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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 pioglitazone on endogenous beta-cell regeneration.(a) Overview of experimental design. Following treatment with STZ, diabetic mice (BG >400 mg/dl) received approximately 200 syngeneic C57BL/6 islets under the kidney capsule for 6 weeks (Islet Txp), and then underwent a nephrectomy to remove the transplanted islets. (b) BG was monitored every 1–2 weeks after nephrectomy and the number of mice with normoglycemia (<250 mg/dl) at ≥13 weeks post-STZ ± Pio treatment for 30 or 100 days (Pio-30D or Pio-100D) are indicated. Data are presented as mean (N = 11–16/group) ± standard error of mean (SEM). (c) After 4 h fasting, IPGTT was performed on only the mice with normoglycemia (<250 mg/dl) at ≥12 weeks post-STZ compared to control non-diabetic C57BL/6 mice. (d) Pancreatic beta-cell mass at week 2 post-STZ or week 14 post-STZ and islet transplant receiving CMC (No Rx) or Pio (25 mg/kg/day; Pio) of 3–4 randomly selected mice still alive and with normoglycemia (<250 mg/dl). Data are mean beta-cell mass of 3–4/group (mg/pancreas ± SEM).
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pone-0065777-g001: Effect of pioglitazone on endogenous beta-cell regeneration.(a) Overview of experimental design. Following treatment with STZ, diabetic mice (BG >400 mg/dl) received approximately 200 syngeneic C57BL/6 islets under the kidney capsule for 6 weeks (Islet Txp), and then underwent a nephrectomy to remove the transplanted islets. (b) BG was monitored every 1–2 weeks after nephrectomy and the number of mice with normoglycemia (<250 mg/dl) at ≥13 weeks post-STZ ± Pio treatment for 30 or 100 days (Pio-30D or Pio-100D) are indicated. Data are presented as mean (N = 11–16/group) ± standard error of mean (SEM). (c) After 4 h fasting, IPGTT was performed on only the mice with normoglycemia (<250 mg/dl) at ≥12 weeks post-STZ compared to control non-diabetic C57BL/6 mice. (d) Pancreatic beta-cell mass at week 2 post-STZ or week 14 post-STZ and islet transplant receiving CMC (No Rx) or Pio (25 mg/kg/day; Pio) of 3–4 randomly selected mice still alive and with normoglycemia (<250 mg/dl). Data are mean beta-cell mass of 3–4/group (mg/pancreas ± SEM).

Mentions: We first investigated the effect of Pio in a previously reported model of functional beta-cell regeneration in the native pancreas following STZ-induced diabetes [17]. Diabetic C57BL/6 mice received ≥200 syngeneic islets under the kidney capsule to maintain normoglycemia for 6 weeks (mean BG ≤150 mg/dl) (Fig. 1a). The transplanted islets were then removed and BG monitored for a further 8 weeks. Functional regeneration of the islet beta-cells in the pancreas, defined as the maintenance of random BG levels at <250 mg/dl after the removal of the transplanted islets, was observed in 37.5% (6 of 16) of the untreated mice, with a mean BG of 340±36 mg/dl over the 8 week monitoring period. In mice that received 25 mg/kg/day Pio for 30 days from the onset of STZ-induced diabetes, stable normoglycemia (<250 mg/dl) was observed in 9 of the 11 mice (Fig. 1b). The mean BG levels in the 30-day Pio-treated mice over the monitoring period was 242±85 mg/dl and was significantly lower (p≤0.01) than the untreated group. To test whether the effect of Pio could be improved, we extended treatment from 30 to 100 days. Stable normoglycemia was observed in 8 of the 11 mice and the overall BG level of the 100-day Pio-treated mice was 219±22 mg/dl. Thus, treatment for 100 days with Pio resulted in significantly lower (p≤0.005) BG levels compared to the untreated and 30-day Pio-treatment groups.


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 pioglitazone on endogenous beta-cell regeneration.(a) Overview of experimental design. Following treatment with STZ, diabetic mice (BG >400 mg/dl) received approximately 200 syngeneic C57BL/6 islets under the kidney capsule for 6 weeks (Islet Txp), and then underwent a nephrectomy to remove the transplanted islets. (b) BG was monitored every 1–2 weeks after nephrectomy and the number of mice with normoglycemia (<250 mg/dl) at ≥13 weeks post-STZ ± Pio treatment for 30 or 100 days (Pio-30D or Pio-100D) are indicated. Data are presented as mean (N = 11–16/group) ± standard error of mean (SEM). (c) After 4 h fasting, IPGTT was performed on only the mice with normoglycemia (<250 mg/dl) at ≥12 weeks post-STZ compared to control non-diabetic C57BL/6 mice. (d) Pancreatic beta-cell mass at week 2 post-STZ or week 14 post-STZ and islet transplant receiving CMC (No Rx) or Pio (25 mg/kg/day; Pio) of 3–4 randomly selected mice still alive and with normoglycemia (<250 mg/dl). Data are mean beta-cell mass of 3–4/group (mg/pancreas ± SEM).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3675063&req=5

pone-0065777-g001: Effect of pioglitazone on endogenous beta-cell regeneration.(a) Overview of experimental design. Following treatment with STZ, diabetic mice (BG >400 mg/dl) received approximately 200 syngeneic C57BL/6 islets under the kidney capsule for 6 weeks (Islet Txp), and then underwent a nephrectomy to remove the transplanted islets. (b) BG was monitored every 1–2 weeks after nephrectomy and the number of mice with normoglycemia (<250 mg/dl) at ≥13 weeks post-STZ ± Pio treatment for 30 or 100 days (Pio-30D or Pio-100D) are indicated. Data are presented as mean (N = 11–16/group) ± standard error of mean (SEM). (c) After 4 h fasting, IPGTT was performed on only the mice with normoglycemia (<250 mg/dl) at ≥12 weeks post-STZ compared to control non-diabetic C57BL/6 mice. (d) Pancreatic beta-cell mass at week 2 post-STZ or week 14 post-STZ and islet transplant receiving CMC (No Rx) or Pio (25 mg/kg/day; Pio) of 3–4 randomly selected mice still alive and with normoglycemia (<250 mg/dl). Data are mean beta-cell mass of 3–4/group (mg/pancreas ± SEM).
Mentions: We first investigated the effect of Pio in a previously reported model of functional beta-cell regeneration in the native pancreas following STZ-induced diabetes [17]. Diabetic C57BL/6 mice received ≥200 syngeneic islets under the kidney capsule to maintain normoglycemia for 6 weeks (mean BG ≤150 mg/dl) (Fig. 1a). The transplanted islets were then removed and BG monitored for a further 8 weeks. Functional regeneration of the islet beta-cells in the pancreas, defined as the maintenance of random BG levels at <250 mg/dl after the removal of the transplanted islets, was observed in 37.5% (6 of 16) of the untreated mice, with a mean BG of 340±36 mg/dl over the 8 week monitoring period. In mice that received 25 mg/kg/day Pio for 30 days from the onset of STZ-induced diabetes, stable normoglycemia (<250 mg/dl) was observed in 9 of the 11 mice (Fig. 1b). The mean BG levels in the 30-day Pio-treated mice over the monitoring period was 242±85 mg/dl and was significantly lower (p≤0.01) than the untreated group. To test whether the effect of Pio could be improved, we extended treatment from 30 to 100 days. Stable normoglycemia was observed in 8 of the 11 mice and the overall BG level of the 100-day Pio-treated mice was 219±22 mg/dl. Thus, treatment for 100 days with Pio resulted in significantly lower (p≤0.005) BG levels compared to the untreated and 30-day Pio-treatment groups.

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