Skip to main content
Erschienen in: Diabetologia 12/2012

01.12.2012 | Article

3-D imaging and illustration of the perfusive mouse islet sympathetic innervation and its remodelling in injury

verfasst von: Y.-C. Chiu, T.-E. Hua, Y.-Y. Fu, P. J. Pasricha, S.-C. Tang

Erschienen in: Diabetologia | Ausgabe 12/2012

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

Sympathetic nerves influence islet hormone levels in the circulation. Insights into islet sympathetic innervation and its remodelling in diabetes may impact future therapeutics. However, standard immunohistochemistry and microtome-based microscopy cannot provide an integral view of the islet neurovascular complex. We prepared transparent islet specimens to investigate the spatial relationship between sympathetic nerves, blood vessels and islet cells in normal, streptozotocin-injected and non-obese diabetic mouse models.

Methods

Cardiac perfusion of fluorescent lectin was used to label pancreatic blood vessels. Tyrosine hydroxylase and nuclear staining were used to reveal islet sympathetic innervation and microstructure. Optical clearing (i.e. use of immersion solution to reduce scattering) was applied to enable 3-dimensional confocal microscopy of islets to visualise the sympathetic neurovascular complex in space.

Results

Unlike previously reported morphology, we observed perfusive intra-islet, perivascular sympathetic innervation, in addition to peri-islet contacts of sympathetic nerves with alpha cells and sympathetic fibres encircling the adjacent arterioles. The intra-islet axons became markedly prominent in streptozotocin-injected mice (2 weeks after injection). In non-obese diabetic mice, lymphocytic infiltration remodelled the peri-islet sympathetic axons in early insulitis.

Conclusions/interpretation

We have established an imaging approach to reveal the spatial features of mouse islet sympathetic innervation. The neurovascular complex and sympathetic nerve–alpha cell contact suggest that sympathetic nerves modulate islet hormone secretion through blood vessels, in addition to acting directly on alpha cells. In islet injuries, sympathetic nerves undergo different remodelling in response to different pathophysiological cues.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Woods SC, Porte D Jr (1974) Neural control of the endocrine pancreas. Physiol Rev 54:596–619PubMed Woods SC, Porte D Jr (1974) Neural control of the endocrine pancreas. Physiol Rev 54:596–619PubMed
2.
Zurück zum Zitat Ahren B, Wierup N, Sundler F (2006) Neuropeptides and the regulation of islet function. Diabetes 55:S98–S107CrossRef Ahren B, Wierup N, Sundler F (2006) Neuropeptides and the regulation of islet function. Diabetes 55:S98–S107CrossRef
3.
Zurück zum Zitat Ahren B (2000) Autonomic regulation of islet hormone secretion—implications for health and disease. Diabetologia 43:393–410PubMedCrossRef Ahren B (2000) Autonomic regulation of islet hormone secretion—implications for health and disease. Diabetologia 43:393–410PubMedCrossRef
4.
Zurück zum Zitat Brunicardi FC, Shavelle DM, Andersen DK (1995) Neural regulation of the endocrine pancreas. Int J Pancreatol 18:177–195PubMed Brunicardi FC, Shavelle DM, Andersen DK (1995) Neural regulation of the endocrine pancreas. Int J Pancreatol 18:177–195PubMed
5.
Zurück zum Zitat Coupland RE (1958) The innervation of pancreas of the rat, cat and rabbit as revealed by the cholinesterase technique. J Anat 92(Pt 1):143–149PubMed Coupland RE (1958) The innervation of pancreas of the rat, cat and rabbit as revealed by the cholinesterase technique. J Anat 92(Pt 1):143–149PubMed
6.
Zurück zum Zitat Miller RE (1981) Pancreatic neuroendocrinology: peripheral neural mechanisms in the regulation of the islets of Langerhans. Endocr Rev 2:471–494PubMedCrossRef Miller RE (1981) Pancreatic neuroendocrinology: peripheral neural mechanisms in the regulation of the islets of Langerhans. Endocr Rev 2:471–494PubMedCrossRef
7.
Zurück zum Zitat Lindsay TH, Halvorson KG, Peters CM et al (2006) A quantitative analysis of the sensory and sympathetic innervation of the mouse pancreas. Neuroscience 137:1417–1426PubMedCrossRef Lindsay TH, Halvorson KG, Peters CM et al (2006) A quantitative analysis of the sensory and sympathetic innervation of the mouse pancreas. Neuroscience 137:1417–1426PubMedCrossRef
8.
Zurück zum Zitat Burris RE, Hebrok M (2007) Pancreatic innervation in mouse development and beta-cell regeneration. Neuroscience 150:592–602PubMedCrossRef Burris RE, Hebrok M (2007) Pancreatic innervation in mouse development and beta-cell regeneration. Neuroscience 150:592–602PubMedCrossRef
9.
Zurück zum Zitat Gromada J, Franklin I, Wollheim CB (2007) Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev 28:84–116PubMedCrossRef Gromada J, Franklin I, Wollheim CB (2007) Alpha-cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev 28:84–116PubMedCrossRef
10.
11.
Zurück zum Zitat Fu YY, Tang SC (2010) At the movies: 3-dimensional technology and gastrointestinal histology. Gastroenterology 139:1100–1105PubMedCrossRef Fu YY, Tang SC (2010) At the movies: 3-dimensional technology and gastrointestinal histology. Gastroenterology 139:1100–1105PubMedCrossRef
12.
Zurück zum Zitat Smith K (2011) Neurogastroenterology: improving 3D imaging of the enteric nervous system. Nat Rev Gastroenterol Hepatol 8:600PubMedCrossRef Smith K (2011) Neurogastroenterology: improving 3D imaging of the enteric nervous system. Nat Rev Gastroenterol Hepatol 8:600PubMedCrossRef
13.
Zurück zum Zitat Fu YY, Lu CH, Lin CW et al (2010) Three-dimensional optical method for integrated visualization of mouse islet microstructure and vascular network with subcellular-level resolution. J Biomed Opt 15:046018PubMedCrossRef Fu YY, Lu CH, Lin CW et al (2010) Three-dimensional optical method for integrated visualization of mouse islet microstructure and vascular network with subcellular-level resolution. J Biomed Opt 15:046018PubMedCrossRef
14.
Zurück zum Zitat Tang SC, Fu YY, Lo WF, Hua TE, Tuan HY (2010) Vascular labeling of luminescent gold nanorods enables 3-D microscopy of mouse intestinal capillaries. ACS Nano 4:6278–6284PubMedCrossRef Tang SC, Fu YY, Lo WF, Hua TE, Tuan HY (2010) Vascular labeling of luminescent gold nanorods enables 3-D microscopy of mouse intestinal capillaries. ACS Nano 4:6278–6284PubMedCrossRef
15.
Zurück zum Zitat Fu YY, Lin CW, Enikolopov G, Sibley E, Chiang AS, Tang SC (2009) Microtome-free 3-dimensional confocal imaging method for visualization of mouse intestine with subcellular-level resolution. Gastroenterology 137:453–465PubMedCrossRef Fu YY, Lin CW, Enikolopov G, Sibley E, Chiang AS, Tang SC (2009) Microtome-free 3-dimensional confocal imaging method for visualization of mouse intestine with subcellular-level resolution. Gastroenterology 137:453–465PubMedCrossRef
16.
Zurück zum Zitat Liu YA, Chen Y, Chiang AS, Peng SJ, Pasricha PJ, Tang SC (2011) Optical clearing improves the imaging depth and signal-to-noise ratio for digital analysis and three-dimensional projection of the human enteric nervous system. Neurogastroenterol Motil 23:e446–e457PubMedCrossRef Liu YA, Chen Y, Chiang AS, Peng SJ, Pasricha PJ, Tang SC (2011) Optical clearing improves the imaging depth and signal-to-noise ratio for digital analysis and three-dimensional projection of the human enteric nervous system. Neurogastroenterol Motil 23:e446–e457PubMedCrossRef
17.
Zurück zum Zitat Liu YA, Chung YC, Pan ST et al (2012) 3-D illustration of network orientations of interstitial cells of Cajal subgroups in human colon as revealed by deep-tissue imaging with optical clearing. Am J Physiol Gastrointest Liver Physiol 302:G1099–G1110PubMedCrossRef Liu YA, Chung YC, Pan ST et al (2012) 3-D illustration of network orientations of interstitial cells of Cajal subgroups in human colon as revealed by deep-tissue imaging with optical clearing. Am J Physiol Gastrointest Liver Physiol 302:G1099–G1110PubMedCrossRef
18.
Zurück zum Zitat Tuchin VV, Wang RK, Yeh AT (2008) Optical clearing of tissues and cells. J Biomed Opt 13:021101PubMedCrossRef Tuchin VV, Wang RK, Yeh AT (2008) Optical clearing of tissues and cells. J Biomed Opt 13:021101PubMedCrossRef
19.
Zurück zum Zitat Carl Zeiss Microimaging GmbH (2009) Visualizing the architecture of cells and tissues, Brochures for Laser Scanning Microscopy. Available from http://www.zeiss.de/micro, accessed 5 April 2012. Carl Zeiss Microimaging GmbH (2009) Visualizing the architecture of cells and tissues, Brochures for Laser Scanning Microscopy. Available from http://​www.​zeiss.​de/​micro, accessed 5 April 2012.
20.
Zurück zum Zitat Hama H, Kurokawa H, Kawano H et al (2011) Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain. Nat Neurosci 14:1481–1488PubMedCrossRef Hama H, Kurokawa H, Kawano H et al (2011) Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain. Nat Neurosci 14:1481–1488PubMedCrossRef
21.
Zurück zum Zitat Ravnic DJ, Jiang X, Wolloscheck T et al (2005) Vessel painting of the microcirculation using fluorescent lipophilic tracers. Microvasc Res 70:90–96PubMedCrossRef Ravnic DJ, Jiang X, Wolloscheck T et al (2005) Vessel painting of the microcirculation using fluorescent lipophilic tracers. Microvasc Res 70:90–96PubMedCrossRef
22.
Zurück zum Zitat Taylor-Fishwick DA, Bowman A, Korngiebel-Rosique M, Vinik AI (2008) Pancreatic islet immunoreactivity to the Reg protein INGAP. J Histochem Cytochem 56:183–191PubMedCrossRef Taylor-Fishwick DA, Bowman A, Korngiebel-Rosique M, Vinik AI (2008) Pancreatic islet immunoreactivity to the Reg protein INGAP. J Histochem Cytochem 56:183–191PubMedCrossRef
23.
Zurück zum Zitat Rodriguez-Diaz R, Abdulreda MH, Formoso AL et al (2011) Innervation patterns of autonomic axons in the human endocrine pancreas. Cell Metab 14:45–54PubMedCrossRef Rodriguez-Diaz R, Abdulreda MH, Formoso AL et al (2011) Innervation patterns of autonomic axons in the human endocrine pancreas. Cell Metab 14:45–54PubMedCrossRef
24.
Zurück zum Zitat Beppu H, Maruta K, Kurner T, Kolb H (1987) Diabetogenic action of streptozotocin: essential role of membrane permeability. Acta Endocrinol (Copenh) 114:90–95 Beppu H, Maruta K, Kurner T, Kolb H (1987) Diabetogenic action of streptozotocin: essential role of membrane permeability. Acta Endocrinol (Copenh) 114:90–95
25.
Zurück zum Zitat Papaccio G (1993) Insulitis and islet microvasculature in type 1 diabetes. Histol Histopathol 8:751–759PubMed Papaccio G (1993) Insulitis and islet microvasculature in type 1 diabetes. Histol Histopathol 8:751–759PubMed
26.
Zurück zum Zitat Enghofer M, Usadel KH, Beck O, Kusterer K (1997) Superoxide dismutase reduces islet microvascular injury induced by streptozotocin in the rat. Am J Physiol 273:E376–E382PubMed Enghofer M, Usadel KH, Beck O, Kusterer K (1997) Superoxide dismutase reduces islet microvascular injury induced by streptozotocin in the rat. Am J Physiol 273:E376–E382PubMed
27.
Zurück zum Zitat Denis MC, Mahmood U, Benoist C, Mathis D, Weissleder R (2004) Imaging inflammation of the pancreatic islets in type 1 diabetes. Proc Natl Acad Sci USA 101:12634–12639PubMedCrossRef Denis MC, Mahmood U, Benoist C, Mathis D, Weissleder R (2004) Imaging inflammation of the pancreatic islets in type 1 diabetes. Proc Natl Acad Sci USA 101:12634–12639PubMedCrossRef
28.
Zurück zum Zitat Mignone JL, Kukekov V, Chiang AS, Steindler D, Enikolopov G (2004) Neural stem and progenitor cells in nestin–GFP transgenic mice. J Comp Neurol 469:311–324PubMedCrossRef Mignone JL, Kukekov V, Chiang AS, Steindler D, Enikolopov G (2004) Neural stem and progenitor cells in nestin–GFP transgenic mice. J Comp Neurol 469:311–324PubMedCrossRef
29.
Zurück zum Zitat Larrieta ME, Vital P, Mendoza-Rodriguez A, Cerbon M, Hiriart M (2006) Nerve growth factor increases in pancreatic beta cells after streptozotocin-induced damage in rats. Exp Biol Med (Maywood) 231:396–402 Larrieta ME, Vital P, Mendoza-Rodriguez A, Cerbon M, Hiriart M (2006) Nerve growth factor increases in pancreatic beta cells after streptozotocin-induced damage in rats. Exp Biol Med (Maywood) 231:396–402
30.
Zurück zum Zitat Teitelman G, Guz Y, Ivkovic S, Ehrlich M (1998) Islet injury induces neurotrophin expression in pancreatic cells and reactive gliosis of peri-islet Schwann cells. J Neurobiol 34:304–318PubMedCrossRef Teitelman G, Guz Y, Ivkovic S, Ehrlich M (1998) Islet injury induces neurotrophin expression in pancreatic cells and reactive gliosis of peri-islet Schwann cells. J Neurobiol 34:304–318PubMedCrossRef
31.
Zurück zum Zitat Teff KL, Mattes RD, Engelman K (1991) Cephalic phase insulin release in normal weight males: verification and reliability. Am J Physiol 261:E430–E436PubMed Teff KL, Mattes RD, Engelman K (1991) Cephalic phase insulin release in normal weight males: verification and reliability. Am J Physiol 261:E430–E436PubMed
32.
Zurück zum Zitat Havel PJ, Ahren B (1997) Activation of autonomic nerves and the adrenal medulla contributes to increased glucagon secretion during moderate insulin-induced hypoglycemia in women. Diabetes 46:801–807PubMedCrossRef Havel PJ, Ahren B (1997) Activation of autonomic nerves and the adrenal medulla contributes to increased glucagon secretion during moderate insulin-induced hypoglycemia in women. Diabetes 46:801–807PubMedCrossRef
33.
Zurück zum Zitat Taborsky GJ Jr, Ahren B, Havel PJ (1998) Autonomic mediation of glucagon secretion during hypoglycemia: implications for impaired alpha-cell responses in type 1 diabetes. Diabetes 47:995–1005PubMedCrossRef Taborsky GJ Jr, Ahren B, Havel PJ (1998) Autonomic mediation of glucagon secretion during hypoglycemia: implications for impaired alpha-cell responses in type 1 diabetes. Diabetes 47:995–1005PubMedCrossRef
34.
Zurück zum Zitat Gilliam LK, Palmer JP, Taborsky GJ Jr (2007) Tyramine-mediated activation of sympathetic nerves inhibits insulin secretion in humans. J Clin Endocrinol Metab 92:4035–4038PubMedCrossRef Gilliam LK, Palmer JP, Taborsky GJ Jr (2007) Tyramine-mediated activation of sympathetic nerves inhibits insulin secretion in humans. J Clin Endocrinol Metab 92:4035–4038PubMedCrossRef
35.
Zurück zum Zitat Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A (2006) The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci USA 103:2334–2339PubMedCrossRef Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A (2006) The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci USA 103:2334–2339PubMedCrossRef
36.
Zurück zum Zitat Taborsky GJ Jr, Mei Q, Hackney DJ, Figlewicz DP, LeBoeuf R, Mundinger TO (2009) Loss of islet sympathetic nerves and impairment of glucagon secretion in the NOD mouse: relationship to invasive insulitis. Diabetologia 52:2602–2611PubMedCrossRef Taborsky GJ Jr, Mei Q, Hackney DJ, Figlewicz DP, LeBoeuf R, Mundinger TO (2009) Loss of islet sympathetic nerves and impairment of glucagon secretion in the NOD mouse: relationship to invasive insulitis. Diabetologia 52:2602–2611PubMedCrossRef
37.
Zurück zum Zitat Patel DG (1983) Lack of glucagon response to hypoglycemia in long-term experimental diabetic rats. Diabetes 32:55–60PubMedCrossRef Patel DG (1983) Lack of glucagon response to hypoglycemia in long-term experimental diabetic rats. Diabetes 32:55–60PubMedCrossRef
38.
Zurück zum Zitat Shi ZQ, Rastogi KS, Lekas M, Efendic S, Drucker DJ, Vranic M (1996) Glucagon response to hypoglycemia is improved by insulin-independent restoration of normoglycemia in diabetic rats. Endocrinology 137:3193–3199PubMedCrossRef Shi ZQ, Rastogi KS, Lekas M, Efendic S, Drucker DJ, Vranic M (1996) Glucagon response to hypoglycemia is improved by insulin-independent restoration of normoglycemia in diabetic rats. Endocrinology 137:3193–3199PubMedCrossRef
Metadaten
Titel
3-D imaging and illustration of the perfusive mouse islet sympathetic innervation and its remodelling in injury
verfasst von
Y.-C. Chiu
T.-E. Hua
Y.-Y. Fu
P. J. Pasricha
S.-C. Tang
Publikationsdatum
01.12.2012
Verlag
Springer-Verlag
Erschienen in
Diabetologia / Ausgabe 12/2012
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-012-2699-6

Weitere Artikel der Ausgabe 12/2012

Diabetologia 12/2012 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.