3-D imaging of islets in obesity: formation of the islet-duct complex and neurovascular remodeling in young hyperphagic mice.
BACKGROUND
Obesity and insulin resistance lead to islet hyperplasia. However, how the islet remodeling influences the pancreatic environment and the associated neurovascular networks is largely unknown. The lack of information is primarily due to the difficulty of global visualization of the hyperplasic islet (>200 μm) and the neurovascular environment with high definition.


METHODS
We modulated the pancreatic optical property to achieve 3-dimensional (3-D) whole-islet histology and to integrate transmitted light microscopy (which provides the ground-truth tissue information) with confocal fluorescence imaging. The new optical and imaging conditions were used to globally examine the hyperplastic islets of the young (2 months) obese db/db and ob/ob mice, which otherwise cannot be easily portrayed by the standard microtome-based histology. The voxel-based islet micrographs were digitally processed for stereo projection and qualitative and quantitative analyses of the islet tissue networks.


RESULTS
Paired staining and imaging of the pancreatic islets, ducts and neurovascular networks reveal the unexpected formation of the 'neuro-insular-ductal complex' in the young obese mice. The complex consists of the peri- and/or intra-islet ducts and prominent peri-ductal sympathetic nerves; the latter contributes to a marked increase in islet sympathetic innervation. In vascular characterization, we identify a decreased perivascular density of the ob/ob islet pericytes, which adapt to ensheathing the dilated microvessels with hypertrophic processes.


CONCLUSIONS
Modulation of pancreatic optical property enables 3-D panoramic examination of islets in the young hyperphagic mice to reveal the formation of the islet-duct complex and neurovascular remodeling. On the basis of the morphological proximity of the remodeled tissue networks, we propose a reactive islet microenvironment consisting of the endocrine cells, ductal epithelium and neurovascular tissues in response to the metabolic challenge that is experienced early in life.
Connectomics Research Center, National Tsing Hua University, Hsinchu, Taiwan.|Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.|Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan.
H-J
HJ
Chien
Connectomics Research Center, National Tsing Hua University, Hsinchu, Taiwan.|Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.|Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan.
S-J
SJ
Peng
Connectomics Research Center, National Tsing Hua University, Hsinchu, Taiwan.|Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.|Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan.
T-E
TE
Hua
Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.|Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
C-H
CH
Kuo
Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.|Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
J-H
JH
Juang
Connectomics Research Center, National Tsing Hua University, Hsinchu, Taiwan.|Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.|Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan.
S-C
SC
Tang
D000818:Animals; D006963:Hyperphagia / Q000473:pathology*; D021621:Imaging, Three-Dimensional; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000098:blood supply* / Q000294:innervation* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008820:Mice, Obese; D009473:Neuronal Plasticity; D009765:Obesity / Q000378:metabolism / Q000473:pathology*; D013564:Sympathetic Nervous System / Q000473:pathology*