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miR-375 gene dosage in pancreatic β-cells: implications for regulation of β-cell mass and biomarker development.

Latreille M, Herrmanns K, Renwick N, Tuschl T, Malecki MT, McCarthy MI, Owen KR, Rülicke T, Stoffel M - J. Mol. Med. (2015)

Bottom Line: Furthermore, acute and profound β-cell destruction is sufficient to detect elevations of miR-375 levels in the blood.Together, our data support an essential role for miR-375 in the maintenance of β-cell mass and provide in vivo evidence for release of miRNAs from pancreatic β-cells.Circulating miR-375 levels are not a biomarker for pancreatic β-cell function.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH Zurich), Otto-Stern Weg. 7, 8093, Zurich, Switzerland.

ABSTRACT

Unlabelled: MicroRNAs play a crucial role in the regulation of cell growth and differentiation. Mice with genetic deletion of miR-375 exhibit impaired glycemic control due to decreased β-cell and increased α-cell mass and function. The relative importance of these processes for the overall phenotype of miR-375KO mice is unknown. Here, we show that mice overexpressing miR-375 exhibit normal β-cell mass and function. Selective re-expression of miR-375 in β-cells of miR-375KO mice normalizes both, α- and β-cell phenotypes as well as glucose metabolism. Using this model, we also analyzed the contribution of β-cells to the total plasma miR-375 levels. Only a small proportion (≈1 %) of circulating miR-375 originates from β-cells. Furthermore, acute and profound β-cell destruction is sufficient to detect elevations of miR-375 levels in the blood. These findings are supported by higher miR-375 levels in the circulation of type 1 diabetes (T1D) subjects but not mature onset diabetes of the young (MODY) and type 2 diabetes (T2D) patients. Together, our data support an essential role for miR-375 in the maintenance of β-cell mass and provide in vivo evidence for release of miRNAs from pancreatic β-cells. The small contribution of β-cells to total plasma miR-375 levels make this miRNA an unlikely biomarker for β-cell function but suggests a utility for the detection of acute β-cell death for autoimmune diabetes.

Key messages: • Overexpression of miR-375 in β-cells does not influence β-cell mass and function. • Increased α-cell mass in miR-375KO arises secondarily to loss of miR-375 in β-cells. • Only a small proportion of circulating miR-375 levels originates from β-cells. • Acute β-cell destruction results in measurable increases of miR-375 in the blood. Circulating miR-375 levels are not a biomarker for pancreatic β-cell function.

No MeSH data available.


Related in: MedlinePlus

Correlation between circulating miR-375 levels and β-cell injury. a Blood glucose levels and b pancreatic insulin content in 6-h fasted C57BL/6 (10-week-old) after 72 h treatment with streptozotocin (STZ, 1 × 150 mg/kg) (n = 7–8). c Circulating miR-375 and d miR-16 copy number in plasma of 6-h fasted C57BL/6 WT mice (10-week-old) after being injected with STZ (+, 1 × 150 mg/kg) or PBS as control (−) for 3 days (n = 7–8). e Blood glucose and f circulating miR-375 and g miR-16 levels in WT and db/db (BKS-background) male mice at 8 weeks of age (n = 4–5). h Blood glucose, i pancreatic insulin content, and j circulating miR-375 and k miR-16 in C57BL/6 (WT) mice fed a normal or high-fat diet (HFD, for 25 weeks) and ob/ob (C57BL/6 background) mice (23-week-old) (n = 5). l Circulating miR-375 levels in healthy or no diagnosed metabolic disease patients (n = 51), HNF1α/MODY3 mutation carriers (n = 47), T1D (n = 38) and T2D (n = 58). All data shown are mean ± s.e.m; *p < 0.05, **p < 0.01, ***p < 0.005
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Fig6: Correlation between circulating miR-375 levels and β-cell injury. a Blood glucose levels and b pancreatic insulin content in 6-h fasted C57BL/6 (10-week-old) after 72 h treatment with streptozotocin (STZ, 1 × 150 mg/kg) (n = 7–8). c Circulating miR-375 and d miR-16 copy number in plasma of 6-h fasted C57BL/6 WT mice (10-week-old) after being injected with STZ (+, 1 × 150 mg/kg) or PBS as control (−) for 3 days (n = 7–8). e Blood glucose and f circulating miR-375 and g miR-16 levels in WT and db/db (BKS-background) male mice at 8 weeks of age (n = 4–5). h Blood glucose, i pancreatic insulin content, and j circulating miR-375 and k miR-16 in C57BL/6 (WT) mice fed a normal or high-fat diet (HFD, for 25 weeks) and ob/ob (C57BL/6 background) mice (23-week-old) (n = 5). l Circulating miR-375 levels in healthy or no diagnosed metabolic disease patients (n = 51), HNF1α/MODY3 mutation carriers (n = 47), T1D (n = 38) and T2D (n = 58). All data shown are mean ± s.e.m; *p < 0.05, **p < 0.01, ***p < 0.005

Mentions: Since our findings indicate that circulating miRNAs are released from β-cells, we hypothesized that their levels may correlate with β-cell mass and may serve as a biomarker of β-cell viability in diabetes. To investigate this, we employed different models of β-cell stress: an acute β-cell toxicity model induced by treating mice with STZ (150 mg/kg), obesity mouse models displaying normoglycemia due to increased β-cell proliferation, function and pancreatic insulin content (i.e., dietary (HFD), and genetic (ob/ob mice on C57BL/6N background) [3, 22, 23], as well as diabetic models (db/db mice on BLKS background) exhibiting profound hyperglycemia, reduced plasma insulin levels due to β-cell dysfunction [24, 25] and apoptosis [26, 27]. For the acute toxicity model, blood was analyzed for glucose and serum miRNAs levels 3 days after STZ injection. STZ treatment resulted in elevation of blood glucose levels, which correlated with depletion of β-cells as revealed by pancreatic insulin content measurements (Fig. 6a, b). We observed that circulating miR-375 levels were increased by ≈2-fold in STZ-treated diabetic mice as compared to controls (Fig. 6c), while those of miR-16, a ubiquitously expressed miRNA was unaffected by STZ treatment (Fig. 6d). Interestingly, increased plasma miR-375 levels were also measured in hyperglycemic BKS.db/db mice compared to control littermates, whereas miR-16 levels were similar (Fig. 6e–g). In contrast, our analysis revealed that miR-375 levels were decreased by ≈50 and 20 % in islets of normoglycemic HFD and ob/ob mice compared to lean littermate controls, respectively (Fig. 6h–k). Together, these results indicate that miR-375 levels in the circulation do not correlate with β-cell function or mass but may be a surrogate marker for β-cell injury and cell death.Fig. 6


miR-375 gene dosage in pancreatic β-cells: implications for regulation of β-cell mass and biomarker development.

Latreille M, Herrmanns K, Renwick N, Tuschl T, Malecki MT, McCarthy MI, Owen KR, Rülicke T, Stoffel M - J. Mol. Med. (2015)

Correlation between circulating miR-375 levels and β-cell injury. a Blood glucose levels and b pancreatic insulin content in 6-h fasted C57BL/6 (10-week-old) after 72 h treatment with streptozotocin (STZ, 1 × 150 mg/kg) (n = 7–8). c Circulating miR-375 and d miR-16 copy number in plasma of 6-h fasted C57BL/6 WT mice (10-week-old) after being injected with STZ (+, 1 × 150 mg/kg) or PBS as control (−) for 3 days (n = 7–8). e Blood glucose and f circulating miR-375 and g miR-16 levels in WT and db/db (BKS-background) male mice at 8 weeks of age (n = 4–5). h Blood glucose, i pancreatic insulin content, and j circulating miR-375 and k miR-16 in C57BL/6 (WT) mice fed a normal or high-fat diet (HFD, for 25 weeks) and ob/ob (C57BL/6 background) mice (23-week-old) (n = 5). l Circulating miR-375 levels in healthy or no diagnosed metabolic disease patients (n = 51), HNF1α/MODY3 mutation carriers (n = 47), T1D (n = 38) and T2D (n = 58). All data shown are mean ± s.e.m; *p < 0.05, **p < 0.01, ***p < 0.005
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Related In: Results  -  Collection

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Fig6: Correlation between circulating miR-375 levels and β-cell injury. a Blood glucose levels and b pancreatic insulin content in 6-h fasted C57BL/6 (10-week-old) after 72 h treatment with streptozotocin (STZ, 1 × 150 mg/kg) (n = 7–8). c Circulating miR-375 and d miR-16 copy number in plasma of 6-h fasted C57BL/6 WT mice (10-week-old) after being injected with STZ (+, 1 × 150 mg/kg) or PBS as control (−) for 3 days (n = 7–8). e Blood glucose and f circulating miR-375 and g miR-16 levels in WT and db/db (BKS-background) male mice at 8 weeks of age (n = 4–5). h Blood glucose, i pancreatic insulin content, and j circulating miR-375 and k miR-16 in C57BL/6 (WT) mice fed a normal or high-fat diet (HFD, for 25 weeks) and ob/ob (C57BL/6 background) mice (23-week-old) (n = 5). l Circulating miR-375 levels in healthy or no diagnosed metabolic disease patients (n = 51), HNF1α/MODY3 mutation carriers (n = 47), T1D (n = 38) and T2D (n = 58). All data shown are mean ± s.e.m; *p < 0.05, **p < 0.01, ***p < 0.005
Mentions: Since our findings indicate that circulating miRNAs are released from β-cells, we hypothesized that their levels may correlate with β-cell mass and may serve as a biomarker of β-cell viability in diabetes. To investigate this, we employed different models of β-cell stress: an acute β-cell toxicity model induced by treating mice with STZ (150 mg/kg), obesity mouse models displaying normoglycemia due to increased β-cell proliferation, function and pancreatic insulin content (i.e., dietary (HFD), and genetic (ob/ob mice on C57BL/6N background) [3, 22, 23], as well as diabetic models (db/db mice on BLKS background) exhibiting profound hyperglycemia, reduced plasma insulin levels due to β-cell dysfunction [24, 25] and apoptosis [26, 27]. For the acute toxicity model, blood was analyzed for glucose and serum miRNAs levels 3 days after STZ injection. STZ treatment resulted in elevation of blood glucose levels, which correlated with depletion of β-cells as revealed by pancreatic insulin content measurements (Fig. 6a, b). We observed that circulating miR-375 levels were increased by ≈2-fold in STZ-treated diabetic mice as compared to controls (Fig. 6c), while those of miR-16, a ubiquitously expressed miRNA was unaffected by STZ treatment (Fig. 6d). Interestingly, increased plasma miR-375 levels were also measured in hyperglycemic BKS.db/db mice compared to control littermates, whereas miR-16 levels were similar (Fig. 6e–g). In contrast, our analysis revealed that miR-375 levels were decreased by ≈50 and 20 % in islets of normoglycemic HFD and ob/ob mice compared to lean littermate controls, respectively (Fig. 6h–k). Together, these results indicate that miR-375 levels in the circulation do not correlate with β-cell function or mass but may be a surrogate marker for β-cell injury and cell death.Fig. 6

Bottom Line: Furthermore, acute and profound β-cell destruction is sufficient to detect elevations of miR-375 levels in the blood.Together, our data support an essential role for miR-375 in the maintenance of β-cell mass and provide in vivo evidence for release of miRNAs from pancreatic β-cells.Circulating miR-375 levels are not a biomarker for pancreatic β-cell function.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH Zurich), Otto-Stern Weg. 7, 8093, Zurich, Switzerland.

ABSTRACT

Unlabelled: MicroRNAs play a crucial role in the regulation of cell growth and differentiation. Mice with genetic deletion of miR-375 exhibit impaired glycemic control due to decreased β-cell and increased α-cell mass and function. The relative importance of these processes for the overall phenotype of miR-375KO mice is unknown. Here, we show that mice overexpressing miR-375 exhibit normal β-cell mass and function. Selective re-expression of miR-375 in β-cells of miR-375KO mice normalizes both, α- and β-cell phenotypes as well as glucose metabolism. Using this model, we also analyzed the contribution of β-cells to the total plasma miR-375 levels. Only a small proportion (≈1 %) of circulating miR-375 originates from β-cells. Furthermore, acute and profound β-cell destruction is sufficient to detect elevations of miR-375 levels in the blood. These findings are supported by higher miR-375 levels in the circulation of type 1 diabetes (T1D) subjects but not mature onset diabetes of the young (MODY) and type 2 diabetes (T2D) patients. Together, our data support an essential role for miR-375 in the maintenance of β-cell mass and provide in vivo evidence for release of miRNAs from pancreatic β-cells. The small contribution of β-cells to total plasma miR-375 levels make this miRNA an unlikely biomarker for β-cell function but suggests a utility for the detection of acute β-cell death for autoimmune diabetes.

Key messages: • Overexpression of miR-375 in β-cells does not influence β-cell mass and function. • Increased α-cell mass in miR-375KO arises secondarily to loss of miR-375 in β-cells. • Only a small proportion of circulating miR-375 levels originates from β-cells. • Acute β-cell destruction results in measurable increases of miR-375 in the blood. Circulating miR-375 levels are not a biomarker for pancreatic β-cell function.

No MeSH data available.


Related in: MedlinePlus