For the most informed and to make general "culturilla", here you have a review of diabetes throughout the times, since ancient times, the Renaissance, seventeenth to the nineteenth century, the discovery of insulin and until our days, I hope thatYou like it.
Diabetes in Antiquity.
Papyrus of Ebers.
The first reference to diabetes is found in the Ebers papyrus found in 1862 in Thebes (today Luxor).In the papyrus a symptomalogy reminds of diabetes and remedies based on certain decoctions.
The ancient Hindu literature in the Vedas describes the sticky urine, with honey flavor and that strongly attaches the diabetic ants.
súsrutpeople of a certain age.
Demetrio de Apamea refined the diagnosis of MEMFIS diabetes mellitus of Memfis coined the end of diabetes (from day = day "through" and betes = betes "pass") to define a state of weakness, intense thirst and polyuria.Apollonius believed it was a form of hydropesia.
Pablo de Aegina refined even more the diagnosis of "dypsacus" (diabetes) associated with a state of weakness of the kidneys excess urination that led to dehydration.He prescribed a remedy based on herbs, endivias, lettuce and live red clover with dates of dates and myrtle to drink in the first stages of the disease, followed by poultice based on vinegar and rose oil on the kidneys.Previous on the use of diuretics but allowed venisection (bleeding).
Galen I thought that diabetes was a very rare sick, using alternative terms such as "urine diarrhea" and "Dypsacus" this last term to emphasize the extreme thirst associated with the disease.
Arateus de Capadocia , who also described tetanus used the diabetes term to describe the condition that led to an increase in urine.He predicted a restricted diet and diluted wine and in the terminal states Opio and Mandragora.
Oriental and Arabiga Medicine
The detailed description of diabetes including the fact that urine had sweet taste is already in the work of the famous Indian doctor Súsruta.This remarkable doctor, who probably lived in the fourth century of our wrote an extensive collection of surgery, pathology, anatomy and even psychology and deontology treaties.Súsruta gave extensive instructions regarding diagnosis: he interrogated the patient and examined it with the 5 senses;He watched the pulse and tasted the urine to detect diabetes.In total, Súsruta described more than 1,200 diseases including diabetes, goiter and other endocrine diseases.
Indian medicine already distinguished two forms of diabetes: one that is given thin young people and that do not survive much and another in older and obese people, which clearly correspond to type 1 diabetes and that of type 2, respectively of our day.
Towards the same time, Chinese doctors also knew diabetes and the fact that diabetics urine attracted ants.They also described their propensity to develop divis and a lung disease similar to tuberculosis.For treatment they recommended to avoid wine and cereals.
Arabic medicine can be divided into two eras: a first era that develops mainly in Egypt under the influence of the Nestorians who disseminated Greek medicine, and a second era, in which Arab doctors, even maintaining great respect for the workfrom Hippocrates and Galen begin to print medicine, in particular to theTherapy a personal stamp.A good number of Arab (and exceptionally Jewish) doctor would stand out at that time when Western medicine was in frank decline.Names such as Abû-Bekt-Ibn Razés, Hoy Abbás, Abû Alí Al-Hussein Abdallah Ibn Sina-better known as Avicena (980-1037)-, Abû Walid Muhammad Ibn Ruschid-more known as Averroes (1126-1198)-O Maimonides(1135-1204) stand out in the history of medicine for their contributions especially in the fields of alchemy, pharmacy and the development of social medicine in hospitals (bimarista) that reached a very high level for that time.Avicena, author of the canon, translated into Latin and the first exponent of Arabic medicine, describes diabetes, as hypoglycemic and recommends a treatment seeds of alholva and cedar, both with hypoglumiant properties.
Renaissance and seventeenth century
From the 16th century, medical discoveries begins to happen, mainly in Europe.Paracelsus (1491-1541) wrote that the urine of the diabetics contained an abnormal substance that remained as a white residue when evaporating the urine, believing that it was salt and attributing diabetes to an deposition of it on the kidneys causing polyuriaand the thirst of these patients.
However, the first reference in Western medical literature of a "sweet urine" in diabetes is due to Thomas Willis (1621-1675) author of "Cerebri Anatome" the best anatomy treaty in the brain performed until it date.In this way, a fact already known for oriental medicine more than 1000 years before appears in Western medicine.Willis wrote that ".. This disease was quite rare but in our days, the good life and the fond of wine make us find cases often ..."
The most outstanding figure of 18th-century clinical medicine was Thomas Sydenham (1624-1689), a doctorate in Cambridge who made medicine again to be governed by hypocratic principles.Sydenham speculated that diabetes was a systemic blood disease that appeared due to defective digestion that made part of the food to be excreted in the urine.
18th century
About 100 years later, Mathew Dobson (1725-1784) English doctor from Liverpool did studies in patient groups for the first time.After treating a group of patients Dobson reported that these patients had blood sugar and urine and described the symptoms of diabetes.Dobson thought that sugar was formed in the blood by some defect of digestion limiting the kidneys to eliminating excess sugar.
Some years later another English doctor, John Roll published his observations on two diabetic cases, describing many of the symptoms and the smell of acetone (which confused with a smell of apple) and proposing a diet poor in carbohydrates and rich in meat,With accessories based on antimony, opium and digital.With this anoretical diet Roll observed that blood sugar was reduced and achieved an improvement in symptomatology in some cases.It was the first to coin the term of diabetes mellitus to differentiate the disease from other forms of polyuria.It is also from this time the observation of Thomas Cawley in 1788 that diabetes mellitus had its origin in the pancreas, "for example by the formation of a calculation."
19th century
The era of rationality that began in France with the French Revolution and continued throughout the nineteenth century, with the beginning of an experimental science, allowed more progress in medicine to be achieved than they had achieved in all the previous centuries.
One of the greatest figures was the French physiologist Claude Bernard (1813-1878) that made important discoveries including theObservation that the sugar that appears in the urine of the diabetics had been stored in the liver in the form of glycogen.He also demonstrated that the central nervous system was involved in the control of glucose by inducing transient blood glucose in the conscious rabbit stimulating the marrow.He also conducted numerous experiments with the pancreas developing the pancreatic duct ligation model and although he did not attribute to this organ an endocrine role, he allowed others to demonstrate that with this technique the degeneration of the exocrine pancreas was induced to keep the endocrine function intact.
The functions of the pancreas as a gland capable of reducing blood glucose levels began to clarify in the second half of the nineteenth century.In 1889, Oskar Minskowski and Josef von Mering, drawing to find out if the pancreas was necessary for life, pancreaticized a dog.After the operation, both researchers observed that the dog showed all the symptoms of a severe diabetes, with polyuria, insatiable thirst and hyperphan.Minskowski observed, likely, hyperglycemia and glucosuria.In this way it was shown that the pancreas was necessary to regulate glucose levels and stimulated many researchers to try to isolate the pancreas an active substance as a possible treatment of the disease.
On the other hand, in 1869 a young Berlin doctor, Paul Langerhans while working in his doctoral thesis, had observed some clusters of very differentiated pancreatic cells from the others and that could be separated from the surrounding tissues.Langerhans, who was then 22, just described these cells without trying to find out what his function was.
We had to wait until 1893, when a Belgian doctor, Edouard Laguesse, suggested that these cell clusters, which he had called "Langerhans islets" constituted the exocrine part of the pancreas.His ideas were continued by Jean de Meyer who called "insulin" to the substance from the islets (in Latin islet is called "insula") that he had to possess a hypoglycemic activity but that was still hypothetical.
The 20th century
In the last years of the nineteenth and the first century of the 20th century, great efforts were made to isolate insulin.One of the first researchers to obtain results was the German Georg Zuelger who obtained a series of pancreatic extracts that were able to reduce diabetes symptoms in a previously pancreatomized dog.Zuelger published his results in 1907 and included patented his extract ("accommodol").However, the serious toxic effects he produced caused him to resign to follow his experiments.
Romanian doctor Nicolas Paulesco also prepared an extract from frozen dog and ox pancreas and showed that they were able to reverse hyperglycemia.In fact, one of the extracts prepared by Paulesco was so powerful, that one of the treated dogs died due to hypoglycemia.Due to World War I, Paulesco's observations on the effects of his "pancreatine" were not published until 1921. The same as in the case of Zuelger, the toxic effects of the extracts excluded any possibility of a therapeutic administration.
Although the problem of diabetes was about to solve, the truth is that until entering the 20s, the diabetics had few possibilities to survive.The anorexic diets promoted by Bostonian diabetologist Frederick M. Allen, only managed to prolong life in a few months.The existing treatments in little differed from those proposed by Arateus, almost 2000 years before.
Other diabetes related discoveries also took place in the second halfof the nineteenth century.William Prout (1785-1859) associated the coma to diabetes;The American ophthalmologist, H.D.Noyes observed that the diabetics suffered a form of retinitis and Kussmaul (1822-1902) described ketoacidosis.
Insulin discovery
The insulin was discovered in summer 1921 by Sir Frederick Grant Banting as a result of a series of experiments carried out in the Chair of Prof. John J. R. Macleod, Professor of Physiology at the University of Toronto.
Banting had already shown much interest in diabetes and had closely followed Shafer's work and others, who had observed that diabetes was caused by the lack of a protein originated in the cells of Langerhans Islets and that they had called insulin.Shafer supposed that insulin controlled the metabolism of blood sugar and its elimination in urine, so that its lack caused increased urinary excretion.However, its attempts to replace this insulin deficiency by administering diabetic patients pancreas extracts had failed, probably due to the presence of proteolytic enzymes in pancreatic extracts.
Turning the problem, in 1921, Banting read a publication of one Moses Baron in which it was demonstrated that the pancreatic duct ligation caused the degeneration of the producing cells of the tripsin, while the Langerhans islets remained intact.
Banting managed to convince Macleod so that, during the holidays of this he would assign an assistant and allow him to use his laboratories.Charles Best, a chemistry student was in charge of isolating the alleged protein.
In just 9 weeks, fighting against clock, Banting and Best linked the pancreatic duct of several dogs and obtained a tripsin -free pancreas extract.Then, they caused an experimental diabetes in other dogs and, once the disease was developed, they found that the administration of the pancreas extract of the former reduced or annulled the glycosuria of the seconds.They had discovered insulin.
As a consequence of this discovery, Macleod and Banting received the Nobel Prize in Medicine in 1923.Banting protested because Macleod shared the prize instead of Best, and distributed his Nobel part with the latter.
The insulin structure
The next milestone in the history of insulin was the elucidation of its structure, feat carried out in 1954 by Frederick Sangger and its collaborators of the University of Cambridge.Sanger was interested in the structure of proteins, choosing insulin for being one of the few that could be achieved in a reasonably pure state, for knowing its chemical composition and molecular weight and because its activity should be linked to some componentstructural.
Insulin is a very small molecule: it only contains 254 carbon atoms, 337 hydrogen, 65 nitrogen, 75 oxygen and 6 sulfur.In addition, from Fisher's works it was known that of the 24 possible amino acids, 17 are present in insulin.
The work done by Sanger consisted of elucidating not only the total structure of the insulin molecule, but also the order in which the different subunits of amino acids are alined.This sequence is crucial: a single change in the position of an amino acid inside the molecule can change the functionality of the protein.
To achieve this, Sanger used the traditional method used by chemicals to study the large molecules: break them in fragments and place them together such as the pieces of a puzzle.The complete breakage of the molecule serves to identify amino acids, but it says nothing about how they are ordered.
SangerHe used three tools to assemble the puzzle: the use of a special marker that binds to free NH2 groups, fractional hydrolysis and fine layer chromatography.The marker used by Sanger was the DNP (Dinitrofenol) that binds to the terminal NH2 and resists hydrolysis.In this way, dividing the insulin molecule in different peptides, marking these with DNP and producing the fractional and total hydrolysis of these peptides to identify the amino acids.
First, Sanger managed to fractionate the insulin molecule in his two chains.To do this, he took advantage of the fact that the disulfide bridges between them can be broken selectively by oxidation with performer acid.
Then Sanger separated both chains by electrophoresis.He showed that a chain began with glycocola, while the second began by Phenylalanine.
Sanger initially concentrated on the glycocola chain.Submitting the chain to partial hydrolysis, marking the peptide fragments with DNP, separating them and analyzing them in search of equal sequences in the different fragments, Sanger and its assistants showed that the initial sequence of the glycocola chain was:
glycocola-isoleucine-valine-glutamic-glutamic acid
Proceeding in this way, Sanger came to know the complete sequence of the glycocola chain. The phenylalanine chain, with 30 amino acids was, with great difference, the most complex polypeptide whose analysis had ever tried.Sanger approached the problem using the same technique as that used for the glycocola chain, but also used proteolytic enzymes that cut the polypeptides selectively.
In a year of work, Sanger managed to indentify and place the amino acids of the Phenylalanine chain.Nor was it easy to find out how the disulfide bridges were located between the two chains.
However, Sanger and his collaborators found a way to hydrolyze the chains keeping these bridges intact.The analysis of the united amino acids the bridges allowed, ultimately to reach the structure of insulin.
For this magnificent feat, Sanger received the Nobel Prize in Medicine in 1955
12 more years were needed to discover that insulin is excreted and stored as proinsulin, inactive, which is cleared to active insulin with their chains and a rest called peptide C and until the 70s it did not know exactly its three -dimensional structure.
recombinant insulin production
Simultaneously to the advances obtained in the elucidation of the 3D structure of insulin and its biosynthesis in mammals, molecular biologists isolated the genes responsible for the production of proinsulin (villa-komaroff, L. et al., 1978) and soonThe pharmaceutical industry glimpsed the possibility of obtaining human insulin by cloning genes in bacteria.
Human insulin has been the first commercial product of gene cloning and its success has been due to the small size of the molecule that made possible the chemical synthesis of a gene.
The strategy followed for the production of recombinant human insulin was the following: First, DNA chains were chemically synthesized with the sequences corresponding to glycocol and phenylalanine chains, being necessary 63 nucleotides for the first and 90A triplet to point out the end of translation.Besides.To facilitate the separation of the synthesized products, the triplet corresponding to the methodin was added to each gene.
Synthetic genes A and B were inserted separately into the bacterial gene responsible for the B-galactosidase and present in a plasmid.The recombinant plasmids were introduced in E. coli where they multiplied,Manufacturing an RNM that translated a chimeric protein, in which a part of the sequence of the B-galactosidase was linked by a methodin to the glycocola or phenylalanima chains of insulin.As none of the insulin chains contains Metionine, this was used to separate the insulin chains from the rest of the chimeric protein breaking it with cyanogen bromide that destroys the methodin.After purified, the chains of united by a reaction that forms disulfide bridges,
Future
Development of transgenic pig with biocompatible pancreas
Genetic engineering developments make it possible to obtain transgenic pigs in which the genetic information necessary to create a biocompatible pancreas has been inserted.
The technique is as follows:
- Obtaining DNA of the diabetic patient from a cell
- Isolation of genes that encode pancreatic tissues and secretion products
- Correction of genetic errors
- Insertion of the corrected genes in a pork oocyte
- Implementation of the oocyte in the uterus of a pregnant sow
- Sacrifice of the transgenic pig per year of birth
- pancreas transplant
Development of organs of organs of organs
The factors of differentiation and growth that regulate organogenesis are fully known.Media and techniques of cultivation of organs are developed in laboratories located in orbit to achieve severity 0.
The technique followed is as follows: after correcting the genetic errors of the diabetic, its DNA is inserted in a human oocyte.By adding specific differentiation and growth factors, the oocyte evolves to a pancreas that is subsequently transplanted
Alternatively, the complete pancreas can be replaced by pure islets from manipulated pancreatic cell cultures to correct errors.The transplant is carried out according to the technique followed by Shapiro et al in 2000 without the need to treat patients transplanted with immunosuppressants.
