Beta cell
Details
LocationPancreatic islet
FunctionInsulin secretion
Identifiers
Latinendocrinocytus B; insulinocytus
THH3.04.02.0.00026
FMA85704
Anatomical terms of microanatomy
Human pancreatic islet by immunostaining. Nuclei of cells are shown in blue (DAPI). Beta cells are shown in green (Insulin), Delta cells are shown in white (Somatostatin).

Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin.[1] Constituting ~50–70% of cells in human islets, beta cells play a vital role in maintaining blood glucose levels.[2] Problems with beta cells can lead to disorders such as diabetes.[3]

Function

The function of beta cells is primarily centered around the synthesis and secretion of hormones, particularly insulin and amylin. Both hormones work to keep blood glucose levels within a narrow, healthy range by different mechanisms.[4] Insulin facilitates the uptake of glucose by cells, allowing them to use it for energy or store it for future use.[5] Amylin helps regulate the rate at which glucose enters the bloodstream after a meal, slowing down the absorption of nutrients by inhibit gastric emptying.[6]

Insulin synthesis

Beta cells are the only site of insulin synthesis in mammals.[7] As glucose stimulates insulin secretion, it simultaneously increases proinsulin biosynthesis through translational control and enhanced gene transcription.[4][8]

The insulin gene is first transcribed into mRNA and translated into preproinsulin.[4] After translation, the preproinsulin precursor contains an N-terminal signal peptide that allows translocation into the rough endoplasmic reticulum (RER).[9] Inside the RER, the signal peptide is cleaved to form proinsulin.[9] Then, folding of proinsulin occurs forming three disulfide bonds.[9] 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.[9] After maturation, these secretory vesicles hold insulin, C-peptide, and amylin until calcium triggers exocytosis of the granule contents.[4]

Through translational processing, insulin is encoded as a 110 amino acid precursor but is secreted as a 51 amino acid protein.[9]

Insulin secretion

A diagram of the Consensus Model of glucose-stimulated insulin secretion
The triggering pathway of glucose-stimulated insulin secretion

In beta cells, insulin release is stimulated primarily by glucose present in the blood.[4] As circulating glucose levels rise such as after ingesting a meal, insulin is secreted in a dose-dependent fashion.[4] This system of release is commonly referred to as glucose-stimulated insulin secretion (GSIS).[10] There are four key pieces to the triggering pathway 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.[11][12]

Voltage-gated calcium channels and ATP-sensitive potassium ion channels are embedded in the plasma membrane of beta cells.[12][13] These ATP-sensitive potassium ion channels are normally open and the calcium ion channels are normally closed.[4] 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).[4] At rest, this creates a potential difference across the cell surface membrane of -70mV.[14]

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.[15] Since beta cells use glucokinase to catalyze the first step of glycolysis, metabolism only occurs around physiological blood glucose levels and above.[4] Metabolism of the glucose produces ATP, which increases the ATP to ADP ratio.[16]

The ATP-sensitive potassium ion channels close when this ratio rises.[13] This means that potassium ions can no longer diffuse out of the cell.[17] As a result, the potential difference across the membrane becomes more positive (as potassium ions accumulate inside the cell).[14] 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.[14] 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.[18][19]

In addition to the triggering pathway, the amplifying pathway can cause increased insulin secretion without a further increase in intracellular calcium levels. The amplifying pathway is modulated by byproducts of glucose metabolism along with various intracellular signaling pathways.[11]

Other hormones secreted

Clinical significance

Beta cells have significant clinical relevance as their proper function is essential for glucose regulation, and dysfunction is a key factor in the development and progression of diabetes and its associated complications.[23] Here are some key clinical significances of beta cells:

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.[9] 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 leads to beta-cell destruction.[24] 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.[25] The body destroys 70–80% of beta cells, leaving only 20–30% of functioning cells.[2][26] This can cause the patient to experience hyperglycemia, which leads to other adverse short-term and long-term conditions.[27] The symptoms of diabetes can potentially be controlled with methods such as regular doses of insulin and sustaining a proper diet.[27] However, these methods can be tedious and cumbersome to continuously perform on a daily basis.[27]

Type 2 diabetes

Type 2 diabetes, also known as non insulin dependent diabetes and as chronic hyperglycemia, is caused primarily by genetics and the development of metabolic syndrome.[2][9] The beta cells can still secrete insulin but the body has developed a resistance and its response to insulin has declined.[4] 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.[28][29] In an effort to secrete enough insulin to overcome the increasing insulin resistance, the beta cells increase their function, size and number.[4] Increased insulin secretion leads to hyperinsulinemia, but blood glucose levels remain within their normal range due to the decreased efficacy of insulin signaling.[4] 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.[9] 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.[9]

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.[30]

Medications

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

Research

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.[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][33] 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[34] or alloxan,[35] 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.[36]

Type 1 diabetes

Research has shown that beta cells can be differentiated from human pancreas progenitor cells.[37] These differentiated beta cells, however, often lack much of the structure and markers that beta cells need to perform their necessary functions.[37] 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.[37]

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.[37][38] 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.[38] Targeted manipulation of these two pathways has shown that it is possible to induce beta cell differentiation from stem cells.[38] 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.[38]

Studies have shown that it is possible to regenerate beta cells in vivo in some animal models.[39] 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.[37] 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.[40]

It appears that much work has to be done in the field of regenerating beta cells.[38] 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 with 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.[2][4][9] Another topic of interest for beta-cell physiologists is the mechanism of insulin pulsatility which has been well investigated.[41][42] Many genome studies have been completed and are advancing the knowledge of beta-cell function exponentially.[43][44] Indeed, the area of beta-cell research is very active yet many mysteries remain.

See also

References

  1. ^ Dolenšek J, Rupnik MS, Stožer 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. S2CID 17908732.
  2. ^ 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.
  3. ^ Ashcroft FM, Rorsman P (March 2012). "Diabetes mellitus and the β cell: the last ten years". Cell. 148 (6): 1160–1171. doi:10.1016/j.cell.2012.02.010. PMC 5890906. PMID 22424227.
  4. ^ 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 β-cells". Molecular Metabolism. 6 (9): 958–973. doi:10.1016/j.molmet.2017.04.010. PMC 5605729. PMID 28951821.
  5. ^ Wilcox G (May 2005). "Insulin and insulin resistance". The Clinical Biochemist. Reviews. 26 (2): 19–39. PMC 1204764. PMID 16278749.
  6. ^ Westermark P, Andersson A, Westermark GT (July 2011). "Islet amyloid polypeptide, islet amyloid, and diabetes mellitus". Physiological Reviews. 91 (3): 795–826. doi:10.1152/physrev.00042.2009. PMID 21742788.
  7. ^ Boland BB, Brown C, Alarcon C, Demozay D, Grimsby JS, Rhodes CJ (February 2018). "β-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.
  8. ^ Andrali SS, Sampley ML, Vanderford NL, Ozcan S (October 2008). "Glucose regulation of insulin gene expression in pancreatic beta-cells". The Biochemical Journal. 415 (1): 1–10. doi:10.1042/BJ20081029. PMID 18778246.
  9. ^ 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.
  10. ^ Komatsu M, Takei M, Ishii H, Sato Y (November 2013). "Glucose-stimulated insulin secretion: A newer perspective". Journal of Diabetes Investigation. 4 (6): 511–516. doi:10.1111/jdi.12094. PMC 4020243. PMID 24843702.
  11. ^ a b Kalwat MA, Cobb MH (November 2017). "Mechanisms of the amplifying pathway of insulin secretion in the β cell". Pharmacology & Therapeutics. 179: 17–30. doi:10.1016/j.pharmthera.2017.05.003. PMC 7269041. PMID 28527919.
  12. ^ a b Ramadan JW, Steiner SR, O'Neill CM, Nunemaker CS (December 2011). "The central role of calcium in the effects of cytokines on beta-cell function: implications for type 1 and type 2 diabetes". Cell Calcium. 50 (6): 481–490. doi:10.1016/j.ceca.2011.08.005. PMC 3223281. PMID 21944825.
  13. ^ a b Ashcroft FM, Rorsman P (February 1990). "ATP-sensitive K+ channels: a link between B-cell metabolism and insulin secretion". Biochemical Society Transactions. 18 (1): 109–111. doi:10.1042/bst0180109. PMID 2185070.
  14. ^ a b c MacDonald PE, Joseph JW, Rorsman P (December 2005). "Glucose-sensing mechanisms in pancreatic beta-cells". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 360 (1464): 2211–2225. doi:10.1098/rstb.2005.1762. PMC 1569593. PMID 16321791.
  15. ^ De Vos A, Heimberg H, Quartier E, Huypens P, Bouwens L, Pipeleers D, Schuit F (November 1995). "Human and rat beta cells differ in glucose transporter but not in glucokinase gene expression". The Journal of Clinical Investigation. 96 (5): 2489–2495. doi:10.1172/JCI118308. PMC 185903. PMID 7593639.
  16. ^ Santulli G, Pagano G, Sardu C, Xie W, Reiken S, D'Ascia SL, et al. (May 2015). "Calcium release channel RyR2 regulates insulin release and glucose homeostasis". The Journal of Clinical Investigation. 125 (5): 1968–1978. doi:10.1172/JCI79273. PMC 4463204. PMID 25844899.
  17. ^ Keizer J, Magnus G (August 1989). "ATP-sensitive potassium channel and bursting in the pancreatic beta cell. A theoretical study". Biophysical Journal. 56 (2): 229–242. Bibcode:1989BpJ....56..229K. doi:10.1016/S0006-3495(89)82669-4. PMC 1280472. PMID 2673420.
  18. ^ Lang V, Light PE (2010). "The molecular mechanisms and pharmacotherapy of ATP-sensitive potassium channel gene mutations underlying neonatal diabetes". Pharmacogenomics and Personalized Medicine. 3: 145–161. doi:10.2147/PGPM.S6969. PMC 3513215. PMID 23226049.
  19. ^ Edgerton DS, Kraft G, Smith M, Farmer B, Williams PE, Coate KC, et al. (March 2017). "Insulin's direct hepatic effect explains the inhibition of glucose production caused by insulin secretion". JCI Insight. 2 (6): e91863. doi:10.1172/jci.insight.91863. PMC 5358484. PMID 28352665.
  20. ^ Ido Y, Vindigni A, Chang K, Stramm L, Chance R, Heath WF, et al. (July 1997). "Prevention of vascular and neural dysfunction in diabetic rats by C-peptide". Science. 277 (5325): 563–566. doi:10.1126/science.277.5325.563. PMID 9228006.
  21. ^ Hoogwerf BJ, Goetz FC (January 1983). "Urinary C-peptide: a simple measure of integrated insulin production with emphasis on the effects of body size, diet, and corticosteroids". The Journal of Clinical Endocrinology and Metabolism. 56 (1): 60–67. doi:10.1210/jcem-56-1-60. PMID 6336620.
  22. ^ Moore CX, Cooper GJ (August 1991). "Co-secretion of amylin and insulin from cultured islet beta-cells: modulation by nutrient secretagogues, islet hormones and hypoglycemic agents". Biochemical and Biophysical Research Communications. 179 (1): 1–9. doi:10.1016/0006-291X(91)91325-7. PMID 1679326.
  23. ^ Sakran N, Graham Y, Pintar T, Yang W, Kassir R, Willigendael EM, et al. (January 2022). "The many faces of diabetes. Is there a need for re-classification? A narrative review". BMC Endocrine Disorders. 22 (1): 9. doi:10.1186/s12902-021-00927-y. PMC 8740476. PMID 34991585.
  24. ^ Tomita T (August 2017). "Apoptosis of pancreatic β-cells in Type 1 diabetes". Bosnian Journal of Basic Medical Sciences. 17 (3): 183–193. doi:10.17305/bjbms.2017.1961. PMC 5581966. PMID 28368239.
  25. ^ Eizirik DL, Mandrup-Poulsen T (December 2001). "A choice of death--the signal-transduction of immune-mediated beta-cell apoptosis". Diabetologia. 44 (12): 2115–2133. doi:10.1007/s001250100021. PMID 11793013.
  26. ^ Butler AE, Galasso R, Meier JJ, Basu R, Rizza RA, Butler PC (November 2007). "Modestly increased beta cell apoptosis but no increased beta cell replication in recent-onset type 1 diabetic patients who died of diabetic ketoacidosis". Diabetologia. 50 (11): 2323–2331. doi:10.1007/s00125-007-0794-x. PMID 17805509.
  27. ^ a b c Ciechanowski PS, Katon WJ, Russo JE, Hirsch IB (July–August 2003). "The relationship of depressive symptoms to symptom reporting, self-care and glucose control in diabetes". General Hospital Psychiatry. 25 (4): 246–252. doi:10.1016/s0163-8343(03)00055-0. PMID 12850656.
  28. ^ "U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group". Diabetes. 44 (11): 1249–1258. November 1995. doi:10.2337/diabetes.44.11.1249. PMID 7589820.
  29. ^ Rudenski AS, Matthews DR, Levy JC, Turner RC (September 1991). "Understanding "insulin resistance": both glucose resistance and insulin resistance are required to model human diabetes". Metabolism. 40 (9): 908–917. doi:10.1016/0026-0495(91)90065-5. PMID 1895955.
  30. ^ Yu R, Nissen NN, Hendifar A, Tang L, Song YL, Chen YJ, Fan X (January 2017). "A Clinicopathological Study of Malignant Insulinoma in a Contemporary Series". Pancreas. 46 (1): 48–56. doi:10.1097/MPA.0000000000000718. PMID 27984486. S2CID 3723691.
  31. ^ Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S, et al. (September 2007). "Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus". Annals of Internal Medicine. 147 (6): 386–399. doi:10.7326/0003-4819-147-6-200709180-00178. PMID 17638715.
  32. ^ a b c d e Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. (June 2012). "Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)". Diabetologia. 55 (6): 1577–1596. doi:10.1007/s00125-012-2534-0. PMID 22526604.
  33. ^ Whitticar NB, Strahler EW, Rajan P, Kaya S, Nunemaker CS (2016-11-21). "An Automated Perifusion System for Modifying Cell Culture Conditions over Time". Biological Procedures Online. 18 (1): 19. doi:10.1186/s12575-016-0049-7. PMC 5117600. PMID 27895534.
  34. ^ Wang Z, Gleichmann H (January 1998). "GLUT2 in pancreatic islets: crucial target molecule in diabetes induced with multiple low doses of streptozotocin in mice". Diabetes. 47 (1): 50–56. doi:10.2337/diabetes.47.1.50. PMID 9421374.
  35. ^ 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". Anatomical Record. 298 (2): 396–407. doi:10.1002/ar.23052. hdl:10995/73117. PMID 25251897. S2CID 205412167.
  36. ^ King AJ (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. PMC 3417415. PMID 22352879.
  37. ^ a b c d e Afelik S, Rovira M (April 2017). "Pancreatic β-cell regeneration: Facultative or dedicated progenitors?". Molecular and Cellular Endocrinology. 445: 85–94. doi:10.1016/j.mce.2016.11.008. PMID 27838399. S2CID 21795162.
  38. ^ a b c d e Mahla RS (2016). "Stem Cells Applications in Regenerative Medicine and Disease Therapeutics". International Journal of Cell Biology. 2016 (7): 6940283. doi:10.1155/2016/6940283. PMC 4969512. PMID 27516776.
  39. ^ Jeon K, Lim H, Kim JH, Thuan NV, Park SH, Lim YM, et al. (September 2012). "Differentiation and transplantation of functional pancreatic beta cells generated from induced pluripotent stem cells derived from a type 1 diabetes mouse model". Stem Cells and Development. 21 (14): 2642–2655. doi:10.1089/scd.2011.0665. PMC 3438879. PMID 22512788.
  40. ^ Lam, Carol & Jacobson, Daniel & Rankin, Matthew & Cox, Aaron & Kushner, Jake. (2017). β Cells Persist in T1D Pancreata Without Evidence of Ongoing β-Cell Turnover or Neogenesis. The Journal of clinical endocrinology and metabolism. 102. 10.1210/jc.2016-3806.
  41. ^ Nunemaker CS, Bertram R, Sherman A, Tsaneva-Atanasova K, Daniel CR, Satin LS (September 2006). "Glucose modulates [Ca2+]i oscillations in pancreatic islets via ionic and glycolytic mechanisms". Biophysical Journal. 91 (6): 2082–2096. Bibcode:2006BpJ....91.2082N. doi:10.1529/biophysj.106.087296. PMC 1557567. PMID 16815907.
  42. ^ Bertram R, Sherman A, Satin LS (October 2007). "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. PMID 17666486.
  43. ^ Muraro MJ, Dharmadhikari G, Grün D, Groen N, Dielen T, Jansen E, et al. (October 2016). "A Single-Cell Transcriptome Atlas of the Human Pancreas". Cell Systems. 3 (4): 385–394.e3. doi:10.1016/j.cels.2016.09.002. PMC 5092539. PMID 27693023.
  44. ^ Segerstolpe Å, Palasantza A, Eliasson P, Andersson EM, Andréasson AC, Sun X, et al. (October 2016). "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. PMC 5069352. PMID 27667667.
Category