CoChat
Sign Up
Cited by 902Pancreatic function and diabetesDiabetes and associated disordersDiabetes Treatment and Management

Diabetes Mellitus and the β Cell: The Last Ten Years

Open access
Ashcroft, Frances M., Rorsman, Patrik·2012·Cell
DOI 10.1016/j.cell.2012.02.010PMC PMC5890906
Open this paper in CoChat — free accountOpen PDF

Abstract

Diabetes is a major global problem. During the past decade, the genetic basis of various monogenic forms of the disease, and their underlying molecular mechanisms, have been elucidated. Many genes that increase type 2 diabetes (T2DM) risk have also been identified, but how they do so remains enigmatic. Nevertheless, defective insulin secretion emerges as the main culprit in both monogenic and polygenic diabetes, with environmental and lifestyle factors, via obesity, accounting for the current dramatic increase in T2DM. There also have been significant advances in therapy, particularly for some monogenic disorders. We review here what ails the β cell and how its function may be restored.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.cell.2012.02.010

Cites

11 of 11 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Both defective insulin secretion and impaired insulin action in peripheral tissues contribute to T2DM, but the principal defect lies in the pancreatic β-cell.

    “It is now clear that although both defective insulin secretion and impaired insulin action in peripheral tissues contribute to T2DM, the principal defect lies in the pancreatic β-cell (reviewed in (30, 580)).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [30]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 74

  1. Bennett CL Christie J Ramsdell F Brunkow ME Ferguson PJ Whitesell L Kelly TE Saulsbury FT Chance PF Ochs HD The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3 Nat Genet 2001 27 20 21 11137993
  2. Bergman RN Minimal model: perspective from 2005 Horm Res 2005 64 Suppl 3 8 15 16439839
  3. Bonnefond A Froguel P Vaxillaire M The emerging genetics of type 2 diabetes Trends Mol Med 2010 16 407 416 20728409
  4. Butler AE Janson J Bonner-Weir S Ritzel R Rizza RA Butler PC Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes Diabetes 2003 52 102 110 12502499
  5. Clark A Nilsson MR Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes? Diabetologia 2004 47 157 169 14722650
  6. Clark RH McTaggart JS Webster R Mannikko R Iberl M Sim XL Rorsman P Glitsch M Beeson D Ashcroft FM Muscle dysfunction caused by a KATP channel mutation in neonatal diabetes is neuronal in origin Science 2010 329 458 461 20595581 PMC5890903
  7. Cnop M Hughes SJ Igoillo-Esteve M Hoppa MB Sayyed F van de Laar L Gunter JH de Koning EJ Walls GV Gray DW The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation Diabetologia 2010 53 321 330 19855953
  8. Collins SC Hoppa MB Walker JN Amisten S Abdulkader F Bengtsson M Fearnside J Ramracheya R Toye AA Zhang Q Progression of diet-induced diabetes in C57BL6J mice involves functional dissociation of Ca2(+) channels from secretory vesicles Diabetes 2010 59 1192 1201 20150285 PMC2857899
  9. Deacon CF Carr RD Holst JJ DPP-4 inhibitor therapy: new directions in the treatment of type 2 diabetes Front Biosci 2008 13 1780 1794 17981667
  10. Del Guerra S Lupi R Marselli L Masini M Bugliani M Sbrana S Torri S Pollera M Boggi U Mosca F Functional and molecular defects of pancreatic islets in human type 2 diabetes Diabetes 2005 54 727 735 15734849
  11. Delepine M Nicolino M Barrett T Golamaully M Lathrop GM Julier C EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome Nat Genet 2000 25 406 409 10932183
  12. Dukes ID Sreenan S Roe MW Levisetti M Zhou YP Ostrega D Bell GI Pontoglio M Yaniv M Philipson L Defective pancreatic beta-cell glycolytic signaling in hepatocyte nuclear factor-1alpha-deficient mice J Biol Chem 1998 273 24457 24464 9733737
  13. Eliasson L Ma X Renstrom E Barg S Berggren PO Galvanovskis J Gromada J Jing X Lundquist I Salehi A SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic B-cells J Gen Physiol 2003 121 181 197 12601083 PMC2217330
  14. Ellard S Flanagan SE Girard CA Patch AM Harries LW Parrish A Edghill EL Mackay DJ Proks P Shimomura K Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects Am J Hum Genet 2007 81 375 382 17668386 PMC1950816
  15. Falken Y Hellstrom PM Holst JJ Naslund E Changes in glucose homeostasis after Roux-en-Y gastric bypass surgery for obesity at day three, two months, and one year after surgery: role of gut peptides J Clin Endocrinol Metab 2011 96 2227 2235 21543426
  16. Flanagan SE Clauin S Bellanne-Chantelot C de Lonlay P Harries LW Gloyn AL Ellard S Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism Hum Mutat 2009 30 170 180 18767144
  17. Flanagan SE Patch AM Mackay DJ Edghill EL Gloyn AL Robinson D Shield JP Temple K Ellard S Hattersley AT Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood Diabetes 2007 56 1930 1937 17446535 PMC7611811
  18. Garin I Edghill EL Akerman I Rubio-Cabezas O Rica I Locke JM Maestro MA Alshaikh A Bundak R del Castillo G Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis Proc Natl Acad Sci U S A 107 3105 3110 PMC2840338 20133622
  19. Garin I Edghill EL Akerman I Rubio-Cabezas O Rica I Locke JM Maestro MA Alshaikh A Bundak R del Castillo G Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis Proc Natl Acad Sci U S A 2010 107 3105 3110 20133622 PMC2840338
  20. Girard CA Wunderlich FT Shimomura K Collins S Kaizik S Proks P Abdulkader F Clark A Ball V Zubcevic L Expression of an activating mutation in the gene encoding the KATP channel subunit Kir6.2 in mouse pancreatic beta cells recapitulates neonatal diabetes J Clin Invest 2009 119 80 90 19065048 PMC2613450
  21. Hattersley AT Ashcroft FM Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy Diabetes 2005 54 2503 2513 16123337
  22. Holst JJ The physiology of glucagon-like peptide 1 Physiol Rev 2007 87 1409 1439 17928588
  23. Hoppa MB Collins S Ramracheya R Hodson L Amisten S Zhang Q Johnson P Ashcroft FM Rorsman P Chronic palmitate exposure inhibits insulin secretion by dissociation of Ca(2+) channels from secretory granules Cell Metab 2009 10 455 465 19945403 PMC2814048
  24. Hosker JP Rudenski AS Burnett MA Matthews DR Turner RC Similar reduction of first- and second-phase B-cell responses at three different glucose levels in type II diabetes and the effect of gliclazide therapy Metabolism 1989 38 767 772 2668699
  25. Iafusco D Bizzarri C Cadario F Pesavento R Tonini G Tumini S Cauvin V Colombo C Bonfanti R Barbetti F No beta cell desensitisation after a median of 68 months on glibenclamide therapy in patients with KCNJ11-associated permanent neonatal diabetes Diabetologia 2011 54 2736 2738 21822789
  26. Isbell JM Tamboli RA Hansen EN Saliba J Dunn JP Phillips SE Marks-Shulman PA Abumrad NN The importance of caloric restriction in the early improvements in insulin sensitivity after Roux-en-Y gastric bypass surgery Diabetes Care 2010 33 1438 1442 20368410 PMC2890335
  27. Karra E Yousseif A Batterham RL Mechanisms facilitating weight loss and resolution of type 2 diabetes following bariatric surgery Trends Endocrinol Metab 2010 21 337 344 20133150
  28. Kashyap S Belfort R Gastaldelli A Pratipanawatr T Berria R Pratipanawatr W Bajaj M Mandarino L DeFronzo R Cusi K A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes Diabetes 2003 52 2461 2474 14514628
  29. Kebede MA Alquier T Latour MG Poitout V Lipid receptors and islet function: therapeutic implications? Diabetes Obes Metab 2009 11 Suppl 4 10 20 PMC2889915 19817784
  30. Kirkpatrick CL Marchetti P Purrello F Piro S Bugliani M Bosco D de Koning EJ Engelse MA Kerr-Conte J Pattou F Type 2 diabetes susceptibility gene expression in normal or diabetic sorted human alpha and beta cells: correlations with age or BMI of islet donors PLoS ONE 2010 5 e11053 20548773 PMC2883550
  31. Kohler CU Olewinski M Tannapfel A Schmidt WE Fritsch H Meier JJ Cell cycle control of beta-cell replication in the prenatal and postnatal human pancreas Am J Physiol Endocrinol Metab 2011 300 E221 230 20978233
  32. Kulenovic I Robertson A Grujic M Suljevic E Smajkic A The impact of war on Sarajevans with non-insulin-dependent diabetes mellitus European Journal of Public Health 1996 6 252 258
  33. Lee Y Hirose H Ohneda M Johnson JH McGarry JD Unger RH Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships Proc Natl Acad Sci U S A 1994 91 10878 10882 7971976 PMC45129
  34. Leech CA Dzhura I Chepurny OG Kang G Schwede F Genieser HG Holz GG Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic beta cells Prog Biophys Mol Biol 2011 107 236 247 21782840 PMC3200499
  35. Lemaire K Ravier MA Schraenen A Creemers JW Van de Plas R Granvik M Van Lommel L Waelkens E Chimienti F Rutter GA Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice Proc Natl Acad Sci U S A 2009 106 14872 14877 19706465 PMC2736467
  36. Lyssenko V Lupi R Marchetti P Del Guerra S Orho-Melander M Almgren P Sjogren M Ling C Eriksson KF Lethagen AL Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes J Clin Invest 2007 117 2155 2163 17671651 PMC1934596
  37. Ma D Shield JP Dean W Leclerc I Knauf C Burcelin RR Rutter GA Kelsey G Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM J Clin Invest 2004 114 339 348 15286800 PMC484972
  38. Maechler P Wollheim CB Mitochondrial function in normal and diabetic beta-cells Nature 2001 414 807 812 11742413
  39. Mandrup-Poulsen T Pickersgill L Donath MY Blockade of interleukin 1 in type 1 diabetes mellitus Nat Rev Endocrinol 2010 6 158 166 20173777
  40. Matschinsky FM Assessing the potential of glucokinase activators in diabetes therapy Nat Rev Drug Discov 2009 8 399 416 19373249
  41. McCarthy MI Genomics, type 2 diabetes, and obesity N Engl J Med 2010 363 2339 2350 21142536
  42. McTaggart JS Clark RH Ashcroft FM The role of the KATP channel in glucose homeostasis in health and disease: more than meets the islet J Physiol 2010 588 3201 3209 20519313 PMC2976015
  43. Mlynarski W Tarasov AI Gach A Girard CA Pietrzak I Zubcevic L Kusmierek J Klupa T Malecki MT Ashcroft FM Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11 Nat Clin Pract Neurol 2007 3 640 645 17982434
  44. Njolstad PR Sovik O Cuesta-Munoz A Bjorkhaug L Massa O Barbetti F Undlien DE Shiota C Magnuson MA Molven A Neonatal diabetes mellitus due to complete glucokinase deficiency N Engl J Med 2001 344 1588 1592 11372010
  45. Osbak KK Colclough K Saint-Martin C Beer NL Bellanne-Chantelot C Ellard S Gloyn AL Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia Hum Mutat 2009 30 1512 1526 19790256
  46. Parnaud G Bosco D Berney T Pattou F Kerr-Conte J Donath MY Bruun C Mandrup-Poulsen T Billestrup N Halban PA Proliferation of sorted human and rat beta cells Diabetologia 2008 51 91 100 17994216
  47. Pearson ER Flechtner I Njolstad PR Malecki MT Flanagan SE Larkin B Ashcroft FM Klimes I Codner E Iotova V Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations N Engl J Med 2006 355 467 477 16885550
  48. Pearson ER Starkey BJ Powell RJ Gribble FM Clark PM Hattersley AT Genetic cause of hyperglycaemia and response to treatment in diabetes Lancet 2003 362 1275 1281 14575972
  49. Pinnick KE Collins SC Londos C Gauguier D Clark A Fielding BA Pancreatic ectopic fat is characterized by adipocyte infiltration and altered lipid composition Obesity (Silver Spring) 2008 16 522 530 18239594
  50. Rahier J Guiot Y Goebbels RM Sempoux C Henquin JC Pancreatic beta-cell mass in European subjects with type 2 diabetes Diabetes Obes Metab 2008 10 Suppl 4 32 42 18834431
  51. Rorsman P Renstrom E Insulin granule dynamics in pancreatic beta cells Diabetologia 2003 46 1029 1045 12879249
  52. Rosengren AH Jokubka R Tojjar D Granhall C Hansson O Li DQ Nagaraj V Reinbothe TM Tuncel J Eliasson L Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes Science 2010 327 217 220 19965390
  53. Rubio-Cabezas O Flanagan SE Damhuis A Hattersley AT Ellard S K(ATP) channel mutations in infants with permanent diabetes diagnosed after 6 months of life Pediatr Diabetes 2011 21981029
  54. Sellick GS Barker KT Stolte-Dijkstra I Fleischmann C Coleman RJ Garrett C Gloyn AL Edghill EL Hattersley AT Wellauer PK Mutations in PTF1A cause pancreatic and cerebellar agenesis Nat Genet 2004 36 1301 1305 15543146
  55. Senee V Chelala C Duchatelet S Feng D Blanc H Cossec JC Charon C Nicolino M Boileau P Cavener DR Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism Nat Genet 2006 38 682 687 16715098
  56. Servitja JM Ferrer J Transcriptional networks controlling pancreatic development and beta cell function Diabetologia 2004 47 597 613 15298336
  57. Shu L Sauter NS Schulthess FT Matveyenko AV Oberholzer J Maedler K Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets Diabetes 2008 57 645 653 18071026
  58. Slingerland AS Nuboer R Hadders-Algra M Hattersley AT Bruining GJ Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene Diabetologia 2006 49 2559 2563 17047922
  59. Smith SB Qu HQ Taleb N Kishimoto NY Scheel DW Lu Y Patch AM Grabs R Wang J Lynn FC Rfx6 directs islet formation and insulin production in mice and humans Nature 2010 463 775 780 20148032 PMC2896718
  60. Stefanovski D Richey JM Woolcott O Lottati M Zheng D Harrison LN Ionut V Kim SP Hsu I Bergman RN Consistency of the disposition index in the face of diet induced insulin resistance: potential role of FFA PLoS ONE 2011 6 e18134 21479217 PMC3068147
  61. Stoffers DA Zinkin NT Stanojevic V Clarke WL Habener JF Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence Nat Genet 1997 15 106 110 8988180
  62. Stoy J Edghill EL Flanagan SE Ye H Paz VP Pluzhnikov A Below JE Hayes MG Cox NJ Lipkind GM Insulin gene mutations as a cause of permanent neonatal diabetes Proc Natl Acad Sci U S A 2007 104 15040 15044 17855560 PMC1986609
  63. Stoy J Steiner DF Park SY Ye H Philipson LH Bell GI Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene Rev Endocr Metab Disord 2010 11 205 215 20938745 PMC2974937
  64. Takahashi N Hatakeyama H Okado H Noguchi J Ohno M Kasai H SNARE conformational changes that prepare vesicles for exocytosis Cell Metab 2010 12 19 29 20620992
  65. Temple IK Shield JP 6q24 transient neonatal diabetes Rev Endocr Metab Disord 2010 11 199 204 20922569
  66. Turkkahraman D Bircan I Tribble ND Akcurin S Ellard S Gloyn AL Permanent neonatal diabetes mellitus caused by a novel homozygous (T168A) glucokinase (GCK) mutation: initial response to oral sulphonylurea therapy J Pediatr 2008 153 122 126 18571549
  67. Tushuizen ME Bunck MC Pouwels PJ Bontemps S van Waesberghe JH Schindhelm RK Mari A Heine RJ Diamant M Pancreatic fat content and beta-cell function in men with and without type 2 diabetes Diabetes Care 2007 30 2916 2921 17666465
  68. Wang J Takeuchi T Tanaka S Kubo SK Kayo T Lu D Takata K Koizumi A Izumi T A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse J Clin Invest 1999 103 27 37 9884331 PMC407861
  69. Xu G Stoffers DA Habener JF Bonner-Weir S Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats Diabetes 1999 48 2270 2276 10580413
  70. Yaney GC Corkey BE Fatty acid metabolism and insulin secretion in pancreatic beta cells Diabetologia 2003 46 1297 1312 13680127
  71. Yasuda K Miyake K Horikawa Y Hara K Osawa H Furuta H Hirota Y Mori H Jonsson A Sato Y Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus Nat Genet 2008 40 1092 1097 18711367
  72. Yoo HW Shin YL Seo EJ Kim GH Identification of a novel mutation in the GLUT2 gene in a patient with Fanconi-Bickel syndrome presenting with neonatal diabetes mellitus and galactosaemia Eur J Pediatr 2002 161 351 353 12029458
  73. Zhang CL Katoh M Shibasaki T Minami K Sunaga Y Takahashi H Yokoi N Iwasaki M Miki T Seino S The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs Science 2009 325 607 610 19644119
  74. Zung A Glaser B Nimri R Zadik Z Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2 J Clin Endocrinol Metab 2004 89 5504 5507 15531505

Cited by

Sorted by citations

Authors
Ashcroft, F. M., & Rorsman, P.
Affiliations
  • University of Oxford (GB)
  • Churchill Hospital (GB)
Corresponding author
Ashcroft, Frances M.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2012-03
Volume
148
Issue
6
Pages
1160-1171
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2012.02.010
PMC
PMC5890906
OpenAlex
W2025447674
Cited by
902
References
11
Citations by year
2026: 38 · 2025: 41 · 2024: 54 · 2023: 51 · 2022: 58 · 2021: 77 · 2020: 65 · 2019: 66 · 2018: 81 · 2017: 71 · 2016: 61 · 2015: 65 · 2014: 78 · 2013: 67 · 2012: 29
FWCI
14.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Wellcome Trust (084655, 095531/Z/11/Z, 095531)
  • Diabetes UK
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
diabetes mellitus, pancreatic beta cells, type 2 diabetes, monogenic diabetes, insulin secretion, risk genes, obesity, beta-cell dysfunction, diabetes treatment
MeSH terms
Animals, Diabetes Mellitus, Diabetes Mellitus, Type 2, Diet, Humans, Insulin-Secreting Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review