Dataset Information

Functional Inactivation of Drosophila GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2.

ABSTRACT: Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In the pancreas GCK regulates insulin secretion, while in the liver it promotes glucose utilization and storage. We showed that silencing the Drosophila GCK orthologs Hex-A and Hex-C results in a MODY-2-like hyperglycemia. Targeted knock-down revealed that Hex-A is expressed in insulin producing cells (IPCs) whereas Hex-C is specifically expressed in the fat body. We showed that Hex-A is essential for insulin secretion and it is required for Hex-C expression. Reduced levels of either Hex-A or Hex-C resulted in chromosome aberrations (CABs), together with an increased production of advanced glycation end-products (AGEs) and reactive oxygen species (ROS). This result suggests that CABs, in GCK depleted cells, are likely due to hyperglycemia, which produces oxidative stress through AGE metabolism. In agreement with this hypothesis, treating GCK-depleted larvae with the antioxidant vitamin B6 rescued CABs, whereas the treatment with a B6 inhibitor enhanced genomic instability. Although MODY-2 rarely produces complications, our data revealed the possibility that MODY-2 impacts genome integrity.

SUBMITTER: Mascolo E

PROVIDER: S-EPMC7831483 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Functional Inactivation of Drosophila GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2.

Mascolo Elisa E Liguori Francesco F Stufera Mecarelli Lorenzo L Amoroso Noemi N Merigliano Chiara C Amadio Susanna S Volonté Cinzia C Contestabile Roberto R Tramonti Angela A Vernì Fiammetta F

International journal of molecular sciences 20210118 2

Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In the pancreas GCK regulates insulin secretion, while in the liver it promotes glucose utilization and storage. We showed that silencing the Drosophila GCK orthologs Hex-A and Hex-C results in a MODY-2-like hyperglycemia. Targeted knock-down revealed that Hex-A is expressed in insu ...[more]

PMID: 33477627

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Project description:AimsGlucokinase-maturity-onset diabetes of the young (GCK-MODY) is the most common monogenic diabetes in China. We have previously reported on the low levels of high-sensitivity C-reactive protein (hsCRP) in patients with GCK-MODY. In this study, we further explored the correlation between the serum lipid profiles and hsCRP levels of patients with different types of diabetes. We also proposed to determine the possible mechanism of macrovascular protection in GCK genetic variants.MethodsThe serum lipid profiles of the GCK-MODY group (n = 50) were compared with those of the hepatocyte nuclear factor-1 alpha (HNF1A)-MODY group (n = 19), the type 1 diabetes (T1D) group (n = 50), and the type 2 diabetes (T2D) group (n = 54). The associations between the lipid compositions and the hsCRP levels in each group were also explored.ResultsElevated levels of high-density lipoprotein cholesterol (HDL-C) were found in the GCK-MODY group (1.5 ± 0.27) compared with the T1D (1.2 ± 0.47, p < 0.01) and T2D (1.3 ± 0.3, p < 0.01) groups. On the other hand, a significantly lower LDL-C level (2.4 ± 0.69) in the GCK-MODY group compared with the T1D (2.7 ± 0.72, p < 0.01) and T2D (2.9 ± 0.68, p < 0.01) groups was also noted. A lower ratio of triglyceride to HDL-C (TG/HDL) and a lower hsCRP level were also found in the GCK-MODY group [TG/HDL = 0.38 (0.25-0.52), hsCRP = 0.2 mg/L (0.16-0.37)] compared with the T1D group [(TG/HDL = 0.56 (0.39-1.29), hsCRP = 0.56 mg/L (0.39-1.29), p < 0.01] and the T2D group [(TG/HDL = 1.6 (1.1-2.68), hsCRP = 1.11 mg/L (0.66-2.34), p < 0.01]. Although patients with HNF1A-MODY showed similar hsCRP levels [0.17 (0.08-0.52), p > 0.05] compared with the patients in the GCK-MODY group, they had higher TG levels [1.01 (0.66-1.76), p < 0.05] and TG/HDL ratios [0.84 (0.56-1.31), p < 0.05]. Analysis of the correlations between the hsCRP levels and lipid profiles of each group confirmed that the LnhsCRP (natural logarithm-transformed hsCRP level) was positively correlated with the LnTG (natural logarithm-transformed TG) (r = 0.352, p = 0.011) and the Ln(TG/HDL) ratio (r = 0.283, p = 0.047) only in individuals with GCK-MODY.ConclusionsIndividuals harboring GCK variants have the characteristics of protective lipid profiles manifested as a higher level of HDL-C and a lower level of LDL-C compared with type 1 and 2 diabetes milletus (T1DM and T2DM, respectively) patients. In addition, lower ratios of TG/HDL were found to be associated with the inhibition of secretion of hsCRP, even when adjusted for the HbA1c levels in patients with GCK-MODY. It is suggested that the protective effect of macrovascular complications in GCK-MODY patients might partly be due to their unique lipid profiles associated with the suppression of inflammation.

Dataset Information

Functional Inactivation of Drosophila GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2.

Publications

Functional Inactivation of <i>Drosophila</i> <i>GCK</i> Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2.

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