BIOSYNTHESIS OF GLUCOSE – GLUCONEOGENESIS
GLUCONEOGENESIS
In order to provide glucose for vital functions such as the metabolism of RBC’s and the CNS during periods of fasting (greater than about 8 hrs after food absorption in humans), the body needs a way to synthesis glucose from precursors such as pyruvate and amino acids. This process is referred to as gluconeogenesis. It occurs in the liver and in kidney. Most of Glycolysis can be used in this process since most glycolytic enzymes are reversible. However three irreversible enzymes must be bypassed in gluconeogenesis.
Let’s begin with pyruvate. How is pyruvate converted to PEP without using the pyruvate kinase reaction? Formally, pyruvate is first converted to oxaloacetate, which is in turn converted to PEP. In the first reaction of this process Pyruvate carboxylase adds carbon dioxide to pyruvate with the expenditure of one ATP equivalent of energy. Biotin, a carboxyl-group transfer cofactor in animals, is required by this enzyme.
The reaction takes place in two parts on two different sub-sites on the enzyme. In the first part biotin attacks bicarbonate with a simultaneous attack/hydrolysis by bicarbonate on ATP, resulting in the release of ADP and inorganic phosphate (note the coupling by the enzyme of independent processes in this reaction):
Note that the 14 Angstrom arm of biocytin allows biotin to move between the two sites, in this case carrying the activated carboxyl group. In the second site a pyruvate carbanion then attacks the activated carboxyl group, regenerating the biotin cofactor and releasing oxaloacetate.
GLYCOGEN METABOLISM
Glycogen:
Glycogen is the storage form of glucose in animals and humans which is analogous to the starch in plants. Glycogen is synthesized and stored mainly in the liver and the muscles. Structurally, glycogen is very similar to amylopectin with alpha acetallinkages, however, it has even more branching and more glucose units are present than in amylopectin. Various samples of glycogen have been measured at 1,700-600,000 units of glucose.
The structure of glycogen consists of long polymer chains of glucose units connected by an alpha acetal linkage. The graphic on the left shows a very small portion of a glycogen chain. All of the monomer units are alpha-D-glucose, and all the alpha acetal links connect C # 1 of one glucose to C # 4 of the next glucose.
The branches are formed by linking C # 1 to a C # 6 through an acetal linkages. In glycogen, the branches occur at intervals of 8-10 glucose units, while in amylopectin the branches are separated by 12-20 glucose units.
Acetal Functional Group:
Carbon # 1 is called the anomeric carbon and is the center of an acetal functional group. A carbon that has two ether oxygensattached is an acetal.
The Alpha position is defined as the ether oxygen being on the opposite side of the ring as the C # 6. In the chair structure this results in a downward projection. This is the same definition as the -OH in a hemiacetal.
Starch vs. Glycogen:
Plants make starch and cellulose through the photosynthesis processes. Animals and human in turn eat plant materials and products. Digestion is a process of hydrolysis where the starch is broken ultimately into the various monosaccharides. A major product is of course glucose which can be used immediately for metabolism to make energy. The glucose that is not used immediately is converted in the liver and muscles into glycogen for storage by the process of glycogenesis. Any glucose in excess of the needs for energy and storage as glycogen is converted to fat.
http://www.youtube.com/watch?v=oBL0OC3IavI
Start with G-6-P, agaiote that this molecule is at a metabolic crossroads. First convert to G-1-P using Phosphoglucomutase:
This reaction is very much like PGA Mutase, requiring the bis phosphorylated intermediate to form and to regenerate thephosphorylated enzyme intermediate. Again a separate “support” enzyme, Phosphoglucokinase, is required to form the intermediate, this time using ATP as the energy source:
Note that this reaction is easily reversible, though it favors G-6-P.
UDP-glucose pyrophosphorylase, which catalyzes the next reaction, has a near zero DG° ‘:
It is driven to completion by the hydrolysis of the PPi to 2 Pi by Pyrophosphatase with a DG° ‘ of about -32 kJ (approx. one ATP’s worth of energy).
Finally glycogen is synthesized with Glycogen Synthase:
UDPGlucose + (glucose)n Æ UDP + (glucose)n+1
This reaction is favored by a DG° ‘ of about 12 kcal, thus the overall synthesis of glycogen from G-1-P is favored by a standard free energy of about 40 kJ. Note that the glucose is added to the non-reducing end of a glycogen strand, and that there is a net investment of 2 ATP equivalents per glucose (ATP to ADP and UTP to UDP, regenerated with ATP to ADP). Note also that glycogen synthase requires a ‘primer.’ That is it needs to have a glycogen chain to add on to. What happens then iew cells to make now glycogen granules? Can use a special primer protein (glycogenin). Thus glycogen granules have a protein core.
These reactions will give linear glycogen strands, additional reactions are required to produce branching. Branching enzyme [amylo-a-(1,4) to a-(1,6)-transglycosylase] transfers a block of residues from the end of one chain to another chain making a 1,6-linkage (cannot be closer than 4 residues to a previous branch). (For efficient release of glucose residues it has been determined that the optimum branching pattern is a new branch every 13 residues, with two branchs per strand.)
Glycogen is broken down using Phosphorylase to phosphorylize off glucose residues:
(glucose)n + Pi Æ (glucose)n-1 + G-1-P
Note that no ATP is required to recover Glucose phosphate from glycogen. This is a major advantage in anaerobic tissues, get one more ATP/glucose (3 instead of 2!). [Phosphorylase was originally thought to be the synthetic as well as breakdown enzyme since the reaction is readily reversible in vitro. However it was found that folks lacking this enzyme – McArdle’s disease – can still make glycogen, though they can’t break it down.]
Glycogen synthesis and degradation occurs in the liver cells. It is here that the hormone insulin (the primary hormone responsible for converting glucose to glycogen) acts to lower blood glucose concentration. Insulin stimulates glycogen synthesis; thereby, inhibiting glycogen degradation as shown in the figure. 3
Crystal structure of glycogen synthase: homologous enzymes catalyze glycogen synthesis and degradation
Alejandro Buschiazzo, Juan E Ugalde, Marcelo E Guerin, William Shepard, Rodolfo A Ugalde and Pedro M Alzari
Figure 6
Molecular surface representation of the GS core, showing the equivalent position of the arginine clusters in the mammalian/yeast (GT3) allosteric site (in red) with respect to the active center. Assuming an extended main-chain conformation, approximate distances are shown for two relevant phosphorylation sites, one in the N-terminal (2a) and the other in the C-terminal (3a) extensions of GT3 enzymes.
2. Liver – excess glycose production – gluconeogenesis and glycogenolysis
animation
Investigation of mechanisms of metabolism hormonal regulation and significance in medical practice.
Investigation of mechanisms of metabolism hormonal regulation and significance in medical practice.
Insulin. Chemical structure: protein. Insulin is formed in b-cells of Langerhans islets (specialized endocrine regions of the pancreas).
Proinsulin is the biosynthetic precursor of insulin.
Effect of insulin on carbohydrate metabolism:
– increases the permeability of cell membranes for glucose;
– activates the first enzyme of glycolysis – glucokinase and prevent the inactivation of hexokinase;
– activates some enzymes of Krebs cycle (citrate synthase);
– activates the pentose phosphate cycle;
– activates glycogen synthetase;
– activates pyruvate dehydrogenase and a-ketoglutarate dehydrogenase;
– inhibits the gluconeogenesis;
– inhibits the decomposition of glycogen.
Effect of insulin on protein metabolism:
– increases the permeability of cell membranes for amino acids;
– activates synthesis of proteins and nucleic acids;
– inhibits the gluconeogenesis.
Effect of insulin on lipid metabolism:
– enhances the synthesis of lipids;
– promotes the lipid storage activating the carbohydrate decomposition;
– inhibits the gluconeogenesis.
Effect of insulin on mineral metabolism:
– activates Na+, K+-ATP-ase (transition of K into the cells and Na from the cells).
Target tissue for insulin – liver, muscles and lipid tissue.
The release of insulin from pancreas depends on the glucose concentration in the blood. Some other hormones, sympathetic and parasympathetic nervous system also can influence on the rate of insulin secretion.
The deficiency of insulin causes diabetes mellitus.
Insulin is destroyed in the organism by the enzyme insulinase that is produced by liver.
Insulin
Insulin crystals
Other names: insulin
Taxa expressing: Homo sapiens; homologs: in metazoan taxa from invertebrates to
Antagonists: glucagon, steroids, most stress hormomes
http://www.youtube.com/watch?v=X0ezy1t6N08&feature=related
http://www.youtube.com/watch?v=BfZks1SjStA
Insulin (from Latin insula, “island”, as it is produced in the Islets of Langerhans in the pancreas) is a polypeptide hormone that regulates carbohydrate metabolism. Apart from being the primary agent in carbohydrate homeostasis, it has effects on fat metabolism and it changes the liver’s activity in storing or releasing glucose and in processing blood lipids, and in other tissues such as fat and muscle. The amount of insulin in circulation has extremely widespread effects throughout the body.
Insulin is used medically to treat some forms of diabetes mellitus. Patients with type 1 diabetes mellitus depend on external insulin (most commonly injected subcutaneously) for their survival because of an absolute deficiency of the hormone. Patients with type 2 diabetes mellitus have insulin resistance, relatively low insulin production, or both; some type 2 diabetics eventually require insulin when other medications become insufficient in controlling blood glucose levels.
Insulin’s structure varies slightly between species of animal. Insulin from animal sources differs somewhat in regulatory function strength (ie, in carbohydrate metabolism) in humans because of those variations. Porcine (pig) insulin is especially close to the human version.
Discovery and characterization
In 1869 Paul Langerhans, a medical student in Berlin, was studying the structure of the pancreas (the jelly-like gland behind the stomach) under a microscope when he identified some previously un-noticed tissue clumps scattered throughout the bulk of the pancreas. The function of the “little heaps of cells,” later known as the Islets of Langerhans, was unknown, but Edouard Laguesselater suggested that they might produce secretions that play a regulatory role in digestion.
In 1889, the Polish-German physician Oscar Minkowski in collaboration with Joseph von Mehring removed the pancreas from a healthy dog to test its assumed role in digestion. 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. 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. Between 1911 and 1912, E.L. Scott at the University of Chicagoused 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. 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. Nicolae Paulescu, a professor of physiology at the University of Medicine and Pharmacy inBucharest, published similar work in 1921 that had been carried out in France. Use of his techniques was patented in Romania, though no clinical use resulted. It has been argued ever since that he is the rightful discoverer.
In October 1920, 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. 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. Nevertheless, he supplied Banting with a lab at the University, an assistant (medical student Charles Best), and 10 dogs, then left on vacation during the summer of 1921. 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 thehistidine residues involved in zinc binding.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 that November. However, they needed six weeks to extract the isletin, which forced considerable delays. Bantingsuggested 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.
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. However, the extract was so impure that Thompson suffered a severe allergic reaction, and further injections were canceled. Over the next 12 days, Collip worked day and night to improve the ox-pancreas extract, and a second dose injected on the 23rd. This was completely successful, not only iot having obvious side-effects, but in completely eliminating the glycosuriasign of diabetes. However, Banting and Best never worked well with Collip, regarding him as something of an interloper, and Collipleft the project soon after.
The exact sequence of amino acids comprising the insulin molecule, the so-called primary structure, was determined by British molecular biologist Frederick Sanger. It was the first protein to have its sequence be determined. He was awarded the 1958 Nobel Prize in Chemistry for this work.
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. She had been awarded a Nobel Prize in Chemistry in 1964 for the development of crystallography.
Rosalyn Sussman Yalow received the 1977 Nobel Prize in Medicine for the development of the radioimmunoassay for insulin.
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.
Within vertebrates, the similarity of insulins is very close. Bovine insulin differs from human in only three amino acid residues, and porcine insulin in one. Even insulin from some species of fish is similar enough to human to be effective in humans. The C-peptide of proinsulin (discussed later), however, is very divergent from species to species.
In mammals, insulin is synthesized in the pancreas within the beta cells (β-cells) of the islets of Langerhans.
One to three million islets of Langerhans (pancreatic islets) form the endocrine part of the pancreas, which is primarily an exocrine gland. 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 asprohormone convertases (PC1 and PC2), as well as the exoprotease carboxypeptidase E. These modifications of proinsulin remove the center portion of the molecule, or C-peptide, from the C- and N- terminal ends of the proinsulin. The remaining polypeptides (51 amino acids in total), the B- and A- chains, are bound together by disulfide bonds. Confusingly, the primary sequence of proinsulingoes 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.
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor which in turn starts many protein activation cascades. These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose, glycogen synthesis,glycolysis and fatty acid synthesis.
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor which in turn starts many protein activation cascades. These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose, glycogen synthesis ,glycolysis and fatty acid synthesis.
Control of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about ⅔ of body cells).
Increase of DNA replication and protein synthesis via control of amino acid uptake.
Modification of the activity of numerous enzymes (allosteric effect).
The actions of insulin on cells include:
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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.
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.
Increased esterification of fatty acids – forces adipose tissue to make fats (ie, triglycerides) from fatty acid esters; lack of insulin causes the reverse.
Decreased proteinolysis – forces reduction of protein degradation; lack of insulin increases protein degradation.
Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse.
Decreased gluconeogenesis – decreases production of glucose from various substrates in liver; lack of insulin causes glucose production from assorted substrates in the liver and elsewhere.
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.
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.
Regulatory action on blood glucose
human blood glucose levels normally remain within a narrow range. In most humans this varies from about 70 mg/dl to perhaps 110 mg/dl (3.9 to 6.1 mmol/litre) except shortly after eating when the blood glucose level rises temporarily. This homeostatic effect is the result of many factors, of which hormone regulation is the most important.
It is usually a surprise to realize how little glucose is actually maintained in the blood, and body fluids. The control mechanism works on very small quantities. In a healthy adult male of 75 kg with a blood volume of 5 litres, a blood glucose level of 100 mg/dl or 5.5 mmol/l corresponds to about 5 g (1/5 ounce) of glucose in the blood and approximately 45 g (1½ ounces) in the total body water (which obviously includes more than merely blood and will be usually about 60% of the total body weight in
growth hormone men). A more familiar comparison may help — 5 grams of glucose is about equivalent to a commercial sugar packet (as provided in many restaurants with coffee or tea).
There are two types of mutually antagonistic metabolic hormones affecting blood glucose levels: catabolic hormones (such as glucagon, growth hormone, and catecholamines), which increase blood glucose and one anabolic hormone (insulin), which decreases blood glucose
Mechanisms which restore satisfactory blood glucose levels after hypoglycemia must be quick, and effective, because of the immediate serious consequences of insufficient glucose (in the extreme, coma, less immediately dangerously, confusion or unsteadiness, amongst many other effects). This is because, at least in the short term, it is far more dangerous to have too little glucose in the blood than too much. In healthy individuals these mechanisms are indeed generally efficient, and symptomatichypoglycemia is generally only found in diabetics using insulin or other pharmacologic treatment. Such hypoglycemic episodes vary greatly between persons and from time to time, both in severity and swiftness of onset. In severe cases prompt medical assistance is essential, as damage (to brain and other tissues) and even death will result from sufficiently low blood glucose levels.
Diabetic Retinopathy
Diabetes causes an excessive amount of glucose to remain in the blood stream which may cause damage to the blood vessels. Within the eye the damaged vessels may leak blood and fluid into the surrounding tissues and cause vision problems.
Mechanism of glucose dependent insulin releaseBeta cells in the islets of Langerhans are sensitive to variations in blood glucose levels through the following mechanism (see figure to the right):
Mechanism of glucose dependent insulin release
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 blood glucose levels and hence ATP levels, the ATP controlled potassium channels (K+) close and the cell membranes depolarize
On depolarisation, 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 phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-triphosphate and diacylglycerol.
Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the membrane of endoplasmic reticulum (ER). 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 insecretory vesicles
This is the main mechanism for release of insulin and regulation of insulin synthesis. 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. The signalling mechanisms controlling this are not fully understood.
Other substances known which stimulate insulin release are acetylcholine, released from vagus nerve endings (parasympathetic nervous system), cholecystokinin, released by enteroendocrine cells of intestinal mucosa and glucose-dependent insulinotropicpeptide (GIP). The first of these act similarly as glucose through phospholipase C, while the last acts through the mechanism ofadenylate cyclase.
The sympathetic nervous system (via α2-adrenergic agonists such as norepinephrine) inhibits the release of insulin.
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. 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.
Signal transduction
There are special transporter proteins in cell membranes
through which glucose from the blood can enter a cell. These transporters are, indirectly, under insulin control in certain body cell types (eg, muscle cells). Low levels of circulating insulin, or its absence, will prevent glucose from entering those cells (eg, in untreated Type 1 diabetes). However, more commonly there is a decrease in the sensitivity of cells to insulin (eg, 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 which directly affect glucose uptake by regulating the number and operation of protein molecules in the cell membrane which transport glucose into the cell. The genes which specify the proteins which 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). The former are important because of their central role in movement,
Together, they account for about two-thirds of all cells in a typical human body.
Hypoglycemia
Although other cells can use other fuels for a while growth hormone
(most prominently fatty acids), neuron
breathing, circulation, etc, and the latter because they accumulate excess food energy against future ..
s
depend on glucose as a source of energy in the non-starving human. 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.
Exhaustion of these sources can, either temporarily or on a sustained basis, if reducing blood glucose to a sufficiently low level, first and most dramatically manifest itself in impaired functioning of the central nervous system – dizziness, speech problems, even loss of consciousness, are not unknown. This is known as hypoglycemia or, in cases producing unconsciousness, “hypoglycemiccoma” (formerly termed “insulin shock” from the most common causative agent). Endogenous causes of insulin excess (such as aninsulinoma)
are very rare, and the overwhelming majority of hypoglycemia cases are caused by human action (e.g., iatrogenic, caused by medicine) and are usually accidental. 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 mismanagement of insulin (didn’t eat as much as anticipated, or exercised more than expected), or a mistake (e.g., 20 units of insulin instead of 2).
Possible causes of hypoglycemia include:
Diabetic Nephropathy (kidney diseases) Diabetic Neuropathy (nervous systems diseases)
Diabetic Retinopathy (eye diseases) Hypoglycemia (low blood sugar)
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).
External insulin (usually injected subcutaneously).
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 2005, p18).
Diabetes mellitus – general term referring to all states characterized by hyperglycemia.
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For the disease characterized by excretion of large amounts of very dilute urine, see diabetes insipidus. For diabetes mellitus in pets, see diabetes in cats and dogs.
Diabetes mellitus (IPA pronunciation: is a metabolic disorder characterized by hyperglycemia (high blood sugar) and other signs, as distinct from a single illness or condition.
The World Health Organization recognizes three main forms of diabetes: type 1, type 2, and gestational diabetes (occurring during pregnancy),[ which have similar signs, symptoms, and consequences, but different causes and population distributions. Ultimately, all forms are due to the beta cells of the pancreas being unable to produce sufficient insulin to prevent hyperglycemiaType 1 is usually due to autoimmune destruction of the pancreatic beta cells which produce insulin. Type 2 is characterized by tissue-wide insulin resistance and varies widely; it sometimes progresses to loss of beta cell function. Gestational diabetes is similar to type 2 diabetes, in that it involves insulin resistance; the hormones of pregnancy cause insulin resistance in those women genetically predisposed to developing this condition.
Types 1 and 2 are incurable chronic conditions, but have been treatable since insulin became medically available in 1921, and are nowadays usually managed with a combination of dietary treatment, tablets (in type 2) and, frequently, insulin supplementation. Gestational diabetes typically resolves with delivery.
Diabetes can cause many complications. Acute complications (hypoglycemia, ketoacidosis or nonketotic hyperosmolar coma) may occur if the disease is not adequately controlled. Serious long-term complications include cardiovascular disease (doubled risk), chronic renal failure (diabetic nephropathy is the main cause of dialysis in developed world adults), retinal damage (which can lead to blindness and is the most significant cause of adult blindness in the non-elderly in the developed world), nerve damage (of several kinds), and microvascular damage, which may cause erectile dysfunction (impotence) and poor healing. Poor healing of wounds, particularly of the feet, can lead to gangrene which can require amputation — the leading cause of non-traumatic amputation in adults in the developed world. Adequate treatment of diabetes, as well as increased emphasis on blood pressure control and lifestyle factors (such as smoking and keeping a healthy body weight), may improve the risk profile of most aforementioned complications.
Diabetes mellitus
Terminology
The term diabetes (Greek: διαβήτης) was coined by Aretaeus of Cappadocia. It is derived from the Greek word διαβαίνειν,diabaínein that literally means “passing through,” or “siphon”, a reference to one of diabetes’ major symptoms—excessive urine production. In 1675 Thomas Willis added the word mellitus to the disease, a word from Latin meaning “honey”, a reference to the sweet taste of the urine. This sweet taste had beeoticed in urine by the ancient Greeks, Chinese, Egyptians, and Indians. 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.[3]
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 Korean, Chinese, and Japanese words for diabetes are based on the same ideographs which mean “sugar urine disease”.
Diabetes, without qualification, usually refers to diabetes mellitus, but there are several rarer conditions also named diabetes. The most common of these is diabetes insipidus (insipidus meaning “without taste” in Latin) in which the urine is not sweet; it can be caused by either kidney (nephrogenic DI) or pituitary gland (central DI) damage.
The term “type 1 diabetes” has universally replaced several former terms, including childhood-onset diabetes, juvenile diabetes, and insulin-dependent diabetes. “Type 2 diabetes” has also replaced several older terms, including adult-onset diabetes, obesity-related diabetes, and non-insulin-dependent diabetes. Beyond these numbers, there is no agreed standard. Various sources have defined “type 3 diabetes” as, among others:
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Gestational diabetes
Insulin-resistant type 1 diabetes (or “double diabetes”)
Type 2 diabetes which has progressed to require injected insulin.
Latent autoimmune diabetes of adults (or LADA or “type 1.5” diabetes)
The distinction between what is now known as type 1 diabetes and type 2 diabetes was first clearly made by Sir Harold Percival (Harry) Himsworth, and published in January 1936.
Other landmark discoveries include: identification of the first of the sulfonylureas in 1942 the determination of the amino acid order of insulin (by Sir Frederick Sanger, for which he received a Nobel Prize) the radioimmunoassay for insulin, as discovered by
identification of the first thiazolidinedione as an effective insulin sensitizer during the 1990s .
Type 1 diabetes mellitus
Type 1 diabetes mellitus—formerly known as insulin-dependent diabetes (IDDM), childhood diabetes or also known as juvenile diabetes, is characterized by loss of the insulin-producing beta cells of the islets of Langerhans of the pancreas leading to a deficiency of insulin. It should be noted that there is no known preventative measure that can be taken against type 1 diabetes. Most people affected by type 1 diabetes are otherwise healthy and of a healthy weight when onset occurs. Diet and exercise cannot reverse or prevent type 1 diabetes. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. This type comprises up to 10% of total cases in North America and Europe, though this varies by geographical location. This type of diabetes can affect children or adults but was traditionally termed “juvenile diabetes” because it represents a majority of cases of diabetes affecting children.
The main cause of beta cell loss leading to type 1 diabetes is a T-cell mediated autoimmune attack. The principal treatment of type 1 diabetes, even from the earliest stages, is replacement of insulin. Without insulin, ketosis and diabetic ketoacidosis can develop and coma or death will result.
Currently, type 1 diabetes can be treated only with insulin, with careful monitoring of blood glucose levels using blood testing monitors. Emphasis is also placed on lifestyle adjustments (diet and exercise). Apart from the common subcutaneous injections, it is also possible to deliver insulin by a pump, which allows continuous infusion of insulin 24 hours a day at preset levels and the ability to program doses (a bolus) of insulin as needed at meal times. An inhaled form of insulin, Exubera, was approved by the FDA in January 2006.
Type 1 treatment must be continued indefinitely. Treatment does not impair normal activities, if sufficient awareness, appropriate care, and discipline in testing and medication is taken. The average glucose level for the type 1 patient should be as close to normal (80–120 mg/dl, 4–6 mmol/l) as possible. Some physicians suggest up to 140–150 mg/dl (7-7.5 mmol/l) for those having trouble with lower values, such as frequent hypoglycemic events. Values above 200 mg/dl (10 mmol/l) are often accompanied by discomfort and frequent urination leading to dehydration. Values above 300 mg/dl (15 mmol/l) usually require immediate treatment and may lead toketoacidosis. Low levels of blood glucose, called hypoglycemia, may lead to seizures or episodes of unconsciousness.
Type 2 diabetes mellitus
Main article: Diabetes mellitus type 2
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Type 2 diabetes mellitus—previously known as adult-onset diabetes, maturity-onset diabetes, or non-insulin-dependent diabetes mellitus (NIDDM)—is due to a combination of defective insulin secretion and insulin resistance or reduced insulin sensitivity (defective responsiveness of tissues to insulin), which almost certainly involves the insulin receptor in cell membranes. In the early stage the predominant abnormality is reduced insulin sensitivity, characterized by elevated levels of insulin in the blood. At this stagehyperglycemia can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce glucose production by the liver, but as the disease progresses the impairment of insulin secretion worsens, and therapeutic replacement of insulin often becomes necessary. There are numerous theories as to the exact cause and mechanism for this resistance, but central obesity (fat concentrated around the waist in relation to abdominal organs, and not subcutaneous fat, it seems) is known to predispose individuals for insulin resistance, possibly due to its secretion of adipokines (a group of hormones) that impair glucose tolerance. Abdominal fat is especially active hormonally. Obesity is found in approximately 55% of patients diagnosed with type 2 diabetes.[13] Other factors include aging (about 20% of elderly patients are diabetic in North America) and family history (Type 2 is much more common in those with close relatives who have had it), although in the last decade it has increasingly begun to affect children and adolescents, likely in connection with the greatly increased childhood obesity seen in recent decades in some places.
Type 2 diabetes may go unnoticed for years in a patient before diagnosis, as visible symptoms are typically mild or non-existent, without ketoacidotic episodes, and can be sporadic as well. However, severe long-term complications can result from unnoticed type 2 diabetes, including renal failure, vascular disease (including coronary artery disease), vision damage, etc.
Fetal/neonatal risks associated with GDM include congenital anomalies such as cardiac, central nervous system, and skeletal muscle malformations. Increased fetal insulin may inhibit fetal surfactant production and cause respiratory distress syndrome.Hyperbilirubinemia may result from red blood cell destruction. In severe cases, perinatal death may occur, most commonly as a result of poor placental profusion due to vascular impairment. Induction may be indicated with decreased placental function.Cesarean section may be performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystocia.
Genetics
Both type 1 and type 2 diabetes are at least partly inherited. Type 1 diabetes appears to be triggered by some (mainly viral) infections, or in a less common group, by stress or environmental exposure (such as exposure to certain chemicals or drugs). There is a genetic element in individual susceptibility to some of these triggers which has been traced to particular HLA genotypes (i.e., the genetic “self” identifiers relied upon by the immune system). However, even in those who have inherited the susceptibility, type 1 diabetes mellitus seems to require an environmental trigger. A small proportion of people with type 1 diabetes carry a mutated gene that causes maturity onset diabetes of the young (MODY).
When the glucose concentration in the blood is high (ie, above the “renal threshold”), 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 thus inhibits the resorption of water by the kidney, resulting in an increased urine producton (polyuria) and an increased fluid loss. Lost blood volume will be replaced osmotically from water held in body cells, causing dehydration and increased thirst.
Prolonged high blood glucose causes glucose absorption and so shape changes in the shape of the lens in the eye, leading to vision changes. Blurred vision is a common complaint leading to a diabetes diagnosis; Type 1 should always be suspected in cases of rapid vision change. Type 2 is generally more gradual, but should still be suspected.
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 due to loss of body water. Often, the patient has been drinking extreme amounts of sugar-containing drinks, leading to a vicious circle in regard to the water loss.
Diagnostic approach
The diagnosis of type 1 diabetes, and many cases of type 2, is usually prompted by recent-onset symptoms of excessive urination (polyuria) and excessive thirst (polydipsia), often accompanied by weight loss. These symptoms typically worsen over days to weeks; about 25% of people with new type 1 diabetes have developed some degree of diabetic ketoacidosis by the time the diabetes is recognized. The diagnosis of other types of diabetes is usually made in other ways. The most common are ordinary health screening, detection of hyperglycemia when a doctor is investigating a complication of longstanding, though unrecognized, diabetes,and new signs and symptoms due to the diabetes, such as vision changes or unexplainable fatigue.
Diabetes screening is recommended for many people at various stages of life, and for those with any of several risk factors. The screening test varies according to circumstances and local policy, and may be a random blood glucose test, a fasting blood glucose test, a blood glucose test two hours after 75 g of glucose, or an even more formal glucose tolerance test. Many healthcare providers recommend universal screening for adults at age 40 or 50, and often periodically thereafter. Earlier screening is typically recommended for those with risk factors such as obesity, family history of diabetes, high-risk ethnicity (Mestizo, Native American, African American, Pacific Island, and South Asian ancestry).
Complications
The complications of diabetes are far less common and less severe in people who have well-controlled blood sugar levels. In fact, the better the control, the lower the risk of complications.
Hence patient education, understanding, and participation is vital. Healthcare professionals treating diabetes also often attempt to address health issues that may accelerate the deleterious effects of diabetes. These include smoking (stopping), elevated cholesterol levels (control or reduction with diet, exercise or medication), obesity (even modest weight loss can be beneficial), high blood pressure (exercise or medication if needed), and lack of regular exercise.
Blood Test
To monitor the amount of glucose within the blood a person with diabetes should test their blood regularly. The procedure is quite simple and can often be done at home.
Acute complications
Main articles: Diabetic ketoacidosis , Nonketotic hyperosmolar coma , Hypoglycemia and Diabetic coma
Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) is an acute, dangerous complication and is always a medical emergency. On presentation at hospital, the patient in DKA is typically dehydrated and breathing both fast and deeply. Abdominal pain is common and may be severe. The level of consciousness is typically normal until late in the process, when lethargy (dulled or reduced level of alertness or consciousness) may progress to coma. Ketoacidosis can become severe enough to cause hypotension, shock, and death. Prompt proper treatment usually results in full recovery, though death can result from inadequate treatment, delayed treatment or from a variety of complications. It is much more common in type 1 diabetes than type 2, but can still occur in patients with type 2 diabetes.
