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Modulation by dietary fat and carbohydrate of IRS1 association with type 2 diabetes traits in two populations of different ancestries.

ABSTRACT: Insulin receptor substrate 1 (IRS1) is central to insulin signaling pathways. This study aimed to examine the association of IRS1 variants with insulin resistance (IR) and related phenotypes, as well as potential modification by diet.Two IRS1 variants (rs7578326 and rs2943641) identified by genome-wide association studies as related to type 2 diabetes were tested for their associations with IR and related traits and interaction with diet in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 820) and the Boston Puerto Rican Health Study (BPRHS) (n = 844).Meta-analysis indicated that rs7578326 G-allele carriers and rs2943641 T-allele carriers had a lower risk of IR, type 2 diabetes, and metabolic syndrome (MetS). Significant interactions on IR and MetS were found for these two variants and their haplotypes with diet. In GOLDN, rs7578326 G-allele carriers and rs2943641 T-allele carriers and their haplotype G-T carriers had a significantly lower risk of IR and MetS than noncarriers only when the dietary saturated fatty acid-to-carbohydrate ratio was low (? 0.24). In both GOLDN (P = 0.0008) and BPRHS (P = 0.011), rs7578326 G-allele carriers had a lower risk of MetS than noncarriers only when dietary monounsaturated fatty acids were lower than the median intake of each population.IRS1 variants are associated with IR and related traits and are modulated by diet in two populations of different ancestries. These findings suggest that IRS1 variants have important functions in various metabolic disorders and that dietary factors could modify these associations.

SUBMITTER: Zheng JS

PROVIDER: S-EPMC3747864 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Modulation by dietary fat and carbohydrate of IRS1 association with type 2 diabetes traits in two populations of different ancestries.

Zheng Ju-Sheng JS Arnett Donna K DK Parnell Laurence D LD Smith Caren E CE Li Duo D Borecki Ingrid B IB Tucker Katherine L KL Ordovás José M JM Lai Chao-Qiang CQ

Diabetes care 20130417 9

<h4>Objective</h4>Insulin receptor substrate 1 (IRS1) is central to insulin signaling pathways. This study aimed to examine the association of IRS1 variants with insulin resistance (IR) and related phenotypes, as well as potential modification by diet.<h4>Research design and methods</h4>Two IRS1 variants (rs7578326 and rs2943641) identified by genome-wide association studies as related to type 2 diabetes were tested for their associations with IR and related traits and interaction with diet in t ...[more]

PMID: 23596181

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Project description:S100 calcium-binding protein A9 (S100A9) has previously been identified as a type 2 diabetes (T2D) gene. However, this finding requires independent validation and more in-depth analyses in other populations and ancestries.We aimed to replicate the associations between an S100A9 variant and insulin resistance and T2D and to initiate an investigation of potential interactions with the habitual diet in several independent populations.We investigated the association of the S100A9 variant rs3014866 with insulin resistance and T2D risk and its interactions with diet in 3 diverse populations as follows: the CORDIOPREV (Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention; n = 711), which consisted of Spanish white adults; the GOLDN (Genetics of Lipids Lowering Drugs and Diet Network; n = 818), which involved North American non-Hispanic white adults; and Hispanic adults who participated in the BPRHS (Boston Puerto Rican Health Study; n = 1155).Meta-analysis indicated that T carriers presented a lower risk of T2D than CC carriers (pooled OR: 0.714; 95% CI: 0.584, 0.845; P = 0.002). In all 3 populations (CORDIOPREV, GOLDN, and BPRHS), we showed a significant interaction between the rs3014866 single nucleotide polymorphism and dietary SFA:carbohydrate ratio intake for the homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.028, P = 0.017, and P = 0.026, respectively). CC carriers had a significantly higher HOMA-IR only when SFA:carbohydrate intake was high (P = 0.045 for the CORDIOPREV, P = 0.033 for the GOLDN, and P = 0.046 for the BPRHS) but not when SFA:carbohydrate ratio intake was low.The minor allele (T) of the S100A9 variant rs3014866 is associated with lower T2D risk in 3 populations of different ancestries. Note that individuals with the high-risk CC genotype may be more likely to benefit from a low SFA:carbohydrate ratio intake to improve insulin resistance as evaluated with the use of the HOMA-IR. These trials were registered at clinicaltrials.gov as NCT00924937 (CORDIOPREV), NCT00083369 (GOLDN), and NCT01231958 (BPRHS).

Project description:Purpose: Obesity is a global health issue. To investigate if protein and fat contents of the diets had effects on energy balance via the canonical hunger signaling pathways in the hypothalamus, RNAseq was performed on RNA extracted from the hypothalami of mice exposed to the different diets. A suggested mechanism by which animals may avoid obesity is by burning off excess energy via upregulation of white adipose tissue (WAT) browning. To investigate if protein and fat content of the diet had effects on energy balance via the browning related signaling pathways in the WAT, RNAseq was performed on RNA extracted from the subcutaneous WAT (sWAT) and epididymal WAT (eWAT) of mice exposed to the different diets. Methods: C57BL/6 male mice were used in this work. All mice were fed a standard diet with 10% fat and 20% protein (D12450B, Research Diets Ltd) for 2 weeks as the baseline period. Following 2 weeks of baseline monitoring (at age 12 weeks), all mice were randomly allocated to different groups and switched to the experimental diets for 12 weeks. After 12 weeks all mice were sacrificed and dissected. Methods: In total, mice were fed on 4 diet series, each series consisting of 6 different diets (total = 24 diets). In the first two series (Series 1: D14071601–D14071606 and series 2: D14071607 – D14071612) we fixed the level of fat by energy, and varied the protein content. The protein source was casein. The balance was made up by carbohydrate (roughly equal mix of corn starch and maltodextrose). The source of fat was a mix of cocoa butter, coconut oil, menhaden oil, palm oil and sunflower oil. This mix was designed to match the balance of saturated, mono-unsaturated and polyunsaturated fats (ratio 47.5: 36.8: 15.8) and the n-6: n-3 ratio (14.7: 1) in the typical western diet. The proportions of the different fat constituents and hence fatty acid distributions did not change as the total fat content changed. Sucrose and cellulose were both fixed 5% by energy and weight respectively, and all diets were supplemented with a standard vitamin and mineral mix. In the second two series of diets (series 3: D14071613 – D14071618 and series 4: D14071619 – D14071624) we fixed the level of protein by energy and then allowed the fat content to vary. In these diets the sucrose, cellulose and vitamin and mineral contents were the same as the diets in series 1 and 2. All these diets can be ordered direct from research diets (www.researchdiets.com) using the diet codes provided. Methods: From each diet group, the hypothalami of 8/20 individuals were collected. The left halves of two, and the right halves of another two, were pooled together as one sample, and the same was performed with the other 4 hypothalami, resulting in each diet group having 2 pooled samples of 4 hypothalami (n = 48 samples in total across 24 diets). From each diet group, the sWAT and eWAT of 12/20 individuals were also collected. A small piece from each of six sWAT collections were pooled together as one sample, and the same was performed with the other six eWAT collections. In this way each diet group had one pooled sWAT sample and one pooled eWAT sample (also n = 48 across 24 diets). Methods: The total RNA of the hypothalamus and WAT was isolated using the RNeasy Mini Kit (QIAGEN, 74104) according to manufacturer's protocol. All sequencing was carried out using the Illumina NextSeq 500 sequencer. RNA fragments were sequenced by 75 bp long reads from paired ends (PE 2 x 75 bp, 150 bp per fragment). Quality control checks for raw data FASTQ files were done by using FASTQC (a quality control tool for high throughput sequence data; http://www.bioinformatics.babraham.ac.uk/projects/fastqc/). Paired-end reads were mapped to the Mus musculus genome (GRCm38) using Bowtie 2-2.1.0, TopHat-2.0.10, and Samtools-0.1.19; uniquely mapped reads for each gene were counted against the GTF file of GRCm38 provided by Ensembl (release 83) using HTSeq-0.6.1p1 using the strand = reverse; after read count data were obtained from the TopHat-HTSeq pipeline, counts per million (CPM) value for each gene was calculated by using the R package ‘edgeR’ (version 3.12.0, R version 3.2.2) to normalize the count data by the size of the library of each sample. Genes with the CPM value ≥ 1 in at least one of the 24 diets group were retained (Anders et al., 2013). Generalized Linear Modelling (GLM) was applied by R (version 3.2.2). The GLM model used here was: ~p+f+p:f, which regresses gene expression (CPM) against the protein (p) and fat contents (f) of diets, as well as their interaction (p:f). However, when the effect of the interaction was not significant (p value ≥ 0.05), the interaction term was dropped and a revised model (~p+f) was utilized. Results: With TopHat-HTSeq pipeline, reads of each sample were mapped to 46,078 genes. In hypothalamus there were 15,371 genes with the counts per million (CPM) value ≥ 1 in at least one of the 24 diets group; in white adipose tissue there were 18,202 genes with the CPM value ≥ 1 in at least one of the 24 diets group. No major changes in hypothalamic gene expression levels were found in relation to different dietary protein levels at fixed fat contents, however hypothalamic gene expression showed increase in expression of genes in reward pathways in relation to dietary fat, while Agrp and Npy were both downregulated in relation to dietary fat levels. WAT gene expression showed decrease in expression of general thermogenic related genes and WAT browning related genes in relation to both dietary protein and dietary fat, while Tgfb1, Pdk4 and Fgf1 were all upregulated in relation to dietary fat levels. Conclusions: Significant positive associations were evident between the fat levels of the diet and the main hedonic signaling systems linked to food intake. Significant negative associations were found between both protein and fat levels of the diet and WAT browning or general thermogenic signalings linked to energy expenditure.

Dataset Information

Modulation by dietary fat and carbohydrate of IRS1 association with type 2 diabetes traits in two populations of different ancestries.

Publications

Modulation by dietary fat and carbohydrate of IRS1 association with type 2 diabetes traits in two populations of different ancestries.

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