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. 2008:2008:728763.
doi: 10.1155/2008/728763. Epub 2009 Jan 20.

Islet specific Wnt activation in human type II diabetes

Seung-Hee Lee  1 , Carla Demeterco, Ifat Geron, Annelie Abrahamsson, Fred Levine, Pamela Itkin-Ansari
Affiliations

Islet specific Wnt activation in human type II diabetes

Seung-Hee Lee et al. Exp Diabetes Res. 2008.

Abstract

The Wnt pathway effector gene TCF7L2 has been linked to type II diabetes, making it important to study the role of Wnt signaling in diabetes pathogenesis. We examined the expression of multiple Wnt pathway components in pancreases from normal individuals and type II diabetic individuals. Multiple members of the Wnt signaling pathway, including TCF7L2, Wnt2b, beta-catenin, pGSK3beta, TCF3, cyclinD1, and c-myc, were undetectable or expressed at low levels in islets from nondiabetic individuals, but were also upregulated specifically in islets of type II diabetic patients. Culture of pancreatic tissue and islet isolation led to Wnt activation that was reversed by the Wnt antagonist sFRP, demonstrating that Wnt activation in that setting was due to soluble Wnt factors. These data support a model in which the Wnt pathway plays a dynamic role in the pathogenesis of type II diabetes and suggest manipulation of Wnt signaling as a new approach to beta-cell-directed diabetes therapy.

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Figures

Figure 1
Figure 1
Expression of TCF factors in type II diabetes. TCF7L2 (red in (a)–(d)) and TCF3 (red in (f)–(i)) are absent from islets of nondiabetic individuals (a), (b), (f), and (g), but are present in islets from type II diabetics (c), (d), (h), and (i). Islets are identified by insulin (green in (b), (d), (g), and (i)). Quantitation of TCF7L2 (e) and TCF3 (j) expressions in nondiabetic (n = 4) and type II (n = 7) islets: error bars = mean +/− s.e.m. *P < .05. Scale bars = 50 μm.
Figure 2
Figure 2
Expression of Wnt2b, β-catenin, cyclinD1, and c-myc in type II diabetes. Wnt2b (red in (a), (b), (d), and (e)), β-catenin (red in (f), (g), (i), and (j)), cyclinD1 (red in (k), (l), (n), and (o)), and c-myc (red in (q) and (s)) are absent from islets of nondiabetic individuals (a), (b), (f), (g), (k), (l), (p) and (q), but are present in islets from type II diabetics (d), (e), (i), (j), (n), (o), (r), and (s). Islets are identified by insulin (green in (a), (d), (f), (i), (p), and (r)) or glucagon (l) and (o) and are outlined by a dashed line in (g) to better demonstrate the absence of β-catenin. Quantitation of Wnt2b (c), β-catenin (h), and cyclinD1 (m) expression in non-diabetic (n = 5) and type II (n = 7) islets: error bars = mean +/− s.e.m. *P < .05. Scale bars = 100 μm except for f.g.i.j which are 50 μm.
Figure 3
Figure 3
α-cell hyperplasia in type II diabetes and expression of Wnt4 in α-cells. Immunostaining of pancreas from nondiabetic (a), (c), and (e) and type II diabetic (b), (d), and (f) individuals demonstrates α-cell hyperplasia in type II diabetes (a) and (b) and expression of Wnt4 (red in (c)–(f)) predominantly in α-cells (c)–(f). Scale bar in (a) and (b) = 200 μm and in (c)–(f) = 50 μm.
Figure 4
Figure 4
Wnt signaling is induced in islets in vitro. Western blot analysis (a) indicates that β-catenin is expressed in both cultured purified islets and cultured purified nonendocrine pancreatic clusters (NEPCs). Islets were dithizone picked to 99% purity, verified by qPCR as previously reported (23). As expected, the duct marker CK 19 is expressed at higher levels in NEPCs than in purified islets. Actin expression confirmed equivalent sample loading. (b) and (c) β-catenin (green in (b) and (c)) and somatostatin (red to visualize islets) staining demonstrate a low or absent β-catenin expression in islets of pancreatic tissue removed and fixed immediately postmortem (b) compared with high β-catenin expression in islets of pancreas tissue removed and fixed after the entire pancreas was shipped using the bilayer method to an islet isolation center (c). β-catenin is downregulated in cultured human islets following transplantation under the kidney capsule of Scid mice (d) and (e). Scale bars for (b)–(e): 50 μm. Islets isolated from nondiabetic individuals (n = 3) were cultured for 48 hours in the absence (f), (h), and (k) or presence (g), (i), and (l) of 500 ng/mL of the Wnt inhibitor sFRP. Immunohistochemical analysis of insulin (green) and anti-sFRP (red in (f) and (g)) detects sFRP on islet cells only when sFRP has been added to the culture media. sFRP exposure led to inhibition of β-catenin ((h) versus (i), quantitated in (j)) and c-myc ((k) versus (l), quantitated in (m)). Error bars = mean +/− s.e.m. *P < .05. Scale bars in (f)–(m): 25 μm.
Figure 5
Figure 5
β-catenin is upregulated in islets from type II diabetic patients. Insulin (a) and (c) and β-catenin (b) and (d) are inverely expressed in the pancreas of type II diabetic patients (a)–(d). Islets with weak insulin expression (solid lines) had the highest levels of β-catenin and islets with strong insulin expression (dashed lines) had levels of β-catenin intermediate between the weak insulin expressing islets and islets from nondiabetic individuals. Quantitation of β-catenin expression in β-cells from nondiabetic and type II diabetic individuals with strong (S) and weak (W) insulin staining (e). Insulin staining of weak islets was 3.5-fold less intense than in islets with strong insulin staining. More than 200 islets were examined (P < .05). Amylase (red in (f)) and insulin (green in (g)) colocalized in weak insulin-expressing islets in type II diabetes (solid line) but not in high insulin expressing islets (dashed line) (merged in (h)). Weak insulin expressing islets (marked with solid lines) retained PDX-1 expression (red in (i)) but lost γ-catenin ((j) and (k), islet with strong insulin marked with arrowheads). Weak insulin expressing islets (solid line) contained normal glucagon expressing cells that did not express amylase (l). Scale bars: 50 μm. All images are confocal.
Figure 6
Figure 6
Wnt signaling in high-fat fed mice. In normal mouse pancreas, β-catenin (green in (a) and (b)) is expressed in islets as identified by somatostatin (red in (a)) and colocalizes with insulin (red in (c)). c-myc (red in (d) and (e)) was not expressed in islets of normal mice (marked by dotted lines and glucagon in green in (d)) but was induced in islets and some ducts of high-fat fed mice (islets marked by glucagon in green). C-myc expression is quantitated in (f). At 12 weeks, the time of analysis, high-fat mice were obese (g), and nondiabetic but mildly glucose-intolerant as measured by IPGTT (h). Number of normal mice = 3 and number of high-fat mice = 4 for (f), (g), and (h). Error bars = mean +/− s.e.m. *P < .05. Scale bars: 100 μm.
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