2017 Group 4 Project
- 1 Alpha cell
- 1.1 Introduction
- 1.2 History
- 1.3 Structure
- 1.4 Development
- 1.5 Function and Role
- 1.6 Diseases and Abnormalities
- 1.7 Current Research
- 1.8 Glossary
- 1.9 References
The pancreas is a glandular organ with both exocrine and endocrine functionality. The endocrine part is made up of microorgans known as Islets of Langerhans, which are clustered cells throughout the organ. Amongst the islets are also acinar cells and ducts. The islets are made up of hormone secreting cells; alpha, beta, delta, epsilon and pancreatic polypeptide cells. Respectively, these secrete, glucagon, insulin, somatostatin, ghrelin, and pancreatic polypeptide.   Alpha cells synthesise and secrete glucagon, to increase glucose concentrations. Glucagon also has a role in producing ketone bodies, and some studies suggest an influence on weight regulation. 
|1869||Islets of langerhans was discovered in 1869 by german physician Paul Langerhans |
|1893||Although langerhans discovered islets of langerhans he did not give name, after in 1893, the term "islets of langerhans" was introduced by Edouard Lanuesse. He suggest that islets of langerhans may produce internal secretions that regulate glycemia.|
|1908||Lane was who differentiated two type of granular cells in the islets. He found that type of granules that contains chemical that is fixed with alcohol and he called it as alpha cells.|
|1921||Insulin was discovered from the dog by Dr Frederick Banting in Toronto, Canada. it tested to 14 year old boy by banting and best on january 11 in 1922 |
|1923||Glucagon was discovered by Kimball and Murlin and named as a Gluc-ose Agon-ist due to its effect on glucose elevating.  However, this name is not used until 1950s, "the hyperglycemic factor of the pancreas" was more commonly used.|
|1948||In 1948, the expression of glucagon in alpha cells was revealed by Sutherland and de Duve. They presented evidence that glucagon is the hormone produced in non-beta cells.|
The pancreas is composed of endocrine islets of Langerhans and exocrine acini. The islets of Langerhans contain alpha, beta, epsilon and pancreatic polypeptide endocrine cell types, as well as vascular endothelial cells. The acini are made of exocrine acinar cells, as well as centroacinar duct cells that are centrally located within the acini and drain into the pancreatic ducts. The size of the islet of Langerhans is varying, about ~70% are in the range of 50-250μm in diameter, in humans with an average in the range of 100-150μm. 
Each cell type in the islets of langerhans has a different population; in humans, beta cells take about ~60% of the total number of cells, while alpha cells are ~30%, more than 10% are delta cells, and epsilon cells. Pancreatic polypeptide cell population is less than 1%. However, in mice, beta cells are of a higher occurrence, 60-80%, whilst alpha cells and pancreatic polypeptide cells are lower than that of humans, ranging from 10-20%, and less than 5%, respectively.  These different cell types communicate to each other by gap junctions or via paracrine secretion and signalling, this network and cell to cell communication is very important to rapidly respond to change blood glucose level.
Location and Morphology
Human alpha cells are dispersed throughout the entire islet cell similar to that of non-human primate islets. However, this differs to that of the rat and mouse whose alpha cells are restricted to the periphery of the islet, along with delta and pancreatic polypeptide cells.  Moreover, in small human islets (size of 40~60 μm in diameter) alpha cells are located at the mantle position, and vessels are also positioned at their periphery comparing to beta cells which have core position. In bigger islets, alpha cells have a similar mantle position, but it also can find along the vessels that branch inside the islets. As a result of this organisation, the ratio of beta cells to alpha cells is higher in the core of islets than mantle part, but with increasing of islet size, the ratio decreased.
Alpha cells are round shaped cells and distinguished by the granules that they have in the cells, typically alpha cells have slightly smaller granules than beta cells granules (200 nm vs 350 nm).  In the mouse, islet contains approximately 7,000 granules per cell in total and the overall cellular density of glucagon granules is 9 granules/µm3.
The pancreas originates from the endodermal germ layer of embyros. During embryogenesis, there is the formation of duodenal outgrowths known as the ventral and dorsal pancreatic buds. These buds fuse together during rotation of the developing gut to form the pancreas. The accessory pancreatic duct originates form the proximal dorsal bud and the the major pancreatic duct arises form the distal dorsal bud and the ventral bud. The dorsal bud is seen 26 days post fertilisation and the islet cells are observed 52 days post fertilisation in humans. With all the islet cells being present by the first trimester of pregnancy. In week 10 glucagon is present and by week 15 it is detectable in plasma of the fetus. 
Link to a helpful animation: http://www.uco.es/~an1gamoj/MyWeb/pancreas.html
Pancreas Progenitor cell
Pancreas progenitor cells are stem cells originating from the developing foregut endoderm. They have the ability to differentiate into progenitors that are lineage specific (e.g. endocrine and exocrine progenitors) contributing to endocrine, exocrine and ductal cells. The cluster of cells that give rise to the pancreas at stages E9.0 and E9.5 of development are known to be pancreatic progenitor cells because they have multipotent properties. 
Figure 4 - Development of pancreatic cells in mice 
This image shows the development of the endocrine and exocrine pancreatic cells over embryonic days in mice. It shows PDX1 is expressed to convert endoderm cells into the pancreatic progenitor cells. Then PTF1A ( pancreas specific transcription factor 1a) and CPA1(carboxypeptidase A1) are expressed for acini development. The duct cell transcription factors in mice are unknown in this diagram. PDX1 and neurogenin 3 expression is needed for endocrine cell fate.
Endoderm to Pancreatic Progenitor Transition
The developing bud is classified as endoderm until the expression of PDX1 (Pancreatic duodenal homeobox factor 1) transcription factor, as indicated in Figure 5. PDX1 is the first marker for pancreatic differentiation and is the marker for all pancreatic and mid gut progenitor cells. Its expression is essential for the development after the bud stage. 
Regulation of PDX1 expression
Mnx1/ HIbx1 (motor neuron and pancreas homobox 1)
-transcription factor for conversion of foregut endoderm into PDX1 expressing pancreatic progenitor cells
Gata4 and Hnf1b/Tcf2 (GATA binding protein 4 and HNF homobox B gene)
-essential for ventral bud development
-controls Mnx1 expression in the ventral pancreatic bud
Onecut1/ Hnf6 (onecut domain family member 1) transcription factor
-regulates the time of expression of PDX1 in the pancreatic buds 
As shown in Figure 5, progenitor cells to endocrine cell conversion occurs due to Ngn3 expression. Ngn3 (Neurogenin 3) is a bLHLH (basic helix loop helix) protein that acts upstream of NeuoD, a basic helix loop helix transcription factor that is involved in the differentiation to beta cells. Ngn3+ cells express ki-67 (a marker of proliferating) giving evidence for its endocrine precursor cell function. Alpha and beta cells develop independently from PDX1+/ Ngn3+ epithelial cells. Ngn3 expression starts at E9.5, peaks at E15.5 and decreases at birth. Mice lacking Ngn3+ expressing cells fail to develop endocrine cells and die prenatal. 
Arx is a transcription factor and its expression is Ngn3 dependent. Arx expression is required for an alpha cell fate (see Figure 5) and prevents beta and delta cell development. Pax4 is antagonistic to Arx, resulting in a beta or delta cell fate whilst repressing alpha cell destiny actions. 
Pdx1 expression and notch signalling regulate the amount of exocrine and endocrine cells in the pancreas. Notch signalling allows the expansion of non fully differentiated cells such as the pancreatic progenitor cells through lateral inhibition. Lateral inhibition is the capacity of an excited neuron to reduce the activity of its neighbours. One daughter cell adopts a particular fate that causes it to be a copy of the original cell and the other daughter cell is inhibited from becoming a copy. Notch signalling is essential for regulation of embryonic development. Notch signalling is inhibited by Numb gene expression to promote cell differentiation. Protein numb homolog is the protein encoded by the Numb gene and is involved in development by determining the fates of cells. . Notch signalling inhibits premature endocrine cell differentiation. Reduced notch signalling leads to the increase in Ngn3 expression allowing differentiation of endocrine cells. Expression of notch1 in the PDX1 epithelial cells inhibits the Ngn-neuroD cascade.
|Understanding Development: The Notch Signaling Pathway|
This is a helpful youtube video about the notch signalling pathway. It describes the use of the pathway to mediate cell signalling and explains the difference between induction and lateral inhibition. The most useful sections of the video are between the times of 1.09 -2.14, 2.40-3.22 and 3.50-5.41.
Function and Role
|Endocrinology - Glucagon|
Glucagon and Glucagon receptor
The main function of the alpha cell is expressing the peptide hormones which is glucagon. Glucagon is processed from a large precursor preproglucagon. Glucagon is mainly produced by alpha cell in islet of langerhans. However, such cells and tissues like L-cells in the gut, and the hypothalamus and thalamus in the brain are expressing the gene that encodes preproglucagon.
The main glucagon action site is liver. There are the steps for glucagon activation. Glucagon is binding to the glucagon receptor (a 7 transmembrane domain G-protein-coupled receptor) which is localized in both hepatic and non-hepatic tissues, including the islet. Then glucagon activates G-protein and then G-protein stimulate adenylyl cyclase. In result of this, cAMP produces and protein kinase A activates this activation leads to phosphorylate glycogen phosphorylase kinase. The glycogen breaks down by the activated phosphorylase as result of this increase hepatic glucose output. (as reviewed by Jiang and Zhang (2003) ) Moreover, glucagon is also a significant regulator of lipid metabolism, lowering plasma triglycerides and stimulating hepatic fatty acid oxidation. 
Diseases and Abnormalities
Alpha Cell Hyperplasia
Pancreatic alpha-cell hyperplasia is defined as the abnormal increased number of pancreatic alpha cells in the Islets. This leads to an increase in the secretion of glucagon, and eventually the state of hyperglucagonemia. Under normal conditions, the population of cells are maintained and regulated through proliferation, apoptosis, and neogenesis (as reviewed in). However, such abnormality disrupts the balance within the Islets by increasing proliferation and neogenesis while suppressing apoptosis. Such hyperplasia may result in numerous abnormalities and dysfunctions: Glucagonoma syndrome, Mahvash Syndrome, induction of reactive parathyroid hyperfunction, hypercalciuria, lowering of calcium levels, and may also be a predispose the pancreas to pancreatitis (as reviewed in) . There are three types of alpha cell hyperplasia; reactive, non-functional, and functional alpha cell hyperplasia (as reviewed by Yu et al. (2015)).
Glucagonoma syndrome is defined as glucagon-secreting endocrine pancreatic tumor originating from alpha 2-cells of the pancreas and is an extremely rare syndrome . As reviewed by Bloom and Polak (1987), Patients most often present with mild diabetes mellitus, anemia, weight loss, glossitis, neuropsychiatric disturbances, and necrolytic migratory erythematous rash. Glucagonoma are predominantly found at the tail of the pancreas, but most often this type of tumor is diagnosed late and the tumor has most likely metastasized to other parts of the body such as the liver, spleen, and adrenal glands . Diagnosis is made through the elevated levels of plasma glucagon; elevated plasma glucagon levels must not be independent of renal failure and severe stress.
Mahvash Disease is defined as a disease presenting with alpha-cell hyperplasia, hyperglucagonemia, and pancreatic neuroendocrine tumors (PNETs), without presenting with glucagonoma syndrome (as reviewed by Yu et al. (2015)). In a study by Run Yu and others, research was conducted on Gcgr-deficient (Gcgr-/-) mice at different stages of life to study the development of islet dysplasia and the development of PNETs (as reviewed by Yu et al. (2015)). Results demonstrate that in the younger mice (2-3 months) islet cell hyperplasia was dominant with no evidence of dysplasia and PNETs. In middle aged mice (5-7 months), islet dysplasia was more evident. In older mice (10-12 months) PNETs and dysplastic background were both present (as reviewed by Yu et al. (2015)). This research also indicates that Mahvash Disease can affect both genders and that there isn’t a prevalence in one specific gender. However, older age is associated with a higher risk of Mahvash Disease.
Current research is unable to answer the implications and transition of dysplastic islet cells and its relation to PNETs and more significantly, tumorigenesis. Dysplastic islet cells largely consists of pancreatic alpha-cells and PNETs are largely classified as glucagonomas, suggesting PNETs are likely to have been a derivative of alpha cells (as reviewed by Yu et al. (2015)). Secondly, through observation, alpha cells had the capacity to differentiate into a hybrid of alpha and beta cell type which indicates the genomic and epigenomic instability. This research has also indicated that through the inhibition of glucagon signaling, it is not a viable treatment method for diabetes.
Role in Type 2 Diabetes
Pancreatic alpha cells are crucial for maintaining glucose levels, it will counteract hypoglycemia in a state of glucose deficiency (as reviewed by Moon and Won (2015) ). Also, in a normal state pancreatic alpha-cells are regulated by various mechanisms glycemia, neural input, and secretion from neighboring pancreatic beta-cells Dysfunctional pancreatic alpha-cells contributes to a number of different results: disruption of the glucose homeostasis and triggers the hyper secretion of insulin. Eventually leading up to the hallmark features of both type 1 and type 2 diabetes. Type 2 diabetes is known to be a "bihormonal" dysfunction, involving both pancreatic β-cell and α-cell dysfunction (as reviewed by Moon and Won (2015) ). However, the dysfunction and abnormality of pancreatic alpha cell role is overshadowed by the type 2 diabetes which is most often related to insulin and pancreatic beta-cell dysfunction.
After the consumption of food, carbohydrates are converted to glucose; elevating the blood glucose level. Then triggering the release of insulin and the suppression and control of glucagon secretion in the pancreas. Glucagon is secreted when blood glucose levels are low and is required to maintain a glucose homeostasis. However, in a Type 2 diabetic situation, despite having high blood glucose levels circulating, dysfunctional pancreatic alpha cells continuously secrete glucagon leading to an even higher blood glucose level. In addition, as glucagon signaling pathway plays a leading role in type II diabetes it is often a targeted as a potential treatment for diabetes. However, such action will potentially promote potential side-effects such as hyperglucagonemia and alpha-cell hyperplasia .
Treatment for Diabetes - Angptl4
As glucagon secretion by alpha-cell in the pancreas is associated with the increase in blood glucose level, pharmacological and genetic treatments for the inhibition of glucagon would assist in lowering blood glucose level. However, such treatment methods are found to result in compensatory increase in pancreatic alpha-cell mass and its hyper secretion. In one recent study conducted by Okamoto et al., they investigated angiopoietin-like protein 3 (Angptl4); this protein inhibits lipoprotein lipase-mediated plasma triglyceride clearance . In Angptl4-/- mice it was reported that the mice underwent elevation of glucagon levels as well as increase in alpha-cell mass. However the results indicated that an overexpression of Angptl14 does not disturb the plasma triglyceride metabolism and thus does not have an effect on alpha-cell in the pancreas. This research further demonstrated with an elevated plasma amino acid level and its transport, it has a direct relation to the blockage to alpha-cell hyperplasia .
Conversely, another research conducted in the same area concluded that treatments with Angptl4 increased alpha-cell proliferation by a large margin but did not contribute to glucagon hypersecretion . Such results indicate that glucagon secretion levels and alpha-cell proliferation can be considered independent of each other.
Treatment for Diabetes - GABA- induced alpha to beta-like cell conversion
Diabetes causes chronic hyperglycemia due to beta cell loss, both in type 1 and type 2 diabetes.  Whilst there are current treatment options for diabetes, studies into beta cell replacement via stem cells, precursor cells or differentiated cells, will provide alternative treatments. Ben-Othman et al., (2017) implemented the use of GABA as an inducer to create a beta-like cell from alpha cells. GABA is synthesised in beta cells as an extracellular signalling molecule to act on pancreatic islets.
The research found that there was GABA induced conversion of alpha to beta-like cells by downregulation of Arx expression via GABAA receptors on alpha cells, with compensatory alpha neogenesis. The duration of the GABA treatment had corresponding effects on beta-like cell hyperplasia; increased doses and duration increased hyperplasia. .
|Apoptosis||Regulated and controlled cell death|
|Cyclic AMP||A second messenger within cells that is a derivative of ATP in response to hormonal stimulation of cell-surface receptors; activating A-kinase helps cAMP to act as a signalling molecule.|
|Diabetes mellitus||Abnormally high blood glucose level caused by destruction or dysfunction of the beta cells of the pancreas or cellular resistance to insulin.|
|Dysplasia||Abnormal growth or development of a tissue. May precede the development of cancer.|
|Embryogenesis||The formation and development of an embryo.|
|Endocrine gland||A ductless gland produces the hormonal secretions that pass directly into the blood stream or lymph.|
|GABA||Gamma-aminobutyric acid is one of many neurotransmitters. GABA opens the channel that leads to the exit of positively charged potassium ions and more negative interior.|
|Glucagon||Pancreatic hormone that stimulates the catabolism of glycogen to glucose, in the result of this increasing blood glucose levels.|
|Hyperplasia||Increase in amount of tissue.|
|Hypoglycemia||when the blood sugar decreases to below normal levels.|
|Insulin||Pancreatic hormone that lifts the cellular uptake and utilization of glucose, thereby decreasing blood glucose levels.|
|Islets of Langerhans||the small endocrine secretory glands in pancreas that produce the hormones, which are insulin and glucose.|
|Kinases||Enzymes that using ATP to catalyze the phosphorylation of certain molecules.|
|Progenitor cells||Early descendants of stem cells that can differentiate to form one or more kinds of cells, but cannot divide and reproduce indefinitely.|
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