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Beta cell

Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are diminished, leading to insufficient insulin secretion and hyperglycemia.

Beta cell
Details
LocationPancreatic islet
FunctionInsulin secretion
Identifiers
Latinendocrinocytus B; insulinocytus
THH3.04.02.0.00026
FMA85704
Anatomical terms of microanatomy

Contents

The primary function of a beta cell is to produce and release insulin and amylin. Both are hormones which reduce blood glucose levels by different mechanisms. Beta cells can respond quickly to spikes in blood glucose concentrations by secreting some of their stored insulin and amylin while simultaneously producing more.

Insulin synthesis

Beta cells are the only site of insulin synthesis in mammals. As glucose stimulates insulin secretion, it simultaneously increases proinsulin biosynthesis, mainly through translational control.

The insulin gene is first transcribed into mRNA and translated into preproinsulin. After translation, the preproinsulin precursor contains an N-terminal signal peptide that allows translocation into the rough endoplasmic reticulum (RER). Inside the RER, the signal peptide is cleaved to form proinsulin. Then, folding of proinsulin occurs forming three disulfide bonds. Subsequent to protein folding, proinsulin is transported to the Golgi apparatus and enters immature insulin granules where proinsulin is cleaved to form insulin and C-peptide. After maturation, these secretory vesicles hold insulin, C-peptide, and amylin until calcium triggers exocytosis of the granule contents.

Through translational processing, insulin is encoded as a 110 amino acid precursor but is secreted as a 51 amino acid protein.

Insulin secretion

The Consensus Model of glucose-stimulated insulin secretion

In beta cells, insulin release is stimulated primarily by glucose present in the blood. As circulating glucose levels rise such as after ingesting a meal, insulin is secreted in a dose-dependent fashion. This system of release is commonly referred to as glucose-stimulated insulin secretion (GSIS). There are four key pieces to the "Consensus Model" of GSIS: GLUT2 dependent glucose uptake, glucose metabolism, KATP channel closure, and the opening of voltage gated calcium channels causing insulin granule fusion and exocytosis.

Voltage-gated calcium channels and ATP-sensitive potassium ion channels are embedded in the plasma membrane of beta cells. These ATP-sensitive potassium ion channels are normally open and the calcium ion channels are normally closed. Potassium ions diffuse out of the cell, down their concentration gradient, making the inside of the cell more negative with respect to the outside (as potassium ions carry a positive charge). At rest, this creates a potential difference across the cell surface membrane of -70mV.

When the glucose concentration outside the cell is high, glucose molecules move into the cell by facilitated diffusion, down its concentration gradient through the GLUT2 transporter. Since beta cells use glucokinase to catalyze the first step of glycolysis, metabolism only occurs around physiological blood glucose levels and above. Metabolism of the glucose produces ATP, which increases the ATP to ADP ratio.

The ATP-sensitive potassium ion channels close when this ratio rises. This means that potassium ions can no longer diffuse out of the cell. As a result, the potential difference across the membrane becomes more positive (as potassium ions accumulate inside the cell). This change in potential difference opens the voltage-gated calcium channels, which allows calcium ions from outside the cell to diffuse in down their concentration gradient. When the calcium ions enter the cell, they cause vesicles containing insulin to move to, and fuse with, the cell surface membrane, releasing insulin by exocytosis into the hepatic portal vein.

Other hormones secreted

  • C-peptide, which is secreted into the bloodstream in equimolar quantities to insulin. C-peptide helps to prevent neuropathy and other vascular deterioration related symptoms of diabetes mellitus. A practitioner would measure the levels of C-peptide to obtain an estimate for the viable beta cell mass.
  • Amylin, also known as islet amyloid polypeptide (IAPP). The function of amylin is to slow the rate of glucose entering the bloodstream. Amylin can be described as a synergistic partner to insulin, where insulin regulates long term food intake and amylin regulates short term food intake.

Type 1 diabetes

Type 1 diabetes mellitus, also known as insulin dependent diabetes, is believed to be caused by an auto-immune mediated destruction of the insulin producing beta cells in the body. The process of beta-cell destruction begins with insulitis activating antigen presenting cells (APCs). APCs then trigger activation of CD4+ helper-T cells, and chemokines/cytokines release. Then the cytokines activate CD8+ cytotoxic–T cells, which lead to beta-cell destruction. The destruction of these cells reduces the body's ability to respond to glucose levels in the body, therefore making it nearly impossible to properly regulate glucose and glucagon levels in the bloodstream. The body destroys 70–80% of beta cells, leaving only 20–30% of functioning cells. This can cause the patient to experience hyperglycemia, which leads to other adverse short-term and long-term conditions. The symptoms of diabetes can potentially be controlled with methods such as regular doses of insulin and sustaining a proper diet. However, these methods can be tedious and cumbersome to continuously perform on a daily basis.

Type 2 diabetes

Type 2 diabetes mellitus, also known as non insulin dependent diabetes and as chronic hyperglycemia, is caused primarily by genetics and the development of metabolic syndrome. The beta cells can still secrete insulin but the body has developed a resistance and its response to insulin has declined. It is believed to be due to the decline of specific receptors on the surface of the liver, adipose, and muscle cells which lose their ability to respond to insulin that circulates in the blood. In an effort to secrete enough insulin to overcome the increasing insulin resistance, the beta cells increase their function, size and number. Increased insulin secretion leads to hyperinsulinemia, but blood glucose levels remain within their normal range due to the decreased efficacy of insulin signaling. However, the beta cells can become overworked and exhausted from being overstimulated, leading to a 50% reduction in function along with a 40% decrease in beta-cell volume. At this point, not enough insulin can be produced and secreted to keep blood glucose levels within their normal range, causing overt type 2 diabetes.

Insulinoma

Insulinoma is a rare tumor derived from the neoplasia of beta cells. Insulinomas are usually benign, but may be medically significant and even life-threatening due to recurrent and prolonged attacks of hypoglycemia.

Medications

Many drugs to combat diabetes are aimed at modifying the function of the beta cell.

  • Sulfonylureas are insulin secretagogues that act by closing the ATP-sensitive potassium channels, thereby causing insulin release. These drugs are known to cause hypoglycemia and can lead to beta-cell failure due to overstimulation. Second-generation versions of sulfonylureas are shorter acting and less likely to cause hypoglycemia.
  • GLP-1 receptor agonists stimulate insulin secretion by simulating activation of the body's endogenous incretin system. The incretin system acts as an insulin secretion amplifying pathway.
  • DPP-4 inhibitors block DPP-4 activity which increases postprandial incretin hormone concentration, therefore increasing insulin secretion.

Experimental techniques

Many researchers around the world are investigating the pathogenesis of diabetes and beta-cell failure. Tools used to study beta-cell function are expanding rapidly with technology.

For instance, transcriptomics have allowed researchers to comprehensively analyze gene transcription in beta-cells to look for genes linked to diabetes. A more common mechanism of analyzing cellular function is calcium imaging. Fluorescent dyes bind to calcium and allow in vitro imaging of calcium activity which correlates directly with insulin release. A final tool used in beta-cell research are in vivo experiments. Diabetes mellitus can be experimentally induced in vivo for research purposes by streptozotocin or alloxan, which are specifically toxic to beta cells. Mouse and rat models of diabetes also exist including ob/ob and db/db mice which are a type 2 diabetes model, and non-obese diabetic mice (NOD) which are a model for type 1 diabetes.

Type 1 diabetes

Research has shown that beta cells can be differentiated from human pancreas progenitor cells. These differentiated beta cells, however, often lack much of the structure and markers that beta cells need to perform their necessary functions. Examples of the anomalies that arise from beta cells differentiated from progenitor cells include a failure to react to environments with high glucose concentrations, an inability to produce necessary beta cell markers, and abnormal expression of glucagon along with insulin.

In order to successfully re-create functional insulin producing beta cells, studies have shown that manipulating cell-signal pathways in early stem cell development will lead to those stem cells differentiating into viable beta cells. Two key signal pathways have been shown to play a vital role in the differentiation of stem cells into beta cells: the BMP4 pathway and the kinase C. Targeted manipulation of these two pathways has shown that it is possible to induce beta cell differentiation from stem cells. These variations of artificial beta cells have shown greater levels of success in replicating the functionality of natural beta cells, although the replication has not been perfectly re-created yet.

Studies have shown that it is possible to regenerate beta cells in vivo in some animal models. Research in mice has shown that beta cells can often regenerate to the original quantity number after the beta cells have undergone some sort of stress test, such as the intentional destruction of the beta cells in the mice subject or once the auto-immune response has concluded. While these studies have conclusive results in mice, beta cells in human subjects may not possess this same level of versatility. Investigation of beta cells following acute onset of Type 1 diabetes has shown little to no proliferation of newly synthesized beta cells, suggesting that human beta cells might not be as versatile as rat beta cells, but there is actually no comparison that can be made here because healthy (non-diabetic) rats were used to prove that beta cells can proliferate after intentional destruction of beta cells, while diseased (type-1 diabetic) humans were used in the study which was attempted to use as evidence against beta cells regenerating.

It appears that much work has to be done in the field of regenerating beta cells. Just as in the discovery of creating insulin through the use of recombinant DNA, the ability to artificially create stem cells that would differentiate into beta cells would prove to be an invaluable resource to patients suffering from Type 1 diabetes. An unlimited amount of beta cells produced artificially could potentially provide therapy to many of the patients who are affected by Type 1 diabetes.

Type 2 diabetes

Research focused on non insulin dependent diabetes encompasses many areas of interest. Degeneration of the beta cell as diabetes progresses has been a broadly reviewed topic. Another topic of interest for beta-cell physiologists is the mechanism of insulin pulsatility which has been well investigated. Many genome studies have been completed and are advancing the knowledge of beta-cell function exponentially. Indeed, the area of beta-cell research is very active yet many mysteries remain.

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Beta cell
Beta cell Language Watch Edit 160 160 Redirected from B cells Beta cells b cells are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin Beta cells make up 50 70 of the cells in human islets 1 In patients with Type 1 diabetes beta cell mass and function are diminished leading to insufficient insulin secretion and hyperglycemia 2 Beta cellDetailsLocationPancreatic isletFunctionInsulin secretionIdentifiersLatinendocrinocytus B insulinocytusTHH3 04 02 0 00026FMA85704Anatomical terms of microanatomy edit on Wikidata Contents 1 Function 1 1 Insulin synthesis 1 2 Insulin secretion 1 3 Other hormones secreted 2 Clinical significance 2 1 Type 1 diabetes 2 2 Type 2 diabetes 2 3 Insulinoma 2 4 Medications 3 Research 3 1 Experimental techniques 3 2 Type 1 diabetes 3 3 Type 2 diabetes 4 See also 5 ReferencesFunction EditThe primary function of a beta cell is to produce and release insulin and amylin Both are hormones which reduce blood glucose levels by different mechanisms Beta cells can respond quickly to spikes in blood glucose concentrations by secreting some of their stored insulin and amylin while simultaneously producing more 3 Insulin synthesis Edit Beta cells are the only site of insulin synthesis in mammals 4 As glucose stimulates insulin secretion it simultaneously increases proinsulin biosynthesis mainly through translational control 3 The insulin gene is first transcribed into mRNA and translated into preproinsulin 3 After translation the preproinsulin precursor contains an N terminal signal peptide that allows translocation into the rough endoplasmic reticulum RER 5 Inside the RER the signal peptide is cleaved to form proinsulin 5 Then folding of proinsulin occurs forming three disulfide bonds 5 Subsequent to protein folding proinsulin is transported to the Golgi apparatus and enters immature insulin granules where proinsulin is cleaved to form insulin and C peptide 5 After maturation these secretory vesicles hold insulin C peptide and amylin until calcium triggers exocytosis of the granule contents 3 Through translational processing insulin is encoded as a 110 amino acid precursor but is secreted as a 51 amino acid protein 5 Insulin secretion Edit The Consensus Model of glucose stimulated insulin secretion In beta cells insulin release is stimulated primarily by glucose present in the blood 3 As circulating glucose levels rise such as after ingesting a meal insulin is secreted in a dose dependent fashion 3 This system of release is commonly referred to as glucose stimulated insulin secretion GSIS 6 There are four key pieces to the Consensus Model of GSIS GLUT2 dependent glucose uptake glucose metabolism KATP channel closure and the opening of voltage gated calcium channels causing insulin granule fusion and exocytosis 7 Voltage gated calcium channels and ATP sensitive potassium ion channels are embedded in the plasma membrane of beta cells 7 8 These ATP sensitive potassium ion channels are normally open and the calcium ion channels are normally closed 3 Potassium ions diffuse out of the cell down their concentration gradient making the inside of the cell more negative with respect to the outside as potassium ions carry a positive charge 3 At rest this creates a potential difference across the cell surface membrane of 70mV 9 When the glucose concentration outside the cell is high glucose molecules move into the cell by facilitated diffusion down its concentration gradient through the GLUT2 transporter 10 Since beta cells use glucokinase to catalyze the first step of glycolysis metabolism only occurs around physiological blood glucose levels and above 3 Metabolism of the glucose produces ATP which increases the ATP to ADP ratio 11 The ATP sensitive potassium ion channels close when this ratio rises 8 This means that potassium ions can no longer diffuse out of the cell 12 As a result the potential difference across the membrane becomes more positive as potassium ions accumulate inside the cell 9 This change in potential difference opens the voltage gated calcium channels which allows calcium ions from outside the cell to diffuse in down their concentration gradient 9 When the calcium ions enter the cell they cause vesicles containing insulin to move to and fuse with the cell surface membrane releasing insulin by exocytosis into the hepatic portal vein 13 14 Other hormones secreted Edit C peptide which is secreted into the bloodstream in equimolar quantities to insulin C peptide helps to prevent neuropathy and other vascular deterioration related symptoms of diabetes mellitus 15 A practitioner would measure the levels of C peptide to obtain an estimate for the viable beta cell mass 16 Amylin also known as islet amyloid polypeptide IAPP 17 The function of amylin is to slow the rate of glucose entering the bloodstream Amylin can be described as a synergistic partner to insulin where insulin regulates long term food intake and amylin regulates short term food intake Clinical significance EditType 1 diabetes Edit Type 1 diabetes mellitus also known as insulin dependent diabetes is believed to be caused by an auto immune mediated destruction of the insulin producing beta cells in the body 5 The process of beta cell destruction begins with insulitis activating antigen presenting cells APCs APCs then trigger activation of CD4 helper T cells and chemokines cytokines release Then the cytokines activate CD8 cytotoxic T cells which lead to beta cell destruction 18 The destruction of these cells reduces the body s ability to respond to glucose levels in the body therefore making it nearly impossible to properly regulate glucose and glucagon levels in the bloodstream 19 The body destroys 70 80 of beta cells leaving only 20 30 of functioning cells 2 20 This can cause the patient to experience hyperglycemia which leads to other adverse short term and long term conditions 21 The symptoms of diabetes can potentially be controlled with methods such as regular doses of insulin and sustaining a proper diet 21 However these methods can be tedious and cumbersome to continuously perform on a daily basis 21 Type 2 diabetes Edit Type 2 diabetes mellitus also known as non insulin dependent diabetes and as chronic hyperglycemia is caused primarily by genetics and the development of metabolic syndrome 2 5 The beta cells can still secrete insulin but the body has developed a resistance and its response to insulin has declined 3 It is believed to be due to the decline of specific receptors on the surface of the liver adipose and muscle cells which lose their ability to respond to insulin that circulates in the blood 22 23 In an effort to secrete enough insulin to overcome the increasing insulin resistance the beta cells increase their function size and number 3 Increased insulin secretion leads to hyperinsulinemia but blood glucose levels remain within their normal range due to the decreased efficacy of insulin signaling 3 However the beta cells can become overworked and exhausted from being overstimulated leading to a 50 reduction in function along with a 40 decrease in beta cell volume 5 At this point not enough insulin can be produced and secreted to keep blood glucose levels within their normal range causing overt type 2 diabetes 5 Insulinoma Edit Insulinoma is a rare tumor derived from the neoplasia of beta cells Insulinomas are usually benign but may be medically significant and even life threatening due to recurrent and prolonged attacks of hypoglycemia 24 Medications Edit Many drugs to combat diabetes are aimed at modifying the function of the beta cell Sulfonylureas are insulin secretagogues that act by closing the ATP sensitive potassium channels thereby causing insulin release 25 26 These drugs are known to cause hypoglycemia and can lead to beta cell failure due to overstimulation 2 Second generation versions of sulfonylureas are shorter acting and less likely to cause hypoglycemia 26 GLP 1 receptor agonists stimulate insulin secretion by simulating activation of the body s endogenous incretin system 26 The incretin system acts as an insulin secretion amplifying pathway 26 DPP 4 inhibitors block DPP 4 activity which increases postprandial incretin hormone concentration therefore increasing insulin secretion 26 Research EditExperimental techniques Edit Many researchers around the world are investigating the pathogenesis of diabetes and beta cell failure Tools used to study beta cell function are expanding rapidly with technology For instance transcriptomics have allowed researchers to comprehensively analyze gene transcription in beta cells to look for genes linked to diabetes 2 A more common mechanism of analyzing cellular function is calcium imaging Fluorescent dyes bind to calcium and allow in vitro imaging of calcium activity which correlates directly with insulin release 2 27 A final tool used in beta cell research are in vivo experiments Diabetes mellitus can be experimentally induced in vivo for research purposes by streptozotocin 28 or alloxan 29 which are specifically toxic to beta cells Mouse and rat models of diabetes also exist including ob ob and db db mice which are a type 2 diabetes model and non obese diabetic mice NOD which are a model for type 1 diabetes 30 Type 1 diabetes Edit Research has shown that beta cells can be differentiated from human pancreas progenitor cells 31 These differentiated beta cells however often lack much of the structure and markers that beta cells need to perform their necessary functions 31 Examples of the anomalies that arise from beta cells differentiated from progenitor cells include a failure to react to environments with high glucose concentrations an inability to produce necessary beta cell markers and abnormal expression of glucagon along with insulin 31 In order to successfully re create functional insulin producing beta cells studies have shown that manipulating cell signal pathways in early stem cell development will lead to those stem cells differentiating into viable beta cells 31 32 Two key signal pathways have been shown to play a vital role in the differentiation of stem cells into beta cells the BMP4 pathway and the kinase C 32 Targeted manipulation of these two pathways has shown that it is possible to induce beta cell differentiation from stem cells 32 These variations of artificial beta cells have shown greater levels of success in replicating the functionality of natural beta cells although the replication has not been perfectly re created yet 32 Studies have shown that it is possible to regenerate beta cells in vivo in some animal models 33 Research in mice has shown that beta cells can often regenerate to the original quantity number after the beta cells have undergone some sort of stress test such as the intentional destruction of the beta cells in the mice subject or once the auto immune response has concluded 31 While these studies have conclusive results in mice beta cells in human subjects may not possess this same level of versatility Investigation of beta cells following acute onset of Type 1 diabetes has shown little to no proliferation of newly synthesized beta cells suggesting that human beta cells might not be as versatile as rat beta cells but there is actually no comparison that can be made here because healthy non diabetic rats were used to prove that beta cells can proliferate after intentional destruction of beta cells while diseased type 1 diabetic humans were used in the study which was attempted to use as evidence against beta cells regenerating 34 It appears that much work has to be done in the field of regenerating beta cells 32 Just as in the discovery of creating insulin through the use of recombinant DNA the ability to artificially create stem cells that would differentiate into beta cells would prove to be an invaluable resource to patients suffering from Type 1 diabetes An unlimited amount of beta cells produced artificially could potentially provide therapy to many of the patients who are affected by Type 1 diabetes Type 2 diabetes Edit Research focused on non insulin dependent diabetes encompasses many areas of interest Degeneration of the beta cell as diabetes progresses has been a broadly reviewed topic 2 3 5 Another topic of interest for beta cell physiologists is the mechanism of insulin pulsatility which has been well investigated 35 36 Many genome studies have been completed and are advancing the knowledge of beta cell function exponentially 37 38 Indeed the area of beta cell research is very active yet many mysteries remain See also EditGastric inhibitory polypeptide receptor List of terms associated with diabetes Guangxitoxin Alpha cell Pancreatic development Islets of LangerhansReferences Edit Dolensek J Rupnik MS Stozer A 2015 01 02 Structural similarities and differences between the human and the mouse pancreas Islets 7 1 e1024405 doi 10 1080 19382014 2015 1024405 PMC 4589993 PMID 26030186 a b c d e f g Chen C Cohrs CM Stertmann J Bozsak R Speier S September 2017 Human beta cell mass and function in diabetes Recent advances in knowledge and technologies to understand disease pathogenesis Molecular Metabolism 6 9 943 957 doi 10 1016 j molmet 2017 06 019 PMC 5605733 PMID 28951820 a b c d e f g h i j k l m Boland BB Rhodes CJ Grimsby JS September 2017 The dynamic plasticity of insulin production in b cells Molecular Metabolism 6 9 958 973 doi 10 1016 j molmet 2017 04 010 PMC 5605729 PMID 28951821 Boland BB Brown C Alarcon C Demozay D Grimsby JS Rhodes CJ February 2018 b Cell Control of Insulin Production During Starvation Refeeding in Male Rats Endocrinology 159 2 895 906 doi 10 1210 en 2017 03120 PMC 5776497 PMID 29244064 a b c d e f g h i j Fu Z Gilbert ER Liu D January 2013 Regulation of insulin synthesis and secretion and pancreatic Beta cell dysfunction in diabetes Current Diabetes Reviews 9 1 25 53 doi 10 2174 157339913804143225 PMC 3934755 PMID 22974359 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of streptozotocin in mice Diabetes 47 1 50 6 doi 10 2337 diabetes 47 1 50 PMID 9421374 Danilova IG Sarapultsev PA Medvedeva SU Gette IF Bulavintceva TS Sarapultsev AP February 2015 Morphological restructuring of myocardium during the early phase of experimental diabetes mellitus PDF Anatomical Record 298 2 396 407 doi 10 1002 ar 23052 hdl 10995 73117 PMID 25251897 S2CID 205412167 King Aileen JF June 2012 The use of animal models in diabetes research British Journal of Pharmacology 166 3 877 894 doi 10 1111 j 1476 5381 2012 01911 x ISSN 0007 1188 PMC 3417415 PMID 22352879 a b c d e Afelik Solomon Rovira Meritxell 2017 04 15 Pancreatic b cell regeneration Facultative or dedicated progenitors Molecular and Cellular Endocrinology 445 85 94 doi 10 1016 j mce 2016 11 008 ISSN 1872 8057 PMID 27838399 S2CID 21795162 a b c d e Mahla RS 2016 Stem Cells Applications in Regenerative Medicine and Disease Therapeutics International Journal of Cell Biology 2016 7 1 24 doi 10 1155 2016 6940283 PMC 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PMC 1557567 PMID 16815907 Bertram Richard Sherman Arthur Satin Leslie S 2007 10 01 Metabolic and electrical oscillations partners in controlling pulsatile insulin secretion American Journal of Physiology Endocrinology and Metabolism 293 4 E890 E900 doi 10 1152 ajpendo 00359 2007 ISSN 0193 1849 PMID 17666486 Muraro Mauro J Dharmadhikari Gitanjali Grun Dominic Groen Nathalie Dielen Tim Jansen Erik van Gurp Leon Engelse Marten A Carlotti Francoise 2016 10 26 A Single Cell Transcriptome Atlas of the Human Pancreas Cell Systems 3 4 385 394 e3 doi 10 1016 j cels 2016 09 002 ISSN 2405 4712 PMC 5092539 PMID 27693023 Segerstolpe Asa Palasantza Athanasia Eliasson Pernilla Andersson Eva Marie Andreasson Anne Christine Sun Xiaoyan Picelli Simone Sabirsh Alan Clausen Maryam 2016 10 11 Single Cell Transcriptome Profiling of Human Pancreatic Islets in Health and Type 2 Diabetes Cell Metabolism 24 4 593 607 doi 10 1016 j cmet 2016 08 020 ISSN 1550 4131 PMC 5069352 PMID 27667667 Retrieved from https en 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