Higher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 CHARGE Consortium Studies.

Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes.

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3.

Aims/hypothesis: The rs738409 C>G single-nucleotide polymorphism in PNPLA3 leads to a missense mutation (I148M) which increases liver fat but does not cause insulin resistance. We hypothesised that patients with non-alcoholic fatty liver disease (NAFLD) due to the PNPLA3 variant ('PNPLA3 NAFLD' = PNPLA3-148MM) do not have adipose tissue (AT) inflammation in contrast with those with NAFLD due to obesity ('obese NAFLD').

Methods: Biopsy specimens of AT were taken, and PNPLA3 genotype and liver fat ((1)H-magnetic resonance spectroscopy) were determined in 82 volunteers, who were divided into groups based on either median BMI (obese 36.

Meta-analysis investigating associations between healthy diet and fasting glucose and insulin levels and modification by loci associated with glucose homeostasis in data from 15 cohorts.

Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 U.S.

A diabetes-predictive amino acid score and future cardiovascular disease.

Aims: We recently identified a metabolic signature of three amino acids (tyrosine, phenylalanine, and isoleucine) that strongly predicts diabetes development. As novel modifiable targets for intervention are needed to meet the expected increase of cardiovascular disease (CVD) caused by the diabetes epidemic, we investigated whether this diabetes-predictive amino acid score (DM-AA score) predicts development of CVD and its functional consequences.

Methods And Results: We performed a matched case-control study derived from the population-based Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC), all free of CVD.

Sex-specific interactions between the IRS1 polymorphism and intakes of carbohydrates and fat on incident type 2 diabetes.

Background: The minor T allele of rs2943641 near the gene encoding for insulin receptor substrate 1 (IRS1) has been associated with decreased risk of type 2 diabetes (T2D) and adiposity in genome-wide association studies. Dietary intake can influence the regulation of IRS1, and studies have indicated sex-specific associations between IRS1 and adiposity.

Objective: The objective was to examine the interaction between IRS1 rs2943641 and macronutrient intakes on incident T2D and percentage body fat in the Malmö Diet and Cancer cohort.

Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes.

The major histocompatibility complex class II transactivator (CIITA) gene (16p13) has been reported to associate with susceptibility to multiple sclerosis, rheumatoid arthritis and myocardial infarction, recently also to celiac disease at genome-wide level. However, attempts to replicate association have been inconclusive. Previously, we have observed linkage to the CIITA region in Scandinavian type 1 diabetes (T1D) families.

Plasma proneurotensin and incidence of diabetes, cardiovascular disease, breast cancer, and mortality.

Context: Neurotensin regulates both satiety and breast cancer growth in the experimental setting, but little is known about its role in the development of breast cancer or cardiometabolic disease in humans.

Objective: To test if fasting plasma concentration of a stable 117-amino acid fragment from the neurotensin precursor hormone proneurotensin is associated with development of diabetes mellitus, cardiovascular disease, breast cancer, and mortality.

Design, Setting, And Participants: Proneurotensin was measured in plasma from 4632 fasting participants of the population-based Malmö Diet and Cancer Study baseline examination 1991-1994.

Dietary fiber, carbohydrate quality and quantity, and mortality risk of individuals with diabetes mellitus.

Background: Dietary fiber, carbohydrate quality and quantity are associated with mortality risk in the general population. Whether this is also the case among diabetes patients is unknown.

Objective: To assess the associations of dietary fiber, glycemic load, glycemic index, carbohydrate, sugar, and starch intake with mortality risk in individuals with diabetes.

Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro.

Background & Aims: The robust association between non-alcoholic fatty liver disease (NAFLD) and the genetic variant I148M (rs738409) in PNPLA3 has been widely replicated. The aim of this study was to investigate the effect of the PNPLA3 I148M mutation on: (1) hepatic secretion of very low density lipoproteins (VLDL) in humans; and (2) secretion of apolipoprotein B (apoB) from McA-RH 7777 cells, which secrete VLDL-sized apoB-containing lipoproteins.

Methods: VLDL kinetics was analyzed after a bolus infusion of stable isotopes in 55 overweight/obese men genotyped for the PNPLA3 I148M variant.

High intakes of protein and processed meat associate with increased incidence of type 2 diabetes.

Diets high in protein have shown positive effects on short-term weight reduction and glycaemic control. However, the understanding of how dietary macronutrient composition relates to long-term risk of type 2 diabetes is limited. The aim of the present study was to examine intakes of macronutrients, fibre and protein sources in relation to incident type 2 diabetes.

Role of TCF7L2 risk variant and dietary fibre intake on incident type 2 diabetes.

Aims/hypothesis: The T allele of transcription factor 7-like 2 gene variant, TCF7L2 rs7903146, increases the risk of type 2 diabetes by 40-50%. As TCF7L2 rs7903146 has been associated with diminished incretin effect we investigated whether interaction between dietary intake of carbohydrate, fat, protein or fibre and this variant affects the risk of type 2 diabetes.

Methods: A cohort of 24,799 non-diabetic individuals from the Malmö Diet and Cancer Study (MDCS), with dietary data obtained by a modified diet history method, were followed up for 12 years, with 1,649 recordings of incident type 2 diabetes made.

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.

Intake levels of dietary long-chain PUFAs modify the association between genetic variation in FADS and LDL-C.

Polymorphisms of the FA desaturase (FADS) gene cluster have been associated with LDL, HDL, and triglyceride concentrations. Because FADS converts α-linolenic acid (ALA) and linoleic acid into PUFAs, we investigated the interaction between different PUFA intakes and the FADS polymorphism rs174547 (T>C) on fasting blood lipid and lipoprotein concentrations. We included 4,635 individuals (60% females, 45-68 years) from the Swedish population-based Malmö Diet and Cancer cohort.

Genetic variation in the glucose-dependent insulinotropic polypeptide receptor modifies the association between carbohydrate and fat intake and risk of type 2 diabetes in the Malmo Diet and Cancer cohort.

Context: A common genetic variant (rs10423928, A-allele) in the glucose-dependent insulinotropic polypeptide receptor gene (GIPR) is associated with decreased insulin secretion. Glucose-dependent insulinotropic polypeptide is secreted after food consumption and gipr knockout mice fed a high-fat diet are protected against obesity and disturbances in glucose homeostasis.

Objective: Our objective was to examine the interactions between rs10423928 and macronutrients and fiber intakes on body mass index and type 2 diabetes risk.

Genetic variation in PNPLA3 but not APOC3 influences liver fat in non-alcoholic fatty liver disease.

Background And Aim: A recent study in Indian subjects suggested common variants in apolipoprotein C3 (APOC3) (T-455C at rs2854116 and C-482T at rs2854117) to contribute to non-alcoholic fatty liver disease (NAFLD), plasma apoC3 and triglyceride concentrations. Our aim was to determine the contribution of genetic variation in APOC3 on liver fat content and plasma triglyceride and apoC3 concentrations in a larger European cohort.

Methods: A total of 417 Finnish individuals were genotyped for rs2854116 and rs2854117 in APOC3 and the known rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3) influencing liver fat.

Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.

Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268).

High disaccharide intake associates with atherogenic lipoprotein profile.

Increased plasma concentrations of small LDL particles denote an atherogenic lipoprotein phenotype (ALP) that is correlated with increased circulating TAG and reduced HDL-cholesterol. Principal component analyses of subfraction concentrations have previously been used in the Swedish population-based Malmö Diet and Cancer (MDC) cohort to identify three independent components, one pattern representing the ALP. The aim of the present study was to examine the associations between macronutrient intakes and the principal component representing the ALP.

Pleiotropic effects of GIP on islet function involve osteopontin.

Objective: The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function.

Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis.

Objective: Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.

Dual metabolic defects are required to produce hypertriglyceridemia in obese subjects.

Objective: Obesity increases the risk of cardiovascular disease and premature death. However, not all obese subjects develop the metabolic abnormalities associated with obesity. The aim of this study was to clarify the mechanisms that induce dyslipidemia in obese subjects.

Dairy products and its association with incidence of cardiovascular disease: the Malmö diet and cancer cohort.

It is unclear whether specific dairy products are associated with risk of cardiovascular disease (CVD). The aim of this project was therefore to examine the association between intake of milk, cheese, cream and butter, and incidence of CVD in the Swedish Malmö Diet and Cancer cohort. Milk was separated into fermented (yoghurt and cultured sour milk) versus non-fermented milk, and low-fat versus high-fat milk.

Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans.

Background: The rs738409 C→G single nucleotide polymorphism in the patatin-like phospholipase domain-containing 3 (PNPLA3; adiponutrin) leads to a missense mutation (I148M), which is associated with increased liver fat but not insulin resistance. The I148M mutation impedes triglyceride hydrolysis in vitro, and its carriers have an increased risk of developing severe liver disease.

Objective: We explored whether the rs738409 PNPLA3 G allele influences the ability of weight loss to decrease liver fat or change insulin sensitivity.

The mouse QTL map helps interpret human genome-wide association studies for HDL cholesterol.

Genome-wide association (GWA) studies represent a powerful strategy for identifying susceptibility genes for complex diseases in human populations but results must be confirmed and replicated. Because of the close homology between mouse and human genomes, the mouse can be used to add evidence to genes suggested by human studies. We used the mouse quantitative trait loci (QTL) map to interpret results from a GWA study for genes associated with plasma HDL cholesterol levels.