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Differential hexosamine biosynthetic pathway gene expression with type 2 diabetes

View Article: PubMed Central - PubMed

ABSTRACT

The hexosamine biosynthetic pathway (HBP) culminates in the attachment of O-linked β-N-acetylglucosamine (O-GlcNAc) onto serine/threonine residues of target proteins. The HBP is regulated by several modulators, i.e. O-linked β-N-acetylglucosaminyl transferase (OGT) and β-N-acetylglucosaminidase (OGA) catalyze the addition and removal of O-GlcNAc moieties, respectively; while flux is controlled by the rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase (GFPT), transcribed by two genes, GFPT1 and GFPT2. Since increased HBP flux is glucose-responsive and linked to insulin resistance/type 2 diabetes onset, we hypothesized that diabetic individuals exhibit differential expression of HBP regulatory genes. Volunteers (n = 60; n = 20 Mixed Ancestry, n = 40 Caucasian) were recruited from Stellenbosch and Paarl (Western Cape, South Africa) and classified as control, pre- or diabetic according to fasting plasma glucose and HbA1c levels, respectively. RNA was purified from leukocytes isolated from collected blood samples and OGT, OGA, GFPT1 and GFPT2 expressions determined by quantitative real-time PCR. The data reveal lower OGA expression in diabetic individuals (P < 0.01), while pre- and diabetic subjects displayed attenuated OGT expression vs. controls (P < 0.01 and P < 0.001, respectively). Moreover, GFPT2 expression decreased in pre- and diabetic Caucasians vs. controls (P < 0.05 and P < 0.01, respectively). We also found ethnic differences, i.e. Mixed Ancestry individuals exhibited a 2.4-fold increase in GFPT2 expression vs. Caucasians, despite diagnosis (P < 0.01). Gene expression of HBP regulators differs between diabetic and non-diabetic individuals, together with distinct ethnic-specific gene profiles. Thus differential HBP gene regulation may offer diagnostic utility and provide candidate susceptibility genes for different ethnic groupings.

No MeSH data available.


Related in: MedlinePlus

Distinct GFPT isoform gene expression with ethnicity. A. Lower Caucasian GFPT2/GUSB gene expression levels in diabetic vs. control individuals (**P < 0.01) and pre-diabetic vs. control individuals (#P < 0.05) (n = 34) (HbA1c characterization). B. Scatter plot demonstrating the distribution of GFPT2/GUSB expression levels between study groups (n = 34) (HbA1c characterization). C. Comparison of GFPT2/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (**P < 0.01; n = 36). D. Comparison of GFPT1/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (n = 36). E. Comparison of OGA/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (n = 32). F. Comparison of OGT/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (n = 36). Note: to generate comparisons in C, D, E, and F. above, the 36 individuals were equally divided between the Caucasian and Mixed Ancestry groups for respective control, pre-diabetic and diabetic categories (with matched blood glucose levels).
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f0020: Distinct GFPT isoform gene expression with ethnicity. A. Lower Caucasian GFPT2/GUSB gene expression levels in diabetic vs. control individuals (**P < 0.01) and pre-diabetic vs. control individuals (#P < 0.05) (n = 34) (HbA1c characterization). B. Scatter plot demonstrating the distribution of GFPT2/GUSB expression levels between study groups (n = 34) (HbA1c characterization). C. Comparison of GFPT2/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (**P < 0.01; n = 36). D. Comparison of GFPT1/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (n = 36). E. Comparison of OGA/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (n = 32). F. Comparison of OGT/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (n = 36). Note: to generate comparisons in C, D, E, and F. above, the 36 individuals were equally divided between the Caucasian and Mixed Ancestry groups for respective control, pre-diabetic and diabetic categories (with matched blood glucose levels).

Mentions: No significant differences were found (for all three groups) when evaluating gene expression levels of GFPT1 and GFPT2 according to HbA1c and fasting plasma glucose classifications (Fig. 3A–D). Since a previous study reported ethnic-related changes in GFPT gene expression [26], we decided to separately evaluate GFPT for the Caucasian and Mixed Ancestry participants. Due to the relatively small number of Mixed Ancestry participants we were unable to determine GFPT expression for this group alone; however, we were able to do so for the Caucasian population. Here there were no changes in GFPT1 expression levels for control, pre-diabetic and diabetic individuals. However, we found attenuated GFPT2 gene expression (by 54.7 ± 5.3%) for the Caucasian diabetic vs. control groups, and a 38.8 ± 12.2% decrease for the Caucasian pre-diabetic vs. control groups (Fig. 4A and B).


Differential hexosamine biosynthetic pathway gene expression with type 2 diabetes
Distinct GFPT isoform gene expression with ethnicity. A. Lower Caucasian GFPT2/GUSB gene expression levels in diabetic vs. control individuals (**P < 0.01) and pre-diabetic vs. control individuals (#P < 0.05) (n = 34) (HbA1c characterization). B. Scatter plot demonstrating the distribution of GFPT2/GUSB expression levels between study groups (n = 34) (HbA1c characterization). C. Comparison of GFPT2/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (**P < 0.01; n = 36). D. Comparison of GFPT1/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (n = 36). E. Comparison of OGA/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (n = 32). F. Comparison of OGT/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (n = 36). Note: to generate comparisons in C, D, E, and F. above, the 36 individuals were equally divided between the Caucasian and Mixed Ancestry groups for respective control, pre-diabetic and diabetic categories (with matched blood glucose levels).
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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f0020: Distinct GFPT isoform gene expression with ethnicity. A. Lower Caucasian GFPT2/GUSB gene expression levels in diabetic vs. control individuals (**P < 0.01) and pre-diabetic vs. control individuals (#P < 0.05) (n = 34) (HbA1c characterization). B. Scatter plot demonstrating the distribution of GFPT2/GUSB expression levels between study groups (n = 34) (HbA1c characterization). C. Comparison of GFPT2/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (**P < 0.01; n = 36). D. Comparison of GFPT1/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (n = 36). E. Comparison of OGA/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (n = 32). F. Comparison of OGT/GUSB gene expression levels for Caucasians versus Mixed Ancestry individuals (n = 36). Note: to generate comparisons in C, D, E, and F. above, the 36 individuals were equally divided between the Caucasian and Mixed Ancestry groups for respective control, pre-diabetic and diabetic categories (with matched blood glucose levels).
Mentions: No significant differences were found (for all three groups) when evaluating gene expression levels of GFPT1 and GFPT2 according to HbA1c and fasting plasma glucose classifications (Fig. 3A–D). Since a previous study reported ethnic-related changes in GFPT gene expression [26], we decided to separately evaluate GFPT for the Caucasian and Mixed Ancestry participants. Due to the relatively small number of Mixed Ancestry participants we were unable to determine GFPT expression for this group alone; however, we were able to do so for the Caucasian population. Here there were no changes in GFPT1 expression levels for control, pre-diabetic and diabetic individuals. However, we found attenuated GFPT2 gene expression (by 54.7 ± 5.3%) for the Caucasian diabetic vs. control groups, and a 38.8 ± 12.2% decrease for the Caucasian pre-diabetic vs. control groups (Fig. 4A and B).

View Article: PubMed Central - PubMed

ABSTRACT

The hexosamine biosynthetic pathway (HBP) culminates in the attachment of O-linked &beta;-N-acetylglucosamine (O-GlcNAc) onto serine/threonine residues of target proteins. The HBP is regulated by several modulators, i.e. O-linked &beta;-N-acetylglucosaminyl transferase (OGT) and &beta;-N-acetylglucosaminidase (OGA) catalyze the addition and removal of O-GlcNAc moieties, respectively; while flux is controlled by the rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase (GFPT), transcribed by two genes, GFPT1 and GFPT2. Since increased HBP flux is glucose-responsive and linked to insulin resistance/type 2 diabetes onset, we hypothesized that diabetic individuals exhibit differential expression of HBP regulatory genes. Volunteers (n&nbsp;=&nbsp;60; n&nbsp;=&nbsp;20 Mixed Ancestry, n&nbsp;=&nbsp;40 Caucasian) were recruited from Stellenbosch and Paarl (Western Cape, South Africa) and classified as control, pre- or diabetic according to fasting plasma glucose and HbA1c levels, respectively. RNA was purified from leukocytes isolated from collected blood samples and OGT, OGA, GFPT1 and GFPT2 expressions determined by quantitative real-time PCR. The data reveal lower OGA expression in diabetic individuals (P&nbsp;&lt;&nbsp;0.01), while pre- and diabetic subjects displayed attenuated OGT expression vs. controls (P&nbsp;&lt;&nbsp;0.01 and P&nbsp;&lt;&nbsp;0.001, respectively). Moreover, GFPT2 expression decreased in pre- and diabetic Caucasians vs. controls (P&nbsp;&lt;&nbsp;0.05 and P&nbsp;&lt;&nbsp;0.01, respectively). We also found ethnic differences, i.e. Mixed Ancestry individuals exhibited a 2.4-fold increase in GFPT2 expression vs. Caucasians, despite diagnosis (P&nbsp;&lt;&nbsp;0.01). Gene expression of HBP regulators differs between diabetic and non-diabetic individuals, together with distinct ethnic-specific gene profiles. Thus differential HBP gene regulation may offer diagnostic utility and provide candidate susceptibility genes for different ethnic groupings.

No MeSH data available.


Related in: MedlinePlus