OBJECTIVE-Three independent studies have shown that variation in the fat mass and obesity-associated (FTO) gene associates with BMI and obesity. In the present study, the effect of FTO variation on metabolic traits including obesity, type 2 diabetes, and related quantitative phenotypes was examined. RESEARCH DESIGN AND METHODS-The FTO rs9939609 polymorphism was genotyped in a total of 17,508 Danes from five different study groups.RESULTS-In studies of 3,856 type 2 diabetic case subjects and 4,861 normal glucose-tolerant control subjects, the minor A-allele of rs9939609 associated with type 2 diabetes (odds ratio 1.13 [95% CI 1.06 -1.20], P ϭ 9 ϫ 10 Ϫ5 ). This association was abolished when adjusting for BMI (1.06 [0.97-1.16], P ϭ 0.2). Among 17,162 middle-aged Danes, the A-allele associated with overweight (1.19 [1.13-1.24], P ϭ 1 ϫ 10 Ϫ12 ) and obesity (1.27 [1.20 -1.34], P ϭ 2 ϫ 10 Ϫ16 ). Furthermore, obesity-related quantitative traits such as body weight, waist circumference, fat mass, and fasting serum leptin levels were significantly elevated in A-allele carriers. An interaction between the FTO rs9939609 genotype and physical activity (P ϭ 0.007) was found, where physically inactive homozygous risk A-allele carriers had a 1.95 Ϯ 0.3 kg/m 2 increase in BMI compared with homozygous T-allele carriers.CONCLUSIONS-We validate that variation in FTO is associated with type 2 diabetes when not adjusted for BMI and with an overall increase in body fat mass. Furthermore, low physical activity seems to accentuate the effect of FTO rs9939609 on body fat accumulation. Diabetes 57:95-101, 2008 W orldwide incidence of obesity has increased dramatically and is today one of the leading causes of lifestyle-related disorders such as type 2 diabetes and premature cardiovascular disease. Association between common forms of obesity and genes such as GAD2 (1), ENPP1 (2), and INSIG2 (3) have been reported but difficult to validate (4 -6). Recently, variation in the fat mass and obesity-associated (FTO) gene was reported to associate with type 2 diabetes and increased fat mass. As a part of the Wellcome Trust Case Control Consortium genome-wide association study, which included 1,924 U.K. type 2 diabetic patients and 2,938 U.K. normoglycemic control subjects, an FTO variant (rs9939609) was found to associate with type 2 diabetes; however, this association abolished following adjustment for BMI (7). Subsequently, an association with overweight and obesity was demonstrated in seven population-based study samples comprising a total of 19,424 white European adults and two birth cohorts including 10,172 white European children. Moreover, evidence was presented that the increase in BMI resulted from an overall increase in body fat, evaluated by waist circumference and fat mass estimates, including skinfold measures (7).In another independent study, the effect of 48 neutral single-nucleotide polymorphisms (SNPs) on obesity was tested in 2,900 obese and 5,100 control subjects of European ancestry, and the FTO rs1121980 polymorphism, also ...

Postprandial glucose, together with related hyperinsulinemia and lipidaemia, has been implicated in the development of chronic metabolic diseases like obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). In this review, available evidence is discussed on postprandial glucose in relation to body weight control, the development of oxidative stress, T2DM, and CVD and in maintaining optimal exercise and cognitive performance. There is mechanistic evidence linking postprandial glycaemia or glycaemic variability to the development of these conditions or in the impairment in cognitive and exercise performance. Nevertheless, postprandial glycaemia is interrelated with many other (risk) factors as well as to fasting glucose. In many studies, meal-related glycaemic response is not sufficiently characterized, or the methodology with respect to the description of food or meal composition, or the duration of the measurement of postprandial glycaemia is limited. It is evident that more randomized controlled dietary intervention trials using effective low vs. high glucose response diets are necessary in order to draw more definite conclusions on the role of postprandial glycaemia in relation to health and disease. Also of importance is the evaluation of the potential role of the time course of postprandial glycaemia.

Sustained weight loss is a preferred intervention in a wide range of metabolic conditions, but the effects on an individual's health state remain ill‐defined. Here, we investigate the plasma proteomes of a cohort of 43 obese individuals that had undergone 8 weeks of 12% body weight loss followed by a year of weight maintenance. Using mass spectrometry‐based plasma proteome profiling, we measured 1,294 plasma proteomes. Longitudinal monitoring of the cohort revealed individual‐specific protein levels with wide‐ranging effects of losing weight on the plasma proteome reflected in 93 significantly affected proteins. The adipocyte‐secreted SERPINF1 and apolipoprotein APOF1 were most significantly regulated with fold changes of −16% and +37%, respectively (P < 10−13), and the entire apolipoprotein family showed characteristic differential regulation. Clinical laboratory parameters are reflected in the plasma proteome, and eight plasma proteins correlated better with insulin resistance than the known marker adiponectin. Nearly all study participants benefited from weight loss regarding a ten‐protein inflammation panel defined from the proteomics data. We conclude that plasma proteome profiling broadly evaluates and monitors intervention in metabolic diseases.

The role of glucose-stimulated release of GLP-1 in the development of obesity and type 2 diabetes is unclear.We assessed GLP-1 response to oral glucose in a large study population of lean and obese men and women with normal and impaired glucose regulation. Circulating concentrations of glucose, insulin, and GLP-1 during an oral glucose tolerance test (OGTT) were analyzed in individuals with normal glucose tolerance (NGT) (n = 774), prediabetes (n = 525), or screen-detected type 2 diabetes (n = 163) who attended the Danish ADDITION-PRO study (n = 1,462). Compared with individuals with NGT, women with prediabetes or type 2 diabetes had 25% lower GLP-1 response to an OGTT, and both men and women with prediabetes or type 2 diabetes had 16-21% lower 120-min GLP-1 concentrations independent of age and obesity. Obese and overweight individuals had up to 20% reduced GLP-1 response to oral glucose compared with normal weight individuals independent of glucose tolerance status. Higher GLP-1 responses were associated with better insulin sensitivity and b-cell function, older age, and lesser degree of obesity. Our findings indicate that a reduction in GLP-1 response to oral glucose occurs prior to the development of type 2 diabetes and obesity, which can have consequences for early prevention strategies for diabetes.

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Incretin-based therapies, such as the injectable glucagon-like peptide-1 (GLP-1) receptor agonists and orally administered dipeptidyl peptidase-4 (DPP-4) inhibitors, have recently been introduced into clinical practice. At present, the GLP-1 receptor agonists need to be administered once or twice daily. Several once-weekly GLP-1 receptor agonists are in phase 3 development. This review examines the efficacy, safety and perspective for the future of the once-weekly GLP-1 receptor agonists: exenatide once weekly, taspoglutide, albiglutide, LY2189265 and CJC-1134-PC, and compared them to the currently available agonists, exenatide BID and liraglutide QD. A greater reduction in haemoglobin A1c (HbA1c) and fasting plasma glucose was found with the once-weekly GLP-1 receptor agonists compared with exenatide BID, while the effect on postprandial hyperglycaemia was modest with the once-weekly GLP-1 receptor agonist. The reduction in HbA1c was in most studies greater compared to oral antidiabetic drugs and insulin glargine. The reduction in weight did not differ between the short- and long-acting agonists. The gastrointestinal side effects were less with the once-weekly agonists compared with exenatide BID, except for taspoglutide. Antibodies seem to be most frequent with exenatide once weekly, while hypersensitivity has been described in few patients treated with taspoglutide. Injection site reactions differ among the long-acting GLP-1 receptor agonists and are observed more frequently than with exenatide BID and liraglutide. In humans, no signal has been found indicating an association between the once-weekly agonists and C-cell cancer. The cardiovascular safety, durability of glucose control and effect on weight will emerge from several ongoing major long-term trials. The once-weekly GLP-1 receptor analogues are promising candidates for the treatment of type 2 diabetes, although their efficacy may not be superior to once-daily analogue liraglutide.

Hyperinsulinemia is an adaptive mechanism that enables the maintenance of normoglycemia in the presence of insulin resistance. We assessed whether glucagon is also involved in the adaptation to insulin resistance. A total of 1,437 individuals underwent an oral glucose tolerance test with measurements of circulating glucose, insulin, and glucagon concentrations at 0, 30 and 120 min. Early glucagon suppression was defined as suppression in the period from 0 to 30 min, and late glucagon suppression as 30 to 120 min after glucose intake. Insulin sensitivity was estimated by the validated insulin sensitivity index. Individuals with screen-detected diabetes had 30% higher fasting glucagon levels and diminished early glucagon suppression, but greater late glucagon suppression when compared with individuals with normal glucose tolerance (P ≤ 0.014). Higher insulin resistance was associated with higher fasting glucagon levels, less early glucagon suppression, and greater late glucagon suppression (P < 0.001). The relationship between insulin sensitivity and fasting glucagon concentrations was nonlinear (P < 0.001). In conclusion, increased fasting glucagon levels and delayed glucagon suppression, together with increased circulating insulin levels, develop in parallel with insulin resistance. Therefore, glucose maintenance during insulin resistance may depend not only on hyperinsulinemia but also on the ability to suppress glucagon early after glucose intake.

Objective: The hormones glucagon-like peptide 1 (GLP-1), peptide YY ), ghrelin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon have all been implicated in the pathogenesis of obesity. However, it is unknown whether they exhibit adaptive changes with respect to postprandial secretion to a sustained weight loss. Design: The study was designed as a longitudinal prospective intervention study with data obtained at baseline, after 8 weeks of weight loss and 1 year after weight loss. Methods: Twenty healthy obese individuals obtained a 13% weight loss by adhering to an 8-week very low-calorie diet (800 kcal/day). After weight loss, participants entered a 52-week weight maintenance protocol. Plasma levels of GLP-1, PYY 3-36 , ghrelin, GIP and glucagon during a 600-kcal meal were measured before weight loss, after weight loss and after 1 year of weight maintenance. Area under the curve (AUC) was calculated as total AUC (tAUC) and incremental AUC (iAUC). Results: Weight loss was successfully maintained for 52 weeks. iAUC for GLP-1 increased by 44% after weight loss (P < 0.04) and increased to 72% at week 52 (P = 0.0001). iAUC for PYY 3-36 increased by 74% after weight loss (P<0.0001) and by 36% at week 52 (P = 0.02). tAUC for ghrelin increased by 23% after weight loss (P<0.0001), but at week 52, the increase was reduced to 16% compared with before weight loss (P = 0.005). iAUC for GIP increased by 36% after weight loss (P = 0.001), but returned to before weight loss levels at week 52. Glucagon levels were unaffected by weight loss. Conclusions: Meal responses of GLP-1 and PYY 3-36 remained increased 1 year after weight maintenance, whereas ghrelin and GIP reverted toward before-weight loss values. Thus, an increase in appetite inhibitory mechanisms and a partly decrease in appetite-stimulating mechanisms appear to contribute to successful long-term weight loss maintenance.