Haplotypes of the genes (GCK and G6PC2) underlying the glucose/glucose-6-phosphate cycle are associated with pancreatic beta cell glucose sensitivity in patients with newly diagnosed type 2 diabetes from the VNDS study (VNDS 11).
Diabetes Mellitus, Type 2
/ diagnosis
Female
Germinal Center Kinases
/ genetics
Glucose
/ metabolism
Glucose-6-Phosphatase
/ genetics
Glucose-6-Phosphate
/ metabolism
Haplotypes
Humans
Insulin
/ biosynthesis
Insulin Secretion
/ genetics
Insulin-Secreting Cells
/ metabolism
Islets of Langerhans
/ metabolism
Italy
/ epidemiology
Male
Middle Aged
Polymorphism, Single Nucleotide
Beta-cell function
Fasting plasma glucose
G6PC2
GCK
Haplotypes
SNP
Journal
Journal of endocrinological investigation
ISSN: 1720-8386
Titre abrégé: J Endocrinol Invest
Pays: Italy
ID NLM: 7806594
Informations de publication
Date de publication:
Dec 2021
Dec 2021
Historique:
received:
21
09
2020
accepted:
07
12
2020
pubmed:
16
6
2021
medline:
19
2
2022
entrez:
15
6
2021
Statut:
ppublish
Résumé
Elevated fasting plasma glucose has been associated with increased risk for development of type 2 diabetes (T2D). The balance between glucokinase (GCK) and glucose-6-phosphate catalytic subunit 2 (G6PC2) activity are involved in glucose homeostasis through glycolytic flux, and subsequent insulin secretion. In this study, we evaluated the association between the genetic variability of G6PC2 and GCK genes and T2D-related quantitative traits. In 794 drug-naïve, GADA-negative, newly diagnosed T2D patients (VNDS; NTC01526720) we performed: genotyping of 6 independent tag-SNPs within GCK gene and 5 tag-SNPs within G6PC2 gene; euglycaemic insulin clamp to assess insulin sensitivity; OGTT to estimate beta-cell function (derivative and proportional control; DC, PC) by mathematical modeling. Genetic association analysis has been conducted using Plink software. Two SNPs within GCK gene (rs882019 and rs1303722) were associated to DC in opposite way (both p < 0.004). Two G6PC2 variants (rs13387347 and rs560887) were associated to both parameters of insulin secretion (DC and PC) and to fasting C-peptide levels (all p < 0.038). Moreover, subjects carrying the A allele of rs560887 showed higher values of 2h-plasma glucose (2hPG) (p = 0.033). Haplotype analysis revealed that GCK (AACAAA) haplotype was associated to decreased fasting C-peptide levels, whereas, the most frequent haplotype of G6PC2 (GGAAG) was associated with higher fasting C-peptide levels (p = 0.001), higher PC (β = 6.87, p = 0.022) and the lower 2hPG (p = 0.012). Our findings confirmed the role of GCK and G6PC2 in regulating the pulsatility in insulin secretion thereby influencing insulin-signaling and leading to a gradual modulation in glucose levels in Italian patients with newly diagnosed T2D.
Sections du résumé
BACKGROUND
BACKGROUND
Elevated fasting plasma glucose has been associated with increased risk for development of type 2 diabetes (T2D). The balance between glucokinase (GCK) and glucose-6-phosphate catalytic subunit 2 (G6PC2) activity are involved in glucose homeostasis through glycolytic flux, and subsequent insulin secretion.
AIM
OBJECTIVE
In this study, we evaluated the association between the genetic variability of G6PC2 and GCK genes and T2D-related quantitative traits.
METHODS
METHODS
In 794 drug-naïve, GADA-negative, newly diagnosed T2D patients (VNDS; NTC01526720) we performed: genotyping of 6 independent tag-SNPs within GCK gene and 5 tag-SNPs within G6PC2 gene; euglycaemic insulin clamp to assess insulin sensitivity; OGTT to estimate beta-cell function (derivative and proportional control; DC, PC) by mathematical modeling. Genetic association analysis has been conducted using Plink software.
RESULTS
RESULTS
Two SNPs within GCK gene (rs882019 and rs1303722) were associated to DC in opposite way (both p < 0.004). Two G6PC2 variants (rs13387347 and rs560887) were associated to both parameters of insulin secretion (DC and PC) and to fasting C-peptide levels (all p < 0.038). Moreover, subjects carrying the A allele of rs560887 showed higher values of 2h-plasma glucose (2hPG) (p = 0.033). Haplotype analysis revealed that GCK (AACAAA) haplotype was associated to decreased fasting C-peptide levels, whereas, the most frequent haplotype of G6PC2 (GGAAG) was associated with higher fasting C-peptide levels (p = 0.001), higher PC (β = 6.87, p = 0.022) and the lower 2hPG (p = 0.012).
CONCLUSION
CONCLUSIONS
Our findings confirmed the role of GCK and G6PC2 in regulating the pulsatility in insulin secretion thereby influencing insulin-signaling and leading to a gradual modulation in glucose levels in Italian patients with newly diagnosed T2D.
Identifiants
pubmed: 34128214
doi: 10.1007/s40618-020-01483-3
pii: 10.1007/s40618-020-01483-3
doi:
Substances chimiques
Germinal Center Kinases
0
Insulin
0
MAP4K2 protein, human
0
Glucose-6-Phosphate
56-73-5
Glucose-6-Phosphatase
EC 3.1.3.9
G6PC2 protein, human
EC 3.1.3.9.
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2567-2574Informations de copyright
© 2021. Italian Society of Endocrinology (SIE).
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