Peroxisome Proliferator-Activated Receptors: Difference between revisions

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</StructureSection>
 


==Binding of Synthetic Agonists and Medical Implications==
==Binding of Synthetic Agonists and Medical Implications==
<applet load=" 3dzy2.pdb" size="450" color="white" frame="true" spin="on" Scene ="Peroxisome_Proliferator-Activated_Receptors/Ppar_opening4/2" caption="Crystal Structure of PPARγ bound to Rosiglitizone, RXRα and PPRE DNA Sequence, [[3dzy]]" align="right"/>
A number of synthetic agonists have been developed to bind to <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening4/2'>PPAR</scene> to fight metabolic diseases like diabetes. These agonists include [http://en.wikipedia.org/wiki/troglitazone troglitazone] ([http://www.rezulin.com Rezulin]), pioglitazone ([[Actos]]), and rosiglitazone ([[Avandia]]). These agonists function in a similar fashion, by binding to the active site of PPARγ, activating the receptor. Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group forming a <scene name='Peroxisome_Proliferator-Activated_Receptors/Rosiglitazone_binding/3'>number of interactions that stabilize the agonist</scene>. Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its TZD group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282, Leu330, Ile326 and Leu469, and the central benzene ring occupies a pocket formed by Cys285 and Met364.<ref name="Nolte"/>
A number of synthetic agonists have been developed to bind to <scene name='Peroxisome_Proliferator-Activated_Receptors/Ppar_opening4/2'>PPAR</scene> to fight metabolic diseases like diabetes. These agonists include [http://en.wikipedia.org/wiki/troglitazone troglitazone] ([http://www.rezulin.com Rezulin]), pioglitazone ([[Actos]]), and rosiglitazone ([[Avandia]]). These agonists function in a similar fashion, by binding to the active site of PPARγ, activating the receptor. Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group forming a <scene name='Peroxisome_Proliferator-Activated_Receptors/Rosiglitazone_binding/3'>number of interactions that stabilize the agonist</scene>. Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its TZD group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282, Leu330, Ile326 and Leu469, and the central benzene ring occupies a pocket formed by Cys285 and Met364.<ref name="Nolte"/>
[[Image: Ciprofibrate.PNG|300px|left|thumb| Human PPARα agonist, Ciprofibrate (Modalim)]]
[[Image: Ciprofibrate.PNG|300px|left|thumb| Human PPARα agonist, Ciprofibrate (Modalim)]]
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Most drugs target the PPARγ LBD, as ligands that bind to RXRα are likely to inadvertently act on other RXRα complexes, resulting in unexpected side effects. <ref name="Berger2"/> Sales of Avandia, marketed by GlaxoSmithKline peaked at $2.5 billion in 2006 but have since dipped dramatically due to health concerns. In response to the health concerns, sales of Actos, marketed by Takeda, have grown to block buster status.<ref>http://uk.reuters.com/article/idUKT7482820080131</ref>
Most drugs target the PPARγ LBD, as ligands that bind to RXRα are likely to inadvertently act on other RXRα complexes, resulting in unexpected side effects. <ref name="Berger2"/> Sales of Avandia, marketed by GlaxoSmithKline peaked at $2.5 billion in 2006 but have since dipped dramatically due to health concerns. In response to the health concerns, sales of Actos, marketed by Takeda, have grown to block buster status.<ref>http://uk.reuters.com/article/idUKT7482820080131</ref>
<br />
<br />
 
</StructureSection>
==Additional 3D Structures of PPAR==
==Additional 3D Structures of PPAR==


Revision as of 17:02, 1 May 2013

Human PPARγ bound to RXRα and PPRE DNA strand, 3dzy

The Peroxisome Proliferator-Activated Receptors (PPAR) α, γ, and δ are members of the nuclear receptor family. Since their discovery in the early 90s, it has become clear that the PPARs are essential modulators of external stimuli, acting as transcription factors to regulate mammalian metabolism, cellular differentiation, and tumorigenesis. The PPARs are the targets of numerous pharmaceutical drugs aimed at treating hypolipidemia and diabetes among other diseases.[1] For details on PPARγ see PPAR-gamma.

Biological Role

PPAR Mechanism of Action in the Human Body

Transcription of individual genes in eukaryotic cells is controlled very precisely at a number of different levels. One key level is the binding of specific DNA binding transcriptional factors such as nuclear receptors, to facilitate RNA polymerase function. Unliganded PPARs form a heterodimer with retinoid X receptor (RXR), specifically RXRα. This heterodimer binds to the Peroxisome Proliferator Response Element (PPRE), a specific DNA sequence present in the promoter region of PPAR-regulated genes. [2] Also associated with this unliganded heterodimer is a co-repressor complex which possesses histone deacetylation activity. This results in a tight chromatin structure, preventing gene transcription. [3] This co-repressor complex is released upon ligand binding (typical ligands include lipids and eicosanoids), allowing various co-activators and co-activator-associated proteins to be recruited. These protein complexes facilitate chromatin remodeling and DNA unwinding along with linkage to RNA polymerase II machinery, necessary steps for transcription. The genes transcribed upon activation are insulin responsive genes involved in the control of glucose production, transport and utilization. This makes agonists of PPAR insulin sensitizers. Some PPAR related co-activators include CBP (Histone Acetylation), SRC-1,2,3 (Chromatin Acetylation), [4] PGC-1 (Recruit HAT activities), PRIC-285,320 (Chromatin Remodeling via Helicase activity)[5]and PIMT (RNA Capping via methyltransferase activity)[6].

PPARs regulate diverse biological processes varying from lipid and carbohydrate metabolism to inflammation and wound healing. While PPARα is the major regulator of fatty acid oxidation and uptake in the liver, PPARγ is expressed at extremely high levels in adipose tissue, macrophages, and the large intestine, and controls lipid adipogenesis and energy conversion. [7]PPARδ is expressed in most tissues and plays diverse roles involved in metabolism and wound healing. [8] These nuclear receptors are of critical importance to the body as exemplified by PPARα knockdown mice suffering from a variety of metabolic defects including hypothermia, elevated plasma free fatty acid levels, and hypoglycemia, potentially leading to death.[9]


Natural Ligands

PPAR gamma binds polyunsaturated fatty acids like linoleic acid, linolenic acid, and eicosapentaenoic acid at affinities that are in line with serum levels found in the blood. PPARα binds a variety of saturated and unsaturated fatty acids including palmitic acid, oleic acid, linoleic acid, and arachidonic acid.[10] PPARδs ligand selectivity is intermediate between that of the other isotypes and is activated by palmitic acid and a number of eicosanoids.[11]


PPAR Structure

Ligand Binding Domain

The structures of the PPARs are very similar over each isotype. All PPAR isotypes have a ligand binding domain (LBD). The LBD, which is located in the C-terminal half of the receptor, is composed of 13 α-helices and a four-stranded ß-sheet. (2f4b) is Y-shaped and consists of an .[12] The ligand binding pocket of PPARs is quite large (about 1400 cubic angstroms) in comparison to that of other nuclear receptors which allows the PPARs to interact with numerous structurally distinct ligands.[12]. Within Arm I, four polar resides are conserved over all PPAR isotypes, in the case of PPARα. These residues are part of a hydrogen bonding network that interacts with the carboxylate group of fatty acids and other ligands upon binding.[13] The (1kkq), whose function is to generate the receptors’ co-activator binding pocket, is located at the C-terminal end of the LBD.[14] The conserved hydrogen bonding network in , promoting co-activator binding.[15] and is thus ideal for binding the hydrophobic tail of fatty acids via Van der Waals interactions.

Despite over 80% of the ligand binding cavity residues being conserved over all PPAR isotypes, it is the remaining 20% that creates the ligand specificity seen between isotypes. A few examples illustrate this point. In PPARδ, the cavity is significantly narrower adjacent to the AF-2 helix and Arm I. This prevents PPARδ from being able to accommode large headed TZDs and L-tyrosine based agonsists. In the case of PPARα, PPARα does not bind ligands with large carboxylate head groups because of as compared to PPARγ which has a smaller equivalent residue in His323.[15] Or in the case of binding some benzenesulfonamide derivatives, the (2g0g) in the case of PPARγ is lost in PPARα (Ile354) and PPARδ(Ile 363)[15]

AF-2 Domain: Structure and Function

As briefly mentioned before, the AF-2 domain is essential for ligand binding and (2prg) function. Upon ligand binding, helix H12 of AF-2 closes on the ligand-binding site, reducing conformational flexibility of the LBD and assuming a structure that is ideal for co-activator binding. Using Molecular Dynamic simulations, it has been determined that residues (in PPARγ) are involved in a hydrogen bond network that stabilizes the AF-2 helix in the active conformation upon ligand binding.[15]


Co-Activator & Co-Repressor Binding

Human PPARγ Co-Activator Binding Site. PPARγ bound to SRC-1, 3dzy
Human PPARγ Co-Activator Binding Site. PPARγ bound to SRC-1, 3dzy

The transcriptional activity of is regulated by its interaction with co-activators like SRC-1 or CBP and co-repressors like SMRT. [15]Co-activators like CBP contain a conserved LXXLL motif where X is any amino acid, and use this to bind a hydrophobic pocket on the receptor surface formed by the stabilized AF-2 helix H12.[16] In the case of the PPARγ/rosiglitazone/SRC-1 complex, the LXXLL motif helix of SRC-1 forms These charged residues are conserved across PPAR isotypes and form the “charge clamp,” an essential component for co-activator stabilization in the PPAR LBD.[17]

When PPAR is bound to a co-repressor, the , preventing the AF-2 H12 helix from occupying its active state. This in turn eliminates the charge clamp between PPAR and a prospective co-activator.[16] Notice the

Formation of Heterodimer with RXR

The interface of PPAR and RXR is composed of an intricate and which show remarkable complementarity. For the PPARγ-RXRα dimer the dimmer interface interactions are particularly extensive. [16]

DNA Binding Domain Structure

PPARs also contain a DNA binding domain (DBD) The (3dzy), one on PPAR and one on RXR, that bind PPREs of PPAR-responsive genes. The consensus sequence of PPREs is AGGTCA and has been found in a number of PPAR inducible genes like acyl-CoA oxidase and adipocyte fatty acid-binding protein.[18] Chandre et al. have demonstrated that the DNA PPRE allosterically contributes to its own binding via a using residues Gln206 and Arg209 on RXRα and Asn160 on PPARγ.[19]




Binding of Synthetic Agonists and Medical Implications

A number of synthetic agonists have been developed to bind to to fight metabolic diseases like diabetes. These agonists include troglitazone (Rezulin), pioglitazone (Actos), and rosiglitazone (Avandia). These agonists function in a similar fashion, by binding to the active site of PPARγ, activating the receptor. Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group forming a . Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its TZD group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282, Leu330, Ile326 and Leu469, and the central benzene ring occupies a pocket formed by Cys285 and Met364.[12]

Human PPARα agonist, Ciprofibrate (Modalim)

Despite their structural similarities, each member of the PPAR family is localized to certain parts of the body. Location of receptor partially determines their function in the body and also the different roles they can play in medicine as drug targets. PPARγ is responsible for lipid metabolism and cellular energy homeostasis. It binds genes that transcribe proteins which act as fatty acid transporters, are critical in insulin signaling and glucose transport, catalyze glycerol synthesis from triglycerides, and catabolize lipids. This makes PPARγ an ideal target to treat Diabetes.[1] Also, recent research has indicated that some PPAR agonists like Rosiglitazone can induce apoptosis of macrophages and would thus serve as excellent anti-inflammatory targets.[20] PPARα has been shown to play a critical role in the regulation of uptake and oxidation of fatty acids. This makes PPARα an excellent target for Atherosclerosis drugs which aim to reduce LDL cholesterol and increase HDL cholesterol, the two most common traits of atherosclerosis. The fibrates are a class of amphipathic carboxylic acids that are PPARα agonists used to treat hypercholesterolemia and hyperlipidemia along with the HMGR inhibitor statins. Some fibrates are Bezafibrate (Marketed by Roche as Bezalip) and Ciprofibrate (Modalim).[1] PPARδ is broadly expressed across the human body and thus is suspected to play a role in a number of diseases. It has been implicated in disorders ranging from fertility problems to types of cancer. Perhaps the most important use of PPARδ agonists will be in treating central nervous system (CNS) diseases as PPARδ has been implicated in neuron myelinogenesis and neuronal signaling as well as lipid metabolism in the CNS.[1]

Most drugs target the PPARγ LBD, as ligands that bind to RXRα are likely to inadvertently act on other RXRα complexes, resulting in unexpected side effects. [20] Sales of Avandia, marketed by GlaxoSmithKline peaked at $2.5 billion in 2006 but have since dipped dramatically due to health concerns. In response to the health concerns, sales of Actos, marketed by Takeda, have grown to block buster status.[21]


Crystal Structure of Human PAPR complex with agonist (1i7g)

Drag the structure with the mouse to rotate

Additional 3D Structures of PPAR

Updated December 2011

PPARα Structures

1k7l – hPPARα LBD + G2409544 + SRC-1
3e94 – hPPARα LBD + tributyltin
1i7g – hPPARα LBD + AZ242
1kkq – hPPARα LBD + GW6471 Antagonist + SMRT
2npa - hPPARα LBD+ propanoic acid derivative + SRC-1
2p54 - hPPARα LBD + SRC-1
2rew - hPPARα LBD + azetidinone derivative activator
2znn, 2zno, 2znp, 2znq, 3kdu - hPPARα LBD+ agonist
3fei, 3fej, 3g8i, 3sp6 - hPPARα LBD+ agonist + SRC-1
3et1 - hPPARα LBD + SRC-1 + indole derivative


PPARγ Structures

3prg, 2qmv, 1prg – hPPARγ LBD
2zk0, 2zk1, 2zk2, 2zk3, 2zk4, 2zk5, 2zk6 – hPPARγ LBD + ligand - human
2prg, 1fm6 – hPPARγ LBD + Rosiglitazone + SRC-1
2xkw - hPPARγ LBD+ pioglitazone
3b0q - hPPARγ LBD+ netoglitazone derivative
4prg – hPPARγ LBD + 2,4-thiazolidinedione deriveative
1fm9 – hPPARγ LBD + GI262570, Farglitazar + SRC-1
1wm0 – hPPARγ LBD + 2-BABA + GRIP-1
3ho0, 3hod – hPPARγ LBD + aryloxy-3phenylpropanoic acid
1k74 – hPPARγ LBD + retinoicic acid receptor + inhibitor
3et0 - hPPARγ LBD + propionic acid moiety
1knu – hPPARγ LBD + Carbazole analogue
1i7i – hPPARγ LBD + AZ242
2fvj – hPPARγ LBD + Isoquinoline derivative + SRC-1
1nyx – hPPARγ LBD + Ragalitazar
1rdt – hPPARγ LBD + GI262570, Fraglitazar + CBP
1zgy – hPPARγ LBD + Rosaglitazone + SHP
2f4b, 1zeo, 2ath, 2hwq, 2hwr, 2i4j, 2q59, 2q8s, 3b3k, 3bc5, 3cds, 3g9e, 3gbk, 3gz9, 3ia6, 3kdt, 3an3, 3an4, 3noa – hPPARγ LBD+ agonists
2g0h, 2g0g, 2i4p, 2i4z, 2q5g, 2q5p, 2q5s, 2q61, 2q6r, 3cdp, 3d6d - hPPARγ LBD+ partial agonists
3lmp – hPPARγ LBD + a cercosporamide derivative modulator
3b1m - hPPARγ LBD+ cercosporamide derivative modulator + SRC-1
2gtk - hPPARγ LBD+ SRC-1 decamer
2om9 - hPPARγ LBD + ajulemic acid
2q6s, 3b0r - hPPARγ LBD + benzoic acid derivative
3osi, 3osw, 3pba - hPPARγ LBD + bisphenol derivative
2p4y, 3adt, 3adu, 3adw, 3et3, 2hfp - hPPARγ LBD+ indole modulator
2pob - hPPARγ LBD + fraglitazar analogue
2vsr, 2vst, 2vv0, 2vv1, 2vv2, 2vv3, 2vv4 - hPPARγ LBD + fatty acid activator
2zvt - hPPARγ LBD + prostaglandin derivative
3ads, 3adx - hPPARγ LBD + indomethacin
3adv - hPPARγ LBD + serotonin
3cs8, 3u9q- hPPARγ LBD + PGC-1A
3cwd - hPPARγ LBD + SRC1-2
3fur, 3kmg - hPPARγ LBD + SRC-1+ modulator
3k8s - hPPARγ LBD + antidiabetic agent
3h0a - hPPARγ LBD + SRC 1 + retinoic acid receptor α + retinoic acid + partial agonist

PPARδ Structures

2baw, 2b50, 2awh – hPPARδ + Vaccenic Acid
1gwx – hPPARδ LBD + GW2433
2gwx – hPPARδ LBD
3gwx –hPPARδ LBD + 5,8,11,14,17-Eicosapentaenoic Acid
1y0s – hPPARδ LBD + GW2331
3dy6 –hPPARδ LBD + anthranilic acid
3et2 – PPARδ + 3-[5-Methoxy-1-(4-methoxy-benzenesulfonyl)-1H-indol-3-yl]-propionic acid
2env – hPPARδ zinc finger domain
2j14, 2xyj, 2xyw, 2xyx, 3oz0, 3sp9 - hPPARδ LBD + agonist
3peq - hPPARδ LBD + partial agonist
3d5f - hPPARδ LBD +phenoxy derivative

Additional Resources



References

  1. ↑ 1.0 1.1 1.2 1.3 Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53:409-35. PMID:11818483 doi:10.1146/annurev.med.53.082901.104018
  2. ↑ Qi C, Zhu Y, Reddy JK. Peroxisome proliferator-activated receptors, coactivators, and downstream targets. Cell Biochem Biophys. 2000;32 Spring:187-204. PMID:11330046
  3. ↑ Guan HP, Ishizuka T, Chui PC, Lehrke M, Lazar MA. Corepressors selectively control the transcriptional activity of PPARgamma in adipocytes. Genes Dev. 2005 Feb 15;19(4):453-61. Epub 2005 Jan 28. PMID:15681609 doi:10.1101/gad.1263305
  4. ↑ Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, Fernandez-Salguero PM, Westphal H, Gonzalez FJ. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol. 1995 Jun;15(6):3012-22. PMID:7539101
  5. ↑ Lee SK, Jung SY, Kim YS, Na SY, Lee YC, Lee JW. Two distinct nuclear receptor-interaction domains and CREB-binding protein-dependent transactivation function of activating signal cointegrator-2. Mol Endocrinol. 2001 Feb;15(2):241-54. PMID:11158331
  6. ↑ Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT, Aswad DW, Stallcup MR. Regulation of transcription by a protein methyltransferase. Science. 1999 Jun 25;284(5423):2174-7. PMID:10381882
  7. ↑ Fajas L, Auboeuf D, Raspe E, Schoonjans K, Lefebvre AM, Saladin R, Najib J, Laville M, Fruchart JC, Deeb S, Vidal-Puig A, Flier J, Briggs MR, Staels B, Vidal H, Auwerx J. The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem. 1997 Jul 25;272(30):18779-89. PMID:9228052
  8. ↑ Girroir EE, Hollingshead HE, He P, Zhu B, Perdew GH, Peters JM. Quantitative expression patterns of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) protein in mice. Biochem Biophys Res Commun. 2008 Jul 4;371(3):456-61. Epub 2008 Apr 28. PMID:18442472 doi:10.1016/j.bbrc.2008.04.086
  9. ↑ Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7473-8. PMID:10377439
  10. ↑ Gottlicher M, Widmark E, Li Q, Gustafsson JA. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4653-7. PMID:1316614
  11. ↑ Amri EZ, Bonino F, Ailhaud G, Abumrad NA, Grimaldi PA. Cloning of a protein that mediates transcriptional effects of fatty acids in preadipocytes. Homology to peroxisome proliferator-activated receptors. J Biol Chem. 1995 Feb 3;270(5):2367-71. PMID:7836471
  12. ↑ 12.0 12.1 12.2 Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature. 1998 Sep 10;395(6698):137-43. PMID:9744270 doi:10.1038/25931
  13. ↑ Fyffe SA, Alphey MS, Buetow L, Smith TK, Ferguson MA, Sorensen MD, Bjorkling F, Hunter WN. Recombinant human PPAR-beta/delta ligand-binding domain is locked in an activated conformation by endogenous fatty acids. J Mol Biol. 2006 Mar 3;356(4):1005-13. Epub 2006 Jan 4. PMID:16405912 doi:10.1016/j.jmb.2005.12.047
  14. ↑ Yang W, Rachez C, Freedman LP. Discrete roles for peroxisome proliferator-activated receptor gamma and retinoid X receptor in recruiting nuclear receptor coactivators. Mol Cell Biol. 2000 Nov;20(21):8008-17. PMID:11027271
  15. ↑ 15.0 15.1 15.2 15.3 15.4 Zoete V, Grosdidier A, Michielin O. Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators. Biochim Biophys Acta. 2007 Aug;1771(8):915-25. Epub 2007 Jan 18. PMID:17317294 doi:10.1016/j.bbalip.2007.01.007
  16. ↑ 16.0 16.1 16.2 Gampe RT Jr, Montana VG, Lambert MH, Miller AB, Bledsoe RK, Milburn MV, Kliewer SA, Willson TM, Xu HE. Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell. 2000 Mar;5(3):545-55. PMID:10882139
  17. ↑ Xu HE, Lambert MH, Montana VG, Plunket KD, Moore LB, Collins JL, Oplinger JA, Kliewer SA, Gampe RT Jr, McKee DD, Moore JT, Willson TM. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13919-24. Epub 2001 Nov 6. PMID:11698662 doi:10.1073/pnas.241410198
  18. ↑ Wahli W, Braissant O, Desvergne B. Peroxisome proliferator activated receptors: transcriptional regulators of adipogenesis, lipid metabolism and more.... Chem Biol. 1995 May;2(5):261-6. PMID:9383428
  19. ↑ Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA. Nature. 2008 Nov 20;456(7220):350-6. PMID:19043829 doi:10.1038/nature07413
  20. ↑ 20.0 20.1 Berger J, Wagner JA. Physiological and therapeutic roles of peroxisome proliferator-activated receptors. Diabetes Technol Ther. 2002;4(2):163-74. PMID:12079620
  21. ↑ http://uk.reuters.com/article/idUKT7482820080131

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