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Enhancing pancreatic Beta-cell regeneration in vivo with pioglitazone and alogliptin.

Yin H, Park SY, Wang XJ, Misawa R, Grossman EJ, Tao J, Zhong R, Witkowski P, Bell GI, Chong AS - PLoS ONE (2013)

Bottom Line: Pioglitazone is a stimulator of nuclear receptor peroxisome proliferator-activated receptor gamma while alogliptin is a selective dipeptidyl peptidase IV inhibitor.In a model of syngeneic islet transplantation, immunosuppression with rapamycin and tacrolimus induced an early loss of beta-cell mass, while treatment with insulin implants to maintain normoglycemia and pioglitazone plus alogliptin was able to partially promote beta-cell mass recovery.They also demonstrate the ability of pioglitazone, used either alone or in combination with alogliptin, to enhance regeneration of endogenous islet beta-cells as well as transplanted islets into recipients treated with rapamycin and tacrolimus.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, The University of Chicago, Chicago, Illinois, United States of America.

ABSTRACT

Aims/hypothesis: Pancreatic beta-cells retain limited ability to regenerate and proliferate after various physiologic triggers. Identifying therapies that are able to enhance beta-cell regeneration may therefore be useful for the treatment of both type 1 and type 2 diabetes.

Methods: In this study we investigated endogenous and transplanted beta-cell regeneration by serially quantifying changes in bioluminescence from beta-cells from transgenic mice expressing firefly luciferase under the control of the mouse insulin I promoter. We tested the ability of pioglitazone and alogliptin, two drugs developed for the treatment of type 2 diabetes, to enhance beta-cell regeneration, and also defined the effect of the immunosuppression with rapamycin and tacrolimus on transplanted islet beta mass.

Results: Pioglitazone is a stimulator of nuclear receptor peroxisome proliferator-activated receptor gamma while alogliptin is a selective dipeptidyl peptidase IV inhibitor. Pioglitazone alone, or in combination with alogliptin, enhanced endogenous beta-cell regeneration in streptozotocin-treated mice, while alogliptin alone had modest effects. In a model of syngeneic islet transplantation, immunosuppression with rapamycin and tacrolimus induced an early loss of beta-cell mass, while treatment with insulin implants to maintain normoglycemia and pioglitazone plus alogliptin was able to partially promote beta-cell mass recovery.

Conclusions/interpretation: These data highlight the utility of bioluminescence for serially quantifying functional beta-cell mass in living mice. They also demonstrate the ability of pioglitazone, used either alone or in combination with alogliptin, to enhance regeneration of endogenous islet beta-cells as well as transplanted islets into recipients treated with rapamycin and tacrolimus.

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Effect of alogliptin alone or in combination with pioglitazone on endogenous beta-cell regeneration.Bioluminescent signal (Photons/sec) from endogenous pancreas of albino MIP-luc mice treated with (a) aloglipin alone (Alog 15 or 45 mg/kg/day; 5X/week) or (b) alogliptin (45 mg/kg/day; 5X/week) plus Pio (Pio+Alog; 25 mg/kg/day; 5X/week) from week 6–12 post-STZ. The control No Rx group in (a) and (b) is from Fig. 2a. (c) Representative bioluminescent images of mice treated with Pio+Alog (top) and Pio (bottom) for 6, 8, 10 and 12 weeks. Overall experimental design was as described for Fig. 2. (d) Correlation between bioluminescent signal and histological measure of beta cell mass are provided for the STZ only, STZ with Pio plus alogliptin (Pio/Alog) and untreated, non-diabetic WT mice (WT) (N = 5/group). Representative histology (20X magnification; bar = 100 µm) and correlation between bioluminescent signal and histological measure of beta-cell mass from STZ-induced diabetic mice that were maintained with insulin implants and were untreated (e) or treated from week 6–12 post-STZ with alogliptin plus Pio (f), and sacrificed at 12 weeks post-STZ. Islets from untreated non-diabetic mice are illustrated (γ). Random BG levels at 12 weeks post-STZ (4 weeks after last insulin implant) for the untreated (No Rx), alogliptin only (Alog; 45 mg/kg/day), Pio only (25 mg/kg/day) and both (Pio+Alog) are illustrated in (h). Data are presented as means ± SEM.
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pone-0065777-g003: Effect of alogliptin alone or in combination with pioglitazone on endogenous beta-cell regeneration.Bioluminescent signal (Photons/sec) from endogenous pancreas of albino MIP-luc mice treated with (a) aloglipin alone (Alog 15 or 45 mg/kg/day; 5X/week) or (b) alogliptin (45 mg/kg/day; 5X/week) plus Pio (Pio+Alog; 25 mg/kg/day; 5X/week) from week 6–12 post-STZ. The control No Rx group in (a) and (b) is from Fig. 2a. (c) Representative bioluminescent images of mice treated with Pio+Alog (top) and Pio (bottom) for 6, 8, 10 and 12 weeks. Overall experimental design was as described for Fig. 2. (d) Correlation between bioluminescent signal and histological measure of beta cell mass are provided for the STZ only, STZ with Pio plus alogliptin (Pio/Alog) and untreated, non-diabetic WT mice (WT) (N = 5/group). Representative histology (20X magnification; bar = 100 µm) and correlation between bioluminescent signal and histological measure of beta-cell mass from STZ-induced diabetic mice that were maintained with insulin implants and were untreated (e) or treated from week 6–12 post-STZ with alogliptin plus Pio (f), and sacrificed at 12 weeks post-STZ. Islets from untreated non-diabetic mice are illustrated (γ). Random BG levels at 12 weeks post-STZ (4 weeks after last insulin implant) for the untreated (No Rx), alogliptin only (Alog; 45 mg/kg/day), Pio only (25 mg/kg/day) and both (Pio+Alog) are illustrated in (h). Data are presented as means ± SEM.

Mentions: Based on a recent report that alogliptin added to Pio improved glycaemic control in patients with type 2 diabletes [46], we tested whether alogliptin could improve on the effects of Pio in STZ-induced diabetic MIP-luc mice. At the initiation of treatment with alogliptin alone or in combination with Pio, the bioluminescent intensities in all the groups (N = 5/group) were equivalent. In mice receiving alogliptin alone, either at the 15 or 45 mg/kg dose, the beta-cell mass remained constant over the 6-week treatment group while the beta-cell mass in the control group continued to decline (Fig. 3a). However the differences between the alogliptin-treated and untreated groups were not significant.


Enhancing pancreatic Beta-cell regeneration in vivo with pioglitazone and alogliptin.

Yin H, Park SY, Wang XJ, Misawa R, Grossman EJ, Tao J, Zhong R, Witkowski P, Bell GI, Chong AS - PLoS ONE (2013)

Effect of alogliptin alone or in combination with pioglitazone on endogenous beta-cell regeneration.Bioluminescent signal (Photons/sec) from endogenous pancreas of albino MIP-luc mice treated with (a) aloglipin alone (Alog 15 or 45 mg/kg/day; 5X/week) or (b) alogliptin (45 mg/kg/day; 5X/week) plus Pio (Pio+Alog; 25 mg/kg/day; 5X/week) from week 6–12 post-STZ. The control No Rx group in (a) and (b) is from Fig. 2a. (c) Representative bioluminescent images of mice treated with Pio+Alog (top) and Pio (bottom) for 6, 8, 10 and 12 weeks. Overall experimental design was as described for Fig. 2. (d) Correlation between bioluminescent signal and histological measure of beta cell mass are provided for the STZ only, STZ with Pio plus alogliptin (Pio/Alog) and untreated, non-diabetic WT mice (WT) (N = 5/group). Representative histology (20X magnification; bar = 100 µm) and correlation between bioluminescent signal and histological measure of beta-cell mass from STZ-induced diabetic mice that were maintained with insulin implants and were untreated (e) or treated from week 6–12 post-STZ with alogliptin plus Pio (f), and sacrificed at 12 weeks post-STZ. Islets from untreated non-diabetic mice are illustrated (γ). Random BG levels at 12 weeks post-STZ (4 weeks after last insulin implant) for the untreated (No Rx), alogliptin only (Alog; 45 mg/kg/day), Pio only (25 mg/kg/day) and both (Pio+Alog) are illustrated in (h). Data are presented as means ± SEM.
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Related In: Results  -  Collection

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pone-0065777-g003: Effect of alogliptin alone or in combination with pioglitazone on endogenous beta-cell regeneration.Bioluminescent signal (Photons/sec) from endogenous pancreas of albino MIP-luc mice treated with (a) aloglipin alone (Alog 15 or 45 mg/kg/day; 5X/week) or (b) alogliptin (45 mg/kg/day; 5X/week) plus Pio (Pio+Alog; 25 mg/kg/day; 5X/week) from week 6–12 post-STZ. The control No Rx group in (a) and (b) is from Fig. 2a. (c) Representative bioluminescent images of mice treated with Pio+Alog (top) and Pio (bottom) for 6, 8, 10 and 12 weeks. Overall experimental design was as described for Fig. 2. (d) Correlation between bioluminescent signal and histological measure of beta cell mass are provided for the STZ only, STZ with Pio plus alogliptin (Pio/Alog) and untreated, non-diabetic WT mice (WT) (N = 5/group). Representative histology (20X magnification; bar = 100 µm) and correlation between bioluminescent signal and histological measure of beta-cell mass from STZ-induced diabetic mice that were maintained with insulin implants and were untreated (e) or treated from week 6–12 post-STZ with alogliptin plus Pio (f), and sacrificed at 12 weeks post-STZ. Islets from untreated non-diabetic mice are illustrated (γ). Random BG levels at 12 weeks post-STZ (4 weeks after last insulin implant) for the untreated (No Rx), alogliptin only (Alog; 45 mg/kg/day), Pio only (25 mg/kg/day) and both (Pio+Alog) are illustrated in (h). Data are presented as means ± SEM.
Mentions: Based on a recent report that alogliptin added to Pio improved glycaemic control in patients with type 2 diabletes [46], we tested whether alogliptin could improve on the effects of Pio in STZ-induced diabetic MIP-luc mice. At the initiation of treatment with alogliptin alone or in combination with Pio, the bioluminescent intensities in all the groups (N = 5/group) were equivalent. In mice receiving alogliptin alone, either at the 15 or 45 mg/kg dose, the beta-cell mass remained constant over the 6-week treatment group while the beta-cell mass in the control group continued to decline (Fig. 3a). However the differences between the alogliptin-treated and untreated groups were not significant.

Bottom Line: Pioglitazone is a stimulator of nuclear receptor peroxisome proliferator-activated receptor gamma while alogliptin is a selective dipeptidyl peptidase IV inhibitor.In a model of syngeneic islet transplantation, immunosuppression with rapamycin and tacrolimus induced an early loss of beta-cell mass, while treatment with insulin implants to maintain normoglycemia and pioglitazone plus alogliptin was able to partially promote beta-cell mass recovery.They also demonstrate the ability of pioglitazone, used either alone or in combination with alogliptin, to enhance regeneration of endogenous islet beta-cells as well as transplanted islets into recipients treated with rapamycin and tacrolimus.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, The University of Chicago, Chicago, Illinois, United States of America.

ABSTRACT

Aims/hypothesis: Pancreatic beta-cells retain limited ability to regenerate and proliferate after various physiologic triggers. Identifying therapies that are able to enhance beta-cell regeneration may therefore be useful for the treatment of both type 1 and type 2 diabetes.

Methods: In this study we investigated endogenous and transplanted beta-cell regeneration by serially quantifying changes in bioluminescence from beta-cells from transgenic mice expressing firefly luciferase under the control of the mouse insulin I promoter. We tested the ability of pioglitazone and alogliptin, two drugs developed for the treatment of type 2 diabetes, to enhance beta-cell regeneration, and also defined the effect of the immunosuppression with rapamycin and tacrolimus on transplanted islet beta mass.

Results: Pioglitazone is a stimulator of nuclear receptor peroxisome proliferator-activated receptor gamma while alogliptin is a selective dipeptidyl peptidase IV inhibitor. Pioglitazone alone, or in combination with alogliptin, enhanced endogenous beta-cell regeneration in streptozotocin-treated mice, while alogliptin alone had modest effects. In a model of syngeneic islet transplantation, immunosuppression with rapamycin and tacrolimus induced an early loss of beta-cell mass, while treatment with insulin implants to maintain normoglycemia and pioglitazone plus alogliptin was able to partially promote beta-cell mass recovery.

Conclusions/interpretation: These data highlight the utility of bioluminescence for serially quantifying functional beta-cell mass in living mice. They also demonstrate the ability of pioglitazone, used either alone or in combination with alogliptin, to enhance regeneration of endogenous islet beta-cells as well as transplanted islets into recipients treated with rapamycin and tacrolimus.

Show MeSH
Related in: MedlinePlus