Genetics of Glucose Homeostasis Implications for Insulin Resistance and Metabolic Syndrome
ABSTRACT This review summarizes the current understanding of the genetic basis of glucose homeostasis through genome-wide association scans and candidate gene studies of case-control and family-based designs. We highlight the implications of phenotype-direct (euglycemic clamp or frequently sampled intravenous glucose tolerance test) and indirect (fasting insulin and fasting glucose) measures on the determinants of insulin resistance and β-cell response that precede and contribute to the development of type 2 diabetes mellitus (T2DM) and the metabolic syndrome. Finally, we examine future approaches that may aid in understanding the biology of insulin resistance and T2DM. Over the past 2 decades, the prevalence of insulin resistance, the metabolic syndrome, and T2DM has increased. Ethnic differences in T2DM and insulin resistance are evident, with nonwhite populations having the greatest risk. There continue to be significant gaps in our knowledge regarding the metabolic, behavioral, and genetic determinants of these conditions. Understanding the genetic basis of glucose homeostasis, insulin resistance, and T2DM should provide insight on known and novel metabolic pathways that identify potential therapeutic targets and mechanisms for intervention.
- SourceAvailable from: Agustín Martín-Morales
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- "Obesity, and more specifically the accretion of excess adipose tissue, is associated with elevated chronic systemic low-grade inflammation and increased risk of metabolic diseases, such as type 2 diabetes and cardiovascular disease (CVD) . The pathogenesis of these conditions is attributable to a complex interaction between genetic, metabolic, environmental and behavioural factors, however the specific contribution of each of these determinants is not fully understood . The composition and metabolic activity of microbial inhabitants of the human gut has recently been acknowledged as an environmental factor that may influence the development of obesity and associated metabolic diseases [4,5]. "
ABSTRACT: Wheat dextrin soluble fibre may have metabolic and health benefits, potentially acting via mechanisms governed by the selective modulation of the human gut microbiota. Our aim was to examine the impact of wheat dextrin on the composition and metabolic activity of the gut microbiota. We used a validated in vitro three-stage continuous culture human colonic model (gut model) system comprised of vessels simulating anatomical regions of the human colon. To mimic human ingestion, 7 g of wheat dextrin (NUTRIOSE(®) FB06) was administered to three gut models, twice daily at 10.00 and 15.00, for a total of 18 days. Samples were collected and analysed for microbial composition and organic acid concentrations by 16S rRNA-based fluorescence in situ hybridisation and gas chromatography approaches, respectively. Wheat dextrin mediated a significant increase in total bacteria in vessels simulating the transverse and distal colon, and a significant increase in key butyrate-producing bacteria Clostridium cluster XIVa and Roseburia genus in all vessels of the gut model. The production of principal short-chain fatty acids, acetate, propionate and butyrate, which have been purported to have protective, trophic and metabolic host benefits, were increased. Specifically, wheat dextrin fermentation had a significant butyrogenic effect in all vessels of the gut model and significantly increased production of acetate (vessels 2 and 3) and propionate (vessel 3), simulating the transverse and distal regions of the human colon, respectively. In conclusion, wheat dextrin NUTRIOSE(®) FB06 is selectively fermented in vitro by Clostridium cluster XIVa and Roseburia genus and beneficially alters the metabolic profile of the human gut microbiota.PLoS ONE 10/2013; 8(10):e77128. DOI:10.1371/journal.pone.0077128 · 3.23 Impact Factor
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- "In recent years, numerous genome-wide association studies of individual traits related to MS have successfully localized susceptibility variants/genes for such phenotypes as obesity, T2DM, dyslipidemia, and hypertension, as well as childhood obesity; a few studies have also localized variants/genes with potential pleiotropic influences on MS (McCarthy 2010; Zeller et al. 2012; Fall and Ingelsson 2012; Norris and Rich 2012; Manco and Dallapiccola 2012). Our immediate plans are to conduct genome-wide screenings for the identification of genetic variants influencing individual MS traits—most importantly, those pleiotropically influencing multivariate MS traits in our data. "
ABSTRACT: Pediatric metabolic syndrome (MS) and its cardiometabolic components (MSCs) have become increasingly prevalent, yet little is known about the genetics underlying MS risk in children. We examined the prevalence and genetics of MS-related traits among 670 non-diabetic Mexican American (MA) children and adolescents, aged 6-17 years (49 % female), who were participants in the San Antonio Family Assessment of Metabolic Risk Indicators in Youth study. These children are offspring or biological relatives of adult participants from three well-established Mexican American family studies in San Antonio, TX, at increased risk of type 2 diabetes. MS was defined as ≥3 abnormalities among 6 MSC measures: waist circumference, systolic and/or diastolic blood pressure, fasting insulin, triglycerides, HDL-cholesterol, and fasting and/or 2-h OGTT glucose. Genetic analyses of MS, number of MSCs (MSC-N), MS factors, and bivariate MS traits were performed. Overweight/obesity (53 %), pre-diabetes (13 %), acanthosis nigricans (33 %), and MS (19 %) were strikingly prevalent, as were MS components, including abdominal adiposity (32 %) and low HDL-cholesterol (32 %). Factor analysis of MS traits yielded three constructs: adipo-insulin-lipid, blood pressure, and glucose factors, and their factor scores were highly heritable. MS itself exhibited 68 % heritability. MSC-N showed strong positive genetic correlations with obesity, insulin resistance, inflammation, and acanthosis nigricans, and negative genetic correlation with physical fitness. MS trait pairs exhibited strong genetic and/or environmental correlations. These findings highlight the complex genetic architecture of MS/MSCs in MA children, and underscore the need for early screening and intervention to prevent chronic sequelae in this vulnerable pediatric population.Human Genetics 06/2013; 132(9). DOI:10.1007/s00439-013-1315-2 · 4.52 Impact Factor
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ABSTRACT: Diabetes is one of the most important risk factor for stroke and cardiovascular disease (CVD), especially in young patients. The control of classical vascular risk factors failed in terms of prevention of stroke in patients with diabetes. In addiction, in these patients the glycemic control showed a benefit on microvascular disease but lacked an established benefit in macrovascular disease. Therefore, implementations of effective stroke prevention strategies appear necessary in patients with diabetes. Ultrasound surrogate or intermediate markers of carotid atherosclerosis include carotid intima-media thickness (cIMT), carotid plaque (CP), and carotid stiffness (STIFF) have been demonstrated to increase in patients with diabetes and to be able to predict risk for stroke. In this editorial we discuss the opportunity to prevent the onset of vascular disease in their "preclinical or subclinical" stage in patients with higher risk for stroke such as diabetic patients.Metabolic Brain Disease 02/2013; DOI:10.1007/s11011-013-9385-3 · 2.40 Impact Factor