Stephen L Atkin

Weill Cornell Medical College in Qatar, Ad Dawḩah, Baladīyat ad Dawḩah, Qatar

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Publications (272)1161.47 Total impact

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    ABSTRACT: Scope: Quercetin is reported to reduce blood pressure in hypertensive but not normotensive humans, but the role of endothelial redox signalling in this phenomenon has not been assessed. This study investigated the effects of physiologically-obtainable quercetin concentrations in a human primary cell model of endothelial dysfunction in order to elucidate the mechanism of action of its antihypertensive effects. Methods and results: Angiotensin II (100 nM, 8 h) induced dysfunction, characterised by suppressed nitric oxide availability (85 ± 4% p<0.05) and increased superoxide production (136 ± 5 %, p<0.001). These effects were ablated by an NADPH oxidase inhibitor. Quercetin (3 μM, 8 h) prevented angiotensin II induced changes in nitric oxide and superoxide levels, but no effect on upon nitric oxide or superoxide in control cells. The NADPH oxidase subunit p47(phox) was increased at the mRNA and protein levels in angiotensin II-treated cells (130 ± 14% of control, p<0.05), which was ablated by quercetin co-treatment. Protein kinase C activity was increased after angiotensin II treatment (136 ± 51%), however this was unaffected by quercetin co-treatment. Conclusions: Physiologically-obtainable quercetin concentrations are capable of ameliorating angiotensin II-induced endothelial nitric oxide and superoxide imbalance via protein kinase C-independent restoration of p47(phox) gene and protein expression. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Molecular Nutrition & Food Research
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    ABSTRACT: Objective: Renal impairment in type 2 diabetes limits available glucose-lowering treatment options. This trial was conducted to establish the efficacy and safety of liraglutide as an add-on to existing glucose-lowering medications in patients with inadequately controlled type 2 diabetes and moderate renal impairment. Research design and methods: In this 26-week, double-blind trial, 279 patients with HbA1c 7-10%, BMI 20-45 kg/m(2), and moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-59 mL/min/1.73 m(2); MDRD) were randomized (1:1) to once-daily liraglutide 1.8 mg (n = 140) or placebo (n = 139). Results: The estimated treatment difference in HbA1c from baseline to week 26 was -0.66% (-7.25 mmol/mol [95% CI -0.90 to -0.43 (-9.82 to -4.69 mmol/mol)]; [95% CI 20.90 to 20.43 (29.82 to 24.69 mmol/mol)]; P < 0.0001). Fasting plasma glucose decreased more with liraglutide (-1.22 mmol/L [-22.0 mg/dL]) than with placebo (-0.57 mmol/L [-10.3 mg/dL]; P = 0.036). There was a greater reduction in body weight with liraglutide (-2.41 kg) than with placebo (-1.09 kg; P = 0.0052). No changes in renal function were observed (eGFR relative ratio to baseline: -1% liraglutide, +1% placebo; estimated treatment ratio [ETR] 0.98; P = 0.36). The most common adverse events were gastrointestinal (GI) adverse effects (liraglutide, 35.7%; placebo, 17.5%). No difference in hypoglycemic episodes was observed between treatment groups (event rate/100 patient-years of exposure: liraglutide, 30.47; placebo, 40.08; P = 0.54). The estimated ratio to baseline for lipase was 1.33 for liraglutide and 0.97 for placebo (ETR 1.37; P < 0.0001). Conclusions: Liraglutide did not affect renal function and demonstrated better glycemic control, with no increase in hypoglycemia risk but with higher withdrawals due to GI adverse events than placebo in patients with type 2 diabetes and moderate renal impairment.
    No preview · Article · Dec 2015 · Diabetes care
  • Stephen Atkin · Zeeshan Javed · Gregory Fulcher
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    ABSTRACT: Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal–bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections.
    No preview · Article · Nov 2015 · Therapeutic Advances in Chronic Disease
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    ABSTRACT: Sporopollenin is highly cross-linked polymer composed of carbon, hydrogen, and oxygen that is extraordinarily stable and has been found chemically intact in sedimentary rocks some 500 million years old. It makes up the outer shell (exine) of plant spores and pollen and when extracted it is in the form of an empty exine or microcapsule. The exines resemble the spores and pollen from which they are extracted, in size and morphology. Also, from any one plant such characteristics are incredible uniform. The exines can be used as microcapsules or simply as micron-sized particles due to the variety of functional groups on their surfaces. The loading of a material into the chamber of the exine microcapsule is via multi-directional nano-diameter sized channels. The exines can be filled with a variety of polar and non-polar materials. Enzymes can be encapsulated within the shells and still remain active. In vivo studies in humans have shown that an encapsulated active substance can have a substantially increased bioavailability than if it is taken alone. The sporopollenin exine surface possesses phenolic, alkane, alkene, ketone, lactone, and carboxylic acid groups. Therefore, it can be derivatized in a number of ways, which has given rise to applications in areas, such as solid supported for peptide synthesis, catalysis, and ion-exchange chromatography. Also, the presence of the phenolic groups on sporopollenin endows it with antioxidant activity.
    Full-text · Article · Oct 2015

  • No preview · Article · Oct 2015
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    ABSTRACT: MicroRNAs (miRNA) are a novel class of small noncoding single-stranded RNA molecules that regulate gene expression. There is increasing evidence of their importance in polycystic ovary syndrome (PCOS). The objective was to determine if miRNA-93 and miRNA-223 are differentially expressed in the circulation of women with PCOS compared to age matched women. A case-control study comparing women with PCOS (n = 25) to age and weight matched controls (n = 24) without PCOS was performed. MiRNA-93 and miRNA-223 were determined by total RNA reverse transcription. Both miRNA-93 and miRNA-223 were significantly increased relative to the control group (p < 0.01, p = 0.029 respectively). In both groups there was no correlation of either miRNA-93 or miRNA-223 with insulin, HOMA-IR, HOMA-β or testosterone levels. The area under the receiver operator characteristic curve for miR-223 and miR-93 was 0.66 and 0.72 respectively, suggesting miR-93 is a more efficient biomarker than miR-223 for diagnosis of PCOS. The combination of the two miRNAs together, tested using multiple logistic regression analysis, did not improve the diagnostic potential. In conclusion, circulating miRNA-93 and miRNA-223 were higher in women with PCOS compared to age and weight matched controls independent of insulin resistance and testosterone levels, and miR-93 may represent a novel diagnostic biomarker for PCOS.
    Full-text · Article · Oct 2015

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    Full-text · Dataset · Sep 2015
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    ABSTRACT: Objective: To investigate the dose-response relationship of semaglutide versus placebo and open-label liraglutide in terms of glycemic control in patients with type 2 diabetes. Research design and methods: This was a 12-week, randomized, double-blind phase 2 trial. Patients (n = 415) were randomized to receive a subcutaneous injection of semaglutide once weekly without dose escalation (0.1-0.8 mg) or with dose escalation (E) (0.4 mg steps to 0.8 or 1.6 mg E over 1-2 weeks), open-label liraglutide once daily (1.2 or 1.8 mg), or placebo. The primary end point was change in HbA1c level from baseline. Secondary end points included change in body weight, safety, and tolerability. Results: Semaglutide dose-dependently reduced the level of HbA1c from baseline (8.1 ± 0.8%) to week 12 by up to -1.7%, and body weight by up to -4.8 kg (1.6 mg E, P < 0.001 vs. placebo). Up to 81% of patients achieved an HbA1c level of <7%. HbA1c level and weight reductions with semaglutide 1.6 mg E were greater than those with liraglutide 1.2 and 1.8 mg (based on unadjusted CIs), but adverse events (AEs) and withdrawals occurred more frequently. The incidence of nausea, vomiting, and withdrawal due to gastrointestinal AEs increased with the semaglutide dose; most events were mild to moderate, transient, and ameliorated by dose escalation. There were no major episodes of hypoglycemia and few cases of injection site reactions. Conclusions: After 12 weeks, semaglutide dose-dependently reduced HbA1c level and weight in patients with type 2 diabetes. No unexpected safety or tolerability concerns were identified; gastrointestinal AEs typical of glucagon-like peptide 1 receptor agonists were mitigated by dose escalation. On this basis, weekly semaglutide doses of 0.5 and 1.0 mg with a 4-week dose escalation were selected for phase 3.
    Full-text · Article · Sep 2015 · Diabetes care
  • P. Costanzo · D. Lai · S. L. Atkin
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    ABSTRACT: The term “obesity paradox” corresponds to the research observation that overweight or obese patients may counterintuitively have a survival benefit once a disease is established. This appears also true in type 2 diabetes mellitus, where it has been shown that being overweight or obese is associated with better survival. The reasons behind this paradox remain unclear but likely derive from an intricate relationship between insulin resistance, fat storage, and inflammatory responses in type 2 diabetes. In this review, we look at what the potential mechanisms may be underlying this paradox.
    No preview · Article · Jul 2015 · Current Cardiovascular Risk Reports
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    ABSTRACT: Whether obesity is associated with a better prognosis in patients with type 2 diabetes mellitus is controversial. To investigate the association between body weight and prognosis in a large cohort of patients with type 2 diabetes followed for a prolonged period. Prospective cohort. National Health Service, England. Patients with diabetes. The relationship between body mass index (BMI) and prognosis in patients with type 2 diabetes without known cardiovascular disease at baseline was investigated. Information on all-cause mortality and cardiovascular morbidity (such as the acute coronary syndrome, cerebrovascular accidents, and heart failure) was collected. Cox regression survival analysis, corrected for potential modifiers, including cardiovascular risk factors and comorbid conditions (such as cancer, chronic kidney disease, and lung disease), was done. 10 568 patients were followed for a median of 10.6 years (interquartile range, 7.8 to 13.4). Median age was 63 years (interquartile range, 55 to 71), and 54% of patients were men. Overweight or obese patients (BMI >25 kg/m2) had a higher rate of cardiac events (such as the acute coronary syndrome and heart failure) than those of normal weight (BMI, 18.5 to 24.9 kg/m2). However, being overweight (BMI, 25 to 29.9 kg/m2) was associated with a lower mortality risk, whereas obese patients (BMI >30 kg/m2) had a mortality risk similar to that of normal-weight persons. Patients with low body weight had the worst prognosis. Data about cause of death were not available. In this cohort, patients with type 2 diabetes who were overweight or obese were more likely to be hospitalized for cardiovascular reasons. Being overweight was associated with a lower mortality risk, but being obese was not. National Institute for Health Research and University of Hull.
    No preview · Article · May 2015 · Annals of internal medicine

  • No preview · Article · Apr 2015 · Diabetologie und Stoffwechsel
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    ABSTRACT: Aspartame is a commonly used intense artificial sweetener, being approximately 200 times sweeter than sucrose. There have been concerns over aspartame since approval in the 1980s including a large anecdotal database reporting severe symptoms. The objective of this study was to compare the acute symptom effects of aspartame to a control preparation. This was a double-blind randomized cross over study conducted in a clinical research unit in United Kingdom. Forty-eight individual who has self reported sensitivity to aspartame were compared to 48 age and gender matched aspartame non-sensitive individuals. They were given aspartame (100mg)-containing or control snack bars randomly at least 7 days apart. The main outcome measures were acute effects of aspartame measured using repeated ratings of 14 symptoms, biochemistry and metabonomics. Aspartame sensitive and non-sensitive participants differed psychologically at baseline in handling feelings and perceived stress. Sensitive participants had higher triglycerides (2.05 ± 1.44 vs. 1.26 ± 0.84mmol/L; p value 0.008) and lower HDL-C (1.16 ± 0.34 vs. 1.35 ± 0.54 mmol/L; p value 0.04), reflected in 1H NMR serum analysis that showed differences in the baseline lipid content between the two groups. Urine metabonomic studies showed no significant differences. None of the rated symptoms differed between aspartame and control bars, or between sensitive and control participants. However, aspartame sensitive participants rated more symptoms particularly in the first test session, whether this was placebo or control. Aspartame and control bars affected GLP-1, GIP, tyrosine and phenylalanine levels equally in both aspartame sensitive and non-sensitive subjects. Using a comprehensive battery of psychological tests, biochemistry and state of the art metabonomics there was no evidence of any acute adverse responses to aspartame. This independent study gives reassurance to both regulatory bodies and the public that acute ingestion of aspartame does not have any detectable psychological or metabolic effects in humans. ISRCTN Registry ISRCTN39650237.
    Full-text · Article · Mar 2015 · PLoS ONE
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    ABSTRACT: Polyphenols and other compounds found in cocoa and chocolate have therapeutic potential in the management of diabetes in humans. Polyphenols benefits have been proposed supported by in vitro studies, animal work and clinical trials, which have been conducted mostly in healthy volunteers. The energy dense formulations of many cocoa and chocolate products which can be up to 50% sugar by weight have given the perception that chocolate may be harmful through its contribution to obesity. A review of both clinical trial databases and published literature yielded 15 registered trials and seven published studies. The published data interventions reported are diverse vary widely in quality, including poor selection of control products or inadequate blinding procedures. There are also inconsistencies in reporting of data with limited information on the effect of cocoa and chocolate supplementation on weight and glycemic control despite the potential benefits reported with respect to the cardiovascular risk factors of endothelial function and lipids. More studies are required powered for primary clinical outcomes together with the development of standardized product formulations that optimize the dose of polyphenols within a palatable and energy restricted product.
    No preview · Article · Mar 2015 · Journal of Agricultural and Food Chemistry

  • No preview · Article · Mar 2015 · Diabetes & Metabolism
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    ABSTRACT: Atherothrombosis is associated with platelet hyperactivity. Hypertriglyceridemia and insulin resistance (IR) are features of polycystic ovary syndrome (PCOS). The effect of induced hypertriglyceridemia on IR and platelet function was examined in young women with PCOS. Following overnight fasting, 13 PCOS and 12 healthy women were infused with saline or 20% intralipid for 5 hours on separate days. Insulin sensitivity was measured using a hyperinsulinemic euglycaemic clamp in the final 2 hours of each infusion. Platelet responses to adenosine diphosphate (ADP) and prostacyclin (PGI2) were measured by flow cytometric analysis of platelet fibrinogen binding and P-selectin expression using whole blood taken during each infusion (at 2 hours) and at the end of each clamp. Lipid infusion increased triglycerides and reduced insulin sensitivity in both controls (median, interquartile range ) (5.25 [3.3, 6.48] versus 2.60 [0.88, 3.88] mg kg(-1) min(-1), P<0.001) and PCOS (3.15 [2.94, 3.85] versus 1.06 [0.72, 1.43] mg kg(-1) min(-1), P<0.001). Platelet activation by ADP was enhanced and ability to suppress platelet activation by PGI2 diminished during lipid infusion in both groups when compared to saline. Importantly, insulin infusion decreased lipid-induced platelet hyperactivity by decreasing their response to 1 μmol/L ADP (78.7% [67.9, 82.3] versus 62.8% [51.8, 73.3], P=0.02) and increasing sensitivity to 0.01 μmol/L PGI2 (67.6% [39.5, 83.8] versus 40.9% [23.8, 60.9], P=0.01) in controls, but not in PCOS. Acute hypertriglyceridemia induced IR, and increased platelet activation in both groups that was not reversed by insulin in PCOS subjects compared to controls. This suggests that platelet hyperactivity induced by acute hypertriglyceridemia and IR could contribute athero-thrombotic risk. www.isrctn.org. Unique Identifier: ISRCTN42448814.
    Full-text · Article · Dec 2014 · Journal of the American Heart Association
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    ABSTRACT: ORAI and stromal interaction molecule (STIM) are store-operated channel molecules that play essential roles in human physiology through a coupling mechanism of internal Ca(2+) store to Ca(2+) influx. However, the roles of ORAI and STIM in vascular endothelial cells under diabetic conditions remain unknown. Here, we investigated expression and signalling pathways of ORAI and STIM regulated by high glucose or hyperglycaemia using in vitro cell models, in vivo diabetic mice and tissues from patients. We found that ORAI1-3 and STIM1-2 were ubiquitously expressed in human vasculatures. Their expression was upregulated by chronic treatment with high glucose (HG, 25 mM D-glucose), which was accompanied by enhanced store-operated Ca(2+) influx in vascular endothelial cells. The increased expression was also observed in the aortae from genetically modified Akita diabetic mice (C57BL/6-Ins2(Akita)/J) and streptozocin-induced diabetic mice, and aortae from diabetic patients. HG-induced upregulation of ORAI and STIM genes was prevented by the calcineurin inhibitor cyclosporin A and NFATc3 siRNA. Additionally, in vivo treatment with the nuclear factor of activated T cells (NFAT) inhibitor A-285222 prevented the gene upregulation in Akita mice. However, HG had no direct effects on ORAI1-3 currents and the channel activation process through cytosolic STIM1 movement in the cells co-expressing STIM1-EYFP/ORAIs. We concluded that upregulation of STIM/ORAI through Ca(2+)-calcineurin-NFAT pathway is a novel mechanism causing abnormal Ca(2+) homeostasis and endothelial dysfunction under hyperglycaemia. ORAI1-3 and STIM1-2 are ubiquitously expressed in vasculatures and upregulated by high glucose. Increased expression is confirmed in Akita (Ins2(Akita)/J) and STZ diabetic mice and patients. Upregulation mechanism is mediated by Ca(2+)/calcineurin/NFATc3 signalling. High glucose has no direct effects on ORAI1-3 channel activity and channel activation process.
    Full-text · Article · Dec 2014 · Journal of Molecular Medicine

Publication Stats

4k Citations
1,161.47 Total Impact Points

Institutions

  • 2014-2015
    • Weill Cornell Medical College in Qatar
      Ad Dawḩah, Baladīyat ad Dawḩah, Qatar
  • 1994-2015
    • University of Nottingham
      • School of Biosciences
      Nottigham, England, United Kingdom
    • Liverpool Hospital
      Liverpool, New South Wales, Australia
  • 2006-2014
    • Hull York Medical School
      • Centre for Cardiovascular and Metabolic Research
      York, England, United Kingdom
  • 1993-2014
    • University of Hull
      • • Hull York Medical School (HYMS)
      • • Diabetes and Endocrinology
      Kingston upon Hull, England, United Kingdom
  • 2012
    • San Diego Zoo
      San Diego, California, United States
    • The University of York
      • Hull York Medical School
      York, England, United Kingdom
  • 2010
    • Hull and East Yorkshire Hospitals NHS Trust
      Kingston upon Hull, England, United Kingdom
  • 2009
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
  • 1994-1996
    • Kingston Hospital
      Kingston Seymour, England, United Kingdom
  • 1995
    • Kingston General Hospital
      Kingston, Ontario, Canada
  • 1993-1995
    • Royal Liverpool and Broadgreen University Hospitals NHS Trust
      • Department of Endocrinology
      Liverpool, England, United Kingdom