The endocrine cells of the pancreas are grouped in the islets of Langerhans. Discovered in 1869 by the German pathological anatomist Paul Langerhans, the islets of Langerhans constitute approximately 1 to 2% of the mass of the pancreas. There are about one million islets in a healthy adult human pancreas, which are interspersed evenly throughout the organ, and their combined weight is 1 to 1.5 grams. Each islet contains approximately one thousand cells and is 50-500 um in diameter.

Hormones produced in the Islets of Langerhans are secreted directly into the blood flow by (at least) four different types of cells:

• Beta cells producing Insulin and Amylin (65-80% of the islet cells)
• Alpha cells releasing Glucagon (15-20%)
• Delta cells producing Somatostatin (3-10%)
• PP cells containing polypeptide (1%)

Islets can influence each other through paracrine and autocrine communication, and beta-cells are coupled electrically to beta-cells (but not to other cell-types).

7B2

• a possible marker for nonfunctioning pancreatic islet cell tumor. PMID: 1662184, PMID: 1466150
• secreted by both A- and B-cells of the hamster pancreatic islets and its secretion is regulated under certain conditions. PMID: 1811274
• originally isolated from pituitary, has been shown to be present in endocrine tumors of high concentrations in pancreatic islet tumors. PMID: 2512184, PMID: 3342519
• The high incidence of elevated IR-7B2 concentrations in pancreatic islet tumors and the increase in IR-7B2 concentrations in the term pancreas and particularly in nesidioblastosis suggest that the novel protein 7B2 may serve as an islet marker. PMID: 2822517
• 7B2 immunoreactivity is produced by a variety of different tumors and may serve as a tumor marker, especially in patients with certain pancreatic islet tumors. PMID: 3525602

Adenylylcyclase

• can be used as a marker to assess islet cell viability as well as differences in preservation media and may predict islet cell transplant success. PMID: 10478718, PMID: 10218770

Amylase

• measurement of amylase levels after pancreas preservation may have potential clinical application as a marker to evaluate pancreatic tissue injury. PMID: 14529937

Beta-2/NeuroD

• a key regulator of pancreatic islet morphogenesis and insulin gene transcription. PMID: 10633878
• expressed in both alpha- and beta-cells. PMID: 8799146
• expressed in endocrine cells during pancreas development and is essential for proper islet morphogenesis, and is pancreatic islet-specific marker. PMID: 10757813
• a basic helix-loop-helix transcription factor, is a key regulator of pancreatic islet morphogenesis and insulin gene transcription. PMID: 16186386
• a member of a helix-loop-helix (HLH) family that is specifically expressed in the endocrine pancreas. PMID: 12861411

CGRP (Calcitonin gene-related peptide)

• CGRP-containing cells were found primarily in the peripheral portion of the pancreatic islets. In addition, CGRP-containing cells also contained somatostatin, which identifies the islet CGRP-containing cells as D cells. PMID: 2896352

Chromogranin A/B

• In porcine pancreas at early fetal stage, CgA was visualized throughout the immature granules in all neuroendocrine cells. Later, CgB also was expressed with the same pattern in most granules in all types of cells. In neonatal islets, CgA was localized in the periphery of immature alpha- and beta-cell granules and throughout the matrix of delta-cell granules; CgB was distributed throughout the matrix of these granules. In adult islets, alpha-cell granules stored CgA in the halo and CgB in both the core and the halo, beta-cell granules stored both CgA and CgB in their cores, and in delta-cell granules, both substances were mixed throughout the matrix. PMID: 12826904
• CgA molecule is cleaved in different ways in the various pancreatic endocrine cell types, giving rise to a variety of biologically functional fragments. PMID: 11259451
• Chromogranin A is a useful immunohistochemical marker for pancreatic tumors of neuroendocrine origin and their metastases. PMID: 9185968
• At the light microscopic level, CGA-like immunoreactivity was found in the same cells that react with antibodies against insulin, glucagon, and somatostatin. PMID: 2878021

C-reactive protein (CRP)

• a very early marker for islet stress in the rat pancreas. PMID: 9704587

FoxA1

• a novel function for Foxa1 in the regulation of oxidative phosphorylation in pancreatic beta-cells. PMID: 17003337

FoxA3

• a member of the proglucagon gene G2 element binding-protein family that, unlike Foxa1, is not essential for control of islet or intestinal proglucagon gene expression in vivo. PMID: 12000309

GAD (glutamic acid decarboxylase)

• has been identified as one of the major auto-antigens expressed in islet cells, and used as a targeting moiety for islet cell targeting. PMID: 16139384

GAD65/GAD67

• GAD65 was primarily detected in rat pancreatic islet beta-cells, whereas alpha-cells had weak GAD65 staining. In contrast, GAD67 was detected primarily in alpha-cells. PMID: 7822765

Gdf11

• expressed in embryonic pancreatic epithelium during formation of islet progenitor cells that express neurogenin 3, and regulates the production and maturation of islet progenitor cells in pancreas development. PMID: 15548585

GLP-1 (Glucagon-like peptide)

• a gut hormone that stimulates insulin secretion, gene expression, and beta-cell growth. PMID: 15561911
• a growth factor for pancreatic cells and it is a regulator of islet cell mass. PMID: 15289644
• a growth factor for pancreatic endocrine cells and can increase islet cell mass. PMID: 12673779
• a differentiation factor for pancreatic ductal cells and that its effect requires the expression of IDX-1. PMID: 11289043
• enhances beta-cell neogenesis and islet size. Thus, in addition to stimulating insulin secretion, GLP-1 stimulates the expression of the transcription factor IDX-1 while stimulating beta-cell neogenesis and may thereby be an effective treatment for diabetes. PMID: 10905482

Glucagon

• In the native rat pancreas glucagon is expressed by alpha cells in the outer layer of the spheroid islet, producing a circular immunohistochemical staining pattern. PMID: 16298637
• expressed in A cells of the pancreatic islets due to an interaction between multiple regulatory elements within the 5'-flanking region of its gene directing glucagon gene transcription. PMID: 9088537
• chicken pancreatic islet A cells contain glucagon, serotonin, and aromatic L-amino acid decarboxylase, an enzyme involved in the synthesis of serotonin. PMID: 2404608
• a peptide hormone which regulates hepatic carbohydrate metabolism, is processed from a larger precursor, proglucagon. The gene encoding proglucagon is expressed at high levels in the A cells of the pancreatic islets and the L cells of the intestine, indicating that specific factors present in these two phenotypically distinct cells direct cell-specific expression. PMID: 3316202
• glucagon gene is expressed in both pancreatic islets and neuroendocrine L-cells of the gastrointestinal tract. PMID: 2879843

GLUT1/GLUT3 mRNA (Glucose Transporter 1, 3)

• expressed in all human islet cell tumors and normal islets examined. In contrast, GLUT2 mRNA, which is present at high levels in normal islets, was not detected in insulinomas or other types of islet cell tumors. These results imply that GLUT1 and GLUT3 are primarily responsible for glucose uptake by these tumors. PMID: 8421107

GLUT-2 (Glucose Transporter 2)

• specifically localized immunocytochemV cally in beta-islet cells. PMID: 12114701
• an essential component of the glucose-sensing mechanism of the pancreatic beta-cell. PMID: 9451476
• the only detectable transporter isoform in normal islets. PMID: 1489658
• mainly expressed in the hepatocytes of the liver and the beta-cells of the pancreatic islets. PMID: 1683793

GLUT-4 (Glucose transporter 4)

• is present in human and rat pancreatic islets and may suggest its specific role in glucose homeostasis in conjunction with IRAP/P-LAP. PMID: 14751249

hCG (human chorionic gonadotropin)

• hCG and its subunits are prevalent and specific markers for islet-cell carcinoma, and suggest that ectopic secretion results from malignant derepression of the genome rather than overproduction by an aberrant "cell rest." PMID: 196194

IA2/ICA512

• the precursor of the islet 40- and 37-kDa polypeptide autoantigens and as one of the ICA specificities. PMID: 7594559
• a novel autoantigen of type 1 diabetes. PMID: 9024221

IAPP/Amylin (Islet amyloid polypeptide)

• a normal secretory product of the beta cells, is synthesized in the islets of Langerhans. PMID: 7771063, PMID: 1618637
• a novel peptide recently isolated from the amyloid substance of pancreatic islets, has been localized in normal islet B cell granules, suggesting its physiological action in exocrine pancreatic function. PMID: 1724710
• co-stored with insulin in secretory granules of pancreatic islet beta-cells. PMID: 14565847
• an increased beta cell storage of IAPP independent of insulin may be an important factor in the early phase of the development of islet amyloid in this form of diabetes. PMID: 10036583
• the protein component of amyloid deposits commonly seen in pancreatic islets of patients with type 2 diabetes mellitus. PMID: 9281227
• may be useful as an additional marker for neuroendocrine tumour growth in selected cases. PMID: 7754100
• a novel peptide which was extracted from islet amyloid deposits in patients with non-insulin-dependent diabetes mellitus (NIDDM). PMID: 1541240, PMID: 1541234
• originally identified by chemical analysis of the amyloid component in a human pancreatic islet cell tumor, can be used as a tumor marker in pancreatic islet cell tumors and that high plasma levels of IAPP can inhibit glucose stimulated insulin secretion. PMID: 1854502
• a pancreatic islet hormone which was first found in amyloid in insulinomas and in pancreases of patients with type 2 diabetes. PMID: 2223885
• a 37-amino-acid putative hormone which is expressed by islet B-cells and most probably is co-released with insulin. PMID: 2691219
• more widely distributed within the pancreatic islet cell types than are any of the other islet hormones. PMID: 8940352
• a secretory product of the pancreatic beta-cell, which is the primary constituent of the islet amyloid that develops in type II diabetes. PMID: 7958499

ICA (Islet cell antibodies)

• the classical autoimmunity marker for insulin-dependent diabetes mellitus (IDDM). PMID: 9439455
• present in all Japanese Type 1 diabetic patients whose diabetic manifestations are less than 0.5 years duration from onset. PMID: 3527837
• important markers for two subtypes of insulin-dependent diabetes mellitus and stain the entire islet in the standard immunofluorescence test. PMID: 81509

IGRP

• selectively expressed in islet beta cells and is a major autoantigen in a mouse model of type I diabetes. PMID: 15180990

INGAP (islet neogenesis-associated protein)

• participates in the regulation of islet neogenesis. PMID: 12740013
• INGAP-PP enhances specifically the secretion of insulin and the transcription of several islet genes, many of them directly or indirectly involved in the control of islet metabolism, beta-cell mass and islet neogenesis. These results, together with other previously reported, strongly indicate an important role of INGAP-PP, and possibly of INGAP, in the regulation of islet function and development. PMID: 16764950
• INGAP gene is a novel pancreatic gene expressed during islet neogenesis whose protein product is a constituent of Ilotropin and is capable of initiating duct cell proliferation, a prerequisite for islet neogenesis. PMID: 9151782

Insulin

• is both a hormone regulating energy metabolism and a growth factor, and can act as a master regulator of islet survival by regulating Pdx1. PMID: 17158802
• can stimulate islet beta-cell replication directly, possibly through a receptor for MSA or another insulin-like growth factor. PMID: 6759233

IPF1 (Insulin promoter factor 1)

• a member of the homeodomain protein family, serves an early role in pancreas formation. In adults, IPF1 expression is restricted to the beta-cells in the islets of Langerhans. PMID: 8799146

Islet-1

• one of the earliest markers for motor neuron differentiation, is also expressed in all classes of islet cells in the pancreas. PMID: 14664703

MafB

• plays a previously uncharacterized role by regulating transcription of key factors during development that are required for the production of mature alpha and beta cells. PMID: 17360442
• the adult pancreas, MafB is only expressed in islet alpha-cells and contributes to cell type-specific expression of the glucagon gene through activation of a conserved control element found between nucleotides -77 to -51. MafB was also shown to be expressed in developing alpha- and beta-cells as well as in proliferating hormone-negative cells during pancreatogenesis. These results indicate that MafB is not only important to islet alpha-cell function but may also be involved in regulating genes required in both endocrine alpha- and beta-cell differentiation. PMID: 16443760

Nestin

• may not be a suitable marker solely for the identification of endocrine precursor cells in the pancreas. PMID: 14765974
• expanded nestin-expressing cells in vitro from islet-derived epithelial monolayers are heterogeneous; clonal analysis of nestin-positive cells reveals that a distinct subpopulation of nestin/PDX-1-expressing cells is capable of forming insulin-producing cells. PMID: 15684341
• at least in vitro, nestin-positive cells may undergo the early stages of differentiation to an islet cell phenotype and that long-term cultures of nestin-positive human islet cells may be considered as a potential source of precursor cells to generate fully differentiated/ functional beta cells. PMID: 15590972
• c-Kit- and nestin-expressing cells represent endocrine precursor cells that undergo marked changes in population dynamics during the transition from prenatal to postnatal pancreatic development in the rat. PMID: 15042705
• nestin-positive cells play an important role in the growth and maintenance of the islet. PMID: 14514633

Neurogenin 3 (Ngn3)

• controls endocrine cell fate specification in uncommitted pancreatic progenitor cells, is a marker of islet precursor cells. PMID: 15297605, PMID: 11973276

Neuropeptide Y (NPY)

• known to occur in the autonomic nervous system, including the pancreatic islet innervation, is also expressed in endocrine islet cells in hamster pancreas. PMID: 7644704

Neuropilin-2

• a novel marker expressed in pancreatic islet cells and endocrine pancreatic tumours. PMID: 12210066

NKX6.1

• play roles in suppression of glucagon expression and control of GSIS in islet beta cells. PMID: 15883383

NSE (neuron-specific enolase)

• a good marker for islet cell tumor, and is valuable for examining islets in pancreas with various disorders both alone and in combination with other tumor markers. PMID: 3015709
• serum NSE levels can aid in the diagnosis and monitoring of the course of nonfunctining islet cell carcinoma. PMID: 6295198

Pancreatic Polypeptide

• a useful plasma marker for radiographically evident pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1. PMID: 9426414
• presence of a markedly elevated fasting plasma human pancreatic polypeptide (hPP) level in patients with MEN 1 is 95% sensitive and 88% specific for the presence of radiographically detectable pancreatic islet cell tumors. PMID: 9426414
• A small population of pancreatic islet cells showed strong immunofluorescence after staining with anti-HPP serum. PMID: 1091353

Pax4

• the mouse Pax-4 gene is expressed in pancreatic islets, cultured islet beta cell lines of MIN6, beta TC, and NIT-1 cells, but not detectable in any of 13 adult mouse organs examined. PMID: 9439631

Pax6

• Pax-6 protein(s) expressed in adult pancreatic islets function differently from the ones in the eye and cerebellum. PMID: 10319322
• a key regulator of pancreatic islet hormone gene transcription and is required for normal islet development. PMID: 9224716

PDX-1 (Pancreatic duodenal homeobox factor-1)

• normally mediate pancreatic development are capable of inducing hepatic progenitor cells to differentiate into cells with pancreatic islet characteristics. PMID: 17239820
• highly enriched in beta and delta cells. PMID: 9115263
• exogenous expression of Pdx-1 should provide a promising approach for efficiently producing islet-like cells from BMSCs for the future therapeutic use in diabetic patients. PMID: 17172056
• regulates transcription of genes involved in islet beta cell function and pancreas development. PMID: 16147997
• a transcription factor required for normal pancreatic development, also plays a key role in normal insulin secretion by islets. PMID: 15562255
• a critical regulator of beta cell replication and is required for the compensatory response to insulin resistance. PMID: 15372107
• also known as IDX-1/STF-1/IPF1, a homeodomain-containing transcription factor, plays a central role in regulating pancreatic development and insulin gene transcription. PMID: 12829640
• required for pancreas development, islet cell differentiation, and the maintenance of beta cell function. PMID: 12551916

PEK

• only detected in human pancreatic islets, and co-localized with somatostatin, a pancreatic delta cell-specific hormone. Thus PEK is believed to play an important role in regulating protein synthesis in the pancreatic islet, especially in islet delta cells. PMID: 10026192

Rel B

• an early marker of autoimmune islet inflammation in the biobreeding (BB) rat. PMID: 10630383

Somatostatin/Receptors

• a pancreatic delta cell-specific hormone. PMID: 10026192
• a peptide synthesized in the pancreatic islets, nervous system, gastrointestinal tract, and thyroid gland. PMID: 2566613
• a novel ionic mechanism involved in somatostatin-inhibition of glucagon-secretion from pancreatic alpha cells. PMID: 10050772
• Although there is no absolute specificity of any SSTR for an islet cell type, SSTR1 is beta-cell selective, and SSTR2 is alpha-cell selective. SSTR5 is well expressed in beta-cells and delta-cells and moderately well expressed in alpha-cells, and thereby it lacks the islet cell selectivity displayed by SSTR1 and SSTR2. PMID: 9892225
• chicken islet D-cells contain only SST-14-like peptide, but not SST-28-like peptide, and that this phenomenon may be common to the avian species. PMID: 8760862

STF-1 (somatostatin transactivating factor-1)

• a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells. PMID: 7505393

Synaptophysin

• In all ontogenetic stages, synaptophysin was demonstrated in all pancreatic islet cell types and granules. PMID: 12826904

Tyrosine Hydroxylase

• co-expressed with islet hormones in the fetal mouse pancreas. In the adult animal, the enzyme has been considered as a marker of ageing beta-cells. PMID: 11813861

Other Islet Cell Markers

• Trypan Blue as a marker of plasma membrane permeability in alloxan-treated mouse islet cells. PMID: 226577