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Glucose (C6H12O6, also known as D-glucose, dextrose, or grape sugar) is a simple sugar (monosaccharide) and an important carbohydrate in biology. Cells use it as a source of energy and a metabolic intermediate. Glucose is one of the main products of photosynthesis and starts cellular respiration.
Glucose exists in several different structures, but all of these structures can be divided into two families of mirror-images (stereoisomers). Only one set of these isomers exists in nature, those derived from the "right-handed form" of glucose, denoted D-glucose. D-glucose is often referred to as dextrose. The term dextrose is derived from dextrorotatory glucose. Solutions of dextrose rotate polarized light to the right (in Latin: dexter = "right"). Starch and cellulose are polymers derived from the dehydration of D-glucose. The other stereoisomer, called L-glucose, is hardly found in nature.
The name "glucose" comes from the Greek word glukus (γλυκύς), meaning "sweet". The suffix "-ose" denotes a sugar. The name "dextrose" and the 'D-' prefix come from Latin dexter ("right"), referring to the handedness of the molecules.
Glucose is a monosaccharide with formula C6H12O6 or H-(C=O)-(CHOH)5-H, whose five hydroxyl (OH) groups are arranged in a specific way along its six-carbon backbone.[1]
In its fleeting open-chain form, the glucose molecule has an open (as opposed to cyclic) and unbranched backbone of six carbon atoms, C-1 through C-6; where C-1 is part of an aldehyde group H(C=O)-, and each of the other five carbons bears one hydroxyl group -OH. The remaining bonds of the backbone carbons are satisfied by hydrogen atoms -H. Therefore glucose is an hexose and an aldose, or an aldohexose.
Each of the four carbons C-2 through C-5 is chiral, meaning that its four bonds connect to four distinct parts of the molecule. (Carbon C-2, for example, connects to -(C=O)H, -OH, -H, and -(CHOH)4H.) In D-glucose, these four parts must be in a specific three-dimensional arrangement. Namely, when the molecule is drawn in the Fischer projection, the hydroxyls on C-2, C-4, and C-5 must be on the right side, while that on C-3 must be on the left side.
The positions of those four hydroxyls are exactly reversed in the Fischer diagram of L-Glucose. D- and L-glucose are two of the 16 possible aldohexoses; the other 14 are allose, altrose, mannose, gulose, idose, galactose, and talose, each with two isomers, 'D-' and 'L-.[2]
In solutions, the open-chain form of glucose (either 'D-' or 'L-') exists in equilibrium with several cyclic isomers, each containing a ring of carbons closed by one oxygen atom. In aqueous solution, however, glucose exists as pyranose for more than 99%. The open-chain form is limited to about 0.25% and furanose exists in negligible amounts. The terms "glucose" and "D-glucose" are generally used for these cyclic forms as well. The ring arises from the open-chain form by a nucleophilic addition reaction between the aldehyde group -(C=O)H at C-1 and the hydroxyl group -OH at C-4 or C-5, yielding a hemiacetal group -C(OH)H-O-.
The reaction between C-1 and C-5 creates a molecule with six-membered ring, called pyranose, after the cyclic ether pyran, the simplest molecule with the same carbon-oxygen ring. The (much rarer) reaction between C-1 and C-4 creates a molecule with a five-membered ring, called furanose, after the cyclic ether furan. In either case, each carbon in the ring has one hydrogen and one hydroxyl attached, except for the last carbon (C-4 or C-5) where the hydroxyl is replaced by the remainder of the open molecule (which is -(CHOH)2-H or -(CHOH)-H, respectively).
The ring-closing reaction makes carbon C-1 chiral, too, since its four bonds lead to -H, to -OH, to carbon C-2, and to the ring oxygen. These four parts of the molecule may be arranged around C-1 (the anomeric carbon) in two distinct ways, designated by the prefixes 'α-' and 'β-'. When a glucopyranose molecule is drawn in the Haworth projection, the designation 'α-' means that the hydroxyl group attached to C-1 and the -CH2OH group at C-5 lies on opposite sides of the ring's plane (a trans arrangement), while 'β-' means that they are on the same side of the plane (a cis arrangement).
Therefore, the open isomer D-glucose gives rise to four distinct cyclic isomers: α-D-glucopyranose, β-D-glucopyranose, α-D-glucofuranose, and β-D-glucofuranose; which are all chiral.[3]
Glycogen is the molecule that functions as the secondary long-term energy storage in animal and fungal cells. It is made primarily by the liver and the muscles, but can also be made by glycogenesis within the brain and stomach.
Glycogen is the analogue of starch, a less branched glucose polymer in plants, and is commonly referred to as animal starch, having a similar structure to amylopectin. Glycogen is found in the form of granules in the cytosol in many cell types, and plays an important role in the glucose cycle. Glycogen forms an energy reserve that can be quickly mobilized to meet a sudden need for glucose, but one that is less compact than the energy reserves of triglycerides (lipids). In the liver hepatocytes, glycogen can compose up to 8% of the fresh weight (100–120 g in an adult) soon after a meal. Only the glycogen stored in the liver can be made accessible to other organs. In the muscles, glycogen is found in a low concentration (1% to 2% of the muscle mass). However, the amount of glycogen stored in the body - especially within the red blood cells, liver, and muscles - mostly depends on physical training, basal metabolic rate, and eating habits such as intermittent fasting. Small amounts of glycogen are found in the kidneys, and even smaller amounts in certain glial cells in the brain and white blood cells. The uterus also stores glycogen during pregnancy to nourish the embryo.[4]
Glycogen synthase (UDP-glucose-glycogen glucosyltransferase') is an enzyme involved in converting glucose to glycogen. It takes short polymers of glucose and converts them into long polymers.
It is a glycosyltransferase enzyme (EC 2.4.1.11) that catalyses the reaction of UDP-glucose and (1,4-α-D-glucosyl)n to yield UDP and (1,4-α-D-glucosyl)n+1.
In other words, this enzyme converts excess glucose residues one by one into a polymeric chain for storage as glycogen. Its presence in the bloodstream is highest in the 30 to 60 minutes] following intense exercise. It is a key enzyme in glycogenesis.
Glycogen synthase can be classified in two general protein families. The first family (GT3), which is from mammals and yeast, is approximately 80 kDa, uses UDP-glucose as a sugar donor, and is regulated by phosphorylation and ligand binding.The second family (GT5), which is from bacteria and plants, is approximately 50 kDA, uses ADP-glucose as a sugar donor, and is unregulated.
Isozymes
In humans, there are two paralogous isozymes of glycogen synthase:
isozyme
tissue distribution
gene
glycogen synthase 1
muscle and other tissues
GYS1
glycogen synthase 2
liver
GYS2
The liver enzyme expression is restricted to the liver, whereas the muscle enzyme is widely expressed. Liver glycogen serves as a storage pool to maintain the blood glucose level during fasting, whereas muscle glycogen synthesis accounts for disposal of up to 90% of ingested glucose. The role of muscle glycogen is as a reserve to provide energy during bursts of activity.[5]
The most common disease in which glycogen metabolism becomes abnormal is diabetes, in which, because of abnormal amounts of insulin, liver glycogen can be abnormally accumulated or depleted. Restoration of normal glucose metabolism usually normalizes glycogen metabolism as well.
In hypoglycemia caused by excessive insulin, liver glycogen levels are high, but the high insulin level prevents the glycogenolysis necessary to maintain normal blood sugar levels. Glucagon is a common treatment for this type of hypoglycemia.
Various inborn errors of metabolism are caused by deficiencies of enzymes necessary for glycogen synthesis or breakdown. These are collectively referred to as glycogen storage diseases.[6]
Glycogenin is an enzyme involved in converting glucose to glycogen. It acts as a primer, by polymerizing the first few glucose molecules, after which other enzymes take over.
In humans, there are two isoforms of glycogenin — glycogenin-1, encoded by GYG1, and expressed in muscle; and glycogenin-2, encoded by GYG2,and expressed in the liver and cardiac muscle, but not skeletal muscle. Patients have been found with defective GYG1, resulting in muscle cells with the inability to store glycogen, and consequential weakness and heart disease.
Glycogenin was discovered by Dr. William J. Whelan, a fellow of the Royal Society of London and current professor of Biochemistry at the University of Miami. It is a homodimer of 37-kDa subunits and is classified as a glycosyltransferase.
The main enzyme involved in glycogen polymerisation, glycogen synthase, can only add to an existing chain of at least 4 glucose residues. Glycogenin acts as the primer, to which further glucose monomers may be added. It achieves this by catalyzing the addition of glucose to itself (autocatalysis) by first binding glucose from UDP-glucose to the hydroxyl group of Tyr-194. Seven more glucoses can be added, each derived from UDP-glucose, by glycogenin's glucosyltransferase activity. Once sufficient residues have been added, glycogen synthase takes over extending the chain. Glycogenin remains covalently attached to the reducing end of the glycogen molecule.
Evidence accumulates that a priming protein may be a fundamental property of polysaccharide synthesis in general; the molecular details of mammalian glycogen biogenesis may serve as a useful model for other systems.[8]
As a meal containing carbohydrates is eaten and digested, blood glucose levels rise, and the pancreas secretes insulin. Glucose from the portal vein enters liver cells (hepatocytes). Insulin acts on the hepatocytes to stimulate the action of several enzymes, including glycogen synthase. Glucose molecules are added to the chains of glycogen as long as both insulin and glucose remain plentiful. In this postprandial or "fed" state, the liver takes in more glucose from the blood than it releases.
After a meal has been digested and glucose levels begin to fall, insulin secretion is reduced, and glycogen synthesis stops. When it is needed for energy, glycogen is broken down and converted again to glucose. Glycogen phosphorylase is the primary enzyme of glycogen breakdown. For the next 8–12 hours, glucose derived from liver glycogen will be the primary source of blood glucose to be used by the rest of the body for fuel.
Glucagon is another hormone produced by the pancreas, which in many respects serves as a counter-signal to insulin. When insulin (not blood glucose) begins to fall below normal, glucagon is secreted in increasing amounts to stimulate glycogenolysis and gluconeogenesis pathways.[9]
Muscle cell glycogen appears to function as an immediate reserve source of available glucose for muscle cells. Other cells that contain small amounts use it locally as well. Muscle cells lack the enzyme glucose-6-phosphatase, which is required to pass glucose into the blood, so the glycogen they store is destined for internal use and is not shared with other cells. (This is in contrast to liver cells, which, on demand, readily do break down their stored glycogen into glucose and send it through the blood stream as fuel for the brain or muscles). Glycogen is also a suitable storage substance due to its insolubility in water, which means it does not affect the osmotistic levels and pressure of a cell.[10]
Glycogen phosphorylase is one of the phosphorylase enzymes (EC 2.4.1.1). Glycogen phosphorylase catalyzes the rate-limiting step in the degradation of glycogen in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond. Glycogen phosphorylase is also studied as a model protein regulated by both reversible phosphorylation and allosteric effects.
The overall reaction is written as:
Glycogen phosphorylase breaks up glycogen into glucose subunits. Glycogen is left with one fewer glucose molecule, and the free glucose molecule is in the form of glucose-1-phosphate. In order to be used for metabolism, it must be converted to glucose-6-phosphate by the enzyme phosphoglucomutase.
Although the reaction is reversible in solution, within the cell the enzyme only works in the forward direction as shown above because the concentration of inorganic phosphate is much higher than that of glucose-1-phosphate.
Glycogen phosphorylase can act only on linear chains of glycogen (α1-4 glycosidic linkage). Its work will immediately come to a halt four residues away from α1-6 branch (which are exceedingly common in glycogen). In these situations, a debranching enzyme is necessary, which will straighten out the chain in that area. In addition, the enzyme transferase shifts a block of 3 glucosyl residues from the outer branch to the other end, and then a α1-6 glucosidase enzyme is required to break the remaining (single glucose) α1-6 residue that remains in the new linear chain. After all this is done, glycogen phosphorylase can continue. The enzyme is specific to α1-4 chains, as the molecule contains a 30-angstrom-long crevice with the same radius as the helix formed by the glycogen chain; this accommodates 4-5 glucosyl residues, but is too narrow for branches. This crevice connects the glycogen storage site to the active, catalytic site.
Glycogen phosphorylase has a pyridoxal phosphate (PLP, derived from Vitamin B6) at each catalytic site. Pyridoxal phosphate links with basic residues (in this case Lys680) and covalently forms a Schiff base. Once the Schiff base linkage is formed, holding the PLP molecule in the active site, the phosphate group on the PLP readily donates a proton to an inorganic phosphate molecule, allowing the inorganic phosphate to in turn be deprotonated by the oxygen forming the α-1,4 glycosidic linkage. PLP is readily deprotonated because its negative charge is not only stabilized within the phosphate group, but also in the pyridine ring, thus the conjugate base resulting from the deprotonation of PLP is quite stable. The protonated oxygen now represents a good leaving group, and the glycogen chain is separated from the terminal glycogen in an SN1 fashion, resulting in the formation of a glucose molecule with a secondary carbocation at the 1 position. Finally, the deprotonated inorganic phosphate acts as a nucleophile and bonds with the carbocation, resulting in the formation of glucose-1-phosphate and a glycogen chain shortened by one glucose molecule.
There is also an alternative proposed mechanism involving a positively charged oxygen in a half-chair conformation. [11]
Glycogen phosphorylase is regulated by both allosteric control and by phosphorylation.
Hormones such as epinephrine, insulin and glucagon regulate glycogen phosphorylase using second messenger amplification systems that are linked to G proteins. Glucagon activates adenylate cyclase through a seven transmembrane receptor coupled to Gs which, in turn, activates adenylate cyclase to increase intracellular concentrations of cAMP. cAMP binds to and releases an active form of protein kinase A (PKA). Next, PKA phosphorylates phosphorylase kinase, which, in turn, phosphorylates glycogen phosphorylase b, transforming it into the active glycogen phosphorylase a. This phosphorylation is added onto the glycogen phosphorylase b serine 14. In the liver, epinephrine activates another G-protein-linked receptor that triggers a different cascade, resulting in the activation of Phospholipase C (PLC). PLC indirectly causes the release of calcium from the hepatocytes' endoplasmic reticulum into the cytosol. The increased calcium availability binds to the calmodulin subunit and activates glycogen phosphorylase kinase. Glycogen phosphorylase kinase activates glycogen phosphorylase in the same manner mentioned previously.
Glycogen phosphorylase b is not always inactive in muscle, as it can be activated allosterically by AMP. An increase in AMP concentration, which occurs during strenuous exercise, signals energy demand. AMP activates glycogen phosphorylase b by changing its conformation from a tense to a relaxed form. This relaxed form has similar enzymatic properties as the phosphorylated enzyme. An increase in ATP concentration opposes this activation by displacing AMP from the nucleotide binding site, indicating sufficient energy stores.
Upon eating a meal, there is a release of insulin, signaling glucose availability in the blood. Insulin indirectly activates PP-1 and phosphodiesterase. The PP-1 directly dephosphorylates glycogen phosphorylase a, reforming the inactive glycogen phosphorylase b. The phosphodiesterase converts cAMP to AMP. This activity removes the second messenger (generated by glucagon and epinephrine) and inhibits PKA. In this manner, PKA can no longer cause the phosphorylation cascade that ends with formation of (active) glycogen phosphorylase a. These modifications initiated by insulin end glycogenolysis in order to preserve what glycogen stores are left in the cell and trigger glycogenesis (rebuilding of glycogen).
Phosphorylase a and phosphorylase b each exist in two forms a T (tense) inactive state and R (relaxed) state. Phosphorylase b is normally in the T state, inactive due to the physiological presence of ATP and Glucose 6 phosphate, and Phosphorylase a is normally in the R state (active).
An isoenzyme of glycogen phosphorylase exists in the liver sensitive to glucose concentration, as the liver acts as a glucose exporter. In essence, liver phosphorylase is responsive to glucose, which causes a very responsive transition from the R to T form, inactivating it; furthermore, liver phosphorylase is insensitive to AMP.[12]
Hypoglycemia or hypoglycæmia (not to be confused with Hyperglycemia) is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood" (Gr. υπογλυκαιμία, from hypo-, glykys, haima). It can produce a variety of symptoms and effects but the principal problems arise from an inadequate supply of glucose to the brain, resulting in impairment of function (neuroglycopenia). Effects can range from mild dysphoria to more serious issues such as seizures, unconsciousness, and (rarely) permanent brain damage or death.
The most common forms of hypoglycemia occur as a complication of treatment of diabetes mellitus with insulin or oral medications. Hypoglycemia is less common in non-diabetic persons, but can occur at any age, from many causes. Among the causes are excessive insulin produced in the body (hyperinsulinemia), inborn errors of metabolism, medications and poisons, alcohol, hormone deficiencies, prolonged starvation, alterations of metabolism associated with infection, and organ failure.
Hypoglycemia is treated by restoring the blood glucose level to normal by the ingestion or administration of dextrose or carbohydrate foods. In some circumstances it is treated by injection or infusion of glucagon. Recurrent hypoglycemia may be prevented by reversing or removing the underlying cause, by increasing the frequency of meals, with medications like diazoxide, octreotide, or glucocorticoids, or by surgical removal of much of the pancreas.
The level of blood glucose low enough to define hypoglycemia may be different for different people, in different circumstances, and for different purposes, and occasionally has been a matter of controversy. Most healthy adults maintain fasting glucose levels above 4.0 mmol/L), and develop symptoms of hypoglycemia when the glucose falls below 4 mmol/L. It can sometimes be difficult to determine whether a person's symptoms are due to hypoglycemia. Criteria referred to as Whipple's triad are used to determine a diagnosis of hypoglycemia:
Symptoms known to be caused by hypoglycemia
Low glucose at the time the symptoms occur
Reversal or improvement of symptoms or problems when the glucose is restored to normal
The glycogen phosphorylase monomer is a large protein, composed of 842 amino acids with a mass of 97.434 kDa in muscle cells. While the enzyme can exist as an inactive monomer or tetramer, it is biologically active as a dimer of two identical subunits.[13]
R and T States of Glycogen Phosphorylase b Tower Helices, on the left and right respectively. Note the relative positioning of the central tower helices, as well as the increased interactions between subunits in the R state. PDB3CEH, PDB3E3O
The glycogen phosphorylase dimer has many regions of biological significance, including catalytic sites, glycogen binding sites, allosteric sites, and a reversibly phosphorylated serine residue. First, the catalytic sites are relatively buried, 15Å from the surface of the protein and from the subunit interface.[14] This lack of easy access of the catalytic site to the surface is significant in that it makes the protein activity highly susceptible to regulation, as small allosteric effects could greatly increase the relative access of glycogen to the site.
Perhaps the most important regulatory site is Ser14, the site of reversible phosphorylation very close to the subunit interface. The structural change associated with phosphorylation, and with the conversion of phosphorylase b to phosphorylase a, is the arrangement of the originally disordered residues 10 to 22 into α helices. This change increases phosphorylase activity up to 25% even in the absence of AMP, and enhances AMP activation further.[15]
The allosteric site of AMP binding on muscle isoforms of glycogen phosphorylase are close to the subunit interface just like Ser14. Binding of AMP at this site, corresponding in a change from the T state of the enzyme to the R state, results in small changes in tertiary structure at the subunit interface leading to large changes in quaternary structure.[16] AMP binding rotates the tower helices (residues 262-278) of the two subunits 50˚ relative to one another through greater organization and intersubunit interactions. This rotation of the tower helices leads to a rotation of the two subunits by 10˚ relative to one another, and more importantly disorders residues 282-286 (the 280s loop) that block access to the catalytic site in the T state but do not in the R state.[14]
The final, perhaps most curious site on the glycogen phosphorylase protein is the so-called glycogen storage site. Residues 397-437 form this structure, which allows the protein to covalently bind to the glycogen chain a full 30 Å from the catalytic site . This site is most likely the site at which the enzyme binds to glycogen granules before initiating cleavage of terminal glucose molecules. In fact, 70% of dimeric phosphorylase in the cell exists as bound to glycogen granules rather than free floating.[17]
In mammals, the major isozymes of glycogen phosphorylase are found in muscle, liver, and brain. The brain type is predominant in adult brain and embryonic tissues, whereas the liver and muscle types are predominant in adult liver and skeletal muscle, respectively.[18]
Glycogenolysis (also known as "Glycogenlysis") is the conversion of glycogen polymers to glucose monomers. Glycogen is catabolized by removal of a glucose monomer through cleavage with inorganic phosphate to produce glucose-1-phosphate. This derivative of glucose is then converted to glucose-6-phosphate, an intermediate in glycolysis.
The hormones glucagon and epinephrine stimulate glycogenolysis.
Glycogenolysis takes place in the muscle and liver tissues, where glycogen is stored, as a hormonal response to epinephrine (e.g., adrenergic stimulation) and/or glucagon, a pancreatic peptide triggered by low blood glucose concentrations, and produced in the alpha cells of the islets of Langerhans.
Liver (hepatic) cells can consume the glucose-6-phosphate in glycolysis or remove the phosphate group using the enzyme glucose-6-phosphatase and release the free glucose into the bloodstream for uptake by other cells.
Muscle cells in humans do not possess glucose-6-phosphatase and, hence, will not release glucose, but instead use the glucose-6-phosphate in glycolysis.
First step
The overall reaction for the 1st step is:
Glycogen (n residues) + Pi <-----> Glycogen (n-1 residues)+ G1P
Here, glycogen phosphorylase cleaves the bond at the 1 position by substitution of a phosphoryl group. It breaks down glucose polymer at α-1-4 linkages until 4 linked glucoses are left on the branch. (Glycogen phosphorylase (EC 2.4.1.1) can be used as a marker enzyme to determine glycogen breakdown. )
Second step
The second step involves the enzyme [α[1→4]→α[1→4] glucan transferase]/debranching enzyme, which transfers the three remaining glucose units to another 1,4 terminal of glycogen, which exposes the α[1→6] branching point. The final action of this enzyme is the hydrolysis of the remaining glucose attached at the α[1→6] branch point, which gives one free glucose molecule. This is the only case in which a glycogen metabolite is not glucose-1-phosphate. These glucan transferase and debranching enzyme activities are from two separate catalytic sites on the same protein.
Third step
The third and last stage converts G1P (glucose-1-phosphate) to G6P (glucose-6-phosphate) through the enzyme phosphoglucomutase.
The term diabetes was coined by Aretaeus of Cappadocia. It was derived from the Greek verb diabaínein, itself formed from the prefix dia-, "across, apart," and the verb bainein, "to walk, stand." The verb diabeinein meant "to stride, walk, or stand with legs asunder"; hence, its derivative diabētēs meant "one that straddles," or specifically "a compass, siphon." The sense "siphon" gave rise to the use of diabētēs as the name for a disease involving the discharge of excessive amounts of urine. Diabetes is first recorded in English, in the form diabete, in a medical text written around 1425. In 1675, Thomas Willis added the word mellitus, from the Latin meaning "honey", a reference to the sweet taste of the urine. This sweet taste had been noticed in urine by the ancient Greeks, Chinese, Egyptians, Indians, and Persians. In 1776, Matthew Dobson confirmed that the sweet taste was because of an excess of a kind of sugar in the urine and blood of people with diabetes.
Diabetes mellitus appears to have been a death sentence in the ancient era. Hippocrates makes no mention of it, which may indicate that he felt the disease was incurable. Aretaeus did attempt to treat it but could not give a good prognosis; he commented that "life (with diabetes) is short, disgusting and painful."
Sushruta (6th century BCE) identified diabetes and classified it as Medhumeha. He further identified it with obesity and sedentary lifestyle, advising exercises to help "cure" it. The ancient Indians tested for diabetes by observing whether ants were attracted to a person's urine, and called the ailment "sweet urine disease" (Madhumeha). The Chinese, Japanese and Korean words for diabetes are based on the same ideographs which mean "sugar urine disease".
In medieval Persia, Avicenna (980–1037) provided a detailed account on diabetes mellitus in The Canon of Medicine, "describing the abnormal appetite and the collapse of sexual functions," and he documented the sweet taste of diabetic urine. Like Aretaeus before him, Avicenna recognized a primary and secondary diabetes. He also described diabetic gangrene, and treated diabetes using a mixture of lupine, trigonella (fenugreek), and zedoary seed, which produces a considerable reduction in the excretion of sugar, a treatment which is still prescribed in modern times. Avicenna also "described diabetes insipidus very precisely for the first time", though it was later Johann Peter Frank (1745–1821) who first differentiated between diabetes mellitus and diabetes insipidus.[19]
Diabetes mellitus, often simply referred to as diabetes—is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).
There are three main types of diabetes:
Type 1 diabetes: results from the body's failure to produce insulin, and presently requires the person to inject insulin. (Also referred to as insulin-dependent diabetes mellitus, IDDM for short, and juvenile diabetes.)
Type 2 diabetes: results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency. (Formerly referred to as non-insulin-dependent diabetes mellitus, NIDDM for short, and adult-onset diabetes.)
Gestational diabetes: is when pregnant women, who have never had diabetes before, have a high blood glucose level during pregnancy. It may precede development of type 2 DM.
Mechanism of insulin release in normal pancreatic beta cells. Insulin production is more or less constant within the beta cells, irrespective of blood glucose levels. It is stored within vacuoles pending release, via exocytosis, which is primarily triggered by food, chiefly food containing absorbable glucose. The chief trigger is a rise in blood glucose levels after eatingThe fluctuation of blood sugar (red) and the sugar-lowering hormone insulin (blue) in humans during the course of a day with three meals. One of the effects of a sugar-rich vs a starch-rich meal is highlighted.
Insulin is the principal hormone that regulates uptake of glucose from the blood into most cells (primarily muscle and fat cells, but not central nervous system cells). Therefore deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus.
Humans are capable of digesting some carbohydrates, in particular those most common in food; starch, and some disaccharides such as sucrose, are converted within a few hours to simpler forms most notably the monosaccharide glucose, the principal carbohydrate energy source used by the body. The rest are passed on for processing by gut flora largely in the colon. Insulin is released into the blood by beta cells (β-cells), found in the Islets of Langerhans in the pancreas, in response to rising levels of blood glucose, typically after eating. Insulin is used by about two-thirds of the body's cells to absorb glucose from the blood for use as fuel, for conversion to other needed molecules, or for storage.[20]
Insulin is also the principal control signal for conversion of glucose to glycogen for internal storage in liver and muscle cells. Lowered glucose levels result both in the reduced release of insulin from the beta cells and in the reverse conversion of glycogen to glucose when glucose levels fall. This is mainly controlled by the hormone glucagon which acts in the opposite manner to insulin. Glucose thus forcibly produced from internal liver cell stores (as glycogen) re-enters the bloodstream; muscle cells lack the necessary export mechanism. Normally liver cells do this when the level of insulin is low (which normally correlates with low levels of blood glucose).[21]
Higher insulin levels increase some anabolic ("building up") processes such as cell growth and duplication, protein synthesis, and fat storage. Insulin (or its lack) is the principal signal in converting many of the bidirectional processes of metabolism from a catabolic to an anabolic direction, and vice versa. In particular, a low insulin level is the trigger for entering or leaving ketosis (the fat burning metabolic phase).
If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity or resistance), or if the insulin itself is defective, then glucose will not have its usual effect so that glucose will not be absorbed properly by those body cells that require it nor will it be stored appropriately in the liver and muscles. The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as acidosis.[22]
When the glucose concentration in the blood is raised beyond its renal threshold (about 10 mmol/L, although this may be altered in certain conditions, such as pregnancy), reabsorption of glucose in the proximal renal tubuli is incomplete, and part of the glucose remains in the urine (glycosuria). This increases the osmotic pressure of the urine and inhibits reabsorption of water by the kidney, resulting in increased urine production (polyuria) and increased fluid loss. Lost blood volume will be replaced osmotically from water held in body cells and other body compartments, causing dehydration and increased thirst.[23]
Overview of the most significant symptoms of diabetes.
The classical symptoms of diabetes are polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).[24] Symptoms may develop rapidly (weeks or months) in type 1 diabetes while in type 2 diabetes they usually develop much more slowly and may be subtle or absent.
Prolonged high blood glucose causes glucose absorption, which leads to changes in the shape of the lenses of the eyes, resulting in vision changes; sustained sensible glucose control usually returns the lens to its original shape. Blurred vision is a common complaint leading to a diabetes diagnosis; type 1 should always be suspected in cases of rapid vision change, whereas with type 2 change is generally more gradual, but should still be suspected.
People (usually with type 1 diabetes) may also present with diabetic ketoacidosis, a state of metabolic dysregulation characterized by the smell of acetone; a rapid, deep breathing known as Kussmaul breathing; nausea; vomiting and abdominal pain; and an altered states of consciousness.
A rarer but equally severe possibility is |hyperosmolar nonketotic state, which is more common in type 2 diabetes and is mainly the result of dehydration. Often, the patient has been drinking extreme amounts of sugar-containing drinks, leading to a vicious circle in regard to the water loss.
A number of skin rashes can occur in diabetes that are collectively known as diabetic dermadromes.
Diabetes mellitus type 1 (Type 1 diabetes, IDDM, or, obsoletely, juvenile diabetes) is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose. The classical symptoms are polyuria (frequent urination), polydipsia (increased thirst), polyphagia (increased hunger), and weight loss.
Type 1 diabetes is fatal unless treated with insulin. Injection is the most common method of administering insulin; insulin pumps and inhaled insulin have been available at various times. Pancreas and islet transplants have been used to treat type 1 diabetes; however, islet transplants are currently still at the experimental trial stage.
Most people who develop type 1 are otherwise healthy. Although the cause of type 1 diabetes is still not fully understood it is believed to be of immunological origin.
Type 1 can be distinguished from type 2 diabetes via a C-peptide assay, which measures endogenous insulin production.
Type 1 treatment must be continued indefinitely in all cases. Treatment need not significantly impair normal activities, if sufficient patient training, awareness, appropriate care, discipline in testing and dosing of insulin is taken. However, treatment is burdensome for many people. Complications may be associated with both low blood sugar and high blood sugar. Low blood sugar may lead to seizures or episodes of unconsciousness and requires emergency treatment. High blood sugar may lead to increased fatigue and can also result in long term damage to organs.[25]
Proinsulin C-peptide was first described in 1967 in connection with the discovery of the insulin biosynthesis. It serves as an important linker between the A- and the B- chains of insulin and facilitates the efficient assembly, folding, and processing of insulin in the endoplasmic reticulum. Equimolar amounts of C-peptide and insulin are then stored in secretory granules of the pancreatic beta cells and both are eventually released to the portal circulation. Initially, the sole interest in C-peptide was as a marker of insulin secretion and has as such been of great value in furthering the understanding of the pathophysiology of type 1 and type 2 diabetes. The first documented use of the C-peptide test was in 1972. During the past decade, however, C-peptide has been found to be a bioactive peptide in its own right, with effects on microvascular blood flow and tissue health.
C-peptide should not be confused with c-reactive protein or Protein C.Newly diagnosed diabetes patients often get their C-peptide levels measured as a means of distinguishing type 1 diabetes and type 2 diabetes. C-peptide levels are measured instead of insulin levels because insulin concentration in the portal vein ranges from two to ten times higher than in the peripheral circulation. The liver extracts about half the insulin reaching it in the plasma, but this varies with the nutritional state. The pancreas of patients with type 1 diabetes is unable to produce insulin and therefore they will usually have a decreased level of C-peptide, whereas C-peptide levels in type 2 patients are normal or higher than normal. Measuring C-peptide in patients injecting synthetic insulin can help to determine how much of their own natural insulin these patients are still producing, of if they produce any at all.
The treatment for diabetes type 1:
The level of blood sugar is normally between 70 and 120 mg/ dL. For patient with diabetes, it is higher than 126 mg/dL when fasting. Since the diabetes mellitus type 1 is due to the devastation of insulin-producing beta cells of the pancreas, the treatment is based on the relationship between insulin and blood sugar. Controlling high levels of blood sugar or providing more insulin in the body are used to treat the type 1 diabetes. Exercise and a diabetic diet are the best methods to control the elevation of blood sugar and important for keeping healthy lifestyle. Since exercise makes the body consume energy, it activates the body’s sensitivity to insulin that allows glucose enter to the blood cells producing energy for the body. A diabetic diet is a three-meal per day with low fat, cholesterol, carbohydrates, protein, and simple sugars, but high fiber. Finally, insulin injection is applied if necessary.
Diabetes mellitus type 2 – formerly non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes – is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and dietary modification. As the condition progresses, medications may be needed.
Unlike type 1 diabetes, there is very little tendency toward ketoacidosis though it is not unheard of. One effect that can occur is nonketonic hyperglycemia. Long-term complications from high blood sugar can include increased risk of heart attacks, strokes, amputation, and kidney failure.[26]
There is also a strong inheritable genetic connection in type 2 diabetes: having relatives (especially first degree) with type 2 increases risks of developing type 2 diabetes substantially. In addition, there is also a mutation to the Islet Amyloid Polypeptide gene that results in an earlier onset, more severe, form of diabetes.
About 55 percent of type 2 diabetes patients are obese at diagnosis —chronic obesity leads to increased insulin resistance that can develop into type 2 diabetes, most likely because adipose tissue (especially that in the abdomen around internal organs) is a source of several chemical signals to other tissues (hormones and cytokines).
Other research shows that type 2 diabetes causes obesity as an effect of the changes in metabolism and other deranged cell behavior attendant on insulin resistance.
However, environmental factors (almost certainly diet and weight) play a large part in the development of type 2 diabetes in addition to any genetic component. This can be seen from the adoption of the type 2 diabetes epidemiological pattern in those who have moved to a different environment as compared to the same genetic pool who have not. Immigrants to Western developed countries, for instance, as compared to lower incidence countries of origins.
There is a stronger inheritance pattern for type 2 diabetes. Those with first-degree relatives with type 2 diabetes have a much higher risk of developing type 2 diabetes, increasing with the number of those relatives. Concordance among monozygotic twins is close to 100%, and about 25% of those with the disease have a family history of diabetes. Genes significantly associated with developing type 2 diabetes, include TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX. KCNJ11 (potassium inwardly rectifying channel, subfamily J, member 11), encodes the islet ATP-sensitive potassium channel Kir6.2, and TCF7L2 (transcription factor 7–like 2) regulates proglucagon gene expression and thus the production of glucagon-like peptide-1. Moreover, obesity (which is an independent risk factor for type 2 diabetes) is strongly inherited.
Monogenic forms, e.g., MODY, constitute 1–5 % of all cases.
Various hereditary conditions may feature diabetes, for example myotonic dystrophy and Friedreich's ataxia. Wolfram's syndrome is an autosomal recessive neurodegenerative disorder that first becomes evident in childhood. It consists of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, hence the acronym DIDMOAD.
Gene expression promoted by a diet of fat and glucose as well as high levels of inflammation related cytokines found in the obese results in cells that "produce fewer and smaller mitochondria than is normal," and are thus prone to insulin resistance.[27]
Insulin resistance means that body cells do not respond appropriately when insulin is present.
This is a more complex problem than type 1, but is sometimes easier to treat, especially in the early years when insulin is often still being produced internally. Severe complications can result from improperly managed type 2 diabetes, including renal failure, erectile dysfunction, blindness, slow healing wounds (including surgical incisions), and arterial disease, including coronary artery disease. The onset of type 2 diabetes has been most common in middle age and later life, although it is being more frequently seen in adolescents and young adults due to an increase in child obesity and inactivity. A type of diabetes called MODY is increasingly seen in adolescents, but this is classified as a diabetes due to a specific cause and not as type 2 diabetes.
In the 2008 Banting Lecture of the American Diabetes Association, DeFronzo enumerates eight main pathophysiological factors in the type 2 diabetic organism
Diabetes mellitus with a known etiology, such as secondary to other diseases, known gene defects, trauma or surgery, or the effects of drugs, is more appropriately called secondary diabetes mellitus or diabetes due to a specific cause. Examples include diabetes mellitus such as MODY or those caused by hemochromatosis, pancreatic insufficiencies, or certain types of medications (e.g., long-term steroid use).[28]
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) on the cell membrane 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).
Gestational diabetes (or gestational diabetes mellitus, GDM) is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy (especially during third trimester of pregnancy).
Gestational diabetes generally has few symptoms and it is most commonly diagnosed by screening during pregnancy. Diagnostic tests detect inappropriately high levels of glucose in blood samples. Gestational diabetes affects 3-10% of pregnancies, depending on the population studied.
Babies born to mothers with gestational diabetes are typically at increased risk of problems such as being large for gestational age (which may lead to delivery complications), low blood sugar, and jaundice. Gestational diabetes is a treatable condition and women who have adequate control of glucose levels can effectively decrease these risks.
Women with gestational diabetes are at increased risk of developing type 2 diabetes mellitus (or, very rarely, latent autoimmune diabetes or Type 1) after pregnancy, as well as having a higher incidence of pre-eclampsia and Caesarean section; their offspring are prone to developing childhood obesity, with type 2 diabetes later in life. Most patients are treated only with diet modification and moderate exercise but some take anti-diabetic drugs, including insulin.
Gestational diabetes is formally defined as "any degree of glucose intolerance with onset or first recognition during pregnancy". This definition acknowledges the possibility that patients may have previously undiagnosed diabetes mellitus, or may have developed diabetes coincidentally with pregnancy. Whether symptoms subside after pregnancy is also irrelevant to the diagnosis.
The White classification, named after Priscilla White who pioneered in research on the effect of diabetes types on perinatal outcome, is widely used to assess maternal and fetal risk. It distinguishes between gestational diabetes (type A) and diabetes that existed prior to pregnancy (pregestational diabetes). These two groups are further subdivided according to their associated risks and management.[29]
There are 2 subtypes of gestational diabetes (diabetes which began during pregnancy):
Type A1: abnormal oral glucose tolerance test (OGTT) but normal blood glucose levels during fasting and 2 hours after meals; diet modification is sufficient to control glucose levels
Type A2: abnormal OGTT compounded by abnormal glucose levels during fasting and/or after meals; additional therapy with insulin or other medications is required
The second group of diabetes which existed prior to pregnancy is also split up into several subtypes.
The precise mechanisms underlying gestational diabetes remain unknown. The hallmark of GDM is increased insulin resistance. Pregnancy hormones and other factors are thought to interfere with the action of insulin as it binds to the insulin receptor. The interference probably occurs at the level of the cell signaling pathway behind the insulin receptor.[30] Since insulin promotes the entry of glucose into most cells, insulin resistance prevents glucose from entering the cells properly. As a result, glucose remains in the bloodstream, where glucose levels rise. More insulin is needed to overcome this resistance; about 1.5-2.5 times more insulin is produced than in a normal pregnancy.[30][31]
Insulin resistance is a normal phenomenon emerging in the second trimester of pregnancy, which progresses thereafter to levels seen in non-pregnant patients with type 2 diabetes. It is thought to secure glucose supply to the growing fetus. Women with GDM have an insulin resistance they cannot compensate with increased production in the β-cells of the pancreas. Placental hormones, and to a lesser extent increased fat deposits during pregnancy, seem to mediate insulin resistance during pregnancy. Cortisol and progesterone are the main culprits, but human placental lactogen, prolactin and estradiol contribute too.[30]
It is unclear why some patients are unable to balance insulin needs and develop GDM, however a number of explanations have been given, similar to those in type 2 diabetes: autoimmunity, single gene mutations, obesity, and other mechanisms.[32]
Because glucose travels across the placenta (through diffusion facilitated by GLUT3 carriers), the fetus is exposed to higher glucose levels. This leads to increased fetal levels of insulin (insulin itself cannot cross the placenta). The growth-stimulating effects of insulin can lead to excessive growth and a large body (macrosomia). After birth, the high glucose environment disappears, leaving these newborns with ongoing high insulin production and susceptibility to low blood glucose levels (hypoglycemia).[33]http://en.wikipedia.org/w/index.php?title=Gestational_diabetes&oldid=424072030</ref>
↑Kollberg G, Tulinius M, Gilljam T, Ostman-Smith I, Forsander G, Jotorp P, Oldfors A, Holme E (2007). "Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0". The New England journal of medicine. 357 (15): 1507–14. doi:10.1056/NEJMoa066691. PMID17928598. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
↑ abJohnson LN (1992). "Glycogen phosphorylase: control by phosphorylation and allosteric effectors". FASEB Journal. 6 (6): 2274–82. PMID1544539. {{cite journal}}: Unknown parameter |month= ignored (help)
↑Newgard CB, Hwang PK, Fletterick, RJ (1989). "The family of glycogen phosphorylases: structure and function". Critical Reviews Biochemistry and Molecular Biology. 24 (1): 69–99. doi:10.3109/10409238909082552. PMID2667896. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
↑Johnson LN, Barford, D (1990). "Glycogen phosphorylase. The structural basis of the allosteric response and comparison with other allosteric proteins". Journal of Biological Chemistry. 265 (5): 2409–2412. PMID2137445. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
↑Meyer F, Heilmeyer LM Jr, Haschke RH, Fischer EH (1970). "Control of phosphorylase activity in a muscle glycogen particle. I. Isolation and characterization of the protein-glycogen complex". Journal of Biological Chemistry. 245 (24): 6642–6648. PMID4320610. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
↑David ES, Crerar MM (1986). "Quantitation of muscle glycogen phosphorylase mRNA and enzyme amounts in adult rat tissues". Biochim. Biophys. Acta. 880 (1): 78–90. PMID3510670. {{cite journal}}: Unknown parameter |month= ignored (help)
↑Kelly L, Evans L, Messenger D. Controversies around gestational diabetes. Practical information for family doctors. Can Fam Physician 2005; 51: 688-95. PMID 15934273Template:PMC
