Investigation of catabolism and biosynthesis of glycogen.
Regulation of glycogen metabolism. Biosynthesis of glucose – gluconeogenesis. Hormonal adjusting and pathologies of carbohydrate metabolism.
Metabolic disorders. Diabetes Mellitus.
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 acetal linkages, 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 oxygens attached is an acetal.
The Alpha position is defined as the ether
oxygen being on the opposite side of the ring as the C #
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.
Start with G-6-P, again note 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 the phosphorylated 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 in new 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
Alejandro Buschiazzo, Juan E Ugalde, Marcelo E Guerin, William Shepard, Rodolfo A Ugalde and Pedro M Alzari
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
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 vs. glycolysis: Hexokinase, Phosphofructokinase, and Pyruvate kinase. Phosphofructokinase, and/or hexokinase must also be bypassed in converting other hexoses to glucose.
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:
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:
<![if !supportLists]>- <![endif]>increases the permeability of cell membranes for glucose;
<![if !supportLists]>- <![endif]>activates the first enzyme of glycolysis - glucokinase and prevent the inactivation of hexokinase;
<![if !supportLists]>- <![endif]>activates some enzymes of Krebs cycle (citrate synthase);
<![if !supportLists]>- <![endif]>activates the pentose phosphate cycle;
<![if !supportLists]>- <![endif]>activates glycogen synthetase;
<![if !supportLists]>- <![endif]>activates pyruvate dehydrogenase and a-ketoglutarate dehydrogenase;
<![if !supportLists]>- <![endif]>inhibits the gluconeogenesis;
<![if !supportLists]>- <![endif]>inhibits the decomposition of glycogen.
Effect of insulin on protein metabolism:
<![if !supportLists]>- <![endif]>increases the permeability of cell membranes for amino acids;
<![if !supportLists]>- <![endif]>activates synthesis of proteins and nucleic acids;
<![if !supportLists]>- <![endif]>inhibits the gluconeogenesis.
Effect of insulin on lipid metabolism:
<![if !supportLists]>- <![endif]>enhances the synthesis of lipids;
<![if !supportLists]>- <![endif]>promotes the lipid storage activating the carbohydrate decomposition;
<![if !supportLists]>- <![endif]>inhibits the gluconeogenesis.
Effect of insulin on mineral metabolism:
<![if !supportLists]>- <![endif]>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.
Other names: insulin
Taxa expressing: Homo sapiens; homologs: in metazoan taxa from invertebrates to
Antagonists: glucagon, steroids, most stress hormomes
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 Laguesse later 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 Chicago used aqueous pancreatic extracts and noted a slight diminution of glycosuria but was unable to convince his director of his work's value; it was shut down. 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 in Bucharest, 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 the histidine 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. Banting suggested that they try to use fetal calf pancreas, which
had not yet developed digestive glands; he was relieved to find that this method worked well. With the supply problem solved, the next major effort was to purify the extract. In December 1921, Macleod invited the biochemist James Collip to help with this task, and, within a month, the team felt ready for a clinical test.
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 in not having obvious side-effects, but in completely eliminating the glycosuria sign of diabetes. However, Banting and Best never worked well with Collip, regarding him as something of an interloper, and Collip left 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 as prohormone 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 proinsulin goes in the order "B-C-A", since B and A chains were identified on the basis of mass, and the C peptide was discovered after the others.
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:
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 symptomatic hypoglycemia 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.
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 phosphatidyl inositol 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 in secretory 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 insulinotropic peptide (GIP). The first of these act similarly as glucose through phospholipase C, while the last acts through the mechanism of adenylate 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.
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.
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 ..<![if !vml]><![endif]>
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, "hypoglycemic coma" (formerly termed "insulin shock" from the most common causative agent). Endogenous causes of insulin excess (such as an insulinoma) <![if !vml]><![endif]>
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.
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 hyperglycemia Type 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.
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 been noticed 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.
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:
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 to ketoacidosis. 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
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 stage hyperglycemia 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. 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.
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.
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).
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.
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.
Main articles: Diabetic ketoacidosis , Nonketotic hyperosmolar coma , Hypoglycemia and Diabetic coma
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.
Nonketotic hyperosmolar coma
While not generally progressing to coma, this hyperosmolar nonketotic state (HNS) is another acute problem associated with diabetes mellitus. It has many symptoms in common with DKA, but an entirely different cause, and requires different treatment. In anyone with very high blood glucose levels (usually considered to be above 300 mg/dl (16 mmol/l)), water will be osmotically drawn out of cells into the blood. The kidneys will also be "dumping" glucose into the urine, resulting in concomitant loss of water, and causing an increase in blood osmolality. If fluid is not replaced (by mouth or intravenously), the osmotic effect of high glucose levels combined with the loss of water will eventually result in very high serum osmolality (ie, dehydration). The body's cells will become progressively dehydrated as water is taken from them and excreted. Electrolyte imbalances are also common, and dangerous. This combination of changes, especially if prolonged, will result in symptoms of lethargy (dulled or reduced level of alertness or consciousness) and may progress to coma. As with DKA urgent medical treatment is necessary, especially volume replacement. This is the 'diabetic coma' which more commonly occurs in type 2 diabetics.
Etiology, pathogenesis and genetics of diabetes mellitus.
Proinsulin consists of three domains: an amino-terminal B chain, a carboxy-terminal A chain and a connecting peptide in the middle known as the C peptide.
Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin. Insulin and free C peptide are packaged in the Golgi into secretory granules which accumulate in the cytoplasm.
Control of Insulin Secretion
Insulin is secreted in primarily in response to elevated blood concentrations of glucose. This makes sense because insulin is "in charge" of facilitating glucose entry into cells. Some neural stimuli (e.g. sight and taste of food) and increased blood concentrations of other fuel molecules, including amino acids and fatty acids, also promote insulin secretion.
Our understanding of the mechanisms behind insulin secretion remain somewhat fragmentary. Nonetheless, certain features of this process have been clearly and repeatedly demonstrated, yielding the following model:
Glucose is transported into the B cell by facilitated diffusion through a glucose transporter; elevated concentrations of glucose in extracellular fluid lead to elevated concentrations of glucose within the B cell.
A person with diabetes constantly manages their blood's sugar (glucose) levels. After a blood sample is taken and tested, it is determined whether the glucose levels are low or high. If glucose levels are too low carbohydrates are ingested.If glucose in the blood is too high, the appropriate amount of insulin is administered into the body such as through an insulin pump.
Elevated concentrations of glucose within the B cell ultimately leads to membrane depolarization and an influx of extracellular calcium. The resulting increase in intracellular calcium is thought to be one of the primary triggers for exocytosis of insulin-containing secretory granules. The mechanisms by which elevated glucose levels within the B cell cause depolarization is not clearly established, but seems to result from metabolism of glucose and other fuel molecules within the cell, perhaps sensed as an alteration of ATP:ADP ratio and transduced into alterations in membrane conductance.
Stimulation of insulin release is readily observed in whole animals or people. The normal fasting blood glucose concentration in humans and most mammals is 80 to 90 mg per 100 ml, associated with very low levels of insulin secretion.
Immediately after the increasing the level of glycemia begins, plasma insulin levels increase dramatically. This initial increase is due to secretion of preformed insulin, which is soon significantly depleted. The secondary rise in insulin reflects the considerable amount of newly synthesized insulin that is released immediately. Clearly, elevated glucose not only simulates insulin secretion, but also transcription of the insulin gene and translation of its mRNA.
Physiologic effects opf insulin
Stand on a streetcorner and ask people if they know what insulin is, and many will reply, "Doesn't it have something to do with blood sugar?" Indeed, that is correct, but such a response is a bit like saying "Mozart? Wasn't he some kind of a musician?"
Insulin is a key player in the control of intermediary metabolism. It has profound effects on both carbohydrate and lipid metabolism, and significant influences on protein and mineral metabolism. Consequently, derangements in insulin signalling have widespread and devastating effects on many organs and tissues.
The Insulin Receptor
Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane. The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane.
The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response.
Several intracellular proteins have been identified as phosphorylation substrates for the insulin receptor, the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1 is activated by phosphorylation, a lot of things happen. Among other things, IRS-1 serves as a type of docking center for recruitment and activation of other enzymes that ultimately mediate insulin's effects.
The action of insuin
Insulin is an anabolic hormone (promotes the synthesis of carbohydrates, proteins, lipids and nucleic acids).
The most important target organs for insulin action are:
muscles <![if !vml]><![endif]>
The brain and blood cells are unresponsive to insulin.
Insulin and Carbohydrate Metabolism
Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within the small intestine, and is then absorbed into the blood. Elevated concentrations of glucose in blood stimulate release of insulin, and insulin acts on cells thoughout the body to stimulate uptake, utilization and storage of glucose. The effects of insulin on glucose metabolism vary depending on the target tissue.
The effects of insulin on carbohydrate metabolism include:
1. Insulin facilitates entry of glucose into muscle, adipose and several other tissues.
The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin.
In the absense of insulin, GLUT4 glucose transporters are present in cytoplasmic vesicles, where they are useless for transporting glucose. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose. When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm.
It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent.
2. Insulin stimulates the liver to store glucose in the form of glycogen .
A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen.
Insulin has several effects in liver which stimulate glycogen synthesis. First, it activates the enzyme hexokinase, which phosphorylates glucose, trapping it within the cell. Coincidently, insulin acts to inhibit the activity of glucose-6-phosphatase. Insulin also activates several of the enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and glycogen synthase. The net effect is clear: when the supply of glucose is abundant, insulin "tells" the liver to bank as much of it as possible for use later.
3. Insulin inhibits glucose formation – from glycogen (glycogenolysis) and – from amino-acid precursors (glyconeogenesis).
As aresult - well-known effect of insulin is to decrease the concentration of glucose in blood, which should make sense considering the mechanisms described above. Another important consideration is that, as blood glucose concentrations fall, insulin secretion ceases. In the absense of insulin, a bulk of the cells in the body become unable to take up glucose, and begin a switch to using alternative fuels like fatty acids for energy. Neurons, however, require a constant supply of glucose, which in the short term, is provided from glycogen reserves.
In the absense of insulin, glycogen synthesis in the liver ceases and enzymes responsible for breakdown of glycogen become active. Glycogen breakdown is stimulated not only by the absense of insulin but by the presence of glucagon, which is secreted when blood glucose levels fall below the normal range.
Insulin and Protein Metabolism:
1. Insulin transfers of amino acids across plasma membranes.
2. Insulin stimulates of protein synthesis.
3. Insulin inhibites of proteolysis.
The metabolic pathways for utilization of fats and carbohydrates are deeply and intricately intertwined. Considering insulin's profound effects on carbohydrate metabolism, it stands to reason that insulin also has important effects on lipid metabolism. Important effects of insulin on lipid metabolism include the following:
1. Insulin promotes synthesis of fatty acids in the liver. As discussed above, insulin is stimulatory to synthesis of glycogen in the liver. However, as glycogen accumulates to high levels (roughly 5% of liver mass), further synthesis is strongly suppressed.
When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.
2. Insulin inhibits breakdown of fat in adipose tissue (lipolisis) by inhibiting theintracellular lipase that hydrolyzes triglycerides to release fatty acids.
Insulin facilitates entry of glucose into adipocytes, and within those cells, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride within the adipocyte. By these mechanisms, insulin is involved in further accumulation of triglyceride in fat cells.
From a whole body perspective, insulin has a fat-sparing effect. Not only does it drive most cells to preferentially oxidize carbohydrates instead of fatty acids for energy, insulin indirectly stimulates accumulation of fat is adipose tissue.
1. Insulin stimulates the intracellular flew of potassium, phosphate and magnesium in the heart.
2. Insulin inhibits inotropic and chronoropic action (unrelated to hypoglycemia).
The action of insulin can be decreased by:
- glucagons: stimulates glycogenolysis and glyconeogenesis;
- somatostatin: inhibits secretion of insulin and regulates glucose absorption from alimentary tract into blood;
- glucocorticoids: decrease of glucose utilization by tissues, stimulate glycogenolysis and glyconeogenesis, increase lipogenesis (in patients with insulinorsistancy);
- katecholamines (adrenaline): inhibits β-cells secretion, stimulates glycogenolysis and ACTH secretion;
- somatotropin: stimulates α-cells (which secret glucagon), increases activity of enzymes which destroy the insulin, stimulates glyconeogenesis, increases of glucose exit from the liver veins into blood, decreases of glucose utilization by tissues;
- ACTH: stimulates glucocorticoides secretion and β-cells secretion;
- thyroid hormones: increase glucose absorption into blood, stimulate glycogenolysis, inhibit fat formation from the carbohydrates.
Absolute insulin insufficiency means that pancreas produce insulin in very low quantities or doesn’t produce it at all (due to destruction of beta-cells by inflammative, autoimmune process or surgery).
Relative insulin insufficiency means that pancreas produces or can produce insulin but it doesn’t “work”. (The pathologic process can be on the next levels:
- beta cells: they can be not sensitive for the high level of glycemia;
- insulin: abnormal insulin, insulin antibodies, contrainsulin hormones, absence of enzyme, which activates proinsulin (into insulin));
- receptors (decreased receptor number or diminished binding of insulin).
Type 1, or insulin-dependent diabetes mellitus is characterized by pancreatic islet beta cell destruction and absolute insulinopenia.
Type I Diabetes
In response to high levels of glucose in the blood, the insulin-producing cells in the pancreas secrete the hormone insulin. Type I diabetes occurs when these cells are destroyed by the body's own imune system.
This individuals are ketosis prone under basal conditions. The onset of the disease is generally in youth, but it can occur at any age. Patients have dependence on daily insulin administration for survival.
Current formulation of the pathogenesis of type 1 DM includes the following:
1. A genetic predisposition, conferred by diabetogenic genes on the short arm of chromosome C, either as part of it or in close proximity to the major histocompatibility complex (MMHC) region (more than 95 % of type 1 diabetes individuals are HLA DR3, DR4 or DR3/DR4; on the other hand, HLA DR2 confers protection against the development of type 1 DM);
2. Putative environmental triggers (possibly viral infections (Coxsackie B, rubella, mumps) or chemical toxins (nitrosourea compounds)) that in genetically susceptible individuals might play a role in initiating the disease process.
3. An immune mechanism gone awry, either initiation of immune destruction or loss of tolerance, leading to slow, progressive loss of pancreatic islet beta cells and eventual clinical onset of type 1 diabetes.
Stages of type 1 DM development (by Flier, 1986)
I. A genetic predisposition or changes of immunity.
II. Putative environmental triggers.
III. Active autoimmune insulities with β-cells destruction.
IV. Progression of autoimmune insulities with destruction of >50 % of β-cells.
V. Development of manifest DM.
VI. Total β-cells destruction.
<![if !supportLists]>I. <![endif]>A genetic predisposition or changes of immunity.
<![if !supportLists]>II. <![endif]>Putative environmental triggers.
<![if !supportLists]>III. <![endif]>Active autoimmune insulities with β-cells destruction.
<![if !supportLists]>IV. <![endif]>Progression of autoimmune insulities with destruction of >50 % of β-cells.
<![if !supportLists]>V. <![endif]>Development of manifest DM.
<![if !supportLists]>VI. <![endif]>Total β-cells destruction.
Type 2 or non-insulin-dependent diabetes mellitus is the most common form of diabetes, accounting for 95 – 90 % of the diabetic population. (Video) Most investigators agree that genetic factors underlie NIDDM, but it is probably not caused by defects at a single gene locus. Obesity, diet, physical activity, intrauterine environment, and stress are among the most commonly implicated environmental factors which play a role in the development of the disease. In patients with type 2 DM mostly we can find relative insulin insufficiency (when pancreatic gland secrets insulin but it can have changed structure or weight, or circulating enzymes and antibodies destroy normal insulin, or there are changes of insulin receptors).
Pathogenetic and clinical difference of type 1 and type 2 DM.
I. Type 1 of DM (destruction of β-cells which mostly leads to absolute insulin insufficiency):
II. Type 2 of DM (resistance to insulin and relative insulin insufficiency or defect of insulin secretion with or without resistance to insulin).
III. Other specific types:
- genetic defects of β-cells function;
- genetic defects of insulin action;
- pancreatic diseases (chronic pancreatitis; trauma, pancreatectomy; tumor of pancreatic gland; fibrocalculosis; hemochromatosis);
- endocrine disease;
- drug exposures;
- infections and others.
Diabetes can affect every part of the body, including the skin. The skin is a common target of DM As many as one third of people with diabetes will have a skin disorder caused or affected by diabetes at some time in their lives. In fact, such problems are sometimes the first sign that a person has diabetes. Luckily, most skin conditions can be prevented or easily treated if caught early.
Some of these problems are skin conditions anyone can have, but people with diabetes get more easily. These include bacterial infections, fungal infections, and itching. Other skin problems happen mostly or only to people with diabetes. These include diabetic dermopathy, necrobiosis lipoidica diabeticorum, diabetic blisters, and eruptive xanthomatosis.
Several kinds of bacterial infections occur in people with diabetes. One common one are styes. These are infections of the glands of the eyelid. Another kind of infection are boils, or infections of the hair follicles. Carbuncles are deep infections of the skin and the tissue underneath. Infections can also occur around the nails.
Inflamed tissues are usually hot, swollen, red, and painful. Several different organisms can cause infections. The most common ones are the Staphylococcus bacteria, also called staph.
Once, bacterial infections were life threatening, especially for people with diabetes. Today, death is rare, thanks to antibiotics and better methods of blood sugar control.
But even today, people with diabetes have more bacterial infections than other people do.
The culprit in fungal infections of people with diabetes is often Candida albicans. This yeast-like fungus can create itchy rashes of moist, red areas surrounded by tiny blisters and scales. These infections often occur in warm, moist folds of the skin. Problem areas are under the breasts, around the nails, between fingers and toes, in the corners of the mouth, under the foreskin (in uncircumcised men), and in the armpits and groin.
Common fungal infections include jock itch, athlete's foot, ringworm (a ring-shaped itchy patch), and vaginal infection that causes itching.
Localized itching is often caused by diabetes. It can be caused by a yeast infection, dry skin, or poor circulation. When poor circulation is the cause of itching, the itchiest areas may be the lower parts of the legs.
Diabetes can cause changes in the small blood vessels. These changes can cause skin problems called diabetic dermopathy.
Dermopathy often looks like light brown, scaly patches. These patches may be oval or circular. Some people mistake them for age spots. This disorder most often occurs on the front of both legs. But the legs may not be affected to the same degree. The patches do not hurt, open up, or itch.
Necrobiosis Lipoidica Diabeticorum
Another disease that may be caused by changes in the blood vessels is necrobiosis lipoidica diabeticorum (NLD). NLD is similar to diabetic dermopathy. The difference is that the spots are fewer, but larger and deeper.Iit consists of skin necrosis with lipid infiltration and is also characteristically found in the pretibial area. The lesions resemble red plaques with distinct border.s
NLD often starts as a dull red raised area. After a while, it looks like a shiny scar with a violet border. The blood vessels under the skin may become easier to see. Sometimes NLD is itchy and painful. Sometimes the spots crack open.
NLD is a rare condition. Adult women are the most likely to get it. As long as the sores do not break open, you do not need to have it treated. But if you get open sores, see your doctor for treatment.
Thickening of the arteries - atherosclerosis - can affect the skin on the legs. People with diabetes tend to get atherosclerosis at younger ages than other people do.
As atherosclerosis narrows the blood vessels, the skin changes. It becomes hairless, thin, cool, and shiny. The toes become cold. Toenails thicken and discolor. And exercise causes pain in the calf muscles because the muscles are not getting enough oxygen.
Because blood carries the infection-fighting white cells, affected legs heal slowly when the skin in injured. Even minor scrapes can result in open sores that heal slowly.
People with neuropathy are more likely to suffer foot injuries. These occur because the person does not feel pain, heat, cold, or pressure as well. The person can have an injured foot and not know about it. The wound goes uncared for, and so infections develop easily. Atherosclerosis can make things worse. The reduced blood flow can cause the infection to become severe.
Allergic skin reactions can occur in response to medicines, such as insulin or diabetes pills. You should see your doctor if you think you are having a reaction to a medicine. Be on the lookout for rashes, depressions, or bumps at the sites where you inject insulin.
Diabetic Blisters (Bullosis Diabeticorum)
Rarely, people with diabetes erupt in blisters. Diabetic blisters can occur on the backs of fingers, hands, toes, feet, and sometimes, on legs or forearms.
These sores look like burn blisters. They sometimes are large. But they are painless and have no redness around them. They heal by themselves, usually without scars, in about three weeks. They often occur in people who have diabetic neuropathy. The only treatment is to bring blood sugar levels under control.
Eruptive xanthomas are usually associated with very high serum triglycerides or chylimicrones. They may occur in familial chylomicronaemia syndrome, lipoprotein lipase deficiency, severe familial hypertriglyceridemia, excess alcohol intake, severe uncontrolled diabetes. Treatment is to correct the underlying condition. Lowering triglycerides will result in the clearance of the lesions.
Pict. This shown classic xanthelasma around the eye. It may be associated with genetic hyperlipidaemias, although it may occur with diabetes, biliary cirrhosis or without any associated conditions.
Eruptive xanthomatosis is another condition caused by diabetes that's out of control. It consists of firm, yellow, pea-like enlargements in the skin. Each bump has a red halo and may itch. This condition occurs most often on the backs of hands, feet, arms, legs, elbows, knees and buttocks.
The disorder usually occurs in young men with type 1 diabetes. The person often has high levels of cholesterol and fat (particularly hyperchylomicronemia) in the blood. Like diabetic blisters, these bumps disappear when diabetes control is restored.
Sometimes, people with diabetes develop tight, thick, waxy skin on the backs of their hands. Sometimes skin on the toes and forehead also becomes thick. The finger joints become stiff and can no longer move the way they should. Rarely, knees, ankles, or elbows also get stiff.
This condition happens to about one third of people who have type 1 diabetes. The only treatment is to bring blood sugar levels under control.
Disseminated Granuloma Annulare
In disseminated granuloma annulare, the person has sharply defined ring-shaped or arc-shaped raised areas on the skin. These rashes occur most often on parts of the body far from the trunk (for example, the fingers or ears). But sometimes the raised areas occur on the trunk. They can be red, red-brown, or skin-colored.
Subcutaneous adipose tissue
The abdomen type of obesity is common in patients with type 2 DM. Sometimes generalized subcutaneous adipose tissue atrophy can be observed in diabetics.
Bones and joints
Osteoporosis, osteoarthropaphy, diabetic chairopathy (decreasing of the movements of joints) can be find in patients with DM also.
Diabetic Blood Circulation in Foot
People with diabetes are at risk for blood vessel injury, which may be severe enough to cause tissue damage in the legs and feet.
The heart, arteries, arterioles, and capillaries can be affected. Cardiovascular changes tend to occur earlier in patients with DM when compared with individuals of the same age. Several factors play a role in the high incidence of coronary artery disease seen in patients with DM. These include age of the patient, duration and severity of the diabetes, and presence of other risk factors such as hypertension, smoking and hyperlipoproteinemia. It has been suggested that in some patients with DM, involvement of the small vessels of the heart can lead to cardiomyopathy, independent of narrowing of the major coronary arteries. Myocardial infarction is responsible for at least half of deaths in diabetic patients, and mortality rate for the diabetics is higher than that for nondiabetics of the same age who develop this complication.
Hypertension is common in patients with DM, particularly in the presence of renal disease (as a result of atherosclerosis, destruction of juxtaglomerular cells, sympathetic-nervous-system dysfunction and volume expansion).
Atherosclerosis of femoral, popliteal and calf larger arteries may lead to intermittent claudication, cold extremities, numbness, tingling and gangrene.
Mucomycosis of the nasopharinx, sinusitis, bronchitis, pneumonia, tuberculosis are more common in patients with diabetes than in nondiabetics.
Kidneys and urinary tract
Renal disease include diabetic nephropathy, necrosing renal papillitis, acute tubular necrosis, lupus erythematosus, acute poststreptococcal and membranoproliferative glomerulonephritis, focal glomerulosclerosis, idiopathic membranous nephropathy, nonspecific immune complex glomerulonephritides, infections can occur in any part of the urinary tract. Last are caused when bacteria, usually from the digestive system, reach the urinary tract. If bacteria are growing in the urethra, the infection is called urethritis. The bacteria may travel up the urinary tract and cause a bladder infection, called cystitis. An untreated infection may go farther into the body and cause pyelonephritis, a kidney infection. Some people have chronic or recurrent urinary tract infections.
Complications of the eyes include: ceratities, retinatis, chorioretinatis, cataracts. The last one occurs commonly in the patients with long-standing DM and may be related to uncontrolled hyperglycemia (glucose metabolism by the lens does not require the presence of insulin. The epithelial cells of the lens contain the enzyme aldose reductase, which converts glucose into sorbitol. This sugar may be subsequently converted into fructose by sorbitol dehydrogenase. Sorbitol is retained inside the cells because of its difficulty in transversing plasma membranes. The rise in intracellular osmolality leads to increased water uptake and swelling of the lens).
The diagnosis of DM
The diagnosis of DM may be straightforward or very difficult.
(The presence of the marked hyperglycemia, glucosuria, polyuria, polydipsia, polyphagia, lethargy, a tendency to acquire infections, and physical findings consistent with the disease should offer no difficulty in arriving at the correct diagnosis. On the other hand, mild glucose intolerance in the absence of symptoms or physical findings does not necessarily indicate that DM is present.)
The diagnosis of DM include:
I. Clinical manifestations of DM.
II. Laboratory findings.
1) fasting serum glucose (if the value is over 6,7 mmol/l (120 mg/dl) on two or more separate days, the patient probably has DM);
2) the glucose tolerance test (GTT):
If the diagnosis is still in doubt, then perform a GTT.
The long-term degenerative changes in the blood, vessels, the heart, the kidneys, the nervous system, and the eyes as responsible for the most of the morbidity and mortality of DM. There is a causal relationship and the level of the metabolic control.
It is usually asymptomatic until end stage renal disease develops, but it can course the nephrotic syndrome prior to the development of uremia. Nephropathy develops in 30 to 50 % of type 1 DM patients and in small percentage of type 2 DM patients. Arteriolar hyalinosis, a deposition of hyaline material in the lumen of the afferent and efferent glomerular arterioles, is an almost pathognomic histologic lesion of DM.
In the first few years of type 1 DM there is hyperfiltration which declines fairly steadily to return to a normal value at approximately 10 years (blue line). After sbout 10 years there is sustained proteinurea and by approximately 14 years it has reached nephritic stage (red line). Renal function continues to decline, with the end stage being reached at approximately 16 years
Atherosclerosis of large vessels (macroangiopathy) leads to intermittent claudication, cold extremities and other symptoms which can be also find while arteriols and capillaries are affected (microangiopathy).
Ischemic heart disease.
1. Cardiovascular changes tend to occur earlier in patients with DM when compared with individuals of the same age.
2. Frequency of myocardial infarction (MI) and mortality is higher in diabetics than that in nondiabetis og the same age.
3. The prognosis is even worse if ketoacidosis, or other complications of DM are present.
4. Diabetic patients have more complications of MI (arrhythmias, cardiogenic shock and others) than nondiabetic ones.
5. Often can observe atypical forms (without pain).
6. Male : female = 1 : 1 (nondiabetics = 10 : 1).
It is an old clinical observation that the symptoms of neuropathic dysfunction improve with better control of DM, lending support to the idea that hyperglycemia plays an important role. Accumulation of sorbitol and fructose in the diabetic nerves leads to damage of the Schwann cells and segmental demyelination.
Classification of diabetic neuropathy.
I. Encephalopathy (central neyropathy) is characterized by decreased memory, headache, unadequate actions and others.
II. Peripheral polyneuropathy (radiculoneuropathy). There are three types of radiculoneuropathy:
- distal polyradiculoneuropathy (It is characterized by symmetrical sensory loss, pain at night and during the rest, hyporeflexia, decreased responce touch, burning of heels and soles. The skin becomes atrophic, dry and cold, hair loss may be prominent. The decreased response to touch and pain predisposes to burns and ulcers of the legs and toes.);
- truncal polyradiculoneuropathy (It is an asymmetric, and characterized by pain (which is worse at night), paresthesia and hyperesthesia; muscular weakness involves the muscles of the anterior thigh; reflexes are decreased; weight loss is common.);
- truncal monoradiculoneuropathy (It is usually involves thorasic nerves and the findings are limited to the sensory abnormalities in a radicular distribution.).
III. Visceral dysfunction:
Neuropathic arthropathy (Charcot’s joints)
When you want to lift your arm or take a step, your brain sends nerve signals to the appropriate muscles. Internal organs like the heart and bladder are also controlled by nerve signals, but you do not have the same kind of conscious control over them as you do over your arms and legs. The nerves that control your internal organs are called autonomic nerves, and they signal your body to digest food and circulate blood without your having to think about it. Your body's response to sexual stimuli is also involuntary, governed by autonomic nerve signals that increase blood flow to the genitals and cause smooth muscle tissue to relax. Damage to these autonomic nerves is what can hinder normal function.
1) gastrointestinal tract:
- esophageal neuropathy (It is characterized by segmental distribution with low or absent resting pressure in the low or absent resting pressure in the lower esophageal sphincter and by absence of peristalsis in the body of the esophagus.);
- diabetic gastroparesis (It leads to the irregular food absorption and is characterized by nausea, vomiting, early satiety, bloating and abdomen pain.);
- involvement of the bowel (It is characterized by diarrhea (mostly at night time, postural diarrhea), constipation, malabsorption and fecal incontinence;
2) cardiovascular system:
- orthostatic hypotension (It is characterized by dizziness, vertigo, faintness, and syncope upon assumption of the upright posture and is caused by failure of peripheral arteriolar constriction.);
- tachicardia (but it does not occur in response to hypotension because of sympathetic involvement).
3) urinary tract:
- Bladder dysfunction can have a profound effect on quality of life. Diabetes can damage the nerves that control bladder function. Men and women with diabetes commonly have bladder symptoms that may include a feeling of urinary urgency, frequency, getting up at night to urinate often, or leakage of urine (incontinence). These symptoms have been called overactive bladder. Less common but more severe bladder symptoms include difficulty urinating and complete failure to empty (retention). These symptoms are called a neurogenic bladder. Some evidence indicates that this problem occurs in both men and women with diabetes at earlier ages than in those without diabetes.
is characterized by painless swelling of the feet without edema or signs of infection. The foot becomes shorter and wider, eversion, external rotation, and flattening of the longitudinal arch. This arthropathy is associated with sensory involvelvement, particularly impairment of afferent pain proprioceptive impulses.
Appearance of diabetic foot is caused by a combination of vascular insufficiency, neuropathy, and infection.
<![if !vml]><![endif]><![if !vml]><![endif]>
Sensibility partly decreased or normal decreased or absent
Hypoglycemia, or abnormally low blood glucose, is a complication of several diabetes treatments. It may develop if the glucose intake does not cover the treatment. The patient may become agitated, sweaty, and have many symptoms of sympathetic activation of the autonomic nervous system resulting in feelings similar to dread and immobilized panic. Consciousness can be altered, or even lost, in extreme cases, leading to coma and/or seizures, or even brain damage and death. In patients with diabetes, this can be caused by several factors, such as too much or incorrectly timed insulin, too much exercise or incorrectly timed exercise (exercise decreases insulin requirements) or not enough food (actually an insufficient amount of glucose producing carbohydrates in food). In most cases, hypoglycemia is treated with sugary drinks or food. In severe cases, an injection of glucagon (a hormone with the opposite effects of insulin) or an intravenous infusion of glucose is used for treatment, but usually only if the person is unconscious. In hospital, intravenous dextrose is often used.
Coronary artery disease, leading to angina or myocardial infarction ("heart attack")
Stroke (mainly the ischemic type)
Peripheral vascular disease, which contributes to intermittent claudication (exertion-related foot pain) as well as diabetic foot.
Diabetic myonecrosis ('muscle wasting')
Diabetic foot, often due to a combination of neuropathy and arterial disease, may cause skin ulcer and infection and, in serious cases, necrosis and gangrene. It is the most common cause of adult amputation, usually of toes and or feet, in the developed world.