Differential increments of basal glucagon‐like‐1 peptide concentration among <scp>SLC</scp>47A1 rs2289669 genotypes were associated with inter‐individual variability in glycaemic response to metformin in Chinese people with newly diagnosed Type 2 diabetes

Liang, Huiling; Xu, Wen; Zhou, Ligang; Yang, Wenying; Weng, Jianping

doi:10.1111/dme.13351

Cited by 8 publications

(2 citation statements)

References 20 publications

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“…Therefore, it seems that the increase seen in GLP-1 modulates the effect of metformin on glucagon secretion and consequently on EGP. It is important in this context to highlight that Liang, Xu [58] et al showed that adjustment for basal GLP-1 levels removed the statistical significance of the association between the rs2289669 of the SLC47A1 gene; encoding for the multidrug and toxin extrusion 1, a transporter involved in the hepatic and renal excretion of metformin, and enhanced glycemic response. Altogether these findings may implicate GLP-1 and glucagon in interindividual response variation to metformin.…”

Section: Could Hyperglucagonemia Underly An Adverse Response To Metfo...mentioning

confidence: 99%

Rethinking the Paradoxical Increase in Endogenous Glucose Production in Response to Metformin: Should We Retain the Glucagon Antagonistic Effect of the Drug?

Methnani¹,

Ach²,

Hraïech³

et al. 2022

Preprint

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Metformin, the treatment of first choice in type 2 diabetes (T2D), is known to mainly act by decreasing endogenous glucose production (EGP) in the liver. Paradoxically, in the last decade several reports documented increased EGP after metformin treatment. This increase, was often attributed to pronounced rises in glucagon, consistent with counter-regulatory response to the glucose lowering effect of metformin. However, considering that hyperglucagonemia, but not hypoinsulinemia, is a main driver of EGP in T2D, increased EGP should have been a common finding. This observation, together with the finding that metformin antagonizes glucagon effects on energy expenditure and protein synthesis, concurrently to its effects on EGP and the emerging evidences demonstrating increased branched chain and gluconeogenic amino acids in response to metformin treatment may points to a liver alpha-cell skeletal muscle cross talk similar to that observed in the liver-alpha cell axis. Here, we provide a mechanistic perspective to this latter possibility, based on mechanistic studies of metformin’s transcriptional targets; retaining thus its glucagon antagonistic and presumably anti-gluconeogenic effects on liver and attributing the increase in EGP to renal gluconeogenesis. We finally discuss how increased EGP might reflect an adverse response to metformin treatment, providing support from clinical and epidemiological data.

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Section: Could Hyperglucagonemia Underly An Adverse Response To Metfo...mentioning

confidence: 99%

Rethinking the Paradoxical Increase in Endogenous Glucose Production in Response to Metformin: Should We Retain the Glucagon Antagonistic Effect of the Drug?

Methnani¹,

Ach²,

Hraïech³

et al. 2022

Preprint

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“…Epidemiological evidence indicates that EOD exhibits a tendency of familial aggregation [12,13]. Recently, a large number of single nucleotide polymorphisms (SNPs) associated with the risk of T2DM have been discovered, but only a few studies have examined the infuence of such genetic heterogeneity on the age of onset of T2DM [14][15][16]. Te loss of insulin release, insulin resistance, and increased glucagon secretion also accelerate the development of T2DM.…”

Section: Introductionmentioning

confidence: 99%

GLP1R rs3765467 Polymorphism Is Associated with the Risk of Early Onset Type 2 Diabetes

Fang,

Zhang,

et al. 2023

International Journal of Endocrinology

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Objective. To investigate the relationship between glucagon-like peptide-1 receptor gene polymorphisms and susceptibility to early onset type 2 diabetes. Methods. Samples from 316 type 2 diabetes patients with early onset type 2 diabetes (n = 137) and late-onset type 2 diabetes (n = 179) and 145 nondiabetic individuals were analyzed. Multiplex PCR combined with resequencing Hi-Reseq technology was used to detect single nucleotide polymorphisms of the glucagon-like peptide-1 receptor gene, and the allele frequency, genotype distribution, and clinical parameters were analyzed between each diabetes subgroup and the control group. Results. Sixteen single nucleotide polymorphisms were identified in the exonic region of the glucagon-like peptide-1 receptor gene according to the minor allele frequency (MAF > 0.05) in the participants. Among these, the glucagon-like peptide-1 receptor rs3765467 (G⟶A) mutation was statistically associated with early onset type 2 diabetes. Compared with that of the GG carriers, carriers of genotype AA at rs3765467 had a decreased risk of early onset type 2 diabetes after adjusting for sex and body mass index. In the dominant model, the frequencies of the rs3765467 AA + GA genotype were significantly decreased in the early onset type 2 diabetes group, and carriers of genotype AA + GA at rs3765467 had a decreased risk of early onset type 2 diabetes after adjusting for sex and body mass index. Moreover, fasting C peptide levels were significantly higher in GA + AA genotype carriers than those in GG genotype carriers. Conclusion. The glucagon-like peptide 1 receptor rs3765467 polymorphism was significantly associated with age at type 2 diabetes diagnosis and thus may be used as a marker to screen and detect individuals at risk of developing early onset type 2 diabetes.

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Multidrug and Toxin Extrusion Proteins

2022

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Differential increments of basal glucagon‐like‐1 peptide concentration among SLC47A1 rs2289669 genotypes were associated with inter‐individual variability in glycaemic response to metformin in Chinese people with newly diagnosed Type 2 diabetes

Cited by 8 publications

References 20 publications

Rethinking the Paradoxical Increase in Endogenous Glucose Production in Response to Metformin: Should We Retain the Glucagon Antagonistic Effect of the Drug?

Rethinking the Paradoxical Increase in Endogenous Glucose Production in Response to Metformin: Should We Retain the Glucagon Antagonistic Effect of the Drug?

GLP1R rs3765467 Polymorphism Is Associated with the Risk of Early Onset Type 2 Diabetes

Multidrug and Toxin Extrusion Proteins

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