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Treating diet-induced diabetes and obesity with human embryonic stem cell-derived pancreatic progenitor cells and antidiabetic drugs.

Bruin JE, Saber N, Braun N, Fox JK, Mojibian M, Asadi A, Drohan C, O'Dwyer S, Rosman-Balzer DS, Swiss VA, Rezania A, Kieffer TJ - Stem Cell Reports (2015)

Bottom Line: Human embryonic stem cell (hESC)-derived pancreatic progenitor cells effectively reverse hyperglycemia in rodent models of type 1 diabetes, but their capacity to treat type 2 diabetes has not been reported.All combination therapies rapidly improved body weight and co-treatment with either sitagliptin or metformin improved hyperglycemia after only 12 weeks.Therefore, a stem cell-based therapy may be effective for treating type 2 diabetes, particularly in combination with antidiabetic drugs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

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SCID-Beige Mice Rapidly Develop Obesity, Fasting Hyperglycemia, Glucose Intolerance, and Insulin Resistance Following Exposure to HFDs(A and B) Body weight (A) and fasting blood glucose levels (B) were measured during a 14-day acclimation period on normal chow and for 51 days following administration of one of the following diets: 10% fat (black; n = 11 mice), 45% fat (red; n = 11 mice), 60% fat (blue; n = 11 mice), or Western diet (green; n = 11 mice).(C and D) Blood glucose (C, raw values and area under the curve) and plasma mouse insulin levels (D) were assessed during an oral glucose tolerance test (OGTT; n = 4–6 mice per group) on day 47. See Figure S1 for OGTTs at days 5 and 32.(E) An insulin tolerance test (ITT) was performed on day 42 (n = 9–11 mice per group). Glucose levels are presented as a percentage of basal glucose levels (at time 0) and the area above the curve was calculated using 100% as the baseline.(F) Adiposity (% fat) was assessed by DEXA at day 43 in a subset of mice (n = 3 mice per group).(G) Mouse leptin levels were measured on days 47–49 following a 4- to 6-hr morning fast (dashed line indicates the highest standard concentration in the leptin assay). See Figures S1E–S1G for circulating lipid levels.(H) Immunofluorescent staining of epididymal fat from immunocompromised SCID-beige mice fed either a 10% or 60% fat diet for 36 weeks, and from an immunocompetent adult ob/ob mouse. F4/80 and FGF21 are shown as macrophage and adipocyte markers, respectively. Crown-like structures, representing macrophage infiltration, are shown in insets. Scale bars, 200 μm.(A–C and E–G) ∗p < 0.05 versus 10% controls (two-way ANOVA for comparison of multiple time points in line graphs, and one-way ANOVA for bar graphs); (D) ∗p < 0.05 versus time 0 (one-way ANOVA). Data are represented as mean ± SEM (line graphs) or as box-and-whisker plots with individual mice shown as separate data points.See also Figure S6 and Table S2.
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fig1: SCID-Beige Mice Rapidly Develop Obesity, Fasting Hyperglycemia, Glucose Intolerance, and Insulin Resistance Following Exposure to HFDs(A and B) Body weight (A) and fasting blood glucose levels (B) were measured during a 14-day acclimation period on normal chow and for 51 days following administration of one of the following diets: 10% fat (black; n = 11 mice), 45% fat (red; n = 11 mice), 60% fat (blue; n = 11 mice), or Western diet (green; n = 11 mice).(C and D) Blood glucose (C, raw values and area under the curve) and plasma mouse insulin levels (D) were assessed during an oral glucose tolerance test (OGTT; n = 4–6 mice per group) on day 47. See Figure S1 for OGTTs at days 5 and 32.(E) An insulin tolerance test (ITT) was performed on day 42 (n = 9–11 mice per group). Glucose levels are presented as a percentage of basal glucose levels (at time 0) and the area above the curve was calculated using 100% as the baseline.(F) Adiposity (% fat) was assessed by DEXA at day 43 in a subset of mice (n = 3 mice per group).(G) Mouse leptin levels were measured on days 47–49 following a 4- to 6-hr morning fast (dashed line indicates the highest standard concentration in the leptin assay). See Figures S1E–S1G for circulating lipid levels.(H) Immunofluorescent staining of epididymal fat from immunocompromised SCID-beige mice fed either a 10% or 60% fat diet for 36 weeks, and from an immunocompetent adult ob/ob mouse. F4/80 and FGF21 are shown as macrophage and adipocyte markers, respectively. Crown-like structures, representing macrophage infiltration, are shown in insets. Scale bars, 200 μm.(A–C and E–G) ∗p < 0.05 versus 10% controls (two-way ANOVA for comparison of multiple time points in line graphs, and one-way ANOVA for bar graphs); (D) ∗p < 0.05 versus time 0 (one-way ANOVA). Data are represented as mean ± SEM (line graphs) or as box-and-whisker plots with individual mice shown as separate data points.See also Figure S6 and Table S2.

Mentions: All three of the HFDs used in this study (45% fat, 60% fat, and Western) induced rapid increases in fasting body weight (BW; Figure 1A) and blood glucose levels (Figure 1B) compared with low-fat diet (LFD) controls (10% fat). Moreover, after only 5 days, mice in all three HFD groups were severely glucose intolerant relative to LFD controls (Figure S1A), even though no differences in BW were observed at that time (Figure S1B). At 32 days, HFD mice were both glucose intolerant (Figure S1C) and significantly heavier (Figure S1D) than LFD controls. Mice fed 45% and 60% fat diets were overtly insulin resistant at day 42 (higher glucose levels at 10 and 60–120 min post-insulin, and reduced area above the curve relative to LFD controls), whereas mice on the Western diet only showed significant insulin resistance at 10 min after insulin administration (Figure 1E).


Treating diet-induced diabetes and obesity with human embryonic stem cell-derived pancreatic progenitor cells and antidiabetic drugs.

Bruin JE, Saber N, Braun N, Fox JK, Mojibian M, Asadi A, Drohan C, O'Dwyer S, Rosman-Balzer DS, Swiss VA, Rezania A, Kieffer TJ - Stem Cell Reports (2015)

SCID-Beige Mice Rapidly Develop Obesity, Fasting Hyperglycemia, Glucose Intolerance, and Insulin Resistance Following Exposure to HFDs(A and B) Body weight (A) and fasting blood glucose levels (B) were measured during a 14-day acclimation period on normal chow and for 51 days following administration of one of the following diets: 10% fat (black; n = 11 mice), 45% fat (red; n = 11 mice), 60% fat (blue; n = 11 mice), or Western diet (green; n = 11 mice).(C and D) Blood glucose (C, raw values and area under the curve) and plasma mouse insulin levels (D) were assessed during an oral glucose tolerance test (OGTT; n = 4–6 mice per group) on day 47. See Figure S1 for OGTTs at days 5 and 32.(E) An insulin tolerance test (ITT) was performed on day 42 (n = 9–11 mice per group). Glucose levels are presented as a percentage of basal glucose levels (at time 0) and the area above the curve was calculated using 100% as the baseline.(F) Adiposity (% fat) was assessed by DEXA at day 43 in a subset of mice (n = 3 mice per group).(G) Mouse leptin levels were measured on days 47–49 following a 4- to 6-hr morning fast (dashed line indicates the highest standard concentration in the leptin assay). See Figures S1E–S1G for circulating lipid levels.(H) Immunofluorescent staining of epididymal fat from immunocompromised SCID-beige mice fed either a 10% or 60% fat diet for 36 weeks, and from an immunocompetent adult ob/ob mouse. F4/80 and FGF21 are shown as macrophage and adipocyte markers, respectively. Crown-like structures, representing macrophage infiltration, are shown in insets. Scale bars, 200 μm.(A–C and E–G) ∗p < 0.05 versus 10% controls (two-way ANOVA for comparison of multiple time points in line graphs, and one-way ANOVA for bar graphs); (D) ∗p < 0.05 versus time 0 (one-way ANOVA). Data are represented as mean ± SEM (line graphs) or as box-and-whisker plots with individual mice shown as separate data points.See also Figure S6 and Table S2.
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fig1: SCID-Beige Mice Rapidly Develop Obesity, Fasting Hyperglycemia, Glucose Intolerance, and Insulin Resistance Following Exposure to HFDs(A and B) Body weight (A) and fasting blood glucose levels (B) were measured during a 14-day acclimation period on normal chow and for 51 days following administration of one of the following diets: 10% fat (black; n = 11 mice), 45% fat (red; n = 11 mice), 60% fat (blue; n = 11 mice), or Western diet (green; n = 11 mice).(C and D) Blood glucose (C, raw values and area under the curve) and plasma mouse insulin levels (D) were assessed during an oral glucose tolerance test (OGTT; n = 4–6 mice per group) on day 47. See Figure S1 for OGTTs at days 5 and 32.(E) An insulin tolerance test (ITT) was performed on day 42 (n = 9–11 mice per group). Glucose levels are presented as a percentage of basal glucose levels (at time 0) and the area above the curve was calculated using 100% as the baseline.(F) Adiposity (% fat) was assessed by DEXA at day 43 in a subset of mice (n = 3 mice per group).(G) Mouse leptin levels were measured on days 47–49 following a 4- to 6-hr morning fast (dashed line indicates the highest standard concentration in the leptin assay). See Figures S1E–S1G for circulating lipid levels.(H) Immunofluorescent staining of epididymal fat from immunocompromised SCID-beige mice fed either a 10% or 60% fat diet for 36 weeks, and from an immunocompetent adult ob/ob mouse. F4/80 and FGF21 are shown as macrophage and adipocyte markers, respectively. Crown-like structures, representing macrophage infiltration, are shown in insets. Scale bars, 200 μm.(A–C and E–G) ∗p < 0.05 versus 10% controls (two-way ANOVA for comparison of multiple time points in line graphs, and one-way ANOVA for bar graphs); (D) ∗p < 0.05 versus time 0 (one-way ANOVA). Data are represented as mean ± SEM (line graphs) or as box-and-whisker plots with individual mice shown as separate data points.See also Figure S6 and Table S2.
Mentions: All three of the HFDs used in this study (45% fat, 60% fat, and Western) induced rapid increases in fasting body weight (BW; Figure 1A) and blood glucose levels (Figure 1B) compared with low-fat diet (LFD) controls (10% fat). Moreover, after only 5 days, mice in all three HFD groups were severely glucose intolerant relative to LFD controls (Figure S1A), even though no differences in BW were observed at that time (Figure S1B). At 32 days, HFD mice were both glucose intolerant (Figure S1C) and significantly heavier (Figure S1D) than LFD controls. Mice fed 45% and 60% fat diets were overtly insulin resistant at day 42 (higher glucose levels at 10 and 60–120 min post-insulin, and reduced area above the curve relative to LFD controls), whereas mice on the Western diet only showed significant insulin resistance at 10 min after insulin administration (Figure 1E).

Bottom Line: Human embryonic stem cell (hESC)-derived pancreatic progenitor cells effectively reverse hyperglycemia in rodent models of type 1 diabetes, but their capacity to treat type 2 diabetes has not been reported.All combination therapies rapidly improved body weight and co-treatment with either sitagliptin or metformin improved hyperglycemia after only 12 weeks.Therefore, a stem cell-based therapy may be effective for treating type 2 diabetes, particularly in combination with antidiabetic drugs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

Show MeSH
Related in: MedlinePlus