Dataset Information

Functional Variant in the GCKR Gene Affects Lactate Levels Differentially in the Fasting State and During Hyperglycemia.

ABSTRACT: The rs780094 single nucleotide polymorphism (SNP; C/T) of glucokinase regulatory protein gene (GCKR) is a regulatory genetic variant that has been associated with lactate levels in the fasting state. However, the association of this locus with lactate during hyperglycemia, and the mechanisms underlying these associations remain unknown. We investigated the association of rs780094 with lactate levels in a frequently sampled oral glucose tolerance test in humans and evaluated the effect of increasing GCKR expression on lactate production in liver cells. The C allele of rs780094 was associated with lower lactate levels in fasting but increased lactate level during hyperglycemia independently of insulin levels. Increased expression of GKRP induced higher lactate level in HepG2 cells and in human primary hepatocytes (HPH) upon glucose stimulation by increasing the amount of GCK. Glucagon induced the expression of GCKR in HepG2 and HPH cells. Our results suggest that the association of rs780094 with lactate levels may involve differential GCKR expression between the carriers of the C and T alleles.

SUBMITTER: Lopez Rodriguez M

PROVIDER: S-EPMC6207693 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Functional Variant in the GCKR Gene Affects Lactate Levels Differentially in the Fasting State and During Hyperglycemia.

López Rodríguez Maykel M Fernandes Silva Lilian L Vangipurapu Jagadish J Modi Shalem S Kuusisto Johanna J Kaikkonen Minna U MU Laakso Markku M

Scientific reports 20181030 1

The rs780094 single nucleotide polymorphism (SNP; C/T) of glucokinase regulatory protein gene (GCKR) is a regulatory genetic variant that has been associated with lactate levels in the fasting state. However, the association of this locus with lactate during hyperglycemia, and the mechanisms underlying these associations remain unknown. We investigated the association of rs780094 with lactate levels in a frequently sampled oral glucose tolerance test in humans and evaluated the effect of increas ...[more]

PMID: 30375486

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Project description:ObjectiveInvestigate the DNA damage and its cellular response in blood samples from both mother and the umbilical cord of pregnancies complicated by hyperglycemia.MethodsA total of 144 subjects were divided into 4 groups: normoglycemia (ND; 46 cases), mild gestational hyperglycemia (MGH; 30 cases), gestational diabetes mellitus (GDM; 45 cases) and type-2 diabetes mellitus (DM2; 23 cases). Peripheral blood mononuclear cell (PBMC) isolation and/or leukocytes from whole maternal and umbilical cord blood were obtained from all groups at delivery. Nuclear and mitochondrial DNA damage were measured by gene-specific quantitative PCR, and the expression of mRNA and proteins involved in the base excision repair (BER) pathway were assessed by real-time qPCR and Western blot, respectively. Apoptosis was measured in vitro experiments by caspase 3/7 activity and ATP levels.ResultsGDM and DM2 groups were characterized by an increase in oxidative stress biomarkers, an increase in nuclear and mitochondrial DNA damage, and decreased expression of mRNA (APE1, POL? and FEN1) and proteins (hOGG1, APE1) involved in BER. The levels of hyperglycemia were associated with the in vitro apoptosis pathway. Blood levels of DNA damage in umbilical cord were similar among the groups. Newborns of diabetic mothers had increased expression of BER mRNA (APE1, POL? and FEN1) and proteins (hOGG1, APE1, POL? and FEN1). A diabetes-like environment was unable to induce apoptosis in the umbilical cord blood cells.ConclusionsOur data show relevant asymmetry between maternal and fetal blood cell susceptibility to DNA damage and apoptosis induction. Maternal cells seem to be more predisposed to changes in an adverse glucose environment. This may be due to differential ability in upregulating multiple genes involved in the activation of DNA repair response, especially the BER mechanism. However if this study shows a more effective adaptive response by the fetal organism, it also calls for further studies to determine the limit of this response that definitely changes the fate of a fetus under these conditions of cellular stress.

Project description:ContextPeople with prediabetes are at high risk of developing diabetes.ObjectiveThe objective of this study was to determine the pathogenesis of fasting and postprandial hyperglycemia in prediabetes.DesignGlucose production, gluconeogenesis, glycogenolysis, and glucose disappearance were measured before and during a hyperinsulinemic clamp using [6,6-(2)H2]glucose and the deuterated water method corrected for transaldolase exchange.SettingThe study was conducted at the Mayo Clinic Clinical Research Unit.ParticipantsSubjects with impaired fasting glucose (IFG)/normal glucose tolerance (NGT) (n = 14), IFG/impaired glucose tolerance (IGT) (n = 18), and normal fasting glucose (NFG)/NGT (n = 16) were studied.InterventionA hyperinsulinemic clamp was used.Outcome measuresGlucose production, glucose disappearance, gluconeogenesis, and glycogenolysis were measured.ResultsFasting glucose production was higher (P < .0001) in subjects with IFG/NGT than in those with NFG/NGT because of increased rates of gluconeogenesis (P = .003). On the other hand, insulin-induced suppression of glucose production, gluconeogenesis, glycogenolysis, and stimulation of glucose disappearance all were normal. Although fasting glucose production also was increased (P = .0002) in subjects with IFG/IGT, insulin-induced suppression of glucose production, gluconeogenesis, and glycogenolysis and stimulation of glucose disappearance were impaired (P = .005).ConclusionsFasting hyperglycemia is due to excessive glucose production in people with either IFG/NGT or IFG/IGT. Both insulin action and postprandial glucose concentrations are normal in IFG/NGT but abnormal in IFG/IGT. This finding suggests that hepatic and extrahepatic insulin resistance causes or exacerbates postprandial glucose intolerance in IFG/IGT. Elevated gluconeogenesis in the fasting state in IFG/NGT and impaired insulin-induced suppression of both gluconeogenesis and glycogenolysis in IFG/IGT suggest that alteration in the regulation of these pathways occurs early in the evolution of type 2 diabetes.

Dataset Information

Functional Variant in the GCKR Gene Affects Lactate Levels Differentially in the Fasting State and During Hyperglycemia.

Publications

Functional Variant in the GCKR Gene Affects Lactate Levels Differentially in the Fasting State and During Hyperglycemia.

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