Antidiabetic actions of an estrogen receptor β selective agonist - PubMed (original) (raw)

. 2013 Jun;62(6):2015-25.

doi: 10.2337/db12-1562. Epub 2013 Jan 24.

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Antidiabetic actions of an estrogen receptor β selective agonist

Paloma Alonso-Magdalena et al. Diabetes. 2013 Jun.

Abstract

The estrogen receptor β (ERβ) is emerging as an important player in the physiology of the endocrine pancreas. We evaluated the role and antidiabetic actions of the ERβ selective agonist WAY200070 as an insulinotropic molecule. We demonstrate that WAY200070 enhances glucose-stimulated insulin secretion both in mouse and human islets. In vivo experiments showed that a single administration of WAY200070 leads to an increase in plasma insulin levels with a concomitant improved response to a glucose load. Two-week treatment administration increased glucose-induced insulin release and pancreatic β-cell mass and improved glucose and insulin sensitivity. In addition, streptozotocin-nicotinamide-induced diabetic mice treated with WAY200070 exhibited a significant improvement in plasma insulin levels and glucose tolerance as well as a regeneration of pancreatic β-cell mass. Studies performed in db/db mice demonstrated that this compound restored first-phase insulin secretion and enhanced pancreatic β-cell mass. We conclude that ERβ agonists should be considered as new targets for the treatment of diabetes.

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Figures

FIG. 1.

FIG. 1.

In vitro exposure to an ERβ agonist (WAY200070) induced reduction of KATP channel activity and enhanced glucose-induced intracellular calcium concentration signals and insulin secretion. A: WAY200070 100 pmol/L decreased KATP channel activity in isolated pancreatic β-cells from mice (n = 6). B: This was accompanied by a greater increase in global intracellular Ca2+ entry after glucose stimulation (n = 6), as indicated by a greater AUC (inset). C: Insulin release in response to 8 mmol/L glucose, 8 mmol/L glucose and DPN (1 nmol/L), and 8 mmol/L glucose and WAY200070 (100 pmol/L, 1 nmol/L, and 10 nmol/L) was measured in intact mouse islets of Langerhans. Insulin levels were significantly higher in the presence of WAY200070 (n = 8). D: WAY200070-induced insulin secretion from mouse islets exposed to 3, 8, and 16 mmol/L glucose for 1 h (n = 8). WAY200070 was applied at 100 pmol/L. Note that WAY200070 action was significant only when stimulatory glucose concentrations were used. E: Insulin release in response to 8 mmol/L glucose, 8 mmol/L glucose and DPN (1 nmol/L), and 8 mmol/L glucose and WAY200070 (100 pmol/L, 1 nmol/L, and 100 nmol/L) was measured in intact human islets of Langerhans. Data are mean ± SE. *P < 0.05, ***P < 0.001 versus control (Student t test). Statistical analyses between groups in C, D, and E were evaluated by one-way ANOVA, with P < 0.05 considered significant. G, glucose; W, WAY200070.

FIG. 2.

FIG. 2.

Single in vivo administration of the ERβ agonist (WAY200070) improved glucose tolerance. A: Fasted C57BL/6 male mice were injected intraperitoneally with a single dose of WAY200070 3 mg/kg (W3), 10 mg/kg (W10), or 30 mg/kg (W30). In parallel, they were administered a glucose challenge (2 g/kg). Through an IGTT we observed an improvement in glucose response in animals treated with the ERβ agonist at W10. Thus, the AUC (inset) was significantly reduced in this group (n = 5). B: In addition, we measured plasma insulin levels 30 min after the administration of the glucose challenge and the ERβ agonist and detected that glucose-stimulated insulin release was significantly higher in W10 mice than in controls (8–10 mice/group). C: In the fasted state, a single injection of WAY200070 did not have an effect on glucose sensitivity (5 mice/group). We confirmed that this finding was an ERβ-mediated effect by using WT and BERKO mice. D: Fasted WT mice were injected intraperitoneally with a single dose of W10 or vehicle in parallel with a glucose challenge of 2 g/kg. A better response to the glucose load was observed in the animals that received the agonist, with a decreased AUC (inset) (5–7 mice/group). E: No changes in glucose tolerance or the AUC were observed in BERKO mice in response to the agonist W10-treated mice compared with the vehicle-treated mice. F: Glucose-stimulated insulin release was clearly enhanced in W10 WT mice but not in W10 BERKO mice (5–7 mice/group). Data are mean ± SE. *P < 0.05 versus vehicle (Student t test). In A and C, statistical analysis between groups was evaluated by one-way ANOVA, with P < 0.05 considered significant. BERKO, ERβ knockout.

FIG. 3.

FIG. 3.

In vivo administration of the ERβ agonist (WAY200070) in C57BL/6 mice improved glucose homeostasis. A: IGTT performed in C57BL/6 male mice treated with W10 or vehicle (7 mice/group) during a 14-day period. The treatment resulted in better glucose sensitivity and in the reduction of the AUC (inset). B: Insulin levels during an IGTT performed in the same group of animals. Data are provided as the fold increase in plasma insulin (over basal) at 30 min after the glucose bolus injection. Note that there is a marked increased in in vivo insulin release in W10 mice. C: Measurement of β-cell area (area occupied by insulin-positive cells expressed as a percentage of the total area). W10 showed a clear increase of pancreatic β-cell mass compared with vehicle-treated mice. D: Islet size was also increased in W10 mice. E: β-Cell replication measured as the percentage of BrdU-positive cells (7 mice/group). F: β-Cell proliferation rate in cultures of dispersed primary mouse islet cells. Cells were treated with vehicle or WAY200070 (1, 10, and 100 nmol/L) for 2 days. BrdU was added over the same period. Data are mean ± SE. *P < 0.05 versus vehicle (Student t test). In F, the statistical analysis between groups was evaluated by one-way ANOVA.

FIG. 4.

FIG. 4.

Plasma hormones and lipid metabolites in C57BL/6 mice after administration of WAY200070. Plasma was collected from C57BL/6 mice treated with the ERβ agonist W10 or vehicle (6–7 mice/group) during a 14-day period, and insulin (A), leptin (B), TG (C), and glycerol (D) levels were measured. Data are mean ± SE. *P < 0.05 versus vehicle (Student t test). TG, triglyceride.

FIG. 5.

FIG. 5.

In vivo administration of the ERβ agonist (WAY200070) improved glucose tolerance in mildly diabetic mice and restored plasma insulin levels and pancreatic β-cell mass. A: Mild diabetes was induced by the administration of a single dose of STZ 150 mg/kg and NA 1,000 mg/kg. Ten days after the treatment, these animals exhibited moderate hyperglycemia and impaired glucose tolerance compared with controls (8–15 mice/group). The AUC in these mice was significantly increased (inset). *P < 0.05 versus control (Student t test). B: At this point, 1-week treatment with the ERβ agonist resulted in a decrease of fasting glycemia as well as a better sensitivity to a glucose challenge in the W10 diabetic group compared with the vehicle-treated diabetic group (7–8 mice/group). *P < 0.05 diabetic vehicle vs. diabetic W10; #P < 0.05 diabetic vehicle vs. control. C: Plasma insulin levels in diabetic mice treated with WAY200070 during 1 week compared with control and nontreated diabetic mice. We observed that levels of plasma insulin in treated diabetic mice were similar to controls; meanwhile, levels in diabetic mice were significantly reduced (8–10 mice/group). D, E, and F: Measurement of pancreatic β-cell mass and islet size in treated diabetic mice (5 mice/group) and β-cell replication measured as the percentage of BrdU-positive cells (5 mice/group). Data are mean ± SE. Statistical analysis between groups was evaluated by one-way ANOVA, with *P < 0.05 considered significant.

FIG. 6.

FIG. 6.

In vivo administration of the ERβ agonist (WAY200070) in db/db mice enhanced first-phase insulin secretion. A: IGTT performed in db/db mice treated with W10 or vehicle (6–7 mice/group) during a 14-day period. B: Insulin levels during an IGTT performed in the same group of animals. Data are provided as the fold increase in plasma insulin (over basal) at 30 min after the glucose bolus injection. C and D: Measurement of β-cell area (area occupied by insulin-positive cells expressed as a percentage of the total area) and islet size. W10-treated db/db mice showed an increase of pancreatic β-cell mass compared with vehicle-treated db/db mice. E: β-Cell replication measured as the percentage of BrdU-positive cells (6–7 mice/group). Data are mean ± SE. *P < 0.05 versus vehicle (Student t test).

FIG. 7.

FIG. 7.

Plasma hormones, lipid metabolites, and increment of weight in db/db mice. Plasma was collected from W10 db/db or vehicle-treated db/db mice after 14 days of treatment, and insulin (A), leptin (B), TG (C), and glycerol (D) levels were measured. E: Increment of weight in db/db mice during the treatment with W10 or vehicle (6–7 mice/group). Data are mean ± SE. *P < 0.05 versus vehicle (Student t test). TG, triglyceride.

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