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Insulin Chemistry And Biochemistry

What Is The Biochemistry Of Insulin Resistance?

What Is The Biochemistry Of Insulin Resistance?

Insulin resistance is a condition that impairs the ability to efficiently remove and process glucose from the bloodstream. Glucose, or blood sugar, is a vital energy source required by all cells, organs and systems of the body for normal function. The inability to utilize glucose in the blood results in excess levels in the blood, effects metabolism, and significantly increasing the chances of developing type 2 diabetes. How Does Insulin Resistance Happen Much like leptin resistance, insulin resistance occurs when a needed substance is present in the body, but unable to be utilized by the cells of the body. Specifically, the muscles and cells of the body do not respond or recognize the presence of insulin, resulting in decreased amounts of glucose being delivered to the cells. Insulin is a hormone produced in the pancreas and important for glucose regulation and energy production. The body reacts to this decrease in glucose in the cells by sending signals demanding more glucose for energy, As long as the pancreas can produce enough insulin, meeting the demand for increased amounts of glucose, the body appears to functions normally and glucose levels remain at healthy levels. Should the demand for glucose exceed the ability to produce insulin, blood glucose levels increase which increases the health risks associated with this condition. Causes of Insulin Resistance While researchers have yet to determine an exact cause of insulin resistance, they believe it is closely related to being overweight, having excess fat around the waist and physical inactivity. Genetics and heredity also appear to influence who develops insulin resistance. Insulin resistance risk increases with age; affecting 10% of people between the ages of 20 and 40, but nearly 40% of people over the age of Continue reading >>

Vanadium Chemistry And Biochemistry Of Relevance For Use Of Vanadium Compounds As Antidiabetic Agents

Vanadium Chemistry And Biochemistry Of Relevance For Use Of Vanadium Compounds As Antidiabetic Agents

, Volume 153, Issue12 , pp 1724 | Cite as Vanadium chemistry and biochemistry of relevance for use of vanadium compounds as antidiabetic agents The stability of 11 vanadium compounds is tested under physiological conditions and in administration fluids. Several compounds including those currently used as insulin-mimetic agents in animal and human studies are stable upon dissolution in distilled water but lack such stability in distilled water at pH7. Complex lability may result in decomposition at neutral pH and thus may compromise the effectiveness of these compounds as therapeutic agents; Even well characterized vanadium compounds are surprisingly labile. Sufficiently stable complexes such as the VEDTA complex will only slowly reduce, however, none of the vanadium compounds currently used as insulin-mimetic agents show the high stability of the VEDTA complex. Both the bis(maltolato)oxovanadium(IV) and peroxovanadium complexes extend the insulin-mimetic action of vanadate in reducing cellular environments probably by increased lifetimes under physiological conditions and/or by decomposing to other insulin mimetic compounds. For example, treatment with two equivalents of glutathione or other thiols the (dipicolinato)peroxovanadate(V) forms 9dipicolinato)oxovanadate(V) and vanadate, which are both insulin-mimetic vanadium(V) compounds and can continue to act. The reactivity of vanadate under physiological conditions effects a multitude of biological responses. Other vanadium complexes may mimic insulin but not induce similar responses if the vanadate formation is blocked or reduced. We conclude that three properties, stability, lability and redox chemistry are critical to prolong the half-life of the insulin-mimetic form of vanadium compounds under physiological conditi Continue reading >>

Insulin Chemistry And Functions

Insulin Chemistry And Functions

Insulin Biosynthesis, Secretion, and Action Biosynthesis Insulin is produced in the beta cells of the pancreatic islets. It is initially synthesized as a single-chain 86-amino-acid precursor polypeptide, preproinsulin. Subsequent Proteolytic processing removes the amino terminal signal peptide, giving rise to proinsulin. Proinsulin is structurally related to insulin-like growth factors I and II, which bind weakly to the insulin receptor. Cleavage of an internal 31-residue fragment from proinsulin generates the C peptide and the A (21 amino acids) and B (30 amino acids) chains of insulin, which are connected by disulfide bonds (Figure-1)The mature insulin molecule and C peptide are stored together and co secreted from secretory granules in the beta cells. Because the C peptide is cleared more slowly than insulin, it is a useful marker of insulin secretion and allows discrimination of endogenous and exogenous sources of insulin in the evaluation of hypoglycemia. Secretion Glucose is the key regulator of insulin secretion by the pancreatic beta cell, although amino acids, ketones, various nutrients, gastrointestinal peptides, and neurotransmitters also influence insulin secretion. Glucose levels > 3.9 mmol/L (70 mg/dL) stimulate insulin synthesis, primarily by enhancing protein translation and processing. Glucose stimulation of insulin secretion begins with its transport into the beta cell by the GLUT2 glucose transporter. Glucose phosphorylation by glucokinase is the rate-limiting step that controls glucose-regulated insulin secretion. Further metabolism of glucose-6-phosphate via Glycolysis generates ATP, which inhibits the activity of an ATP-sensitive K+ channel. This channel consists of two separate proteins: one is the binding site for certain oral hypoglycemic (e.g., Continue reading >>

Stimulation Of Insulin Fibrillation By Urea-induced Intermediates*

Stimulation Of Insulin Fibrillation By Urea-induced Intermediates*

Fibrillar deposits of insulin cause serious problems in implantable insulin pumps, commercial production of insulin, and for some diabetics. We performed a systematic investigation of the effect of urea-induced structural perturbations on the mechanism of fibrillation of insulin. The addition of as little as 0.5 m urea to zinc-bound hexameric insulin led to dissociation into dimers. Moderate concentrations of urea led to accumulation of a partially unfolded dimer state, which dissociates into an expanded, partially folded monomeric state. Very high concentrations of urea resulted in an unfolded monomer with some residual structure. The addition of even very low concentrations of urea resulted in increased fibrillation. Accelerated fibrillation correlated with population of the partially folded intermediates, which existed at up to 8 m urea, accounting for the formation of substantial amounts of fibrils under such conditions. Under monomeric conditions the addition of low concentrations of urea slowed down the rate of fibrillation, e.g. 5-fold at 0.75 m urea. The decreased fibrillation of the monomer was due to an induced non-native conformation with significantly increased -helical content compared with the native conformation. The data indicate a close-knit relationship between insulin conformation and propensity to fibrillate. The correlation between fibrillation and the partially unfolded monomer indicates that the latter is a critical amyloidogenic intermediate in insulin fibrillation. Amyloid deposition of proteins has been found to lead to various diseases ( 1 4 ). Typical amyloid protein deposits consist of linear fibrils 60130 wide and 16 microns long ( 5 ) with cross- structure ( 6 , 7 ) and exhibiting birefringence of bound Congo red under polarized light ( 8 Continue reading >>

Structural And Functional Study Of The Glnb22-insulin Mutant Responsible For Maturity-onset Diabetes Of The Young

Structural And Functional Study Of The Glnb22-insulin Mutant Responsible For Maturity-onset Diabetes Of The Young

Abstract The insulin gene mutation c.137G>A (R46Q), which changes an arginine at the B22 position of the mature hormone to glutamine, causes the monogenic diabetes variant maturity-onset diabetes of the young (MODY). In MODY patients, this mutation is heterozygous, and both mutant and wild-type (WT) human insulin are produced simultaneously. However, the patients often depend on administration of exogenous insulin. In this study, we chemically synthesized the MODY mutant [GlnB22]-insulin and characterized its biological and structural properties. The chemical synthesis of this insulin analogue revealed that its folding ability is severely impaired. In vitro and in vivo tests showed that its binding affinity and biological activity are reduced (both approximately 20% that of human insulin). Comparison of the solution structure of [GlnB22]-insulin with the solution structure of native human insulin revealed that the most significant structural effect of the mutation is distortion of the B20-B23 β-turn, leading to liberation of the B chain C-terminus from the protein core. The distortion of the B20-B23 β-turn is caused by the extended conformational freedom of the GlnB22 side chain, which is no longer anchored in a hydrogen bonding network like the native ArgB22. The partially disordered [GlnB22]-insulin structure appears to be one reason for the reduced binding potency of this mutant and may also be responsible for its low folding efficiency in vivo. The altered orientation and flexibility of the B20-B23 β-turn may interfere with the formation of disulfide bonds in proinsulin bearing the R46Q (GlnB22) mutation. This may also have a negative effect on the WT proinsulin simultaneously biosynthesized in β-cells and therefore play a major role in the development of MODY i Continue reading >>

Plos One: Structural And Functional Study Of The Glnb22-insulin Mutant Responsible For Maturity-onset Diabetes Of The Young

Plos One: Structural And Functional Study Of The Glnb22-insulin Mutant Responsible For Maturity-onset Diabetes Of The Young

Structural and Functional Study of the GlnB22-Insulin Mutant Responsible for Maturity-Onset Diabetes of the Young Affiliation Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nm. 2, 166 10 Prague 6, Czech Republic Affiliation Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nm. 2, 166 10 Prague 6, Czech Republic Affiliation Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nm. 2, 166 10 Prague 6, Czech Republic Affiliation Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nm. 2, 166 10 Prague 6, Czech Republic Affiliation York Structural Biology Laboratory, Department of Chemistry, The University of York, Heslington, York, YO10 5DD, United Kingdom Affiliation Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nm. 2, 166 10 Prague 6, Czech Republic Affiliation Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nm. 2, 166 10 Prague 6, Czech Republic Continue reading >>

Insulin

Insulin

This article is about the insulin protein. For uses of insulin in treating diabetes, see insulin (medication). Not to be confused with Inulin. Insulin (from Latin insula, island) is a peptide hormone produced by beta cells of the pancreatic islets, and it is considered to be the main anabolic hormone of the body.[5] It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of, especially, glucose from the blood into fat, liver and skeletal muscle cells.[6] In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both.[6] Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood.[7] Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat. Beta cells are sensitive to glucose concentrations, also known as blood sugar levels. When the glucose level is high, the beta cells secrete insulin into the blood; when glucose levels are low, secretion of insulin is inhibited.[8] Their neighboring alpha cells, by taking their cues from the beta cells,[8] secrete glucagon into the blood in the opposite manner: increased secretion when blood glucose is low, and decreased secretion when glucose concentrations are high.[6][8] Glucagon, through stimulating the liver to release glucose by glycogenolysis and gluconeogenesis, has the opposite effect of insulin.[6][8] The secretion of insulin and glucagon into the Continue reading >>

Chemistry, Structure, And Function Of Insulin-like Growth Factors And Their Receptors: A Review

Chemistry, Structure, And Function Of Insulin-like Growth Factors And Their Receptors: A Review

Human serum contains two classes of somatomedins (Sin) with similar three-dimensional structures and mass (i.e., ~7500 kdaltons (kd)), but that can be distinguished from each other by their isoelectric point (pI) values. Those with alkaline pI's include the presumably identical molecules of insulin-like growth factor I (IGF-I), SmA, SmC, and basic Sm. In humans, the neutral–acidic class of Sm is represented by IGF-II. The sera of rats and other animals contain similar classes of Sm. In normal children and adults, plasma levels of both IGF-I and -II are under growth hormone control, although only elevated concentrations of the former can be positively correlated with adolescent skeletal growth. Elevated blood levels of IGF-II or an embryonic form of it, however, are correlated with fetal development of rats, sheep, and possibly in humans. As evidenced from competitive radioreceptor binding studies and affinity-labelling techniques, receptors that bind insulin and IGF-I are immunologically, structurally, and functionally related: (a) monoclonal and polyclonal antibodies to insulin receptors recognize determinants on receptors that bind IGF-I; (b) both receptors have 140-, 95-, and possibly 45-kd subunits that are interchain disulfide-bonded to form glycoprotein complexes of relative masses (Mr) 300 000 – 400 000; and (c) occupancy of the 140-kd subunits by hormone or growth factor stimulates the phosphorylation of tyrosine residues on the 95-kd subunit by receptor-associated protein kinases. Receptors that bind IGF-II are very different from insulin or IGF-I receptors: (a) there is no evidence of immunological cross-reactivity to the insulin receptors or of intrinsic protein kinase activity and (b) estimates of the molecular weight of the detergent-solubilized IGF-II Continue reading >>

The Chemistry And Biochemistry Of Insulin

The Chemistry And Biochemistry Of Insulin

The Chemistry and Biochemistry of Insulin Please review our Terms and Conditions of Use and check box below to share full-text version of article. I have read and accept the Wiley Online Library Terms and Conditions of Use. Use the link below to share a full-text version of this article with your friends and colleagues. Learn more. Get access to the full version of this article. View access options below. You previously purchased this article through ReadCube. View access options below. Purchase options have been disabled temporarily. Please try again later. The protein hormone insulin occurs widely in the animal kingdom. Although its biological function is always the same, its aminoacid composition varies widely. Insulin consists of two polypeptide chains, which are linked by three cystine residues to form a bicyclic system with a 20membered and an 85membered ring. The protein crystallizes in various forms with foreign ions. In solution, insulin normally forms aggregates of 2n molecules. The hormone can be regenerated from the separated polypeptide chains, and its total synthesis has been achieved in a similar manner from synthesized peptide chains. In the biosynthesis of insulin, the two chains are evidently built up separately and subsequently linked together. Insulin promotes the synthesis of glycogen, fat, and protein in the organism; insulin deficiency leads to an increase in the bloodsugar level. At the molecular level, the mechanism of action of the hormone is still unknown. Current hypotheses are discussed. No specific active center has so far been detected in the insulin molecule, which contains several antigenic regions. Continue reading >>

Nutrient Intake And Hormonal Control Of Insulin Action

Nutrient Intake And Hormonal Control Of Insulin Action

Insulin and Metabolism Insulin is a major metabolism regulating hormone secreted by β-cells of the islets of Langerhans of the pancreas. The major function of insulin is to counter the concerted actions of a number of hyperglycemia-generating hormones and to maintain low blood glucose levels. In addition to its role in regulating glucose metabolism, insulin stimulates lipogenesis, diminishes lipolysis, and increases amino acid transport into cells. Because there are numerous hyperglycemic hormones, untreated disorders associated with insulin generally lead to severe hyperglycemia and shortened life span. Insulin as Growth Factor Insulin also exerts activities typically associated with growth factors. Insulin is a member of a family of structurally and functionally similar molecules that includes the insulin-like growth factors (IGF-1 and IGF-2), and relaxin. The tertiary structure of all four molecules is similar, and all have growth-promoting activities. Insulin modulates transcription and stimulates protein translocation, cell growth, DNA synthesis, and cell replication, effects that it holds in common with the insulin-like growth factors and relaxin. back to the top Insulin is synthesized, from the INS gene, as a preprohormone in the β-cells of the islets of Langerhans. The INS gene is located on chromosome 11p15.5 and is composed of 3 exons that generate four alternatively spliced mRNAs, all of which encode the same 110 amino acid preproprotein. The signal peptide of preproinsulin is removed in the cisternae of the endoplasmic reticulum. The insulin proprotein is packaged into secretory vesicles in the Golgi, folded into its native structure, and locked in this conformation by the formation of two disulfide bonds. Specific protease activity cleaves the center thir Continue reading >>

Structural Biochemistry/cell Signaling Pathways/insulin Signaling

Structural Biochemistry/cell Signaling Pathways/insulin Signaling

Insulin is a hormone released by pancreatic beta cells in response to elevated levels of nutrients in the blood. Insulin causes cells in the liver, muscle, and fat tissue to take glucose from the blood, promoting the storage of these nutrients as glycogen in the liver and muscle and stop using fat as an energy source. When fails to control the insulin levels, diabetes will result. Patients with Type 1 diabetes is characterized by the inability to produce the hormone internally, whereas in Type 2 diabetes, the body becomes resistant to the effects of insulin presumably due to the failure of controlling glucose levels. As a peptide hormone, insulin consists of 51 amino acids and has a molecular weight of 5808Da. Produced in the islets of Langerhans in the pancreas, insulin's name stems from Latin insula for "island." The receptor of insulin is a dimer of two identical subunits that spans the cell membrane. Each of the two subunits is made of one α-chain and one β-chain, connected together by a single disulfide bond. The α-chain lies on the exterior of the cell membrane, while the β-chain spans the cell membrane in a single segment, and with the exception of this segment lies on the inside of the cell membrane.[1] The two α-chains on the exterior of a cell move together when insulin is detected and fold around the insulin. This action moves the β-chains together, thus making the β-chains an active tyrosine kinase. The tyrosine kinase catalyzes the transfer of phosphoryl groups from ATP to tyrosine in the activation loops of the β-chains. The phosphorylated activation loop then drastically changes conformation, causing the kinase to become fully active.[2] Insulin-Receptor Substrates are a special group of proteins that are attracted to the phosphorylated sites on t Continue reading >>

The History Of Biochemistry At Mcgill

The History Of Biochemistry At Mcgill

2007 marks one century of Biochemistry taught at McGill. In the year 1907, Dr Robert F. Ruttan was appointed the first Professor of Biochemistry!! This is certainly a reason to celebrate! This Article is an abridged version entitled "A Sixty-Year Evolution of Biochemistry at McGill University", Scientia Canadensis, V. 27 (2003) pp. 27-84 published by Rose Johnstone, Professor Emeritus, McGill Gilman Cheney Chair in Biochemistry. Biochemistry at McGill began with members of the Medical Faculty teaching chemistry to medical students enrolled in the fledgling medical school. As the University grew to include other disciplines, chemistry was also taught to students enrolled in other Faculties by the same core of people. The Chemistry Department at McGill was established at least 20 years before the appearance of a Department of Biochemistry. Ironically, the individual who became the first Chairman of the Department of Chemistry, Robert F. Ruttan, was a physician who had been hired to teach chemistry to medical students. The instruction of chemistry to medical students now fell under the wing of the Chemistry Department. Ruttan was named Professor of Biochemistry in 1907. He was the first person to hold this title. It was only in 1920 that the Department of Biochemistry was finally launched. The current Chairof the Department of Biochemistry, Prof. Albert Berghuis, is the ninth person to hold this position. He is preceded by: and the first Chairman, Archibald Macallum (1920-1928) The first Chair of our Department was a Fellow of the Royal Society of London, and a distinguished scientist with an international reputation. He was also the founder of the National Research Council of Canada and its first President. The NRC was established to give the Government of Canada advice Continue reading >>

Research Highlight - Stable Analog Of Insulin Needs No Refrigeration

Research Highlight - Stable Analog Of Insulin Needs No Refrigeration

Research Faculty Graduate Programs Undergrad Programs Dual Degree Programs Facilities Contact Visit Stockroom Events BioChemBook Home Research Highlights The need to refrigerate certain temperature-sensitive vaccines and drugs, insulin in particular, is a major challenge for people living in tropical and subtropical regions of the developing world. A major health challenge for people living in tropical and subtropical regions of the developing world is the “cold chain,” the need to refrigerate certain vaccines and drugs, particularly insulin. It’s a nearly impossible-to-fill requirement in poor, technology-starved countries. But a solution is on the horizon. With members of his laboratory, Dr. Michael Weiss has invented a new type of insulin that is ultra-stable and fully active for many months, even at temperatures above 100o F. Diabetic Africans without access to refrigeration or air conditioning are unable to keep their insulin at or below what would be room temperature in an affluent household. They resort to burying their insulin in the ground to protect it from the heat of the day. “The thermometer in villages and towns can soar to 120◦ F, causing the potency and shelf life of insulin and other medications to break down,” explains Dr. Weiss “With each degree the temperature rises, the rate of insulin’s degradation goes up.” “At above-room temperature, insulin can get tangled,” Weiss explains. The tangled insulin, called amyloid, has no activity and can cause painful reactions when injected. “We were able to change the molecular design of insulin to allow us to produce a new kind of clear, stable analog that has the desired properties of regular insulin but does not degrade, even at extremely high temperatures,” he says. “This new insuli Continue reading >>

Chemical Alteration May Speed Up Insulin Availability

Chemical Alteration May Speed Up Insulin Availability

Scientists suggest that a small chemical alteration to insulin makes the molecule act more rapidly while preserving its function in the organism. In the Journal of Biological Chemistry, researchers describe how they predicted the effect with computer simulations and then confirmed it with laboratory experiments. The researchers - from Switzerland, the United States, and Australia - found that they could speed up the disassembly and release of insulin from its complex structure to its available form by replacing a single hydrogen atom with an iodine atom in its molecular structure. Insulin is a small protein that regulates blood glucose by passing signals into cells. In the body, it exists in two forms: a complex one for storage and a simpler one for action. In its storage form, insulin exists as a zinc-bound complex of six identical molecules called a hexamer. The simple, active form is an unbound single molecule, or monomer. When the body requires insulin to regulate blood sugar, the hexamer disassembles into monomers. The insulin molecule then has to bind to a partner molecule - known as the insulin receptor - that sits on the surface of cells. This binding allows signals from the insulin to pass into the cell. For some time, researchers have been experimenting with ways to control this disassembly process to improve the treatment of diabetes - a disease that occurs when insulin production is impaired or when the body cannot use it properly. Protein engineering Researchers use various approaches to explore and discover new ways to fight disease with molecules that do not exist in nature. This includes creating synthetic versions, or analogs, of naturally occurring compounds. Protein engineering involves altering the structure and function of proteins - the chemical wo Continue reading >>

Insulin-like Growth Factor

Insulin-like Growth Factor

Insulin-like growth factor (IGF), formerly called somatomedin, any of several peptide hormones that function primarily to stimulate growth but that also possess some ability to decrease blood glucose levels. IGFs were discovered when investigators began studying the effects of biological substances on cells and tissues outside the body. The name insulin-like growth factor reflects the fact that these substances have insulin-like actions in some tissues, though they are far less potent than insulin in decreasing blood glucose concentrations. Furthermore, their fundamental action is to stimulate growth, and, though IGFs share this ability with other growth factors—such as epidermal growth factor, platelet-derived growth factor, and nerve growth factor—IGFs differ from these substances in that they are the only ones with well-described endocrine actions in humans. There are two IGFs: IGF-1 and IGF-2. These two factors, despite the similarity of their names, are distinguishable in terms of specific actions on tissues because they bind to and activate different receptors. The major action of IGFs is on cell growth. Indeed, most of the actions of pituitary growth hormone are mediated by IGFs, primarily IGF-1. Growth hormone stimulates many tissues, particularly the liver, to synthesize and secrete IGF-1, which in turn stimulates both hypertrophy (increase in cell size) and hyperplasia (increase in cell number) of most tissues, including bone. Serum IGF-1 concentrations progressively increase during childhood and peak at the time of puberty, and they progressively decrease thereafter (as does growth hormone secretion). Children and adults with deficiency of growth hormone have low serum IGF-1 concentrations compared with healthy individuals of the same age. In contrast, pa Continue reading >>

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