Forma&on of a Baseline Pancrea&c ß‐Cell Mass in Humans is Completed Early in Life Christopher J. Rhodes Ph.D.
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Forma&on of a Baseline Pancrea&c ß‐Cell Mass in Humans is Completed Early in Life
Christopher J. Rhodes Ph.D.
Normal !
Insulin/Glucagon/Somatostatin/Nuclei !
The Study: - 44 normal pancreatic specimens (BMI ≤30), age 24 weeks premature – 72 years.
- Immunofluorescence analysis, confocal microscopy, morphometric counting.
- Examine the growth and formation of the pancreatic ß-cell population relative to other associated cell types
- Insulin/Glucagon/Somatostatin/Nuclei (DAPI)
Type-1 !
Insulin/Glucagon/Somatostatin/Nuclei !
Average islet d
iameter (µ
m)
0
50
100
150
200
‐4 ‐1.5 0 0.5 7 8 2 4 6 8 10 20 80
AGE (Months) AGE (Years)
Average islet diameter
Islet ß
‐Cell: α‐Cell R
a>o
0
0.5
1.0
1.5
2.0
‐4 ‐1.5 0 0.5 7 8 AGE (Months)
2 4 6 8 10 20 80
AGE (Years)
2.5
3.0
Human ß-Cell to α-Cell Ratio
Human ß-Cell to δ-Cell Ratio
Islet ß
‐Cell: δ‐Ce
ll Ra
>o
0
2
4
6
8
‐4 ‐1.5 0 AGE (Months)
2 4 6 8 10 20 80
AGE (Years)
10
12
14
0.5 7 8
Neuronal Associa&on to Pancrea&c Islets ‐ ‐ Insulin/Tuj‐1(Neuronal Specific MAP2)/Nuclei (DAPI)
Insulin/Tuj-1/Nuclei ! Insulin/Tuj-1/Nuclei !
Axons!
‐ Insulin/Glial fibrillary acidic protein (GFAP)/Nuclei (DAPI)
Insulin/GFAP/Nuclei !Insulin/GFAP/Nuclei ! Glial Cells!
Human Pancrea&c Neurons and ß‐Cells Stay Proximal to Each Other Throughout Life
≤25 ≤50 ≤100 ≥200 Distance of a neuron from an islet (µm)
Percen
tage of n
eurons
proxim
al to
an islet
Developmental
0
20
40
60
≤25 ≤50 ≤100 ≥200 Distance of a neuron from an islet (µm)
0
20
40
60 Pe
rcen
tage of n
eurons
proxim
al to
an islet
Neonatal
≤25 ≤50 ≤100 ≥200 Distance of a neuron from an islet (µm)
0
20
40
60 Pe
rcen
tage of n
eurons
proxim
al to
an islet
Childhood
Adolescence
≤25 ≤50 ≤100 ≥200 Distance of a neuron from an islet (µm)
0
20
40
60 Pe
rcen
tage of n
eurons
proxim
al to
an islet
Adulthood
≤25 ≤50 ≤100 ≥200 Distance of a neuron from an islet (µm)
0
20
40
60 Pe
rcen
tage of n
eurons
proxim
al to
an islet
Pancrea&c ß‐Cell and Ductal Cell Growth ‐ ‐ Insulin/Cytokera&n‐19 (CK‐19)/Ki67/Nuclei (DAPI) ‐ ß‐Cell/Ductal Cell/Prolifera&on/Nuclei
6 Months 8 Months 17 Months
‘ß-Cell Neogenesis’! ß-Cell Proliferation! Ductal-Cell Proliferation!
% In
sulin
+/CK
‐19+ cells & insulin
+ cells associated
in pan
crea>c ducts
0
1
2
3
4
‐4 ‐1.5 0 0.5 7 8 AGE (Months)
2 4 6 8 10 20 80
AGE (Years)
5
6
Human ß-Cell Neogenesis
% In
sulin
+/Ki67
+ cells of total insulin
+ cells
0
1
2
3
4
‐4 ‐1.5 0 0.5 7 8 2 4 6 8 10 20 80
AGE (Months) AGE (Years)
Human ß-Cell Replication
% CK‐19
+/Ki67
+ cells of total CK‐19
+ cells
0
2
4
6
8
‐4 ‐1.5 0 0.5 7 8 AGE (Months)
2 4 6 8 10 20 80
AGE (Years)
Human Pancreatic Ductal Cell Replication
% cross se
c>on
al area occupied
by islet cells
0
5
10
15
20
25
30
‐4 ‐1.5 0 0.5 7 8 AGE (Months)
2 4 6 8 10 20 80
AGE (Years)
Cross‐sec&onal islet area of pancreas
Summary:
• Pancrea&c islet size ~doubles in the first 2 years of life • ß‐cell to a‐cell ra&o ~triples in the first 2 years of life • ß‐cell to δ‐cell ra&o increases ~20‐fold in the first 20 years of life • Pancrea&c neurons and islets closely associate throughout life • ‘ß‐cell neogenesis’ mostly observed developmentally • Neonatal burst of ß‐cell prolifera&on drives early increase in ß‐cell numbers • Neonatal burst of ductal‐cell prolifera&on associated with exocrine expansion
• Baseline complement of ß‐cells is set ≤ 5 years human life
Acknowledgements:
Brigid Gregg Patrick Moore Damien Demozay Mei Li Aliya Husain Amy J. Wright Mark A. Atkinson
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