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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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Leptin treatment of leptin-deficient ob/ob mice causes a reversal of the diabetic phenotype and an upregulation of islet Trpm5 expression. Metabolic phenotype of ob/ob mice that were injected either with 1 mg leptin/kg bodyweight or with vehicle during 5 weeks. a–c Bodyweight (a), plasma glucose (b), and plasma insulin levels (c) were measured on a daily (bodyweight) or a weekly (plasma glucose and insulin) basis. There was a statistically significant difference of bodyweight between the two groups starting from day 8. dTrpm5 mRNA expression in freshly isolated pancreatic islets from vehicle- and leptin-injected ob/ob mice after 5 weeks of treatment. Data were normalized to the average Trpm5 expression in islets from vehicle-injected mice. N = 10 mice per group, **p < 0.01, ***p < 0.001
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Fig4: Leptin treatment of leptin-deficient ob/ob mice causes a reversal of the diabetic phenotype and an upregulation of islet Trpm5 expression. Metabolic phenotype of ob/ob mice that were injected either with 1 mg leptin/kg bodyweight or with vehicle during 5 weeks. a–c Bodyweight (a), plasma glucose (b), and plasma insulin levels (c) were measured on a daily (bodyweight) or a weekly (plasma glucose and insulin) basis. There was a statistically significant difference of bodyweight between the two groups starting from day 8. dTrpm5 mRNA expression in freshly isolated pancreatic islets from vehicle- and leptin-injected ob/ob mice after 5 weeks of treatment. Data were normalized to the average Trpm5 expression in islets from vehicle-injected mice. N = 10 mice per group, **p < 0.01, ***p < 0.001

Mentions: Five-week-old ob/ob mice were daily injected with a dose of 1 mg/kg bodyweight leptin i.p. during 5 weeks and compared to ob/ob mice that received daily vehicle injections. Leptin injections decreased the daily food intake per mouse (vehicle-injected 5.83 ± 0.05 vs. leptin-injected 3.31 ± 0.19 g/day/mouse). During the course of the experiment, the bodyweight of the vehicle-treated group increased much faster as compared to the leptin-injected group, with a statistically significant difference starting from day 8, reaching bodyweights of 44.5 ± 1.7 g for the vehicle-injected group and 35.6 ± 1.0 g for the leptin-injected group after 36 days (n = 10 per group, p = 0.000663, see also Fig. 4a). After 5 weeks, both plasma glucose levels (vehicle-injected 188.2 ± 9.6 mg/dl vs. leptin-injected 152.2 ± 7.7 mg/dl; p = 0.0098, n = 10 per group) and plasma insulin levels (vehicle-injected 16.2 ± 2.0 ng/ml vs. leptin-injected 5.7 ± 1.2 ng/ml; p = 0.00025, n = 10 per group) were dramatically decreased due to leptin treatment (see Fig. 4b, c). Moreover, the leptin treatment restored glucose tolerance in ob/ob mice (Fig. 5). Interestingly, islet Trpm5 expression in islets of leptin-treated mice was upregulated as compared to islets of vehicle-injected mice (vehicle 0.96 ± 0.25 vs. leptin 6.52 ± 0.61; p = 2.1−6, n = 7 per group). These data imply that downregulation of Trpm5 expression in islets from ob/ob and db/db mice results from the disruption of the leptin pathway and/or the consequent diabetic phenotype.Fig. 4


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)

Leptin treatment of leptin-deficient ob/ob mice causes a reversal of the diabetic phenotype and an upregulation of islet Trpm5 expression. Metabolic phenotype of ob/ob mice that were injected either with 1 mg leptin/kg bodyweight or with vehicle during 5 weeks. a–c Bodyweight (a), plasma glucose (b), and plasma insulin levels (c) were measured on a daily (bodyweight) or a weekly (plasma glucose and insulin) basis. There was a statistically significant difference of bodyweight between the two groups starting from day 8. dTrpm5 mRNA expression in freshly isolated pancreatic islets from vehicle- and leptin-injected ob/ob mice after 5 weeks of treatment. Data were normalized to the average Trpm5 expression in islets from vehicle-injected mice. N = 10 mice per group, **p < 0.01, ***p < 0.001
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Related In: Results  -  Collection

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Fig4: Leptin treatment of leptin-deficient ob/ob mice causes a reversal of the diabetic phenotype and an upregulation of islet Trpm5 expression. Metabolic phenotype of ob/ob mice that were injected either with 1 mg leptin/kg bodyweight or with vehicle during 5 weeks. a–c Bodyweight (a), plasma glucose (b), and plasma insulin levels (c) were measured on a daily (bodyweight) or a weekly (plasma glucose and insulin) basis. There was a statistically significant difference of bodyweight between the two groups starting from day 8. dTrpm5 mRNA expression in freshly isolated pancreatic islets from vehicle- and leptin-injected ob/ob mice after 5 weeks of treatment. Data were normalized to the average Trpm5 expression in islets from vehicle-injected mice. N = 10 mice per group, **p < 0.01, ***p < 0.001
Mentions: Five-week-old ob/ob mice were daily injected with a dose of 1 mg/kg bodyweight leptin i.p. during 5 weeks and compared to ob/ob mice that received daily vehicle injections. Leptin injections decreased the daily food intake per mouse (vehicle-injected 5.83 ± 0.05 vs. leptin-injected 3.31 ± 0.19 g/day/mouse). During the course of the experiment, the bodyweight of the vehicle-treated group increased much faster as compared to the leptin-injected group, with a statistically significant difference starting from day 8, reaching bodyweights of 44.5 ± 1.7 g for the vehicle-injected group and 35.6 ± 1.0 g for the leptin-injected group after 36 days (n = 10 per group, p = 0.000663, see also Fig. 4a). After 5 weeks, both plasma glucose levels (vehicle-injected 188.2 ± 9.6 mg/dl vs. leptin-injected 152.2 ± 7.7 mg/dl; p = 0.0098, n = 10 per group) and plasma insulin levels (vehicle-injected 16.2 ± 2.0 ng/ml vs. leptin-injected 5.7 ± 1.2 ng/ml; p = 0.00025, n = 10 per group) were dramatically decreased due to leptin treatment (see Fig. 4b, c). Moreover, the leptin treatment restored glucose tolerance in ob/ob mice (Fig. 5). Interestingly, islet Trpm5 expression in islets of leptin-treated mice was upregulated as compared to islets of vehicle-injected mice (vehicle 0.96 ± 0.25 vs. leptin 6.52 ± 0.61; p = 2.1−6, n = 7 per group). These data imply that downregulation of Trpm5 expression in islets from ob/ob and db/db mice results from the disruption of the leptin pathway and/or the consequent diabetic phenotype.Fig. 4

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