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Molecular mechanism by which pioglitazone preserves pancreatic beta-cells in obese diabetic mice: evidence for acute and chronic actions as a PPARgamma agonist.

Kanda Y, Shimoda M, Hamamoto S, Tawaramoto K, Kawasaki F, Hashiramoto M, Nakashima K, Matsuki M, Kaku K - Am. J. Physiol. Endocrinol. Metab. (2009)

Bottom Line: Pioglitazone preserves pancreatic beta-cell morphology and function in diabetic animal models.The above-mentioned effects of pioglitazone treatment were also observed after 2 days of treatment.Morphometric results for proliferative cell number antigen and 4-hydroxy-2-noneal modified protein were consistent with the results of gene expression analysis.

View Article: PubMed Central - PubMed

Affiliation: Diabetes and Endocrine Division, Kawasaki Medical School, Kurashiki, Japan.

ABSTRACT
Pioglitazone preserves pancreatic beta-cell morphology and function in diabetic animal models. In this study, we investigated the molecular mechanisms by which pioglitazone protects beta-cells in diabetic db/db mice. In addition to the morphological analysis of the islets, gene expression profiles of the pancreatic islet were analyzed using laser capture microdissection and were compared with real-time RT-PCR of db/db and nondiabetic m/m mice treated with or without pioglitazone for 2 wk or 2 days. Pioglitazone treatment (2 wk) ameliorated dysmetabolism, increased islet insulin content, restored glucose-stimulated insulin secretion, and preserved beta-cell mass in db/db mice but had no significant effects in m/m mice. Pioglitazone upregulated genes that promote cell differentiation/proliferation in diabetic and nondiabetic mice. In db/db mice, pioglitazone downregulated the apoptosis-promoting caspase-activated DNase gene and upregulated anti-apoptosis-related genes. The above-mentioned effects of pioglitazone treatment were also observed after 2 days of treatment. By contrast, the oxidative stress-promoting NADPH oxidase gene was downregulated, and antioxidative stress-related genes were upregulated, in db/db mice treated with pioglitazone for 2 wk, rather than 2 days. Morphometric results for proliferative cell number antigen and 4-hydroxy-2-noneal modified protein were consistent with the results of gene expression analysis. The present results strongly suggest that pioglitazone preserves beta-cell mass in diabetic mice mostly by two ways; directly, by acceleration of cell differentiation/proliferation and suppression of apoptosis (acute effect); and indirectly, by deceleration of oxidative stress because of amelioration of the underlying metabolic disorder (chronic effect).

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Effects of 2 wk of pioglitazone treatment on islet morphology (at 12 wk of age). A: representative immunostaining for insulin in pancreatic islet tissue sections from m/m and db/db mice with or without pioglitazone treatment. Effect of pioglitazone on the β-cell ratio (B) and β-cell mass (C). The β-cell ratio and cell mass of each group at 12 wk of age are shown. The β-cell ratio was calculated as a percentage of β-cells to whole islet cells. Open bars, control group; filled bars, pioglitazone group. Data are means ± SE for 5 mice/group. P < 0.05 vs. m/m mice (*) and vs. control group (†).
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Figure 2: Effects of 2 wk of pioglitazone treatment on islet morphology (at 12 wk of age). A: representative immunostaining for insulin in pancreatic islet tissue sections from m/m and db/db mice with or without pioglitazone treatment. Effect of pioglitazone on the β-cell ratio (B) and β-cell mass (C). The β-cell ratio and cell mass of each group at 12 wk of age are shown. The β-cell ratio was calculated as a percentage of β-cells to whole islet cells. Open bars, control group; filled bars, pioglitazone group. Data are means ± SE for 5 mice/group. P < 0.05 vs. m/m mice (*) and vs. control group (†).

Mentions: Figure 2 shows typical immunostaining patterns of pancreatic islet tissues from m/m and db/db mice treated with or without pioglitazone for 2 wk. The islets of db/db mice appeared much larger and more varied in size than m/m mice. Moreover, the islet architecture of db/db mice was disrupted, whereas that of m/m mice appeared normal. The intensity of immunostaining for insulin in islets from db/db mice was less than that in m/m mice.


Molecular mechanism by which pioglitazone preserves pancreatic beta-cells in obese diabetic mice: evidence for acute and chronic actions as a PPARgamma agonist.

Kanda Y, Shimoda M, Hamamoto S, Tawaramoto K, Kawasaki F, Hashiramoto M, Nakashima K, Matsuki M, Kaku K - Am. J. Physiol. Endocrinol. Metab. (2009)

Effects of 2 wk of pioglitazone treatment on islet morphology (at 12 wk of age). A: representative immunostaining for insulin in pancreatic islet tissue sections from m/m and db/db mice with or without pioglitazone treatment. Effect of pioglitazone on the β-cell ratio (B) and β-cell mass (C). The β-cell ratio and cell mass of each group at 12 wk of age are shown. The β-cell ratio was calculated as a percentage of β-cells to whole islet cells. Open bars, control group; filled bars, pioglitazone group. Data are means ± SE for 5 mice/group. P < 0.05 vs. m/m mice (*) and vs. control group (†).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2822485&req=5

Figure 2: Effects of 2 wk of pioglitazone treatment on islet morphology (at 12 wk of age). A: representative immunostaining for insulin in pancreatic islet tissue sections from m/m and db/db mice with or without pioglitazone treatment. Effect of pioglitazone on the β-cell ratio (B) and β-cell mass (C). The β-cell ratio and cell mass of each group at 12 wk of age are shown. The β-cell ratio was calculated as a percentage of β-cells to whole islet cells. Open bars, control group; filled bars, pioglitazone group. Data are means ± SE for 5 mice/group. P < 0.05 vs. m/m mice (*) and vs. control group (†).
Mentions: Figure 2 shows typical immunostaining patterns of pancreatic islet tissues from m/m and db/db mice treated with or without pioglitazone for 2 wk. The islets of db/db mice appeared much larger and more varied in size than m/m mice. Moreover, the islet architecture of db/db mice was disrupted, whereas that of m/m mice appeared normal. The intensity of immunostaining for insulin in islets from db/db mice was less than that in m/m mice.

Bottom Line: Pioglitazone preserves pancreatic beta-cell morphology and function in diabetic animal models.The above-mentioned effects of pioglitazone treatment were also observed after 2 days of treatment.Morphometric results for proliferative cell number antigen and 4-hydroxy-2-noneal modified protein were consistent with the results of gene expression analysis.

View Article: PubMed Central - PubMed

Affiliation: Diabetes and Endocrine Division, Kawasaki Medical School, Kurashiki, Japan.

ABSTRACT
Pioglitazone preserves pancreatic beta-cell morphology and function in diabetic animal models. In this study, we investigated the molecular mechanisms by which pioglitazone protects beta-cells in diabetic db/db mice. In addition to the morphological analysis of the islets, gene expression profiles of the pancreatic islet were analyzed using laser capture microdissection and were compared with real-time RT-PCR of db/db and nondiabetic m/m mice treated with or without pioglitazone for 2 wk or 2 days. Pioglitazone treatment (2 wk) ameliorated dysmetabolism, increased islet insulin content, restored glucose-stimulated insulin secretion, and preserved beta-cell mass in db/db mice but had no significant effects in m/m mice. Pioglitazone upregulated genes that promote cell differentiation/proliferation in diabetic and nondiabetic mice. In db/db mice, pioglitazone downregulated the apoptosis-promoting caspase-activated DNase gene and upregulated anti-apoptosis-related genes. The above-mentioned effects of pioglitazone treatment were also observed after 2 days of treatment. By contrast, the oxidative stress-promoting NADPH oxidase gene was downregulated, and antioxidative stress-related genes were upregulated, in db/db mice treated with pioglitazone for 2 wk, rather than 2 days. Morphometric results for proliferative cell number antigen and 4-hydroxy-2-noneal modified protein were consistent with the results of gene expression analysis. The present results strongly suggest that pioglitazone preserves beta-cell mass in diabetic mice mostly by two ways; directly, by acceleration of cell differentiation/proliferation and suppression of apoptosis (acute effect); and indirectly, by deceleration of oxidative stress because of amelioration of the underlying metabolic disorder (chronic effect).

Show MeSH
Related in: MedlinePlus