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Insulin downregulates the expression of the Ca2+-activated nonselective cation channel TRPM5 in pancreatic islets from leptin-deficient mouse models.

Colsoul B, Jacobs G, Philippaert K, Owsianik G, Segal A, Nilius B, Voets T, Schuit F, Vennekens R - Pflugers Arch. (2013)

Bottom Line: The glucose-induced Ca(2+) oscillation pattern in db/db and ob/ob islets mimicked those of Trpm5 (-/-) islets.Leptin treatment had no additional effect on Trpm5 expression levels when plasma insulin levels were comparable to those of the vehicle-injected control group.In murine β cell line, MIN6, insulin downregulated TRPM5 expression in a dose-dependent manner, unlike glucose or leptin.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Ion Channel Research, KU Leuven, Herestraat 49, bus 802, Leuven, 3000, Belgium.

ABSTRACT
We recently proposed that the transient receptor potential melastatin 5 (TRPM5) cation channel contributes to glucose-induced electrical activity of the β cell and positively influences glucose-induced insulin release and glucose homeostasis. In this study, we investigated Trpm5 expression and function in pancreatic islets from mouse models of type II diabetes. Gene expression analysis revealed a strong reduction of Trpm5 mRNA levels in pancreatic islets of db/db and ob/ob mice. The glucose-induced Ca(2+) oscillation pattern in db/db and ob/ob islets mimicked those of Trpm5 (-/-) islets. Leptin treatment of ob/ob mice not only reversed the diabetic phenotype seen in these mice but also upregulated Trpm5 expression. Leptin treatment had no additional effect on Trpm5 expression levels when plasma insulin levels were comparable to those of the vehicle-injected control group. In murine β cell line, MIN6, insulin downregulated TRPM5 expression in a dose-dependent manner, unlike glucose or leptin. In conclusion, our data show that increased plasma insulin levels downregulate TRPM5 expression in pancreatic islets from leptin-deficient mouse models of type 2 diabetes.

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No effect of dietary compounds on Trpm5 expression. a–c Metabolic phenotype of WT mice that received either a high glucose diet (containing ≥50 % glucose and ≥12+ oligosaccharides/dextrines) or a high fat diet (containing 30.2 % fat) during 14 weeks. a Bodyweight in WT mice that had received a normal, a high glucose, or a high fat diet during 14 weeks. b, c Average plasma glucose (b) and insulin levels (c) over the course of the experiment in mice receiving a normal, a high glucose, or a high fat diet during 14 weeks. d Islet Trpm5 expression levels after 14 weeks of diet. Trpm5 expression is normalized to the average Trpm5 expression in islets from age-matched mice that received a normal diet. N = 4–6 mice per group, *p < 0.05, ***p < 0.001 vs. WT mice on a normal diet
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Fig3: No effect of dietary compounds on Trpm5 expression. a–c Metabolic phenotype of WT mice that received either a high glucose diet (containing ≥50 % glucose and ≥12+ oligosaccharides/dextrines) or a high fat diet (containing 30.2 % fat) during 14 weeks. a Bodyweight in WT mice that had received a normal, a high glucose, or a high fat diet during 14 weeks. b, c Average plasma glucose (b) and insulin levels (c) over the course of the experiment in mice receiving a normal, a high glucose, or a high fat diet during 14 weeks. d Islet Trpm5 expression levels after 14 weeks of diet. Trpm5 expression is normalized to the average Trpm5 expression in islets from age-matched mice that received a normal diet. N = 4–6 mice per group, *p < 0.05, ***p < 0.001 vs. WT mice on a normal diet

Mentions: One of the most striking features of db/db and ob/ob mice is the pronounced obesity, caused by hyperphagia. This increased food intake leads to higher intake of specific dietary compounds, such as glucose and fat. To investigate whether this could influence Trpm5 expression levels in pancreatic islets, we fed normal WT mice during 14 weeks with a diet containing either ≥50 % glucose and ≥12 % oligosaccharides/dextrines (= high glucose diet) or 30.2 % fat (= high fat diet). After 14 weeks, the high fat (but not the high glucose) fed mice had a significantly increased bodyweight (normal diet 29.71 ± 0.53 g; high glucose diet 30.34 ± 1.04 g, p = 0.56 vs. normal diet; high fat diet 46.23 ± 0.67 g, p = 5.13−11 vs. normal diet; n = 4–6 per group; see Fig. 3a). There was a tendency in both groups towards higher plasma glucose levels (normal diet 166.6 ± 2.8 mg/dl; high glucose diet 177.7 ± 4.4 mg/dl, p = 0.042 vs. normal diet; high fat diet 175.5 ± 4.0 mg/dl, p = 0.078 vs. normal diet, n = 4–6 per group; see Fig. 3b) and plasma insulin levels were slightly elevated by both diets (normal diet 0.8 ± 0.07 ng/ml; high glucose diet 1.36 ± 0.22 ng/ml, p = 0.025 vs. normal diet; high fat diet 2.9 ± 0.37 ng/ml, p = 0.00046 vs. normal diet, n = 4–6 per group; see Fig. 3c). However, neither the high glucose diet (normal diet 1.0 ± 0.07 vs. high glucose diet 0.93 ± 0.1, p = 0.7096; n = 4–6 per group) nor the high fat diet (normal diet 0.99 ± 0.14 vs. high fat diet 0.98 ± 0.18, p = 0.92, n = 4–6 per group; see Fig. 3d) altered islet Trpm5 expression, suggesting that dietary compounds are not responsible for the altered Trpm5 expression in db/db and ob/ob islets. As the high fat mice also developed obesity, comparable to that observed in db/db mice, these data exclude obesity as such being causative of impaired Trpm5 expression.Fig. 3


Insulin downregulates the expression of the Ca2+-activated nonselective cation channel TRPM5 in pancreatic islets from leptin-deficient mouse models.

Colsoul B, Jacobs G, Philippaert K, Owsianik G, Segal A, Nilius B, Voets T, Schuit F, Vennekens R - Pflugers Arch. (2013)

No effect of dietary compounds on Trpm5 expression. a–c Metabolic phenotype of WT mice that received either a high glucose diet (containing ≥50 % glucose and ≥12+ oligosaccharides/dextrines) or a high fat diet (containing 30.2 % fat) during 14 weeks. a Bodyweight in WT mice that had received a normal, a high glucose, or a high fat diet during 14 weeks. b, c Average plasma glucose (b) and insulin levels (c) over the course of the experiment in mice receiving a normal, a high glucose, or a high fat diet during 14 weeks. d Islet Trpm5 expression levels after 14 weeks of diet. Trpm5 expression is normalized to the average Trpm5 expression in islets from age-matched mice that received a normal diet. N = 4–6 mice per group, *p < 0.05, ***p < 0.001 vs. WT mice on a normal diet
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig3: No effect of dietary compounds on Trpm5 expression. a–c Metabolic phenotype of WT mice that received either a high glucose diet (containing ≥50 % glucose and ≥12+ oligosaccharides/dextrines) or a high fat diet (containing 30.2 % fat) during 14 weeks. a Bodyweight in WT mice that had received a normal, a high glucose, or a high fat diet during 14 weeks. b, c Average plasma glucose (b) and insulin levels (c) over the course of the experiment in mice receiving a normal, a high glucose, or a high fat diet during 14 weeks. d Islet Trpm5 expression levels after 14 weeks of diet. Trpm5 expression is normalized to the average Trpm5 expression in islets from age-matched mice that received a normal diet. N = 4–6 mice per group, *p < 0.05, ***p < 0.001 vs. WT mice on a normal diet
Mentions: One of the most striking features of db/db and ob/ob mice is the pronounced obesity, caused by hyperphagia. This increased food intake leads to higher intake of specific dietary compounds, such as glucose and fat. To investigate whether this could influence Trpm5 expression levels in pancreatic islets, we fed normal WT mice during 14 weeks with a diet containing either ≥50 % glucose and ≥12 % oligosaccharides/dextrines (= high glucose diet) or 30.2 % fat (= high fat diet). After 14 weeks, the high fat (but not the high glucose) fed mice had a significantly increased bodyweight (normal diet 29.71 ± 0.53 g; high glucose diet 30.34 ± 1.04 g, p = 0.56 vs. normal diet; high fat diet 46.23 ± 0.67 g, p = 5.13−11 vs. normal diet; n = 4–6 per group; see Fig. 3a). There was a tendency in both groups towards higher plasma glucose levels (normal diet 166.6 ± 2.8 mg/dl; high glucose diet 177.7 ± 4.4 mg/dl, p = 0.042 vs. normal diet; high fat diet 175.5 ± 4.0 mg/dl, p = 0.078 vs. normal diet, n = 4–6 per group; see Fig. 3b) and plasma insulin levels were slightly elevated by both diets (normal diet 0.8 ± 0.07 ng/ml; high glucose diet 1.36 ± 0.22 ng/ml, p = 0.025 vs. normal diet; high fat diet 2.9 ± 0.37 ng/ml, p = 0.00046 vs. normal diet, n = 4–6 per group; see Fig. 3c). However, neither the high glucose diet (normal diet 1.0 ± 0.07 vs. high glucose diet 0.93 ± 0.1, p = 0.7096; n = 4–6 per group) nor the high fat diet (normal diet 0.99 ± 0.14 vs. high fat diet 0.98 ± 0.18, p = 0.92, n = 4–6 per group; see Fig. 3d) altered islet Trpm5 expression, suggesting that dietary compounds are not responsible for the altered Trpm5 expression in db/db and ob/ob islets. As the high fat mice also developed obesity, comparable to that observed in db/db mice, these data exclude obesity as such being causative of impaired Trpm5 expression.Fig. 3

Bottom Line: The glucose-induced Ca(2+) oscillation pattern in db/db and ob/ob islets mimicked those of Trpm5 (-/-) islets.Leptin treatment had no additional effect on Trpm5 expression levels when plasma insulin levels were comparable to those of the vehicle-injected control group.In murine β cell line, MIN6, insulin downregulated TRPM5 expression in a dose-dependent manner, unlike glucose or leptin.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Ion Channel Research, KU Leuven, Herestraat 49, bus 802, Leuven, 3000, Belgium.

ABSTRACT
We recently proposed that the transient receptor potential melastatin 5 (TRPM5) cation channel contributes to glucose-induced electrical activity of the β cell and positively influences glucose-induced insulin release and glucose homeostasis. In this study, we investigated Trpm5 expression and function in pancreatic islets from mouse models of type II diabetes. Gene expression analysis revealed a strong reduction of Trpm5 mRNA levels in pancreatic islets of db/db and ob/ob mice. The glucose-induced Ca(2+) oscillation pattern in db/db and ob/ob islets mimicked those of Trpm5 (-/-) islets. Leptin treatment of ob/ob mice not only reversed the diabetic phenotype seen in these mice but also upregulated Trpm5 expression. Leptin treatment had no additional effect on Trpm5 expression levels when plasma insulin levels were comparable to those of the vehicle-injected control group. In murine β cell line, MIN6, insulin downregulated TRPM5 expression in a dose-dependent manner, unlike glucose or leptin. In conclusion, our data show that increased plasma insulin levels downregulate TRPM5 expression in pancreatic islets from leptin-deficient mouse models of type 2 diabetes.

Show MeSH
Related in: MedlinePlus