Amphioxus Insulin

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Insulin - Wikipedia    "Insulin (from the Latin, insula meaning island) is a peptide hormone produced by beta cells of the pancreatic islets, and by the Brockmann body in some teleost fish.[1] It has important effects on the metabolism of carbohydrates, fats and protein by promoting the absorption of, especially, glucose from the blood into fat, liver and skeletal muscle cells.[2] In these tissues the absorbed glucose is converted into either glycogen or fats (triglycerides), or, in the case of the liver, into both.[2] Glucose production (and excretion into the blood) by the liver is strongly inhibited by high concentrations of insulin in the blood.[3] Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. In high concentrations in the blood it is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism.

The pancreatic beta cells (β cells) are known to be sensitive to the glucose concentration in the blood. When the blood glucose levels are high they secrete insulin into the blood; when the levels are low they cease their secretion of this hormone into the general circulation.[4] Their neighboring alpha cells, probably by taking their cues from the beta cells,[4] secrete glucagon into the blood in the opposite manner: high secretion rates when the blood glucose concentrations are low, and low secretion rates when the glucose levels are high.[2][4] High glucagon concentrations in the blood plasma powerfully stimulate the liver to release glucose into the blood by glycogenolysis and gluconeogenesis, thus having the opposite effect on the blood glucose level to that produced by high insulin concentrations.[2][4] The secretion of insulin and glucagon into the blood in response to the blood glucose concentration is the primary mechanism responsible for keeping the glucose levels in the extracellular fluids within very narrow limits at rest, after meals, and during exercise and starvation.[4]

When the pancreatic beta cells are destroyed by an autoimmune process, insulin can no longer be synthesized or be secreted into the blood. This results in type 1 diabetes mellitus, which is characterized by very high blood sugar levels, and generalized body wasting, which is fatal if not treated. This can only be corrected by injecting the hormone, either directly into the blood if the patient is very ill and confused or comatosed, or subcutaneously for routine maintenance therapy, which must be continued for the rest of the person’s life.[5] The exact details of how much insulin needs to be injected, and when during the day, has to be adjusted according to the patient’s daily routine of meals and exercise, in order to mimic the physiological secretion of insulin as closely as is practically possible.

In type 2 diabetes mellitus the destruction of beta cells is less pronounced than in type 1 diabetes, and probably not due to an autoimmune process. Instead there is an accumulation of amyloid in the pancreatic islets, which disrupts the anatomy and physiology of the pancreatic islets.[4] What causes this amyloid deposition is unknown, and precisely how it affects the secretion of insulin and glucagon is not known. What is known is that type 2 diabetes is characterized by high rates of glucagon secretion into the blood which are unaffected by, and unresponsive to the blood glucose levels. Insulin is still secreted into the blood in response to the blood glucose level, but there seems to be a “resistance” to its actions, which may be, at least partly, due to the high glucagon concentrations in the blood.[4] As a result, the insulin levels, even when the blood sugar level is normal, are much higher than they are in healthy persons. There are a variety of treatment regimens, very few of which are entirely satisfactory. When the pancreas’ capacity to secrete insulin can no longer keep the blood sugar level within normal bounds, insulin injections are given. Over 40% of patients with type 2 diabetes require insulin injections as part of their diabetes management plan.

Insulin may have originated more than a billion years ago.[6] The molecular origins of insulin go at least as far back as the simplest unicellular eukaryotes.[7] Apart from animals, insulin-like proteins are also known to exist in the Fungi and Protista kingdoms.[6] The human insulin protein is composed of 51 amino acids, and has a molecular mass of 5808 Da. It is a dimer of an A-chain and a B-chain, which are linked together by disulfide bonds. Insulin's structure varies slightly between species of animals. Insulin from animal sources differs somewhat in effectiveness (in carbohydrate metabolism effects) from human insulin because of these variations. Porcine insulin is especially close to the human version, and was widely used to treat type 1 diabetics before human insulin could be produced in large quantities by recombinant DNA technologies.[8][9][10][11]

The crystal structure of insulin in the solid state was determined by Dorothy Hodgkin; she was awarded the Nobel Prize in Chemistry in 1964. It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[12]


1990     68<72 
Evolution of the insulin superfamily: cloning of a hybrid insulin/insulin-like growth factor cDNA from amphioxus.     "Although insulin and the insulin-like growth factors (IGFs) share marked similarities in amino acid sequence and biological activity, their evolutionary origins have not been resolved. To investigate this issue, we recently cloned a cDNA encoding an insulin-like peptide (ILP) from a primitive chordate species, amphioxus (Branchiostoma californiensis). The deduced sequence of amphioxus preproILP indicates that it is a hybrid molecule containing features characteristic of both insulin and IGF. Like proinsulin, amphioxus proILP contains a C-peptide, which is flanked by paired basic residues and is probably removed by proteolysis. However, proILP also contains an extended carboxyl-terminal peptide region that can be divided into D and E domains similar to those of proIGF. Sequence comparisons show that the amphioxus ILP A and B domains are equally homologous to those of human insulin and IGF-I and -II. Based on these results and the exon-intron organization of the amphioxus ILP gene, we propose that IGF emerged at a very early stage in vertebrate evolution from an ancestral insulin-type gene."   
    - Free PMC Article -   

1994    64<72 
Insulin-like compounds related to the amphioxus insulin-like peptide.   
These results suggest that amphioxus ILP has retained an overall structural similarity to mammalian insulin and IGF-I but has also accumulated substantial mutations which markedly reduce its ability to bind and activate their cognate receptors."  

1997    61<72 
Ancient divergence of insulin and insulin-like growth factor.   
Studies on the evolutionary pathway of the insulin gene family suggest that insulin and insulin-like growth factor (IGF) became distinct molecules only after the vertebrates arose.  
    A single molecule with identity to both insulin and IGF was reported in amphioxus. To study the origin of insulin, we selected tunicates because their ancestors are thought to be a nodal point in the evolution of vertebrates. This is the first report of separate insulin and IGF molecules from invertebrates.  
    Two cDNAs were isolated from the tunicate Chelyosoma productum: One cDNA encodes a distinct preproinsulin with B, C, and A domains, whereas the other encodes tunicate preproIGF, including all five domains in their proper sequence. Both mRNAs are expressed in the nervous system, digestive tract, heart, and possibly the gonad but not in branchial basket or tunic. Hence, insulin and igf genes have similar expression patterns. In situ methods confirm the polymerase chain reaction evidence that tunicate insulin and igf mRNAs are expressed in cortical cells of the neural ganglion.  
    We conclude that insulin and IGF have maintained separate gene lineages in both vertebrate and protochordate evolution and, thus, a distinct evolutionary history of more than 600 million years." 

2002    57<7
  In vitro evolution of amphioxus insulin-like peptide to mammalian insulin.
    "The natural evolution of amphioxus ILP to mammalian insulin is a possible process and can be mimicked in the laboratory."  

2004    51<72 
In vitro refolding/unfolding pathways of amphioxus insulin-like peptide: implications for folding behavior of insulin family proteins   
Amphioxus insulin-like peptide (AILP) belongs to the insulin superfamily and is proposed as the common ancestor of insulin and insulin-like growth factor 1."   

2014    11<73 
Characterization of insulin-like peptides (ILPs) in the sea urchin Strongylocentrotus purpuratus: insights on the evolution of the insulin family.   
We found that SpILP1 gene structure is more similar to the cephalochordate amphioxus ILP, while the SpILP2 gene shows a completely different organization. "  
In the model we put forward, the last common ancestor of all deuterostomes presented an ILP composed of the B-C-A-D-E domains, and successive lineage specific independent gene duplication events resulted in the presence of several ILPs in vertebrates and in echinoderms."  

2015    8<73 
Identification, evolution and expression of an insulin-like peptide in the cephalochordate Branchiostoma lanceolatum.   
We hypothesize that ILP has critical implications in both developmental processes and metabolism and could display IGF- and insulin-like functions in amphioxus supporting the idea of a common ancestral protein. "  
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Demonstration of an endocrine signaling circuit for insulin in the sponge Geodia cydonium
    See:  Parazoa Hormones