Signe S. Torekov

Low Physical Activity Accentuates the Effect of the FTO rs9939609 Polymorphism on Body Fat Accumulation

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 = 9 × 10−5). This association was abolished when adjusting for BMI (1.06 [0.97–1.16], P = 0.2). Among 17,162 middle-aged Danes, the A-allele associated with overweight (1.19 [1.13–1.24], P = 1 × 10−12) and obesity (1.27 [1.20–1.34], P = 2 × 10−16). 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 = 0.007) was found, where physically inactive homozygous risk A-allele carriers had a 1.95 ± 0.3 kg/m2 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.

An overview of once-weekly glucagon-like peptide-1 receptor agonists—available efficacy and safety data and perspectives for the future

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.

Impact of postprandial glycaemia on health and prevention of disease.

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.

GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study

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 β-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.

Obesity - an indication for GLP-1 treatment? Obesity pathophysiology and GLP-1 treatment potential

Obesity is common and associated with a high rate of morbidity and mortality; therefore, treatment is of great interest. At present, bariatric surgery is the only truly successful treatment of severe obesity. Mimicking one of the effects of bariatric surgery, namely the increased secretion of glucagon‐like peptide (GLP)‐1, by artificially increasing the levels of GLP‐1 might prove successful as obesity treatment. Recent studies have shown that GLP‐1 is a physiological regulator of appetite and food intake. The effect on food intake and satiety is preserved in obese subjects and GLP‐1 may therefore have a therapeutic potential. The GLP‐1 analogues result in a moderate average weight loss, which is clinically relevant in relation to reducing the risk of type 2 diabetes and cardiovascular disease. Inspired by the hormone profile after gastric bypass, a future strategy in obesity drug development could be to combine several hormones, and thereby produce a superior appetite suppressing hormone profile that may result in a weight loss exceeding that seen in single‐agent trials. In conclusion, with the GLP‐1 analogues combining a moderate weight loss with beneficial effects on metabolic and cardiovascular risk factors, it seems that we are on the right track for future treatment of obesity.

GLP-1 Receptor Agonist Treatment Increases Bone Formation and Prevents Bone Loss in Weight-Reduced Obese Women

CONTEXT Recent studies indicate that glucagon-like peptide (GLP)-1 regulates bone turnover, but the effects of GLP-1 receptor agonists (GLP-1 RAs) on bone in obese weight-reduced individuals are unknown. OBJECTIVE To investigate the role of GLP-1 RAs on bone formation and weight loss-induced bone mass reduction. DESIGN Randomized control study. SETTING Outpatient research hospital clinic. PARTICIPANTS Thirty-seven healthy obese women with body mass index of 34 ± 0.5 kg/m(2) and age 46 ± 2 years. INTERVENTION After a low-calorie-diet-induced 12% weight loss, participants were randomized to treatment with or without administration of the GLP-1 RA liraglutide (1.2 mg/d) for 52 weeks. In case of weight gain, up to two meals per day could be replaced with a low-calorie-diet product to maintain the weight loss. MAIN OUTCOME MEASURES Total, pelvic, and arm-leg bone mineral content (BMC) and bone markers [C-terminal telopeptide of type 1 collagen (CTX-1) and N-terminal propeptide of type 1 procollagen (P1NP)] were investigated before and after weight loss and after 52-week weight maintenance. Primary endpoints were changes in BMC and bone markers after 52-week weight maintenance with or without GLP-1 RA treatment. RESULTS Total, pelvic, and arm-leg BMC decreased during weight maintenance in the control group (P < .0001), but not significantly in the liraglutide group. Thus, total and arm-leg BMC loss was four times greater in the control group compared to the liraglutide group (estimated difference, 27 g; 95% confidence interval, 5-48; P = .01), although the 12% weight loss was maintained in both groups. In the liraglutide group, the bone formation marker P1NP increased by 16% (7 ± 3 μg/L) vs a 2% (-1 ± 4 μg/L) decrease in the control group (P < .05). The bone resorption marker CTX-1 collagen did not change during the weight loss maintenance phase. CONCLUSIONS Treatment with a long-acting GLP-1 RA increased bone formation by 16% and prevented bone loss after weight loss obtained through a low-calorie diet, supporting its role as a safe weight-lowering agent.

Proteomics reveals the effects of sustained weight loss on the human plasma proteome

Sustained weight loss is a preferred intervention in a wide range of metabolic conditions, but the effects on an individuals 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.

Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss.

Background:Recent studies indicate that glucagon-like peptide (GLP)-1 inhibits appetite in part through regulation of soluble leptin receptors. Thus, during weight loss maintenance, GLP-1 receptor agonist (GLP-1RA) administration may inhibit weight loss-induced increases in soluble leptin receptors thereby preserving free leptin levels and preventing weight regain.Methods:In a randomized controlled trial, 52 healthy obese individuals were, after a diet-induced 12% body weight loss, randomized to treatment with or without administration of the GLP-1RA liraglutide (1.2 mg per day). In case of weight gain, low-calorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor plasma levels and decrease in free leptin index after 52 weeks weight loss maintenance.Results:Soluble leptin receptor increase was 59% lower; 2.1±0.7 vs 5.1±0.8 ng ml−1 (−3.0 (95% confidence interval (CI)=−0.5 to −5.5)), P<0.001 and free leptin index decrease was 43% smaller; −62±15 vs −109±20 (−47 (95% CI=−11 to −83)), P<0.05 with administration of GLP-1RA compared with control group. The 12% weight loss was successfully maintained in both the groups with no significant change in weight after 52 weeks follow-up. The GLP-1RA group had greater weight loss during the weight maintenance period (−2.3 kg (95% CI=−0.6 to −4.0)), and had fewer meal replacements per day compared with the control group (minus one meal per day (95% CI=−0.6 to −1)), P<0.001. Fasting glucose was decreased by an additional −0.2±0.1 mmol l−1 in the GLP-1RA group in contrast to the control group, where glucose increased 0.3±0.1 mmol l−1 to the level before weight loss (−0.5mmol l−1 (95% CI=−0.1 to −0.9)), P<0.005. Meal response of peptide PYY3–36 was higher at week 52 in the GLP-1RA group compared with the control group, P<0.05.Conclusions:The weight maintaining effect of GLP-1RAs may be mediated by smaller decrease in free leptin and higher PYY3–36 response. Low dose GLP-1RA therapy maintained 12% weight loss for 1 year and may prevent pre-diabetes in obesity.

Liraglutide for Type 2 diabetes and obesity: a 2015 update

Subcutaneous liraglutide (Victoza®, Novo Nordisk) was approved for the treatment of Type 2 diabetes mellitus (T2DM) in Europe in 2009 and in the USA in 2010. In December 2014, liraglutide 3.0 mg was approved by the Food and Drug Administration (FDA) and in March 2015 by the European Medicines Agency (EMA) for the treatment of chronic weight management under the brand name Saxenda® Novo Nordisk. Liraglutide causes a glucose-dependent increase in insulin secretion, decreases glucagon secretion and promotes weight loss by inhibiting appetite. Liraglutide probably induces satiety through activation of different areas in the hind brain and possibly by preserving free leptin levels. Recently, liraglutide has been suggested to protect against prediabetes and seems to prevent bone loss by increasing bone formation following diet-induced weight loss in obesity. This article not only covers the major clinical trials evaluating the effects of liraglutide in obesity and T2DM but also provides novel insights into the pharmacological mechanisms of liraglutide.

A Functional Amino Acid Substitution in the Glucose-Dependent Insulinotropic Polypeptide Receptor (GIPR) Gene Is Associated With Lower Bone Mineral Density and Increased Fracture Risk

CONTEXT Food ingestion decreases bone resorption, and glucose-dependent insulinotropic polypeptide (GIP) may mediate this effect. Mice overexpressing GIP have increased osteoblast activity and are rescued from age-related bone loss, whereas GIPR knockout mice have decreased cortical bone mass and compromised bone quality. Carriers of the functional variant GIPR Glu354Gln (rs1800437) have higher plasma glucose 2 hours after glucose ingestion, suggesting that the variant encoding GIPR 354Gln decreases the effect of GIP. OBJECTIVE The objective of the study was to investigate the effect of GIPR Glu354Gln on bone mineral density (BMD) and fracture risk. DESIGN This was a prospective, comprehensive, cohort study (number NCT00252408). PARTICIPANTS A total of 1686 perimenopausal women were included. MAIN OUTCOME MEASURES Dual-energy X-ray absorptiometry was performed at baseline and after 10 years. Incident fractures were recorded during the follow-up and were obtained from the Danish National Patient Registry, giving a total follow-up time of a minimum 16 years. RESULTS After 10 years, women with the minor frequency C allele of rs1800437 (354Gln) had significantly lower BMD at the femoral neck compared with carriers of the major G-allele (CC: 0.755 ± 0.015 g/cm(2) vs CG: 747 ± 0.005 g/cm(2); GG: 0.766 ± 0.004 g/cm(2), P < .001). Correspondingly, total hip BMD was significantly lower among C allele carriers (CC: 0.881 ± 0.016 g/cm(2); CG: 0.884 ± 0.005 g/cm(2); and GG: 0.906 ± 0.004 g/cm(2), P < .001). Finally, women homozygous for the variant C allele had an increased risk (hazard ratio 1.6, confidence interval 1.0-2.6, P < .05) of nonvertebral fractures. CONCLUSION This study demonstrates an association between a functional GIPR polymorphism Glu354Gln (rs1800437) and BMD and fracture risk. These findings further establish GIP to be involved in the regulation of bone density.