The fat mass and obesity-associated (FTO) gene allele rs9939609 and glucose tolerance, hepatic and total insulin sensitivity, in adults with obesity

Abstract

The objective of the study was to assess associations of the rs9939609 FTO allele to glucose tolerance, hepatic and total insulin sensitivity (IS) in individuals with obesity. From a low-dose hyperinsulinemic euglycemic clamp with glucose-tracer, hepatic IS was assessed by rates of basal and suppressed glucose appearance (Ra), a measure of endogenous glucose production (EGP), and the hepatic insulin resistance index (HIR). Total IS was assessed by rates of glucose infusion (GIR), disappearance (Rd), and metabolic clearance (MCR). From a meal test we assessed IS by the Matsuda index and glucose tolerance by glucose and insulin measurements in the fasted state and postprandially for 2.5 h. The meal test was performed in 97 healthy individuals with BMI ≥35 in similar-sized risk-allele groups (n = 32 T/T, 31 A/T, and 34 A/A), and 79 of them performed the clamp. We analyzed outcomes separately for males and females, and adjusted glucose Ra, Rd, MCR, GIR, and HIR for fat mass. We did not find genotype effects on EGP. Among males, genotype A/A was associated with a significantly lower glucose Rd, MCR, and Matsuda index score relative to genotype T/T. Glucose tolerance was significantly lower in males with genotype A/T vs. T/T and A/A. For females, there were no genotype effects on hepatic or total IS, or on glucose tolerance. Independently of genotypes, females displayed a significantly better hepatic and total IS, and better glucose tolerance than males. We conclude that in subjects with similar obesity we did not register any FTO risk-allele effect on hepatic IS. A FTO risk-allele effect on total IS was registered in males only, findings which need to be reproduced in further studies. Results confirm marked differences in IS between the biological sexes and extend present knowledge by demonstrating a lower endogenous glucose production in females vs. males in uniformly obese individuals.

Whole‐genome sequencing study to identify candidate markers indicating susceptibility to type 2 diabetes in Bama miniature pigs

“…The polymorphisms of HHEX rs1111875 and rs5015480 are also considered to be associated with insulin secretion and beta‐cell dysfunction 17,25,26 . FTO has been reported to increase the risk of T2DM by affecting insulin sensitivity 27,28 . This study showed that minipigs with diabetes also had diabetes‐related SNPs in these genes or their adjacent intergenic regions.…”

“…17,25,26 FTO has been reported to increase the risk of T2DM by affecting insulin sensitivity. 27,28 This study showed that minipigs with diabetes also had diabetes-related SNPs in these genes or their adjacent intergenic regions. In addition, loci related to diabetes have also been found in some less-reported genes, such as CCND2, CDKN2B, MRPL34, PXMP4, and GPRIN2, or in their vicinity in human T2DM GWAS studies.…”

Genetic architecture for skeletal muscle glycolytic potential in Chinese Erhualian pigs revealed by a genome-wide association study using 1.4M SNP array

“…Melina Claussnitzer et al found that the SNP rs1421085 in FTO gene disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and an increase in lipid storage with the increasing expression of IRX3 and IRX5 (Claussnitzer et al, 2015). Moreover, FTO's related pathways include Glucose/Energy Metabolism and many studies have shown that FTO is closely related to glucose metabolism (Maia-Landim et al, 2018;Yang et al, 2019;Krüger et al, 2020;De Soysa et al, 2021). So, FTO is likely involved in regulating muscle glycogen content.…”

Linking Mitochondrial Function to Insulin Resistance: Focusing on Comparing the Old and the Young

“…The prevalence of obesity and type 2 diabetes in animals will increase significantly with age, due to which aging will lead to a progressive decline in most endocrine functions and meanwhile result in severe metabolic disorder (9). Previous studies have shown that the prevalence of diabetes in the elderly is high, but at present, many studies show significantly lower insulin sensitivity in obese young adults (10). Young people with T2DM or abnormal glucose tolerance have lower βcell sensitivity than healthy old people, which may be related to the great demand for a role of β cells in regulating blood glucose in young people (11).…”