding zinc for longer lasting insulin
• 1955 Frederick Sanger determines the amino acid sequence of insulin
• 1965 Synthesized by total synthesis by C. Novo Nordisk () manufactures and markets Pharmaceutical products and services Neutral Protamine Hagedorn was created in 1936 when Nordisk formulated "isophane" porcine Insulin by adding Neutral Protamine to regular Neutral Protamine Hagedorn was created in 1936 when Nordisk formulated "isophane" porcine Insulin by adding Neutral Protamine to regular Frederick Sanger, OM, CH, CBE, FRS (born 13 August 1918) is an English biochemist and twice Peptide sequence or amino acid sequence is the order in which Amino acid residues connected by Peptide bonds lie in the chain in Peptides L. Tsou and coworkers
• 1969 Dorothy Crowfoot Hodgkin solves the crystal structure of insulin by x-ray crystallography
• 1973 Purified monocomponent (MC) insulin is introduced
• 1973 The U. Dorothy Crowfoot Hodgkin, born Dorothy Mary Crowfoot OM, FRS ( 12 May 1910 &ndash 29 July 1994) was a British X-ray crystallography is a method of determining the arrangement of Atoms within a Crystal, in which a beam of X-rays strikes a crystal and scatters S. officially "standardized" insulin sold for human use in the U. S. to U-100 (100 units per milliliter). Prior to that, insulin was sold in different strengths, including U-80 (80 units per milliliter) and U-40 formulations (40 units per milliliter), so the effort to "standardize" the potency aimed to reduce dosage errors and ease doctors' job of prescribing insulin for patients. Other countries also followed suit.
• 1978 Genentech produces synthetic 'human' insulin in Escheria coli bacteria using recombinant DNA techniques, licenses to Eli Lilly
• 1981 Novo Nordisk chemically and enzymatically converts porcine to human insulin
• 1982 Genentech synthetic 'human' insulin (above) approved
• 1983 Eli Lilly and Company produces synthetic 'human' insulin with recombinant DNA technology, Humulin
• 1985 Axel Ullrich sequences a human cell membrane insulin receptor. Genentech Inc ( a composite of Genetic Engineering Technology Inc Novo Nordisk () manufactures and markets Pharmaceutical products and services Genentech Inc ( a composite of Genetic Engineering Technology Inc Eli Lilly and Company ( is a global Pharmaceutical company and one of the world's largest corporations Recombinant DNA is a form of synthetic DNA that is engineered through the combination or insertion of one or more DNA strands thereby combining DNA sequences Axel Ullrich born October 19, 1943) Lauban, Schlesien, Germany in is a German Cancer researcher and has been the Director
• 1988 Novo Nordisk produces recombinant human insulin
• 1996 Lilly Humalog "lispro" insulin analogue approved. Novo Nordisk () manufactures and markets Pharmaceutical products and services Eli Lilly and Company ( is a global Pharmaceutical company and one of the world's largest corporations
• 2000 Sanofi Aventis Lantus "glargine" insulin analogue approved for clinical use in the US and Europe. Sanofi-Aventis () headquartered in Paris, France, is a multinational pharmaceutical company
• 2004 Sanofi Aventis insulin glulisine insulin analogue approved for clinical use in the US. Sanofi-Aventis () headquartered in Paris, France, is a multinational pharmaceutical company
• 2006 Novo Nordisk Levemir "detemir" insulin analogue approved for clinical use in the US. Novo Nordisk () manufactures and markets Pharmaceutical products and services Insulin detemir is a long-acting human Insulin analogue for maintaining the basal level of insulin

See also

• Insulin analog
• Anatomy and physiolology
  • Glucagon
  • Pancreas
  • Islets of Langerhans
  • Endocrinology
• Forms of diabetes mellitus
  • Diabetes mellitus
  • Diabetes mellitus type 1
  • Diabetes mellitus type 2
• Treatment
  • Diabetic coma
  • Intensive insulinotherapy
  • Insulin pump
  • Conventional insulinotherapy
• Other medical / diagnostic uses
  • Insulin tolerance test
  • Triple bolus test

References

Footnotes

External links

• The Insulin Protein
• Inspired by Insulin article by parent of a diabetic child
• Frederick Sanger, Nobel Prize for sequencing Insulin Freeview video with John Sanger and John Walker by the Vega Science Trust.
• Insulin: entry from protein databank
• The History of Insulin
• Insulin Lispro
• CBC Digital Archives - Banting, Best, Macleod, Collip: Chasing a Cure for Diabetes
• Cosmos Magazine: Insulin mystery cracked after 20 years
• National Diabetes Information Clearinghouse
• Discovery and Early Development of Insulin, 1920–1925
• Secretion of Insulin and Glucagon
• Insulin Types Comparison Chart