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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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Changes in body weight (A), fasting blood glucose (B), fasting plasma insulin (C), serum adiponectin (D), triglyceride (TG; E), nonesterified fatty acid (NEFA; F), islet TG content (G), and islet insulin content (H) in nondiabetic m/m mice and diabetic db/db mice treated with or without pioglitazone for 2 wk (long-term study). The daily dose of pioglitazone was 30 mg/kg body wt, and the control group was administered vehicle. Open bars, control group; filled bars, pioglitazone group. Data are means ± SE for 5 mice/group. *P < 0.05
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Figure 1: Changes in body weight (A), fasting blood glucose (B), fasting plasma insulin (C), serum adiponectin (D), triglyceride (TG; E), nonesterified fatty acid (NEFA; F), islet TG content (G), and islet insulin content (H) in nondiabetic m/m mice and diabetic db/db mice treated with or without pioglitazone for 2 wk (long-term study). The daily dose of pioglitazone was 30 mg/kg body wt, and the control group was administered vehicle. Open bars, control group; filled bars, pioglitazone group. Data are means ± SE for 5 mice/group. *P < 0.05

Mentions: At baseline (10 wk of age), body weight, fasting blood glucose (FBG) and fasting plasma insulin (FIRI) concentrations were similar between the control and pioglitazone groups for either db/db or m/m mice (data not shown). At 12 wk of age, body weight, FBG, FIRI, TG, and NEFA were significantly greater, and plasma adiponectin concentration was lower in db/db mice compared with m/m mice (Fig. 1, A–F).


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)

Changes in body weight (A), fasting blood glucose (B), fasting plasma insulin (C), serum adiponectin (D), triglyceride (TG; E), nonesterified fatty acid (NEFA; F), islet TG content (G), and islet insulin content (H) in nondiabetic m/m mice and diabetic db/db mice treated with or without pioglitazone for 2 wk (long-term study). The daily dose of pioglitazone was 30 mg/kg body wt, and the control group was administered vehicle. Open bars, control group; filled bars, pioglitazone group. Data are means ± SE for 5 mice/group. *P < 0.05
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Changes in body weight (A), fasting blood glucose (B), fasting plasma insulin (C), serum adiponectin (D), triglyceride (TG; E), nonesterified fatty acid (NEFA; F), islet TG content (G), and islet insulin content (H) in nondiabetic m/m mice and diabetic db/db mice treated with or without pioglitazone for 2 wk (long-term study). The daily dose of pioglitazone was 30 mg/kg body wt, and the control group was administered vehicle. Open bars, control group; filled bars, pioglitazone group. Data are means ± SE for 5 mice/group. *P < 0.05
Mentions: At baseline (10 wk of age), body weight, fasting blood glucose (FBG) and fasting plasma insulin (FIRI) concentrations were similar between the control and pioglitazone groups for either db/db or m/m mice (data not shown). At 12 wk of age, body weight, FBG, FIRI, TG, and NEFA were significantly greater, and plasma adiponectin concentration was lower in db/db mice compared with m/m mice (Fig. 1, A–F).

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