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    ABSTRACT: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of type 2 diabetes mellitus (T2DM). This randomised, double-blind, placebo-controlled, Phase 3 study evaluated the efficacy and safety of canagliflozin as an add-on to metformin plus sulphonylurea in patients with T2DM. Patients (N = 469) received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period and a 26-week extension. Prespecified primary end-point was change in HbA1c at 26 weeks. Secondary end-points included change in HbA1c at week 52 as well as proportion of patients achieving HbA1c < 7.0%, change in fasting plasma glucose (FPG) and systolic blood pressure, and per cent change in body weight, high-density lipoprotein cholesterol, and triglycerides (weeks 26 and 52). HbA1c was significantly reduced with canagliflozin 100 and 300 mg vs. placebo at week 26 (-0.85%, -1.06%, and -0.13%; p < 0.001); these reductions were maintained at week 52 (-0.74%, -0.96%, and 0.01%). Both canagliflozin doses reduced FPG and body weight vs. placebo at week 26 (p < 0.001) and week 52. Overall adverse event (AE) rates were similar across groups over 52 weeks, with higher rates of genital mycotic infections and osmotic diuresis-related AEs seen with canagliflozin vs. placebo; these led to few discontinuations. Increased incidence of documented, but not severe, hypoglycaemia episodes was seen with canagliflozin vs. placebo. Canagliflozin improved glycaemic control, reduced body weight, and was generally well tolerated in T2DM patients on metformin plus sulphonylurea over 52 weeks.
    International Journal of Clinical Practice 10/2013;
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    ABSTRACT: OBJECTIVE Fasting is not routinely recommended for renal function tests, despite the known effects of cooked meat on creatinine. We therefore studied variation in creatinine and estimate glomerular filtration rate (eGFR) following a standardised cooked meat meal in 80 subjects: healthy volunteers, diabetes patients with chronic kidney disease (CKD) stages 1 & 2, 3A, 3B and 4 (n=16/group).RESEARCH DESIGN AND METHODS The interventions were a standardised cooked meat and a non-meat meal, each providing approximately 54g protein, together with 250 mls of water, on separate days. Fasting and post-prandial blood samples at 1, 2, and 4 hours were drawn for creatinine measurement using kinetic alkaline picrate assay on an Olympus AU640 analyser. The modified 4-variable MDRD equation traceable to isotope dilution mass spectrometry creatinine was used to calculate eGFR.RESULTSConsumption of a standardised cooked meat meal significantly increased serum creatinine and resulted in significant fall in eGFR in all stages of CKD studied; 6 of 16 CKD 3a patients were misclassified as CKD 3b. This effect of cooked meat on serum creatinine disappears after 12 hours of fasting in all study participants.CONCLUSIONS Creatine in meat is converted to creatinine on cooking which is absorbed causing significant increases in serum creatinine. This could impact management as threshold for commencing and withdrawing certain medications and expensive investigations is defined by eGFR. eGFR calculated using fasting serum creatinine would be a better reflection of kidney function in these patients.
    Diabetes care 09/2013;
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    ABSTRACT: The relationships between night eating, poor sleep quality, and obesity-related comorbidity in a severely obese UK clinic population is unknown. We used validated tools to identify prevalence and to explore this relationship. Consecutive consenting clinic attendees completed the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Score (ESS), and Night Eating Questionnaire (NEQ) to identify sleep quality, excessive daytime sleepiness (EDS) (a surrogate marker for suspected obstructive sleep apnea [OSA]), and night eating, respectively. Proportions of individuals above and below tool cutoff points were compared. Pearson product moment correlation coefficients examined relationships between total scores. Reported prevalence from 144 participants (mean body mass index [BMI] 46.9 [9.5]kg/m(2); age 44.6 [12.1]years; 68% women) had poor sleep quality (73.0%), suspected OSA (30.8%), and night-eating behavior (2.8%). The strongest correlation between PSQI and NEQ scores (r=0.54; P<.001) was undiminished after controlling for EDS. Although significantly correlated, PSQI and ESS scores (r=0.31; P<.001) reduced after controlling for night eating (r=0.21; P=.02). Correlation between NEQ and ESS scores (r=0.26; P=.002) was smaller and nonsignificant after controlling for sleep quality (r=0.12; P=.18). Poor sleep quality is common in severe obesity, though night eating is rare. The association between poor sleep quality and night eating is not influenced by the presence of EDS.
    Sleep Medicine 08/2013;
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    ABSTRACT: Carcinoid heart disease is a rare cause of right-sided valvular dysfunction, primarily mediated by serotonin. It is an important complication of patients with the carcinoid syndrome, and occurs in 20-50% of such patients. Echocardiography is the main tool used for the assessment of carcinoid heart disease but other imaging modalities are also important, particularly in the quantification of the severity of disease. We sought to review the role of cardiac imaging in the assessment of carcinoid heart disease.
    Endocrine Related Cancer 07/2013;
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    ABSTRACT: BACKGROUND: It is recognised that sleep-disordered breathing (SDB), in particular, obstructive sleep apnoea (OSA) is associated with obesity and diabetes. The complications of OSA include dysregulation of metabolic and cardiovascular homeostasis. With the growing population of diabetes and obesity globally, it is becoming apparent that identifying and screening patients who are at risk is becoming increasingly crucial. Many patients may remain unaware of the potential diagnosis and continue to be undiagnosed. The high prevalence of OSA poses a demanding challenge to healthcare providers in order to provide sufficient resources and facilities for patient diagnosis and treatment. DESIGN: In this article, we review the evidence in favour of screening populations deemed to be at increased risk of OSA, with particular reference to patients with obesity and diabetes. We consider the recent advances in potential screening methods that may allow new prognostic and predictive tools to be developed. A detailed search of Medline and Web of Science electronic databases for relevant articles in English was performed. RESULTS: Apart from the use of screening tools such as questionnaires and clinical decision models, there is increasing evidence to suggest that there are differences in biological parameters in patients with OSA. Although further studies are required, there may be potential for such biomarkers to contribute to and augment the screening process. However, the significance of such biological tools remains to be elucidated. CONCLUSIONS: A fundamental role for improved screening in patients with conditions such as obesity and diabetes can enable early interventions that may improve health outcomes relating to the adverse consequences of OSA. The future will see further research being carried out in the development of potential screening methods with emphasis on the selection of patients at risk of sleep disorders, thereby allowing more detailed physiological studies to be carried out where needed.
    European Journal of Clinical Investigation 03/2013;
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    ABSTRACT: Of the environmental factors which have an impact on body weight, nutrients are most influential. Within normal limits, hypothalamic and related neuronal populations correct perturbations in energy metabolism, to return the body to its nutritional set-point, either through direct response to nutrients or indirectly via peripheral appetite signals. Excessive intake of certain macronutrients, such as simple carbohydrates and SFA, can lead to obesity and attendant metabolic dysfunction, also reflected in alterations in structural plasticity, and, intriguingly, neurogenesis, in some of these brain regions. Neurogenesis, previously thought to occur only in the embryo, is now known to take place in the adult brain, dependent on numerous stimulating and inhibiting factors, including dietary components. Because of classic associations between neurogenesis and the hippocampus, in learning and cognition, this brain region has also been the focus of attention in the study of links between diet and neurogenesis. Recently, however, a more complete picture of this relationship has been building: not only has the hypothalamus been shown to satisfy the criteria for a neurogenic niche, but appetite-related mediators, including circulating hormones, such as leptin and ghrelin, pro-inflammatory cytokines and the endocannabinoid intracellular messengers, are also being examined for their potential role in mediating neurogenic responses to macronutrients. The present review draws together these observations and investigates whether PUFA may exert their attenuating effects on body weight through the stimulation of adult neurogenesis. Exploration of the effects of nutraceuticals on neurogenic brain regions may encourage the development of new rational therapies in the fight against obesity.
    The British journal of nutrition 02/2013;
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    ABSTRACT: Increased accumulation of macrophages in adipose tissue in obesity is linked to low-grade chronic inflammation, and associated with features of metabolic syndrome. Vitamin D3 may have immunoregulatory effects and reduce adipose tissue inflammation, although the molecular mechanisms remain to be established. This study investigated the effects of vitamin D3 on macrophage-elicited inflammatory responses in cultured human adipocytes, particularly the signalling pathways involved. Macrophage-conditioned (MC) medium (25% with adipocyte maintenance media) markedly inhibited protein expression of the nuclear factor-κB (NFκB) subunit inhibitor κBα (IκBα) (71%, P<0.001) and increased NFκB p65 (1.5-fold, P = 0.026) compared with controls. Treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) abolished macrophage-induced activation of NFκB signalling by increasing IκBα expression (2.7-fold, P = 0.005) and reducing NFκB p65 phosphorylation (68%; P<0.001). The mitogen-activated protein kinase (MAPK) signalling was activated by MC medium, which was also blunted by 1,25(OH)2D3 with a downregulation of phosphorylated p38 MAPK (32%, P = 0.005) and phosphorylated Erk1/2 (49%, P = 0.001). Furthermore, MC medium (12.5% or 25%) dose-dependently upregulated secretion of key proinflammatory chemokines/cytokines (22-368-fold; all P<0.001) and this was significantly decreased by 1,25(OH)2D3: IL-8 (61% and 31%, P<0.001), MCP-1 (37%, P<0.001 and 36%, P = 0.002), RANTES (78% and 62%, P<0.001) and IL-6 (29%, P<0.001 and 34%, P = 0.019). Monocyte migration-elicited by adipocytes treated with 1,25(OH)2D3 was also reduced (up to 25%, P<0.001). In conclusion, vitamin D3 could be anti-inflammatory in adipose tissue, decreasing macrophage-induced release of chemokines and cytokines by adipocytes and the chemotaxis of monocytes. Our data suggests these effects are mediated by inhibition of the NFκB and MAPK signalling pathways.
    PLoS ONE 01/2013; 8(4):e61707.
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    ABSTRACT: AIMS: Ipragliflozin is a novel, selective inhibitor of sodium glucose co-transporter 2 (SGLT2 inhibitor) in clinical development for type 2 diabetes mellitus (T2DM) treatment. This study assessed the efficacy and safety of different doses of ipragliflozin. MATERIALS AND METHODS: In a 12-week, multicentre, double-blind, randomized, placebo-controlled, dose-finding study patients with inadequate glycaemic control on metformin monotherapy (≥1500 mg/day) were randomized to one of four ipragliflozin treatment groups (12.5, 50, 150, or 300mg once daily) or placebo. Primary efficacy outcome was mean change from baseline in haemoglobin A(1c) (HbA(1c) ) compared to placebo at Week 12. Adverse events (AEs), vital signs, and laboratory safety measurements were assessed. RESULTS: Ipragliflozin dose-dependently decreased HbA(1c) from baseline to Week 12 compared to placebo (-0.22%, -0.34%, -0.40%, -0.48% for ipragliflozin 12.5, 50, 150, and 300mg, respectively). Decreases in body weight and blood pressure were observed for all ipragliflozin groups. AEs occurred in 39.7-51.4% of the ipragliflozin groups and 39.4% of placebo patients. Urinary tract infections (1.4-6.9% vs. 6.1%), genital infections (0-4.3% vs. 1.5%), and hypoglycaemia (0-5.9% vs. 3.0%) were similar in the ipragliflozin and placebo groups, respectively, without dose-dependency. There were no clinically relevant effects on other safety measurements. CONCLUSIONS: Ipragliflozin treatment improved glycaemic control when added to metformin therapy and may be associated with weight loss and reductions in blood pressure compared to placebo. No safety or tolerability concerns were identified at any of the tested doses supporting the further development of ipragliflozin at ≥50 mg doses in T2DM patients.
    Diabetes Obesity and Metabolism 11/2012;
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    ABSTRACT: Evidence-based, weight loss management advice is required to address equine obesity. Changes in body mass (BM), body condition score (BCS), heart (HG) and belly circumference (BG), direct (ultrasonographic) and indirect (D(2)O dilution, bioelectrical impedance analysis [BIA]) measures of body fat as well as indices of insulin resistance (IR) were monitored in 12 overweight (BCS⩾7/9) horses and ponies of mixed breed and gender for 16weeks. Animals were randomly assigned to two groups (Group 1, n=6, BCS 7.6/9±0.6, 489±184.6kg; Group 2, n=6, BCS 8.1/9±0.6, 479±191.5kg). Daily dry matter intake (DMI) was restricted to 1.25% BM as one of two, near-isocaloric (DE ∼0.115MJ/kgBM/day), forage-based diets (Group 1, 0.8% BM chaff-based feed: 0.45% BM hay; Group 2, 1.15% BM hay: 0.1% BM nutrient-balancer). Statistical modelling revealed considerable between-animal heterogeneity in proportional weight losses (0.16-0.55% of Week 1 BM weekly). The magnitude of weight loss resistance (WLR) or sensitivity to dietary restriction was independent of diet or any measured outset variable and was largely (65%) attributed to animal identity. Predicted rates of weight loss decreased over time. BCS and BIA were poor estimates of D(2)O-derived body fat%. Reciprocal changes in depths of retroperitoneal and subcutaneous adipose tissues were evident. Changes in BG were associated with losses in retroperitoneal fat and BM (r(2), 0.67 and 0.79). Indices of IR improved for 9/12 animals by Week 16. For obese animals, weight loss should be initiated by restricting forage DMI to 1.25% BM. Subsequent restriction to 1% BM may be warranted for WLR animals.
    The Veterinary Journal 10/2012;
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    ABSTRACT: Vitamin D deficiency and the rapid increase in the prevalence of obesity are both considered important public health issues. The classical role of vitamin D is in Ca homoeostasis and bone metabolism. Growing evidence suggests that the vitamin D system has a range of physiological functions, with vitamin D deficiency contributing to the pathogenesis of several major diseases, including obesity and the metabolic syndrome. Clinical studies have shown that obese individuals tend to have a low vitamin D status, which may link to the dysregulation of white adipose tissue. Recent studies suggest that adipose tissue may be a direct target of vitamin D. The expression of both the vitamin D receptor and 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) genes has been shown in murine and human adipocytes. There is evidence that vitamin D affects body fat mass by inhibiting adipogenic transcription factors and lipid accumulation during adipocyte differentiation. Some recent studies demonstrate that vitamin D metabolites also influence adipokine production and the inflammatory response in adipose tissue. Therefore, vitamin D deficiency may compromise the normal metabolic functioning of adipose tissue. Given the importance of the tissue in energy balance, lipid metabolism and inflammation in obesity, understanding the mechanisms of vitamin D action in adipocytes may have a significant impact on the maintenance of metabolic health. In the present review, we focus on the signalling role of vitamin D in adipocytes, particularly the potential mechanisms through which vitamin D may influence adipose tissue development and function.
    The British journal of nutrition 10/2012;
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