Islet and stem cell transplantation for treating diabetesBMJ 2001; 322 doi: https://doi.org/10.1136/bmj.322.7277.29 (Published 06 January 2001) Cite this as: BMJ 2001;322:29
Table w1 Vertebral fractures at 36 months in postmenopausal women with osteoporosis28
Fracture rate (%)
% reduction in relative risk (95% CI)
No needed to treat (95% CI)
³75 years of age
38 (5 to 59)
15 (8 to 21)
1 baseline fracture
42 [44?](14 to 61)
28 (16 to 97)
³2 baseline fractures
48 (27 to 63)
8 (6 to 16)
50 (31 to 64)
13 (9 to 23)
No postmenopausal fractures
43 [42?] (13 to 63)
20 (11 to 79)
[Q to A Please check queried numbers]
- Appendix: Origin of pancreatic endocrine cells
Pancreatic endocrine cells were for some years believed to be derived from the neural crest.w1 This idea has now been firmly refuted, and pancreatic cells, as well as other gut endocrine cells, are now known to be endodermally derived.w2 The β cells are widely believed to develop through common pluripotent precursors expressing both insulin and glucagon.w3 w4 However, this notion has been contradicted by several recent experiments.w5-w8 Pancreatic endocrine precursor cells have now been identified as pancreatic epithelial cells that express neurogenin 3, a basic "helix-loop-helix" transcription factor. Targeted disruption of the neurogenin 3 gene in mice results in the complete absence of endocrine cells because of the elimination of the precursor cells without affecting the exocrine pancreas.w8 Furthermore, recent data clearly show that the α and β cells develop independently from the precursor cells.w7 w9
A molecular mechanism has been identified that governs the choice between proliferation and differentiation of the endocrine precursor cells.w6 w10 This so called Delta-Notch pathway specifies, through a process of lateral inhibition, which cells among an equipotent field of precursor cells are to differentiate (fig A). A cell that expresses high levels of neurogenin 3 is destined to differentiate, and neurogenin 3 will induce expression of the Delta in that cell. Delta activates the transmembrane receptor Notch in neighbouring cells, which results in inhibition of their differentiation. This process ensures that only a few cells differentiate at any given time while the remaining cells continue to proliferate, maintaining a sufficient number of precursors.w2 w6 w10
(F1) Fig A Model of "Delta" mediated inhibition of differentiation of pancreatic endocrine precursor cell (lateral inhibition) via the "Notch" signalling pathway. Pancreatic epithelium is composed of endocrine and exocrine precursors marked by expression of neurogenin 3 and p48, respectively. An as yet unknown mechanism or perhaps stochastic variation in neurogenin 3 or Notch activity among endocrine precursors allows a cell destined to differentiate (yellow) to increase Delta expression slightly. Delta, a transmembrane molecule, then acts as a ligand for the transmembrane receptor Notch in neighbouring cells (green). Notch is proteolytically processed in the receiving cell, and the intracellular part of Notch translocates to the nucleus, where, together with cofactors, it activates hes-1 transcription. Hes-1, a transcriptional repressor, inhibits neurogenin 3 activity, thereby preventing activation of downstream targets such as Delta and neuroD. This inhibition prevents the cell from differentiating and, by repressing Delta expression, from activating Notch signalling in its neighbours, allowing them to differentiate. In this way, initially small differences in Delta expression between cells are amplified, leading to selection of a small number of differentiating cells. Migration of differentiated cells away from the epithelium then allows the next round of differentiation.
w1. Pearse AG. Islet cell precursors are neurones. Nature 1982;295:96-7.
w2. Skipper M, Lewis J. Getting to the guts of enteroendocrine differentiation. Nat Gen 2000;24:3-4.
w3. Madsen O, Larsson L, Rehfeld J, Schwartz T, Lernmark A, Labrecque A, et al. Cloned cell lines from a transplantable islet cell tumor are heterogeneous and express cholecystokinin in addition to islet hormones. J Cell Biol 1986;103:2025-34.
w4. Alpert S, Hanahan D, Teitelman G. Hybrid insulin genes reveal a developmental lineage for pancreatic endocrine cells and imply a relationship with neurons. Cell 1988;53:295-308.
w5. Herrera PL, Huarte J, Zufferey R, Nichols A, Mermillod B, Philippe J, et al. Ablation of islet endocrine cells by targeted expression of hormone-promoter-driven toxigenes. Proc Natl Acad Sci U S A 1994;91:12999-3003.
w6. Apelqvist Å, Li H, Sommer L, Beatus P, Anderson D, Honjo T, et al. Notch signalling controls pancreatic cell differentiation. Nature 1999;400:877-81.
w7. Jensen J, Heller RS, Nielsen TF, Pedersen EE, Lindsell C, Weinmaster G, et al. Independent development of pancreatic a- and b-cells from neurogenin3 expressing presursors. A role for the Notch pathway in repression of premature differentiation. Diabetes 2000;49:163-76.
w8. Gradwohl G, Dierich A, LeMeur M, Guillemot F. neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci U S A 2000;97:1607-11.
w9. Herrera PL. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 2000;127:2317-22.
w10. Jensen J, Pedersen EE, Galante P, Hald J, Heller RS, Ishibashi M, et al. Control of endodermal endocrine development by Hes-1. Nat Gen 2000;24:36-44.
- Letter Published: 07 April 2001; BMJ 322 doi:10.1136/bmj.322.7290.861
- Clinical Review Published: 21 January 2011; BMJ 342 doi:10.1136/bmj.d217
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- Islet transplantation in type 1 diabetes
- Biological and Biomaterial Approaches for Improved Islet Transplantation
- Role of the Mitogen-Activated Protein Kinases in Cytokine-Mediated Inhibition of Insulin Gene Expression
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