Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity

Scott, Robert A.; Fall, Tove; Pasko, Dorota; Barker, Adam; Sharp, Stephen J.; Arriola, Larraitz; Balkau, Beverley; Barricarte, Aurelio; Barroso, Inês; Boeing, Heiner; Clavel‐Chapelon, Françoise; Crowe, Francesca L.; Dekker, Joost; Fagherazzi, Guy; Ferrannini, Ele; Forouhi, Nita G.; Franks, Paul W.; Gavrila, Diana; Giedraitis, Vilmantas; Grioni, Sara; Groop, Leif; Kaaks, Rudolf; Key, Timothy J.; Kühn, Tilman; Lotta, Luca A.; Nilsson, Peter M.; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quiŕos, J. Ramón; Rolandsson, Olov; Roswall, Nina; Sacerdote, Carlotta; Sala, Núria; Sánchez, María‐José; Schulze, Matthias B.; Siddiq, Afshan; Slimani, Nadia; Sluijs, Ivonne; Spijkerman, Annemieke M.W.; Tjønneland, Anne; Tumino, Rosario; A, Daphne L. van der; Yaghootkar, Hanieh; McCarthy, Mark I.; Semple, Robert K.; Riboli, Elio; Walker, Mark; Ingelsson, Erik; Frayling, Timothy M.; Savage, David B.; Langenberg, Claudia; Wareham, Nicholas J.

doi:10.2337/db14-0319

Cited by 158 publications

(196 citation statements)

References 44 publications

Supporting

Mentioning

181

Contrasting

Unclassified

Order By: Relevance

“…To improve the specificity of the score, we only included ten fasting serum insulin variants known to be associated with lower HDL-cholesterol and higher triacylglycerol, a biochemical hallmark of insulin resistance [6]. The score was constructed by summing the number of insulin-increasing alleles reported by MAGIC [4].…”

Section: Measurement Of Insulin Resistancementioning

confidence: 99%

“…Three other known variants for circulating BCAA levels are rs10211524, located near to the SLC1A4 gene (encoding solute carrier family 1, member 4), rs7406661 near the ASGR1 gene (encoding asialoglycoprotein receptor 1), and the missense variant rs1260326 in the GCKR gene (encoding glucokinase receptor). GWAS for fasting insulin levels have uncovered 24 loci, of which ten have been robustly associated with insulin resistance [4,6].…”

Section: Introductionmentioning

confidence: 99%

“…Genetic variants identified in genome-wide association studies (GWAS) for circulating BCAA levels and insulin resistance can be utilised as instrumental variables in Mendelian randomisation [4][5][6], to examine causal relations between the two. So far, four variants have been shown to associate with circulating BCAA levels in the fasting state [5].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels

et al. 2017

View full text Add to dashboard Cite

Aims/hypothesis Fasting plasma levels of branched-chain amino acids (BCAAs) are associated with insulin resistance, but it remains unclear whether there is a causal relation between the two. We aimed to disentangle the causal relations by performing a Mendelian randomisation study using genetic variants associated with circulating BCAA levels and insulin resistance as instrumental variables. Methods We measured circulating BCAA levels in blood plasma by NMR spectroscopy in 1,321 individuals from the ADDITION-PRO cohort. We complemented our analyses by using previously published genome-wide association study (GWAS) results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 46,186) and from a GWAS of serum BCAA levels (n = 24,925). We used a genetic risk score (GRS), calculated using ten established fasting serum insulin associated variants, as an instrumental variable for insulin resistance. A GRS of three variants increasing circulating BCAA levels was used as an instrumental variable for circulating BCAA levels. Conclusions/interpretation Our results suggest that higher BCAA levels do not have a causal effect on insulin resistance while increased insulin resistance drives higher circulating fasting BCAA levels. Results

show abstract

Section: Measurement Of Insulin Resistancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The term "diabesity" is used to define the coincidence of obesity with T2D under conditions of exaggerated intake of energy-dense diets (4)(5)(6). Moreover, genomewide association studies (GWAS) have identified polymorphisms associated with obesity and T2D, indicating that genetic factors predispose certain individuals to diabesity (7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Replacing SNAP-25b with SNAP-25a expression results in metabolic disease

Valladolid‐Acebes

Daraio

Brismar

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Synaptosomal-associated protein of 25 kDa (SNAP-25) is a key molecule in the soluble N-ethylmaleimide-sensitive factor attachment protein (SNARE) complex mediating fast Ca 2+ -triggered release of hormones and neurotransmitters, and both splice variants, SNAP-25a and SNAP-25b, can participate in this process. Here we explore the hypothesis that minor alterations in the machinery mediating regulated membrane fusion can increase the susceptibility for metabolic disease and precede obesity and type 2 diabetes. Thus, we used a mouse mutant engineered to express normal levels of SNAP-25 but only SNAP-25a. These SNAP-25b-deficient mice were exposed to either a control or a high-fat/high-sucrose diet. Monitoring of food intake, body weight, hypothalamic function, and lipid and glucose homeostases showed that SNAP-25b-deficient mice fed with control diet developed hyperglycemia, liver steatosis, and adipocyte hypertrophy, conditions dramatically exacerbated when combined with the high-fat/high-sucrose diet. Thus, modified SNARE function regulating stimulus-dependent exocytosis can increase the vulnerability to and even provoke metabolic disease. When combined with a high-fat/high-sucrose diet, this vulnerability resulted in diabesity. Our SNAP-25b-deficient mouse may represent a diabesity model.O n-going lifestyle changes, including oversized meals with excessive amounts of sugar and fat, have led to a worldwide pandemic of obesity and type 2 diabetes (T2D) (1). These diseases and their comorbidities cause individual suffering and represent a heavy financial burden on society (2, 3). The term "diabesity" is used to define the coincidence of obesity with T2D under conditions of exaggerated intake of energy-dense diets (4-6). Moreover, genomewide association studies (GWAS) have identified polymorphisms associated with obesity and T2D, indicating that genetic factors predispose certain individuals to diabesity (7-11).Signs of metabolic diseases include impaired regulated release of hormones, particularly insulin as in T2D (4, 12). Likewise, the secretion of inflammatory markers and other peripheral bioactive peptides is either increased (e.g., leptin, resistin, and adipsin) or decreased (e.g., ghrelin and adiponectin) (13-16). Synaptic and nonsynaptic transmission involving the release of neuropeptides and neurotransmitters, especially in hypothalamic areas controlling eating behavior and energy balance, are involved too (17)(18)(19).In excitable cells, the release of messenger molecules is a consequence of regulated membrane fusion and involves soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAREs) (20, 21), including synaptosomal-associated protein of 25 kDa (SNAP-25). SNAP-25 is expressed as two developmentally regulated and alternatively spliced isoforms, SNAP-25a and SNAP-25b, which differ in only 9 of 206 amino acids (22, 23). In the mouse brain, SNAP-25a precedes SNAP-25b expression during development, but by the second postnatal week SNAP-25b becomes the major splice variant, concomitantly with a dr...

show abstract

“…The FGF21 rs838133 minor allele is not the first common allele to be associated with apparently paradoxical effects on fat mass and metabolic markers. Previous human genetic studies of alleles associated with insulin sensitivity have shown that most are also associated with an apparently paradoxical higher fat mass (and the insulin resistance allele is associated with lower fat mass) [32][33][34][35][36][37]. Like the FGF21 allele, for some of these alleles the apparent paradox is explained by the higher fat mass being concentrated in the lower body, at least in women, (e.g.…”

Section: Discussionmentioning

confidence: 94%

A common allele in FGF21 associated with preference for sugar consumption lowers body fat in the lower body and increases blood pressure

et al. 2017

Preprint

Self Cite

View full text Add to dashboard Cite

word summaryFibroblast Growth Factor 21 (FGF21) is a hormone that induces weight loss in model organisms. These findings have led to trials in humans of FGF21 analogues with some showing weight loss and lipid lowering effects. Recent genetic studies have shown that a common allele in the FGF21 gene alters the balance of macronutrients consumed but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with body fat distribution, with less fat in the lower body, and higher blood pressure, than it is with BMI, where there is only nominal evidence of an effect. These human phenotypes of naturally occurring variation in the FGF21 gene will inform decisions about FGF21's therapeutic potential. IntroductionFGF21 is a hormone secreted primarily by the liver whose multiple functions include signalling to the paraventricular nucleus of the hypothalamus to suppress sugar and alcohol intake [1,2], stimulating insulin-independent glucose uptake by adipocytes [3] and acting as an insulin sensitizer [4]. These features and several other lines of evidence have prompted the development of FGF21 based therapies as potential treatments for obesity and type 2 diabetes, with consistent effects on triglyceride lowering, some effects on weight loss but little effect on glucose tolerance [5,6]. An early trial showed lipid lowering effects in people with type 2 diabetes and obesity but there was only suggestive evidence for effects on weight and glucose tolerance [7]. A recent study suggested that FGF21 analogues may alter not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/214700 doi: bioRxiv preprint first posted online Nov. 6, 2017; blood pressure in humans [8], although changes in blood pressure were not observed in a previous trial [9]. Pre-clinical evidence of FGF21's potential role in metabolism includes resistance to diet induced obesity in mice overexpressing FGF21 [3] and improved glucose tolerance in obese mice through administration of recombinant FGF21 [3]. Subsequent studies have confirmed these findings in mice [10] and shown similar effects in non human primates, including improvement of glucose tolerance and slight weight loss in diabetic rhesus monkeys [11], but other studies are less conclusive [5].Recent studies have shown that FGF21 affects the balance of macronutrients consumed. Studies in mice and non human primates show that genetically and pharmacologically raising FGF21 levels suppresses sugar and alcohol intake [1,2]. Three human genetic studies have shown that the minor A allele at rs838133 (A/G, Minor Allele Frequency=44.7%), which results in a synonymous change to the first exon of FGF21, is associated with higher carbohydrate and lower...

show abstract

Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity

Cited by 158 publications

References 44 publications

Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels

Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels

Replacing SNAP-25b with SNAP-25a expression results in metabolic disease

A common allele in FGF21 associated with preference for sugar consumption lowers body fat in the lower body and increases blood pressure

Contact Info

Product

Resources

About