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MicroRNA-194 Modulates Glucose Metabolism and Its Skeletal Muscle Expression Is Reduced in Diabetes.

Latouche C, Natoli A, Reddy-Luthmoodoo M, Heywood SE, Armitage JA, Kingwell BA - PLoS ONE (2016)

Bottom Line: Twenty-three miRNAs were differentially expressed in patients with T2DM, and 7 in the insulin resistant rat offspring compared to their controls.Moreover, oxidative capacity was also increased as we found an enhanced glucose oxidation in presence of the mitochondrial uncoupler FCCP.Interestingly, miR-194 was a unique miRNA that appeared regulated across different stages of the disease progression, from the early stages of insulin resistance to the development of T2DM.

View Article: PubMed Central - PubMed

Affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.

ABSTRACT

Background: The regulation of microRNAs (miRNAs) at different stages of the progression of type 2 diabetes mellitus (T2DM) and their role in glucose homeostasis was investigated.

Methods: Microarrays were used to assess miRNA expression in skeletal muscle biopsies taken from healthy individuals and patients with pre-diabetes or T2DM, and insulin resistant offspring of rat dams fed a high fat diet during pregnancy.

Results: Twenty-three miRNAs were differentially expressed in patients with T2DM, and 7 in the insulin resistant rat offspring compared to their controls. Among these, only one miRNA was similarly regulated: miR-194 expression was significantly reduced by 25 to 50% in both the rat model and in human with pre-diabetes and established diabetes. Knockdown of miR-194 in L6 skeletal muscle cells induced an increase in basal and insulin-stimulated glucose uptake and glycogen synthesis. This occurred in conjunction with an increased glycolysis, indicated by elevated lactate production. Moreover, oxidative capacity was also increased as we found an enhanced glucose oxidation in presence of the mitochondrial uncoupler FCCP. When miR-194 was down-regulated in vitro, western blot analysis showed an increased phosphorylation of AKT and GSK3β in response to insulin, and an increase in expression of proteins controlling mitochondrial oxidative phosphorylation.

Conclusions: Type 2 diabetes mellitus is associated with regulation of several miRNAs in skeletal muscle. Interestingly, miR-194 was a unique miRNA that appeared regulated across different stages of the disease progression, from the early stages of insulin resistance to the development of T2DM. We have shown miR-194 is involved in multiple aspects of skeletal muscle glucose metabolism from uptake, through to glycolysis, glycogenesis and glucose oxidation, potentially via mechanisms involving AKT, GSK3 and oxidative phosphorylation. MiR-194 could be down-regulated in patients with early features of diabetes as an adaptive response to facilitate tissue glucose uptake and metabolism in the face of insulin resistance.

No MeSH data available.


Related in: MedlinePlus

miR-194 expression in the skeletal muscle of human participants and rat offspring and correlations with HOMA-IR.miR-194 expression was validated by qPCR in human (A) and rat samples (B) (n = 4–6 per group). Values are expressed as mean ± SEM. P-values were determined using 1-way ANOVA followed by Student-Newman-Keuls post-hoc test for human data (*p<0.05 vs healthy), or Student’s t-test for rat data (*p<0.05 vs control). Correlation between miR-194 expression and HOMA-IR in human (C) and rat (D) was assessed using Pearson’s or Spearman’s correlation test as appropriate. R and p-values are indicated on the graphs.
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pone.0155108.g001: miR-194 expression in the skeletal muscle of human participants and rat offspring and correlations with HOMA-IR.miR-194 expression was validated by qPCR in human (A) and rat samples (B) (n = 4–6 per group). Values are expressed as mean ± SEM. P-values were determined using 1-way ANOVA followed by Student-Newman-Keuls post-hoc test for human data (*p<0.05 vs healthy), or Student’s t-test for rat data (*p<0.05 vs control). Correlation between miR-194 expression and HOMA-IR in human (C) and rat (D) was assessed using Pearson’s or Spearman’s correlation test as appropriate. R and p-values are indicated on the graphs.

Mentions: The expression levels of miR-194 were validated by qPCR, demonstrating a 50% reduction in expression in the skeletal muscle of individuals with pre-diabetes and diabetes (Fig 1A) and a 25% decrease in the skeletal muscle of insulin resistant rats (Fig 1B). Moreover, we identified a negative correlation between homeostatic model assessment index of insulin resistance (HOMA-IR, reported in Table 1) and miR-194 expression levels (r = -0.69, p = 0.01 in humans, r = -0.65, p = 0.04 in rats, Fig 1C and 1D), indicating an association of miR-194 with insulin resistance.


MicroRNA-194 Modulates Glucose Metabolism and Its Skeletal Muscle Expression Is Reduced in Diabetes.

Latouche C, Natoli A, Reddy-Luthmoodoo M, Heywood SE, Armitage JA, Kingwell BA - PLoS ONE (2016)

miR-194 expression in the skeletal muscle of human participants and rat offspring and correlations with HOMA-IR.miR-194 expression was validated by qPCR in human (A) and rat samples (B) (n = 4–6 per group). Values are expressed as mean ± SEM. P-values were determined using 1-way ANOVA followed by Student-Newman-Keuls post-hoc test for human data (*p<0.05 vs healthy), or Student’s t-test for rat data (*p<0.05 vs control). Correlation between miR-194 expression and HOMA-IR in human (C) and rat (D) was assessed using Pearson’s or Spearman’s correlation test as appropriate. R and p-values are indicated on the graphs.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4862646&req=5

pone.0155108.g001: miR-194 expression in the skeletal muscle of human participants and rat offspring and correlations with HOMA-IR.miR-194 expression was validated by qPCR in human (A) and rat samples (B) (n = 4–6 per group). Values are expressed as mean ± SEM. P-values were determined using 1-way ANOVA followed by Student-Newman-Keuls post-hoc test for human data (*p<0.05 vs healthy), or Student’s t-test for rat data (*p<0.05 vs control). Correlation between miR-194 expression and HOMA-IR in human (C) and rat (D) was assessed using Pearson’s or Spearman’s correlation test as appropriate. R and p-values are indicated on the graphs.
Mentions: The expression levels of miR-194 were validated by qPCR, demonstrating a 50% reduction in expression in the skeletal muscle of individuals with pre-diabetes and diabetes (Fig 1A) and a 25% decrease in the skeletal muscle of insulin resistant rats (Fig 1B). Moreover, we identified a negative correlation between homeostatic model assessment index of insulin resistance (HOMA-IR, reported in Table 1) and miR-194 expression levels (r = -0.69, p = 0.01 in humans, r = -0.65, p = 0.04 in rats, Fig 1C and 1D), indicating an association of miR-194 with insulin resistance.

Bottom Line: Twenty-three miRNAs were differentially expressed in patients with T2DM, and 7 in the insulin resistant rat offspring compared to their controls.Moreover, oxidative capacity was also increased as we found an enhanced glucose oxidation in presence of the mitochondrial uncoupler FCCP.Interestingly, miR-194 was a unique miRNA that appeared regulated across different stages of the disease progression, from the early stages of insulin resistance to the development of T2DM.

View Article: PubMed Central - PubMed

Affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.

ABSTRACT

Background: The regulation of microRNAs (miRNAs) at different stages of the progression of type 2 diabetes mellitus (T2DM) and their role in glucose homeostasis was investigated.

Methods: Microarrays were used to assess miRNA expression in skeletal muscle biopsies taken from healthy individuals and patients with pre-diabetes or T2DM, and insulin resistant offspring of rat dams fed a high fat diet during pregnancy.

Results: Twenty-three miRNAs were differentially expressed in patients with T2DM, and 7 in the insulin resistant rat offspring compared to their controls. Among these, only one miRNA was similarly regulated: miR-194 expression was significantly reduced by 25 to 50% in both the rat model and in human with pre-diabetes and established diabetes. Knockdown of miR-194 in L6 skeletal muscle cells induced an increase in basal and insulin-stimulated glucose uptake and glycogen synthesis. This occurred in conjunction with an increased glycolysis, indicated by elevated lactate production. Moreover, oxidative capacity was also increased as we found an enhanced glucose oxidation in presence of the mitochondrial uncoupler FCCP. When miR-194 was down-regulated in vitro, western blot analysis showed an increased phosphorylation of AKT and GSK3β in response to insulin, and an increase in expression of proteins controlling mitochondrial oxidative phosphorylation.

Conclusions: Type 2 diabetes mellitus is associated with regulation of several miRNAs in skeletal muscle. Interestingly, miR-194 was a unique miRNA that appeared regulated across different stages of the disease progression, from the early stages of insulin resistance to the development of T2DM. We have shown miR-194 is involved in multiple aspects of skeletal muscle glucose metabolism from uptake, through to glycolysis, glycogenesis and glucose oxidation, potentially via mechanisms involving AKT, GSK3 and oxidative phosphorylation. MiR-194 could be down-regulated in patients with early features of diabetes as an adaptive response to facilitate tissue glucose uptake and metabolism in the face of insulin resistance.

No MeSH data available.


Related in: MedlinePlus