Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study Study protocol: a randomised placebo-controlled clinical trial to study the effect of vitamin D supplementation on glycaemic control in type 2 Diabetes Mellitus SUNNY trial Fish oil supplemented for 9 months does not improve glycaemic control or insulin sensitivity in subjects with impaired glucose regulation: a parallel randomised controlled trial. The effects of vitamin D supplementation on adiponectin level and insulin resistance in first-degree relatives of subjects with type 2 diabetes: a randomized double-blinded controlled trial Effect of cocoa and green tea on biomarkers of glucose regulation, oxidative stress, inflammation and hemostasis in obese adults at risk for insulin resistance Evidence for biological effects of metformin in operable breast cancer: biomarker analysis in a pre-operative window of opportunity randomized trial Supplementation with cholecalciferol does not improve glycaemic control in diabetic subjects with normal serum 25-hydroxyvitamin D levels Increased gut hormones and insulin sensitivity index following a 3-d intervention with a barley kernel-based product: a randomised cross-over study in healthy middle-aged subjects. Mendelian randomization studies of biomarkers and type 2 diabetes Consumption of vitamin D-fortified yogurt drink increased leptin and ghrelin levels but reduced leptin to ghrelin ratio in type 2 diabetes patients: a single blind randomized controlled trial Effect of short-term vitamin D supplementation on markers of vascular health in South Asian women living in the UK--a randomised controlled trial. Clinical effectiveness of a patient decision aid to improve decision quality and glycaemic control in people with diabetes making treatment choices: a cluster randomised controlled trial (PANDAs) in general practice Glycaemic Fluctuation Predicts Mortality in Critically Ill Patients Effect of increasing fruit and vegetable intake by dietary intervention on nutritional biomarkers and attitudes to dietary change: a randomised trial The effect of different doses of vitamin D3 on markers of vascular health in patients with type 2 diabetes: a randomised controlled trial Glycaemic index, glycaemic load and risk of endometrial cancer: a prospective cohort study. The effect of increased dietary fruit and vegetable consumption on endothelial activation, inflammation and oxidative stress in hypertensive volunteers. Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT. Fasting plasma triglycerides predict the glycaemic response to treatment of Type 2 diabetes by gastric electrical stimulation. A novel lipotoxicity paradigm Adrenergic control of plasma magnesium in man. Anti-androgen treatment increases circulating ghrelin levels in obese women with polycystic ovary syndrome Mechanisms behind the superior effects of interval vs continuous training on glycaemic control in individuals with type 2 diabetes: a randomised controlled trial Circulating inflammatory and hemostatic biomarkers are associated with risk of myocardial infarction and coronary death, but not angina pectoris, in older men
Summary Background Low circulating concentrations of 25-hydroxyvitamin D ( 25[OH]D ) , a marker of vitamin D status , are associated with an increased risk of type 2 diabetes  , but whether this association is causal remains unclear . We aim ed to estimate the unconfounded , causal association between 25(OH)D concentration and risk of type 2 diabetes using a mendelian r and omisation approach . Methods Using several data sources from population s of European descent , including type 2 diabetes cases and non-cases , we did a mendelian r and omisation analysis using single nucleotide polymorphisms ( SNPs ) within or near four genes related to 25(OH)D synthesis and metabolism : DHCR7 ( related to vitamin D synthesis ) , CYP2R1 ( hepatic 25-hydroxylation ) , DBP ( also known as GC ; transport ) , and CYP24A1 ( catabolism ) . We assessed each SNP for an association  with circulating 25(OH)D concentration ( 5449 non-cases ; two studies ) , risk of type 2 diabetes ( 28 144 cases , 76 344 non-cases ; five studies ) , and glycaemic traits ( concentrations of fasting glucose , 2-h glucose , fasting insulin , and HbA1c  ; 46 368 non-cases ; study consortium ) . We combined these associations in a likelihood-based mendelian r and omisation analysis to estimate the causal association of 25(OH)D concentration with type 2 diabetes and the glycaemic traits , and compared them with that from a meta- analysis of data from observational studies ( 8492 cases , 89 698 non-cases ; 22 studies ) that assessed the association between 25(OH)D concentration and type 2 diabetes . Findings All four SNPs were associated with 25(OH)D concentrations ( p<10−6 ) . The mendelian r and omisation-derived unconfounded odds ratio for type 2 diabetes was 1·01 ( 95 % CI 0·75–1·36 ; p=0·94 ) per 25·0 nmol/L ( 1 SD ) lower 25(OH)D concentration . The corresponding ( potentially confounded ) relative risk from the meta- analysis of data from observational studies was 1·21 ( 1·16–1·27 ; p=7·3 × 10−19 ) . The mendelian r and omisation-derived estimates for glycaemic traits were not significant ( p>0·25 ) . Interpretation The association between 25(OH)D concentration and type 2 diabetes is unlikely to be causal . Efforts to increase 25(OH)D concentrations might not reduce the risk of type 2 diabetes as would be expected on the basis of observational evidence . These findings warrant further investigations to identify causal factors that might increase 25(OH)D concentration and also reduce the risk of type 2 diabetes . Funding UK Medical Research Council Epidemiology Unit and European Union Sixth Framework Programme Background Besides the classical role of vitamin D on calcium and bone homeostasis , vitamin D deficiency has recently been identified as a contributing factor in the onset of insulin resistance in type 2 diabetes mellitus . However , it is uncertain whether vitamin D deficiency and poor glycaemic control are causally interrelated or that they constitute two independent features of type 2 diabetes mellitus . There are limited clinical trials carried out which measured the effect of vitamin D supplementation on glycaemic control . The objective of this study is to investigate the effect of vitamin D supplementation on glycaemic control and quality of life in patients with type 2 diabetes mellitus . Methods / design In a r and omised double-blind placebo-controlled trial conducted in five general practice s in the Netherl and s three hundred patients with type 2 diabetes mellitus treated with lifestyle advises or metformin or sulphonylurea-derivatives are r and omised to receive either placebo or 50,000 IU Vitamin D3 at monthly intervals . The primary outcome measure is the change in glycated haemoglobin level between baseline and six months . Secondary outcome measures include blood pressure , anthropometric parameters , lipid profile , insulin resistance , quality of life , advanced glycation end products and safety profiles . Quality of life will be measured by The Short Form ( SF-36 ) Health Survey question naire . Advanced glycation end products are measured by an AGE-reader . Discussion This trial will be the first study exploring the effect of vitamin D supplementation on both glycaemic control and quality of life in patients with type 2 diabetes mellitus . Our findings will contribute to the knowledge of the relationship between vitamin D status and insulin resistance in patients with type 2 diabetes mellitus . Trial registration The Netherl and s trial register : The effects of fish oil ( FO ) supplementation on glycaemic control are unclear , and positive effects may occur only when the phospholipid content of tissue membranes exceeds 14 % as n-3 PUFA . Subjects ( n 36 , thirty-three completed ) were paired based on metabolic parameters and allocated into a parallel double-blind r and omised trial with one of each pair offered daily either 6 g of FO ( 3·9 g n-3 PUFA ) or 6 g of maize oil ( MO ) for 9 months . Hyperinsulinaemic-euglycaemic-euaminoacidaemic ( HIEGEAA ) clamps ( with [ 6,6 2H2 glucose ] ) were performed at the start and end of the intervention . Endogenous glucose production ( EGP ) and whole-body protein turnover ( WBPT ) were each measured after an overnight fast . The primary outcome involved the effect of oil type on insulin sensitivity related to glycaemic control . The secondary outcome involved the effect of oil type on WBPT . Subjects on  FO ( n 16 ) had increased erythrocyte n-3 PUFA concentrations > 14 % , whereas subjects on MO ( n 17 ) had unaltered n-3 PUFA concentrations at 9 % . Type of oil had no effect on fasting EGP , insulin sensitivity or total glucose disposal during the HIEGEAA clamp . In contrast , under insulin-stimulated conditions , total protein disposal ( P=0·007 ) and endogenous WBPT ( P=0·001 ) were both increased with FO . In an associated pilot study ( n 4 , three completed ) , although n-3 PUFA in erythrocyte membranes increased to > 14 % with the FO supplement , the enrichment in muscle membranes remained lower ( 8 % ; P<0·001 ) . In conclusion , long-term supplementation with FO , at amounts near the safety limits set by regulatory authorities in Europe and the USA , did not alter glycaemic control but did have an impact on WBPT Background Despite the certain role of both vitamin D and adiponectin in the regulation of insulin sensitivity , the interaction between these two agents has remained uncertain . Objective The present study aim ed to determine whether vitamin D is able to change plasma adiponectin and affect glucose homeostasis and insulin sensitivity in first-degree relatives of subjects with type 2 diabetes . Methods This r and omized clinical trial was conducted at Clinic of Shahid Sadoughi Hospital in Yazd , Iran , from January 25 , 2012 to December 25 , 2014 . In this r and omized , double-blinded controlled trial , 64 first-degree relatives of type 2 diabetic patients were assigned r and omly to receive either vitamin D supplement ( 50000 IU vitamin D tablet weekly ) plus lifestyle change as the intervention group ( n = 32 ) or placebo plus lifestyle change as the control group ( n = 32 ) for twelve weeks ( three months ) . Results Fifty-three patients ( 28 in the intervention group and 25 in the control group ) completed the study . Serum levels of vitamin D  increased while insulin level and consequently insulin resistance ( calculated by HOMA formula ) significantly decreased in the case group ( p-value < 0.001 for all variables ) . Although the values of these three biomarkers showed a slight increase in control group , the changes were not statistically significant . The levels of the changes in other markers including adiponectin , Fasting Blood Sugar ( FBS ) , triglyceride , and total cholesterol remained insignificant in both study groups after completing interventions compared with before interventions . Conclusion This study showed that decreased insulin resistance is expected by administrating vitamin D supplement in first-degree relatives of the patients with diabetes mellitus . Trial Registration The trial was registered at the Iranian Registry of Clinical Trials ( http://www.i rct .ir ) with the I RCT ID : 201105176430N1 . Funding The authors received no financial support for the research or publication of this article Background / Objectives : Flavanols may provide protection against insulin resistance , but little is known about the amounts and types of flavanols that may be efficacious . Subjects/ Methods : This study was design ed to determine whether cocoa flavanols , over a range of intakes , improve biomarkers of glucose regulation , inflammation and hemostasis in obese adults at risk for insulin resistance . As an adjunct , green tea and cocoa flavanols were compared for their ability to modulate these biomarkers . In a r and omized crossover design , 20 adults consumed a controlled diet for 5 days along with four cocoa beverages containing 30–900 mg flavanol per day , or tea matched to a cocoa beverage for monomeric flavanol content . Results : Cocoa beverages produced no significant changes in glucose , insulin , total area under the concentration – time curve ( AUC ) for glucose or total insulin AUC . As the dose of cocoa flavanols increased , total 8-isoprostane concentrations were lowered ( linear contrast , P=0.02 ) , as were C-reactive protein ( CRP ) concentrations ( linear contrast , P=0.01 ) . The relationship between cocoa flavanol levels and interleukin-6 ( IL-6 ) concentrations was quadratic , suggesting that a maximum effective dose was achieved ( quadratic contrast , P=0.01 ) . There were no significant effects on measured indices of glucose regulation , nor on those of total 8-isoprostane , CRP and IL-6 concentrations , when cocoa and green tea were compared . However , relative to cocoa , green tea  lowered fibrinogen concentrations ( P=0.0003 ) . Conclusions : Short-term intake of cocoa and green tea flavanols does not appear to improve glucose metabolism ; they do affect selected markers of one or more measures of oxidative stress , inflammation or hemostasis in obese adults at risk for insulin resistance Metformin has therapeutic potential against breast cancer , but the mechanisms of action in vivo remain uncertain . This study examined biomarker effects of metformin in primary breast cancer in a preoperative window of opportunity trial . Non-diabetic women with operable invasive breast cancer were r and omized to receive open label pre-operative metformin ( 500 mg daily for 1 week then 1 g twice daily for a further week ) or as controls , not receiving metformin .  Patients in both arms had a core biopsy pre-r and omisation and again at the time of surgery . Immunohistochemistry for phospho-AMPK ( pAMPK ) , phospho-Akt ( pAkt ) , insulin receptor , cleaved caspase-3 , and Ki67 was performed on formalin-fixed paraffin-embedded cores , scored blinded to treatment and analysed by paired t test . In metformin-treated patients , significant up-regulation of pAMPK ( paired t test , p = 0.04 ) and down-regulation of pAkt ( paired t test , p = 0.043 ) were demonstrated compared to the control group . Insulin receptor and serum insulin remained similar following metformin treatment compared with a rise in insulin receptor and insulin in controls . Significant falls in Ki67 and cleaved caspase-3 ( paired t test , p = 0.044 ) were seen in the metformin-treated patients but not in the control group . Changes were independent of body mass index . These biomarker data suggest mechanisms for metformin action in vivo in breast cancer patients via up-regulation of tumor pAMPK , down-regulation of pAkt , and suppression of insulin responses reflecting cytostatic rather than cytotoxic mechanisms Background Studies have suggested that vitamin D may be important for both insulin sensitivity and insulin secretion , and that supplementation with vitamin D may subsequently prevent development of type 2 diabetes . Aim of the study The objective of the current study was to test the hypothesis that supplementation with vitamin D would improve glycaemic control in subjects with type 2 diabetes . Methods Thirty-six subjects with type 2 diabetes , treated with metformin and bed-time insulin  , were r and omised to supplementation with cholecalciferol ( 40,000 IU per week ) versus placebo for 6 months . Thirty-two subjects participated throughout the entirety of the study . Fasting blood sample s were drawn before and at the end of the 6 month study without the previous bed-time insulin injection . The insulin and metformin doses were not changed throughout the study . Results After 6 months , the fasting glucose , insulin , C-peptide , fructosamine , and HbA1c levels were not significantly different from baseline values . In addition , changes in these parameters ( values at 6 months minus values at baseline ) did not differ between the vitamin D and the placebo group . Conclusions We were not able to demonstrate that vitamin D supplementation had a significant effect on glucose metabolism in subjects with type 2 diabetes but without vitamin D deficiency . Further studies are needed in larger groups of subjects with type 2 diabetes or impaired glucose tolerance , who also exhibit low serum 25-hydroxyvitamin D levels Certain purified indigestible carbohydrates such as inulin have been shown to stimulate gut-derived hormones involved in glycaemic regulation and appetite regulation , and to counteract systemic inflammation through a gut microbiota-mediated mechanism . Less is known about the properties of indigestible carbohydrates intrinsic to food . The aim of this study was to investigate the possibility to affect release of endogenous gut hormones and ameliorate appetite control and glycaemic control by ingestion of a whole-grain cereal food product rich in NSP and resistant starch in healthy humans . In all , twenty middle-aged subjects were provided with a barley kernel-based bread ( BB ) or a reference white wheat bread during 3 consecutive days , respectively , in a r and omised cross-over design study . At a st and ardised breakfast the following day ( day 4 ) , blood was collected for the analysis of blood ( b ) glucose regulation , gastrointestinal hormones , markers of inflammation and markers of colonic fermentation ; 3 d of intervention with BB increased gut hormones in plasma ( p ) the next morning at fasting ( p-glucagon-like peptide-1 ; 56 % ) and postpr and ially ( p-glucagon-like peptide-2 ; 13 % and p-peptide YY ; 18 % ) . Breath H₂ excretion and fasting serum ( s ) SCFA concentrations were increased ( 363 and 18 % , respectively ) , and b-glucose ( 22 % ) and s-insulin responses ( 17 % ) were decreased after BB intervention . Insulin sensitivity index ( ISI(composite ) ) was also improved ( 25 % ) after BB . In conclusion , 3 d of intervention with BB increased systemic levels of gut hormones involved in appetite regulation , metabolic control and maintenance of gut barrier function , as well as improved markers of glucose homoeostasis in middle-aged subjects , altogether relevant for the prevention of obesity and the metabolic syndrome Many biomarkers are associated with type 2 diabetes ( T2D ) risk in epidemiological observations . The aim of this study was to identify and summarize current evidence for causal effects of biomarkers on T2D . A systematic literature search in PubMed and EMBASE ( until April 2015 ) was done to identify Mendelian r and omization studies that examined potential causal effects of biomarkers on T2D . To replicate the findings of identified studies , data from two large-scale , genome-wide association studies ( GWAS ) were used : DIAbetes  Genetics Replication And Meta- analysis  ( DIAGRAMv3 ) for T2D and the Meta-Analyses of Glucose and Insulin-related traits Consortium ( MAGIC ) for glycaemic traits . GWAS summary statistics were extracted for the same genetic variants ( or proxy variants ) , which were used in the original Mendelian r and omization studies . Of the 21 biomarkers ( from 28 studies ) , ten have been reported to be causally associated with T2D in Mendelian r and omization . Most biomarkers were investigated in a single cohort study or population . Of the ten biomarkers that were identified , nominally significant associations with T2D or glycaemic traits were reached for those genetic variants related to bilirubin , pro-B-type natriuretic peptide , delta-6 desaturase and dimethylglycine based on the summary data from DIAGRAMv3 or MAGIC . Several Mendelian r and omization studies investigated the nature of associations of biomarkers with T2D . However , there were only a few biomarkers that may have causal effects on T2D . Further research is needed to broadly evaluate the causal effects of multiple biomarkers on T2D and glycaemic traits using data from large-scale cohorts or GWAS including many different genetic variants Purpose This study aim ed to evaluate the effect of daily consumption of vitamin D-fortified yogurt drink ( doogh ) in comparison with plain doogh on appetite-regulating hormones including leptin and ghrelin in type 2 diabetes ( T2D ) patients . Methods In a single blind r and omized clinical trial , subjects with T2D were r and omly allocated to one of the two groups and received either vitamin D3-fortified doogh ( FD ; containing 170 mg calcium and 500 IU/250 mL , n2 = 50 ) or plain doogh ( PD ; containing 170 mg calcium and no vitamin D/250 mL , n1 = 50 ) twice a day for 12 weeks . Leptin and ghrelin were evaluated at the beginning and after 12 weeks of intervention . Results The intervention result ed in a significant improvement of circulating 25(OH)D , fasting glucose , Quantitative Insulin Check Index ( QUICKI ) , hs-CRP , in FD compared with PD group . A significant rise in both serum leptin ( + 1.3 ± 7.2 mg/L ; p = 0.013 ) and ghrelin ( 10.1 ± 26.1 ng/L ; p = 0.012 ) was observed in FD group . A between-group difference for ghrelin changes ( p = 0.029 ) remained significant after adjusting for changes QUICKI ( p = 0.039 ) , body mass index ( p = 0.034 ) and hs-CRP ( p = 0.022 ) . Despite an increase in both leptin and ghrelin , leptin to ghrelin ( L/G ) ratio actually decreased in FD . Changes of L/G ratio showed a significant between-group difference ( p = 0.036 ) , which remained significant even after adjusting for changes of hs-CRP ( p = 0.028 ) and fat mass ( p = 0.047 ) but disappeared after adjusting for changes of QUICKI ( p = 0.42 ) . Conclusions Daily intake of vitamin D-fortified doogh may increase circulating leptin and ghrelin but L/G ratio may actually decrease . Our results suggest that improving vitamin D may result in an improvement in insulin sensitivity which may finally regulate beneficially appetite hormones . Further studies with adequate power are needed to confirm the results OBJECTIVE Low vitamin D levels and risk factors for vascular disease are both common in South Asian women . This trial evaluated whether vitamin D supplementation could improve markers of vascular health in South Asian women with low 25-hydroxyvitamin D levels . METHODS Parallel-group , double-blind , r and omised placebo-controlled trial . Healthy South Asian women with baseline serum 25-hydroxyvitamin D levels of < 75 nmol/L were r and omised to receive a single dose of 100,000 units oral vitamin D3 or matching placebo . Outcomes were measured at baseline , 4 and 8 weeks . The primary outcome was change in endothelial function measured using brachial artery flow-mediated dilatation . Secondary outcomes included blood pressure , arterial stiffness , microvascular function measured using laser Doppler iontophoresis , insulin resistance , serum lipids , circulating markers of inflammation , thrombosis and adipokines . RESULTS 50 women were r and omised , 25 to each group . Mean age was 41 years ; mean baseline 25-hydroxyvitamin D level was 27 nmol/L.  25-Hydroxyvitamin D levels rose in the vitamin D group relative to the placebo group by 4 weeks ( 16 nmol/L , 95 % CI 11 to 21 , p < 0.001 ) . There was no improvement in flow-mediated dilatation in the vitamin D group relative to placebo at 4 weeks ( 0.1 % , 95 % CI -0.9 to 1.1 , p = 0.84 ) or 8 weeks ( 0.0 % , 95 % CI -1.4 to 1.4 , p = 0.98 ) . There was no improvement in cholesterol , insulin resistance or markers of inflammation . Both platelet activation inhibitor-1 and tissue plasminogen activator levels fell significantly in the vitamin D group relative to placebo at 8 weeks . CONCLUSION A single large dose of vitamin D3 did not improve blood pressure or endothelial function in South Asian women with low baseline 25-hydroxyvitamin D levels . TRIAL REGISTRATION IS RCT N75081811 Objective To determine the effectiveness of a patient decision aid ( PDA ) to improve decision quality and glycaemic control in people with diabetes making treatment choices using a cluster r and omised controlled trial ( RCT ) . Design A cluster RCT . Setting 49 general practice s in UK r and omised into intervention ( n=25 ) and control ( n=24 ) . Participants General practice s Inclusion criteria : > 4 medical partners ; list size > 7000 ; and a diabetes register with > 1 % of practice population . 191 practice s assessed for eligibility , and 49 practice s r and omised and completed the study . Patients People with type 2 diabetes mellitus ( T2DM ) taking at least two oral glucose-lowering drugs with maximum tolerated dose with a glycosolated haemoglobin ( HbA1c ) greater than 7.4 % ( IFCC HbA1c > 57 mmol/mol ) or advised in the preceeding 6 months to add or consider changing to insulin therapy . Exclusion criteria : currently using insulin therapy ; difficulty reading or underst and ing English ; difficulty in underst and  ing the purpose of the study ; visual or cognitive impairment or mentally ill . A total of 182 assessed for eligibility , 175 r and omised to 95 intervention and 80 controls , and 167 completion and analysis .  Intervention Brief training of clinicians and use of PDA with patients in single consultation . Primary outcomes Decision quality ( Decisional Conflict Scores , knowledge , realistic expectations and autonomy ) and glycaemic control ( glycosolated haemoglobin , HbA1c ) . Secondary outcomes Knowledge and realistic expectations of the risks and benefits of insulin therapy and diabetic complications . Results Intervention group : lower total Decisional Conflict Scores ( 17.4 vs 25.2 , p<0.001 ) ; better knowledge ( 51.6 % vs 28.8 % , p<0.001 ) ; realistic expectations ( risk of ‘ hypo ’ , ‘ weight gain ’ , ‘ complications ’ ; 81.0 % vs 5.2 % , 70.5 % vs 5.3 % , 26.3 % vs 5.0 % respectively , p<0.001 ) ; and were more autonomous in decision-making ( 64.1 % vs 42.9 % , p=0.012 ) . No significant difference in the glycaemic control between the two groups . Conclusions Use of the P AND As decision aid reduces decisional conflict , improves knowledge , promotes realistic expectations and autonomy in people with diabetes making treatment choices in general practice . IS RCT N Trials Register Number 14842077 Growing evidence suggests that glycaemic variability increases diabetic complications . However , the significance of glycaemic variability in critically ill patients remains unclear . We evaluated the predictors of glycaemic fluctuation and its association with critical care outcomes . This is a nested-cohort study within a clinical trial in which 523 patients at a medical surgical intensive care unit were r and omised to either intensive insulin therapy ( target glycaemic control : 4.4 to 6.1 mmol/l ) or conventional insulin therapy ( target control : 10.0 to 11.1 mmol/l ) . Glycaemic fluctuation was defined as the mean difference between the highest and lowest daily blood glucose . Patients were divided into wide and narrow fluctuation groups according to the median glycaemic fluctuation ( 6.0 mmol/l ) . The association between glycaemic fluctuation and different intensive care unit outcomes was studied . Predictors of glycaemic fluctuation were age ( odds ratio for each year increment 1.03 , 95 % confidence interval 1.02 to 1.05 ) , diabetes mellitus ( odds ratio 3.00 , 95 % confidence interval 1.74 to 5.17 ) , and daily insulin dose ( odds ratio for each unit increment 1.04 , 95 % confidence interval 1.03 to 1.05 ) . Similar levels of glucose fluctuation were observed in intensive insulin therapy and conventional insulin therapy patients . Wide glycaemic fluctuation was associated with higher mortality ( 22.2 vs 8.4 % , P < 0.001 ) . Glycaemic fluctuation was identified as an independent predictor of intensive care unit mortality ( odds ratio per mmol 1.08 , 95 % confidence interval 1.00 to 1.18 ) and hospital mortality ( odds ratio per mmol 1.09 , 95 % confidence interval 1.02 to 1.17 ) using multivariate logistic regression analysis . In conclusion , wide glycaemic fluctuation is an independent predictor of mortality  in critically ill patients . Whether reducing glycaemic fluctuation would lead to better outcomes needs further evaluation Purpose Low fruit and vegetable consumption is linked with an increased risk of death from vascular disease and cancer . The benefit of eating fruits and vegetables is attributed in part to antioxidants , vitamins and phytochemicals . Whether increasing intake impacts on markers of disease remains to be established . This study investigates whether increasing daily intake of fruits , vegetables and juices from low ( approx . 3 portions ) , to high intakes ( approx . 8 portions ) impacts on nutritional and clinical biomarkers . Barriers to achieving the recommended fruit and vegetable intakes are also investigated . Method In a r and omised clinical trial , the participants [ 19 men and 26 women ( 39–58 years ) ] with low reported fruit , juice and vegetable intake ( <3 portions/day ) were r and omised to consume either their usual diet or a diet supplemented with an additional 480 g of fruit and vegetables and fruit juice ( 300 ml ) daily for 12 weeks . Nutritional biomarkers ( vitamin C , carotenoids , B vitamins ) , antioxidant capacity and genomic stability were measured pre-intervention , at 4- , 8- and 12 weeks throughout the intervention . Sample s were also taken post-intervention after a 6-week washout period . Glucose , homocysteine , lipids , blood pressure , weight and arterial stiffness were also measured . Intake  of fruit , fruit juice and vegetables was reassessed 12 months after conducting the study and a question naire was developed to identify barriers to healthy eating . Results Intake increased significantly in the intervention group compared to controls , achieving 8.4 portions/day after 12 weeks . Plasma vitamin C ( 35 % ) , folate ( 15 % ) and certain carotenoids [ α-carotene ( 50 % ) and β-carotene ( 70 % ) and lutein/zeaxanthin ( 70 % ) ] were significantly increased ( P < 0.05 ) in the intervention group . There were no significant changes in antioxidant capacity , DNA damage and markers of vascular health . Barriers to achieving recommended intakes of fruits and vegetables measured 12 months after the intervention period were amount , inconvenience and cost . Conclusion While increasing fruit , juice and vegetable consumption increases circulating level of beneficial nutrients in healthy subjects , a 12-week intervention was not associated with effects on antioxidant status or lymphocyte DNA damage . Trial registration This trial was registered at Controlled-Trials.com ; registration IS RCT N71368072 Aims /hypothesisLow 25-hydroxyvitamin D levels predict future cardiovascular events and are common in patients with type 2 diabetes . We compared the effect of 100,000 and 200,000 IU doses of vitamin D3 on endothelial function , blood pressure and markers of glycaemic control in patients with type 2 diabetes . Methods This was a r and omised , parallel group , placebo-controlled trial . Patients with type 2 diabetes and baseline 25-hydroxyvitamin D levels < 100 nmol/l were enrolled from community and hospital-based diabetes clinics . Participants were assessed in a university department of clinical pharmacology and received a single oral dose of placebo or vitamin D3 ( 100,000 IU or 200,000 IU ) at baseline , r and omly allocated via numbered bottles prepared offsite ; participants and investigators were both blinded to treatment allocation . Endothelial function , office blood pressure , B-type natriuretic peptide , insulin resistance and glycosylated haemoglobin were measured at baseline , and at 8 and 16 weeks . Results We r and omised 61 participants to the three groups ( placebo 22 , 100,000 IU vitamin D3 19 , 200,000 IU vitamin D3 20 ) . There was no significant difference in the primary outcome of endothelial function at 8 weeks ( placebo 5.2 % , n = 22 ; 100,000 IU 4.3 % , n = 19 ; 200,000 IU 4.9 % , n = 17 ) or at 16 weeks . Insulin resistance and glycosylated haemoglobin did not improve with either dose of vitamin D3 . On covariate analysis , systolic blood pressure was significantly lower in both treatment arms than in the placebo group at 8 weeks ( placebo 146.4 mmHg , 100,000 IU 141.4 mmHg [ p = 0.04 vs placebo ] , 200,000 IU 136.8 mmHg [ p = 0.03 vs placebo ] ) . B-type natriuretic peptide levels were significantly lower in the 200,000 IU group by 16 weeks ( placebo 34 pg/ml , 200,000 IU 21 pg/ml , p = 0.02 ) . No significant excess of adverse effects was noted in the treatment arms . Conclusions /interpretationHigh-dose vitamin D3 improved systolic blood pressure and B-type natriuretic peptide levels , but not endothelial function , insulin resistance or glycosylated haemoglobin in patients with type 2 diabetes . Trial registration IS RCT N50587697 ( www.controlled-trials.com ) Funding Diabetes UK , grant number 06/0003429 . M. D. Witham is funded by a Scottish Government NES/CSO Clinician Scientist Award OBJECTIVE High-glycaemic-load diets may increase endometrial cancer risk by increasing circulating insulin levels and , as a consequence , circulating oestrogen levels . Given the paucity of epidemiological data regarding the relationship between dietary glycaemic index and glycaemic load and endometrial cancer risk , we sought to examine these associations using data from a prospect i ve cohort study . DESIGN , SETTING AND SUBJECTS We examined the association between dietary glycaemic load and endometrial cancer risk in a cohort of 49,613 Canadian women aged between 40 and 59 years at baseline who completed self-administered food-frequency question naires between 1982 and 1985 . Linkages to national mortality and cancer data bases yielded data on deaths and cancer incidence , with follow-up ending between 1998 and 2000 . RESULTS During a mean of 16.4 years of follow-up , we observed 426 incident cases of endometrial cancer . Hazard ratios for the highest versus the lowest quartile level of overall glycaemic index and glycaemic load were 1.47 ( 95 % confidence interval ( CI ) = 0.90 - 2.41 ; P for trend = 0.14 ) and 1.36 ( 95 % CI = 1.01 - 1.84 ; P for trend = 0.21 ) , respectively . No association was observed between total carbohydrate or total sugar consumption and endometrial cancer risk . Among obese women ( body mass index > 30 kg m(-2 ) ) the hazard ratio for the highest versus the lowest quartile level of glycaemic load was 1.88 ( 95 % CI = 1.08 - 3.29 ; P for trend = 0.54 ) and there was a 55 % increased risk for the highest versus the lowest quartile level of glycaemic load among premenopausal women . There was also evidence to support a positive association between glycaemic load and endometrial cancer risk among postmenopausal women who had used hormone replacement therapy . CONCLUSIONS Our data suggest that diets with high glycaemic index or high glycaemic load may be associated with endometrial cancer risk overall , and particularly among obese women , premenopausal women and postmenopausal women who use hormone replacement therapy BACKGROUND AND AIMS Public health campaigns recommend increased fruit and vegetable ( FV ) consumption as an effective means of cardiovascular risk reduction . During an 8 week r and omised control trial among hypertensive volunteers , we noted significant improvements in endothelium-dependent vasodilatation with increasing FV consumption . Circulating indices of inflammation , endothelial activation and insulin resistance are often employed as alternative surrogates for systemic arterial health . The responses of several such biomarkers to our previously described FV intervention are reported here . METHODS AND RESULTS Hypertensive volunteers were recruited from medical outpatient clinics . After a common 4 week run-in period during which FV consumption was limited to 1 portion per day , participants were r and omised to 1 , 3 or 6 portions daily for 8 weeks . Venous blood sample s for biomarker analyses were collected during the pre and post-intervention vascular assessment s. A total of 117 volunteers completed the 12 week study . Intervention-related changes in circulating levels of high sensitivity C-reactive protein ( hsCRP ) , soluble intracellular adhesion molecule-1 ( sICAM-1 ) , soluble vascular cell adhesion molecule-1 ( sVCAM-1 ) , von Willebr and factor ( vWF ) and plasminogen activator inhibitor-1 ( PAI-1 ) did not differ significantly between FV groups . Similarly , there were no significant between group differences of change in homeostasis model assessment ( HOMA ) scores . CONCLUSIONS Despite mediating a significant improvement in acetylcholine induced vasodilatation , increased FV consumption did not affect a calculated measure of insulin resistance or concentrations of the circulating biomarkers measured during this study . Functional indices of arterial health such as endothelium-dependent vasomotion are likely to provide more informative cardiovascular end-points during short-term dietary intervention trials CONTEXT Observational studies show an association between low vitamin D status assessed by circulating 25-hydroxyvitamin D and cardiovascular events and mortality . Data from r and omized controlled trials are limited . OBJECTIVE The aim of this study was to test whether daily doses of vitamin D(3 ) at 400 or 1000 IU/d for 1 yr affected conventional markers of cardiovascular disease ( CVD ) risk . DESIGN We conducted a parallel-group , double-blind , placebo-controlled r and omized controlled trial . R and omization was computer generated . Participants and study investigators were blinded to intervention groupings throughout the trial . SETTING The study was conducted at the Clinical Research Facility , University of Aberdeen , United Kingdom . PARTICIPANTS A total of 305 healthy postmenopausal women aged 60 - 70 yr were recruited for the study . INTERVENTION Each woman received a daily capsule of 400 or 1000 IU vitamin D(3 ) or placebo r and omly allocated . MAIN OUTCOME MEASURES Primary outcomes were serum lipid profile [ total , high-density lipoprotein , and low-density lipoprotein cholesterol ; triglycerides ; and apolipoproteins A-1 and B100 ] , insulin resistance ( homeostatic model assessment ) , inflammatory biomarkers ( high-sensitivity C-reactive protein , IL-6 , soluble intracellular adhesion molecule-1 ) , and blood pressure . RESULTS A total of 265 ( 87 % ) participants completed all study visits . Small differences between groups for serum apolipoprotein B100 change [ repeated measures ANOVA , P=0.04 ; mean ( sd ) , -1.0 ( 10.0 ) mg/dl ( 400 IU ) ; -1.0 ( 10.0 ) mg/dl ( 1000 IU ) ; and + 0.02 ( 10.0 ) mg/dl ( placebo ) ] were not considered clinical ly significant . Other systemic markers for CVD risk remained unchanged . There was significant seasonal variation in systolic and diastolic blood pressure independent of vitamin D dose ( P<0.001 , linear mixed model ) . Mean ( sd ) reduction in systolic blood pressure from winter to summer was -6.6 ( 10.8 ) mm Hg . CONCLUSIONS Improving vitamin D status through dietary supplementation is unlikely to reduce CVD risk factors . Confounding of seasonality should be recognized and addressed in future studies of vitamin Background Non-stimulatory , meal-mediated electrical stimulation of the stomach ( TANTALUS-DIAMOND ) improves glycaemic control and causes modest weight loss in patients with Type 2 diabetes who are inadequately controlled on oral anti-diabetic medications . The magnitude of the glycaemic response in clinical studies has been variable . A preliminary analysis of data from patients who had completed 6 months of treatment indicated that the glycaemic response to the electrical stimulation was inversely related to the baseline fasting plasma triglyceride level . Method An analysis of 40 patients who had had detailed longitudinal studies for 12 months . Results Twenty-two patients with fasting plasma triglycerides ≤ 1.7 mmol/l had mean decreases in HbA1c after 3 , 6 and 12 months of gastric contraction modulation treatment of −15 ± 2.1 mmol/mol ( −1.39 ± 0.20 % ) , −16 ± 2.2 mmol/mol ( −1.48 ± 0.20 % ) and −14 ± 3.0 mmol/mol ( −1.31 ± 0.26 % ) , respectively . In contrast , 18 patients with fasting plasma triglyceride > 1.7 mmol/l had mean decreases in HbA1c of −7 ± 1.7 mmol/mol ( −0.66 ± 0.16 % ) , −5 ± 1.6 mmol/mol ( −0.44 ± 0.18 % ) and −5 ± 1.7 mmol/mol ( −0.42 ± 0.16 % ) , respectively . Pearson 's correlation coefficient between fasting plasma triglyceride and decreases in HbA1c at 12 months of treatment was 0.34 ( P < 0.05 ) . Homeostasis model assessment of insulin resistance was unchanged during 12 months of treatment in patients with high baseline fasting triglycerides , while it progressively improved in patients with low fasting plasma triglycerides . Patients with low fasting plasma triglycerides had a tendency to lose more weight than those with high fasting plasma triglycerides , but this did not achieve statistical significance . Conclusions The data presented suggest the existance of a triglyceride lipotoxic mechanism that interferes with gastric/neural mediated pathways that can regulate glycaemic control in patients with type 2 diabetes . The data suggest the existence of a triglyceride lipotoxic pathway that interferes with gastric/neural mediated pathways that can regulate glycaemic control Regulation of magnesium balance is poorly understood . However , hypomagnesaemia has been reported in patients in clinical situations where circulating catecholamines are raised including myocardial infa rct ion , cardiac surgery and insulin-induced hypoglycaemia stress tests . The effects of L-adrenaline infusions , sufficient to achieve pathophysiological levels of adrenaline , and of therapeutic intravenous infusions of salbutamol , a beta 2-agonist , on plasma magnesium , plasma potassium , plasma glucose and plasma insulin levels were studied in a placebo-controlled design in eight normal subjects .  Plasma magnesium levels fell significantly during the adrenaline infusion and also during the salbutamol infusion , though more slowly . In a 1 h period of observation after cessation of the infusions no recovery of plasma magnesium levels was seen . Significant falls in plasma potassium levels were also observed during both infusions with spontaneous recovery within 30 min after the infusions . No significant changes in plasma insulin levels occurred with either salbutamol or L-adrenaline compared with control . Plasma glucose levels rose significantly during the adrenaline infusion . The study suggests that both L-adrenaline and salbutamol cause shifts in plasma magnesium which are not mediated by insulin . We propose that intracellular shifts of magnesium occur as a result of beta-adrenergic stimulation In a previous study we were the first to describe a negative correlation between circulating ghrelin concentrations and and rogen levels in human plasma , suggesting an interaction between ghrelin and the endocrine regulation of reproductive physiology . We now investigated a potential direct regulatory influence of circulating and rogens on plasma ghrelin levels . Fourteen obese women with polycystic ovary syndrome ( PCOS ) on a hypocaloric diet were r and omly assigned to treatment groups ( open-labeled design ) , receiving either placebo ( no.= 7 ) or the anti and rogen flutamide ( no.=7 ) for 6 months . Anthropometry , visceral ( VAT ) and subcutaneous ( SAT ) adipose tissue ( quantified by computerized tomography ) , plasma hormone levels , insulin sensitivity indexes ( Quantitative Insulin-Sensitivity Check Index-QUICKI ) and Homeostatic Model Assessment applied to the oral glucose tolerance test ( HOMAOGTT ) were evaluated at baseline and at the end of the study . Body weight decreased and insulin resistance indexes improved in both groups . A tendency toward a greater loss of VAT was observed in the flutamide group . Only in the flutamide group was a significant reduction of and rogens levels observed . Plasma ghrelin levels significantly increased following treatment with flutamide , while ghrelin remained unchanged in the placebo group . We observed a negative correlation between changes of ghrelin levels and changes of and rogen plasma concentration in the flutamide-treated group . In the same group a positive correlation was found between plasma ghrelin changes and insulin sensitivity as expressed by HOMAOGTT . Analysis in a multiple regression model , however , showed that plasma ghrelin changes were mainly due to changes of and rogen levels rather than improved insulin sensitivity . We , therefore , conclude that and rogens are independent modulators of circulating ghrelin concentrations Abstract Aims /hypothesisBy use of a parallel and partly crossover r and omised , controlled trial design we sought to eluci date the underlying mechanisms behind the advantageous effects of interval walking training ( IWT ) compared with continuous walking training ( CWT ) on glycaemic control in individuals with type 2 diabetes . We hypothesised that IWT , more than CWT , would improve insulin sensitivity including skeletal muscle insulin signalling , insulin secretion and disposition index ( DI ) . Methods By simple r and omisation ( sequentially numbered , opaque sealed envelopes ) , eligible individuals ( diagnosed with type 2 diabetes , no exogenous insulin treatment ) were allocated to three groups : a control group ( CON , n = 8) , an IWT group ( n = 12 ) and an energy expenditure-matched CWT group ( n = 12 ) . Training groups were prescribed free-living training , five sessions per week ( 60 min/session ) . A three-stage hyperglycaemic clamp , including glucose isotope tracers and skeletal muscle biopsies , was performed before and after a 4 month intervention in a hospitalised setting . No blinding was performed . Results The improved glycaemic control , which was only seen in the IWT group , was consistent with IWT-induced increases in insulin sensitivity index ( 49.8 ± 14.6 % ; p < 0.001 ) , peripheral glucose disposal ( 14.5 ± 4.9 % ; p < 0.05 ) and DI ( 66.2 ± 21.8 % ; p < 0.001 ) , with no changes in the CWT or CON group . Moreover , only IWT  improved insulin signalling in skeletal muscle via increased insulin-stimulated phosphorylation of AS160 ( 29.0 ± 10.8 % ; p < 0.05 ) . No changes were seen in insulin secretion during hyperglycaemia alone , hyperglycaemia + glucagon-like peptide 1 infusion or arginine injection . Conclusions /interpretationIWT maintains insulin secretion and improves insulin sensitivity and DI , in contrast to energy expenditure-matched CWT . These results suggest that training with alternating intensity , and not just training volume and mean intensity , is a key determinant of changes in whole body glucose disposal in individuals with type 2 diabetes . Trial registration : Clinical Trials ( NCT01234155 ) Aims : The extent to which hemostatic and inflammatory biomarkers are related to angina pectoris as compared with myocardial infa rct ion ( MI ) remains uncertain . We examined the relationship between a wide range of inflammatory and hemostatic biomarkers , including markers of activated coagulation , fibrinolysis and endothelial dysfunction and viscosity , with incident myocardial infa rct ion ( MI ) or coronary heart disease ( CHD ) death and incident angina pectoris uncomplicated by MI or CHD death in older men . Methods : A prospect i ve study of 3217 men aged 60–79 years with no baseline CHD ( angina or MI ) and who were not on warfarin , followed up for 7 years during which there were 198 MI/CHD death cases and 220 incident uncomplicated angina cases . Results : Inflammatory biomarkers [ C-reactive protein ( CRP ) , interleukin-6 , fibrinogen ] , plasma viscosity and hemostatic biomarkers [ von Willebr and factor ( VWF ) and fibrin D-dimer ] were associated with a significant increased risk of MI/CHD death but not with uncomplicated angina even after adjustment for age and conventional risk factors . Adjustment for CRP attenuated the relationships between VWF , fibrin D-dimer and plasma viscosity with MI/CHD death . Comparisons of differing associations with risk of MI/CHD deaths and uncomplicated angina were significant for the inflammatory markers ( P < 0.05 ) and marginally significant for fibrin D-dimer ( P = 0.05 ) . In contrast , established risk factors including blood pressure and high-density lipoprotein (HDL)-cholesterol were associated with both MI/CHD death and uncomplicated angina . Conclusion : Circulating biomarkers of inflammation and hemostasis are associated with incident MI/CHD death but not incident angina uncomplicated by MI or CHD death in older men
Overall , vitamin C did not modify glucose , HbA1c and insulin concentrations .
Meta-regression analyses showed that age was a modifier of the effect of vitamin C on insulin concentration .
Furthermore , the effect size was associated with baseline BMI and plasma glucose levels , and with the duration of the intervention .
In conclusion , greater reduction in glucose concentrations observed in patients with diabetes , older individuals and with more prolonged supplementation .
R and omised controlled trials ( RCTs ) have observed contrasting results on the effects of vitamin C on circulating biomarkers of glycaemic and insulin regulation .