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BACKGROUND: Sugar-sweetened beverages are associated with type 2 diabetes. To assess whether this association holds for the fructose-containing sugars they contain, we conducted a systematic review and meta-analysis of prospective cohort studies. METHODS: We searched MEDLINE, Embase, CINAHL and the Cochrane Library (through June 2016). We included prospective cohort studies that assessed the relation of fructose-containing sugars with incident type 2 diabetes. Two independent reviewers extracted relevant data and assessed risk of bias. We pooled risk ratios (RRs) using random effects meta-analyses. The overall quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Fifteen prospective cohort studies (251 261 unique participants, 16 416 cases) met the eligibility criteria, comparing the highest intake (median 137, 35.2 and 78 g/d) with the lowest intake (median 65, 9.7 and 25.8 g/d) of total sugars, fructose and sucrose, respectively. Although there was no association of total sugars (RR 0.91, 95% confidence interval [CI] 0.76–1.09) or fructose (RR 1.04, 95% CI 0.84–1.29) with type 2 diabetes, sucrose was associated with a decreased risk of type 2 diabetes (RR 0.89, 95% CI 0.80–0.98). Our confidence in the estimates was limited by evidence of serious inconsistency between studies for total sugars and fructose, and serious imprecision in the pooled estimates for all 3 sugar categories. INTERPRETATION: Current evidence does not allow us to conclude that fructose-containing sugars independent of food form are associated with increased risk of type 2 diabetes. Further research is likely to affect our estimates. Trial registration: ClinicalTrials.gov, no. NCT01608620

The relationship between metformin use and prostate cancer risk remains controversial. Genetic variation in metformin metabolism pathways appears to modify metformin glycemic control and the protective association with some cancers. However, no studies to date have examined this pharmacogenetic interaction and prostate cancer chemoprevention. Clinical data and germline DNA were collected from our prostate biopsy database between 1996 and 2014. In addition to a genome-wide association study (GWAS), 27 single nucleotide polymorphisms (SNPs) implicated in metformin metabolism were included on a custom SNP array. Associations between metformin use and risk of high-grade (Grade Group ≥ 2) and overall prostate cancer were explored using a case-control design. Interaction between the candidate/GWAS SNPs and the metformin-cancer association was explored using a case-only design. Among 3481 men, 132 (4%) were taking metformin at diagnosis. Metformin users were older, more likely non-Caucasian, and had higher body mass index, Gleason score, and number of positive cores. Overall, 2061 (59%) were diagnosed with prostate cancer, of which 922 (45%) were high-grade. After adjusting for baseline characteristics, metformin use was associated with higher risk of high-grade prostate cancer (OR = 1.76, 95% CI 1.1–2.9, p = 0.02) and overall prostate cancer (OR = 1.77, 95% CI 1.1–2.9, p = 0.03). None of the 27 candidate SNPs in metformin metabolic pathways had significant interaction with the metformin-cancer association. Among the GWAS SNPs, one SNP (rs149137006) had genome-wide significant interaction with metformin for high-grade prostate cancer, and another, rs115071742, for overall prostate cancer. They were intronic and intergenic SNPs, respectively, with largely uncharacterized roles in prostate cancer chemoprevention. In our cohort, metformin use was associated with increased risk of being diagnosed with prostate cancer. While SNPs involved in metformin metabolism did not have modifying effects on the association with disease risk, one intronic and one intergenic SNP from the GWAS study did, and these require further study.

BACKGROUND Metformin is the first-line oral antihyperglycemic of choice for individuals with type 2 diabetes. Recent evidence supports a role for metformin in prostate cancer chemoprotection. However, whether metformin indeed influences prostate biology is unknown. We aimed to study the association between metformin and serum prostate-specific antigen (PSA) levels—the primary prostate cancer biomarker. METHODS We conducted a cross-sectional study of 326 prostate cancer-free men with type 2 diabetes were recruited between 2004 and 2013 at St. Michael's Hospital. Men were excluded if they had a PSA ≥10-ng/ml, or used >2,550-mg/d metformin or supplemental androgens. Multivariate linear regressions quantified the association between metformin dose and log-PSA. Secondary analyses quantified the association between other antihyperglycemics (sulfonylureas, thiazolidinediones) and PSA; sensitivity analyses tested covariate interactions. RESULTS Median PSA was 0.9-ng/ml (IQR: 0.5–1.6-ng/ml). Metformin dose associated positively with BMI, HbA1c, diabetes duration, and number of statin, acetylsalicylic acid, diuretic users, and number of antihyperglycemics used, and negatively with LDL-C. In multivariate models, PSA changed by −8% (95%CI: −13 to −2%, P = 0.011) per 500-mg/d increase in metformin. Men with diabetes for ≥6 years (n = 163) saw a greater difference in PSA per 500-mg/d metformin (−12% [95% CI: −19 to −4%, P = 0.002], P-interaction = 0.018). Serum PSA did not relate with sulfonylureas, thiazolidinediones, or total number of antihyperglycemic agents used. Our findings are limited by the cross-sectional design of this study. CONCLUSIONS Metformin dose-dependently inversely associated with serum PSA, independent of other antihyperglycemic medications. Whether metformin confers a dose-dependent benefit on prostate tumorigenesis and progression warrants investigation. Prostate 76:1445–1453, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.

Recent evidence suggests that statins may improve prostate cancer outcomes; however, their role in active surveillance (AS) is poorly characterized. We aimed to evaluate the association between statin use at diagnosis and time to progression on AS. Data were obtained from a prospectively maintained cohort of men undergoing AS between 1995 and 2016 at our institution. All men satisfied the low-risk criteria: Gleason score

Objectives: Although most controlled feeding trials have failed to show an adverse effect of fructose on blood pressure, concerns continue to be raised regarding the role of fructose in hypertension. To quantify the association between fructose-containing sugar (high-fructose corn syrup, sucrose, and fructose) intake and incident hypertension, a systematic review and meta-analysis of prospective cohort studies was undertaken. Methods: MEDLINE, EMBASE, CINAHL and the Cochrane Library (through February 5, 2014) were searched for relevant studies. Two independent reviewers reviewed and extracted relevant data. Risk estimates were aggregated comparing the lowest (reference) quintile with highest quintile of intake using inverse variance random effect models and expressed as risk ratios (RR) with 95% confidence intervals (CIs). Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I 2 statistic). The Newcastle–Ottawa Scale assessed study quality. Clinicaltrials.gov NCT01608620. Results: Eligibility criteria were met by 3 prospective cohorts (n = 37,375 men and 185,855 women) with 58,162 cases of hypertension observed over 2,502,357 person-years of follow-up. Median fructose intake was 5.7–6.0% total energy in the lowest quintile and 13.9–14.3% total energy in the highest quintile. Fructose intake was not associated with incident hypertension (RR = 1.02, 95% CI, 0.99–1.04), with no evidence of heterogeneity (I 2 = 0%, p = 0.59). Spline curve modeling showed a U-shaped relationship with a negative association at intakes ≤50th percentile (∼10% total energy) and a positive association at higher intakes. Conclusions: Total fructose intake was not associated with an increased risk of hypertension in 3 large prospective cohorts of U.S. men and women.

Objective: To assess the effect of dietary pulses (beans, peas, chickpeas, lentils) on acute satiety and second meal intake, a systematic review and meta-analysis was conducted. Methods: MEDLINE, EMBASE, CINAHL, and the Cochrane Registry (through May 6, 2013) were searched for acute controlled trials examining the effect of dietary pulses on postprandial satiety or second meal intake compared with isocaloric controls. Two independent reviewers extracted data and assessed methodological quality and risk of bias. Data were pooled by generic inverse variance random effects models and expressed as ratio of means (RoMs) for satiety and mean differences (MDs) for second meal food intake, with 95% confidence intervals (95% CIs). Heterogeneity was assessed (Q statistic) and quantified (I 2 statistic). Protocol registration: clinicaltrials.gov identifier, NCT01605422. Results: Nine trials met the eligibility criteria. Dietary pulses produced a 31% greater satiety incremental area under the curve (IAUC) (RoM 51.31, 95% CI: 1.09 to 1.58, P 50.004; Phet 50.96; I 2 50%) without affecting second meal intake (MD 52 19.94, 95% CI: 275-35, P 50.48; Phet 50.01; I 2 563%). Our data are limited by the small sample sizes, narrow participant characteristics and significant unexplained heterogeneity among the available trials. Conclusions: Pooled analyses show that dietary pulses contribute to acute satiety but not second meal intake.

Background Current guidelines recommend diet and lifestyle modifications for primary prevention and treatment of hypertension, but do not encourage dietary pulses specifically for lowering blood pressure (BP). To quantify the effect of dietary pulse interventions on BP and provide evidence for their inclusion in dietary guidelines, a systematic review and meta-analysis of controlled feeding trials was conducted. Methods MEDLINE, EMBASE, Cochrane Library, and CINAHL were each searched from inception through 5 May 2013. Human trials ≥3 weeks that reported data for systolic, diastolic, and/or mean arterial BPs were included. Two reviewers independently extracted data and assessed methodological quality and risk of bias of included studies. Effect estimates were pooled using random effects models, and reported as mean differences (MD) with 95% confidence intervals (CIs). Heterogeneity was assessed (χ(2) test) and quantified (I(2)). Results Eight isocaloric trials (n = 554 participants with and without hypertension) were included in the analysis. Dietary pulses, exchanged isocalorically for other foods, significantly lowered systolic (MD = -2.25 mm Hg (95% CI, -4.22 to -0.28), P = 0.03) and mean arterial BP (MD = -0.75 mm Hg (95% CI, -1.44 to -0.06), P = 0.03), and diastolic BP non-significantly (MD = -0.71 mm Hg (95% CI, -1.74 to 0.31), P = 0.17). Heterogeneity was significant for all outcomes. Conclusions Dietary pulses significantly lowered BP in people with and without hypertension. Higher-quality large-scale trials are needed to support these findings. Clinical trial registration NCT01594567.

Previous research on the effect of replacing sources of animal protein with plant protein on glycemic control has been inconsistent. We therefore conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effect of this replacement on glycemic control in individuals with diabetes. We searched MEDLINE, EMBASE, and Cochrane databases through 26 August 2015. We included RCTs ≥ 3-weeks comparing the effect of replacing animal with plant protein on HbA1c, fasting glucose (FG), and fasting insulin (FI). Two independent reviewers extracted relevant data, assessed study quality and risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences (MD) with 95% confidence intervals (CIs). Heterogeneity was assessed (Cochran Q-statistic) and quantified (I2-statistic). Thirteen RCTs (n = 280) met the eligibility criteria. Diets emphasizing a replacement of animal with plant protein at a median level of ~35% of total protein per day significantly lowered HbA1c (MD = −0.15%, 95%-CI: −0.26, −0.05%), FG (MD = −0.53 mmol/L, 95%-CI: −0.92, −0.13 mmol/L) and FI (MD = −10.09 pmol/L, 95%-CI: −17.31, −2.86 pmol/L) compared with control arms. Overall, the results indicate that replacing sources of animal with plant protein leads to modest improvements in glycemic control in individuals with diabetes. Owing to uncertainties in our analyses there is a need for larger, longer, higher quality trials. Trial Registration: ClinicalTrials.gov registration number: NCT02037321.

Background and aim Compared to a DASH-type diet, an intensively applied dietary portfolio reduced diastolic blood pressure at 24 weeks as a secondary outcome in a previous study. Due to the importance of strategies to reduce blood pressure, we performed an exploratory analysis pooling data from intensively and routinely applied portfolio treatments from the same study to assess the effect over time on systolic, diastolic and mean arterial pressure (MAP), and the relation to sodium (Na + ), potassium (K + ), and portfolio components. Methods and results 241 participants with hyperlipidemia, from four academic centers across Canada were randomized and completed either a DASH-type diet (control n = 82) or a dietary portfolio that included, soy protein, viscous fibers and nuts (n = 159) for 24 weeks. Fasting measures and 7-day food records were obtained at weeks 0, 12 and 24, with 24-h urines at weeks 0 and 24. The dietary portfolio reduced systolic, diastolic and mean arterial blood pressure compared to the control by 2.1 mm Hg (95% CI, 4.2 to −0.1 mm Hg) (p = 0.056), 1.8 mm Hg (CI, 3.2 to 0.4 mm Hg) (p = 0.013) and 1.9 mm Hg (CI, 3.4 to 0.4 mm Hg) (p = 0.015), respectively. Blood pressure reductions were small at 12 weeks and only reached significance at 24 weeks. Nuts, soy and viscous fiber all related negatively to change in mean arterial pressure (ρ = −0.15 to −0.17, p ≤ 0.016) as did urinary potassium (ρ = −0.25, p = 0.001), while the Na + /K + ratio was positively associated (ρ = 0.20, p = 0.010). Conclusions Consumption of a cholesterol-lowering dietary portfolio also decreased blood pressure by comparison with a healthy DASH-type diet. Clinical Trial Reg. No. NCT00438425, clinicaltrials.gov.

Background: Improving glycemic control with Metformin therapy, glycemic index (GI), and glycemic load (GL) have been protectively associated with prostate cancer risk. No studies have yet assessed ...

Background: Evidence from controlled trials encourages the intake of dietary pulses (beans, chickpeas, lentils and peas) as a method of improving dyslipidemia, but heart health guidelines have stopped short of ascribing specific benefits to this type of intervention or have graded the beneficial evidence as low. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effect of dietary pulse intake on established therapeutic lipid targets for cardiovascular risk reduction. Methods: We searched electronic databases and bibliographies of selected trials for relevant articles published through Feb. 5, 2014. We included RCTs of at least 3 weeks’ duration that compared a diet emphasizing dietary pulse intake with an isocaloric diet that did not include dietary pulses. The lipid targets investigated were low-density lipoprotein (LDL) cholesterol, apolipoprotein B and non–high-density lipoprotein (non-HDL) cholesterol. We pooled data using a random-effects model. Results: We identified 26 RCTs ( n = 1037) that satisfied the inclusion criteria. Diets emphasizing dietary pulse intake at a median dose of 130 g/d (about 1 serving daily) significantly lowered LDL cholesterol levels compared with the control diets (mean difference −0.17 mmol/L, 95% confidence interval −0.25 to −0.09 mmol/L). Treatment effects on apolipoprotein B and non-HDL cholesterol were not observed. Interpretation: Our findings suggest that dietary pulse intake significantly reduces LDL cholesterol levels. Trials of longer duration and higher quality are needed to verify these results. Trial registration: ClinicalTrials.gov, no. NCT01594567.

Background: Tree nut consumption is associated with reduced diabetes risk, however, results from randomized trials on glycemic control have been inconsistent. Aim: We conducted a systematic review and meta-analysis of randomized controlled trials to assess the effect of tree nuts on glycemic control in individuals with diabetes. Methods: We searched MEDLINE, EMBASE, CINAHL, and Cochrane databases through 14 May 2013 for relevant randomized trials 蠅3-weeks reporting HbA1c, fasting glucose, fasting insulin, and/or HOMA-IR. Two independent reviewers extracted relevant data. Data were pooled using the generic inverse variance method and expressed as mean differences (MD) with 95% confidence intervals (CI). Heterogeneity was assessed by Cochran’s Q and quantified by I2. Results: 10 trials (n=374) met the eligibility criteria. Diets emphasizing tree nuts significantly lowered HbA1c (MD=-0.11 %, 95% CI:-0.18, -0.04 %; P=0.001) and fasting glucose (MD=-0.20 mmol/L, 95% CI:-0.38, -0.03 mmol/L; P=0.02) compared wit...

Background and Aims: Elevated postprandial glucose (PPG) levels have been associated with higher incidence of cardiovascular disease and all-cause mortality. Dietary pulses including beans, lentils and chickpeas have resulted in low and medium PPG responses, however most studies have included few subjects and their overall PPG responses, when taken in equicarbohydrate amounts either alone or in mixed meals, have not been systematically summarized and quantitated. Objective: to synthesize the evidence of the effect of dietary pulses on PPG responses in individuals with diabetes. Methods: MEDLINE, EMBASE, CINAHL and Cochrane were searched through Oct 31, 2013 for all acute human trials in individuals with type 1 and type 2 diabetes reporting data for areas under the PPG curve or glycemic indices. Data were pooled by the generic inverse variance method using random effect models and expressed as ratio of means (RoM) with 95% confidence intervals (CI). Heterogeneity was assessed by Chi2 and quantified by I2. ...

Background Tree nut consumption has been associated with reduced diabetes risk, however, results from randomized trials on glycemic control have been inconsistent. Objective To provide better evidence for diabetes guidelines development, we conducted a systematic review and meta-analysis of randomized controlled trials to assess the effects of tree nuts on markers of glycemic control in individuals with diabetes. Data Sources MEDLINE, EMBASE, CINAHL, and Cochrane databases through 6 April 2014. Study Selection Randomized controlled trials ≥3 weeks conducted in individuals with diabetes that compare the effect of diets emphasizing tree nuts to isocaloric diets without tree nuts on HbA1c, fasting glucose, fasting insulin, and HOMA-IR. Data Extraction and Synthesis Two independent reviewer’s extracted relevant data and assessed study quality and risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences (MD) with 95% CI’s. Heterogeneity was assessed (Cochran Q-statistic) and quantified (I2). Results Twelve trials (n = 450) were included. Diets emphasizing tree nuts at a median dose of 56 g/d significantly lowered HbA1c (MD = −0.07% [95% CI:−0.10, −0.03%]; P = 0.0003) and fasting glucose (MD = −0.15 mmol/L [95% CI: −0.27, −0.02 mmol/L]; P = 0.03) compared with control diets. No significant treatment effects were observed for fasting insulin and HOMA-IR, however the direction of effect favoured tree nuts. Limitations Majority of trials were of short duration and poor quality. Conclusions Pooled analyses show that tree nuts improve glycemic control in individuals with type 2 diabetes, supporting their inclusion in a healthy diet. Owing to the uncertainties in our analyses there is a need for longer, higher quality trials with a focus on using nuts to displace high-glycemic index carbohydrates. Trial Registration ClinicalTrials.gov NCT01630980

Importance Despite the widespread use of ginseng in the management of diabetes, supporting evidence of its anti-hyperglycemic efficacy is limited, necessitating the need for evidence-based recommendations for the potential inclusion of ginseng in diabetes management. Objective To elucidate the effect of ginseng on glycemic control in a systematic review and meta-analysis of randomized controlled trials in people with and without diabetes. Data sources MEDLINE, EMBASE, CINAHL and the Cochrane Library (through July 3, 2013). Study selection Randomized controlled trials ≥30 days assessing the glycemic effects of ginseng in people with and without diabetes. Data extraction Relevant data were extracted by 2 independent reviewers. Discrepancies were resolved by consensus. The Heyland Methodological Quality Score and the Cochrane risk of bias tool were used to assess study quality and risk of bias respectively. Data synthesis Sixteen trials were included, in which 16 fasting blood glucose (n = 770), 10 fasting plasma insulin (n = 349), 9 glycated hemoglobin (n = 264), and 7 homeostasis model assessment of insulin resistance (n = 305) comparisons were reported. Ginseng significantly reduced fasting blood glucose compared to control (MD = −0.31 mmol/L [95% CI: −0.59 to −0.03], P = 0.03). Although there was no significant effect on fasting plasma insulin, glycated hemoglobin, or homeostasis model assessment of insulin resistance, a priori subgroup analyses did show significant reductions in glycated hemoglobin in parallel compared to crossover trials (MD = 0.22% [95%CI: 0.06 to 0.37], P = 0.01). Limitations Most trials were of short duration (67% trials

Excessive fructose intake from high-fructose corn syrup (HFCS) and sucrose has been implicated as a driving force behind the increasing prevalence of obesity and its downstream cardiometabolic complications including hypertension, gout, dyslidpidemia, metabolic syndrome, diabetes, and non-alcoholic fatty liver disease (NAFLD). Most of the evidence to support these relationships draws heavily on ecological studies, animal models, and select human trials of fructose overfeeding. There are a number of biological mechanisms derived from animal models to explain these relationships, including increases in de novo lipogenesis and uric acid-mediated hypertension. Differences between animal and human physiology, along with the supraphysiologic level at which fructose is fed in these models, limit their translation to humans. Although higher level evidence from large prospective cohorts studies has shown significant positive associations comparing the highest with the lowest levels of intake of sugar-sweetened beverages (SSBs), these associations do not hold true at moderate levels of intake or when modeling total sugars and are subject to collinearity effects from related dietary and lifestyle factors. The highest level of evidence from controlled feeding trials has shown a lack of cardiometabolic harm of fructose and SSBs under energy-matched conditions at moderate levels of intake. It is only when fructose-containing sugars or SSBs are consumed at high doses or supplement diets with excess energy that a consistent signal for harm is seen. The available evidence suggests that confounding by excess energy is an important consideration in assessing the role of fructose-containing sugars and SSBs in the epidemics of hypertension and other cardiometabolic diseases.

s / Can J Diabetes 36 (2012) S2eS22 S10 tissues insulin resistance and inflammation. In the present study, we investigated the effect of 4-phenylbutyrate (4-PBA), a chemical chaperon that prevents ER stress, on the regulation of tissues’ nonesterified fatty acids metabolism and diet-induced insulin resistance. Research Design and Methods: Control (chow fed) vs. diabetic (high-fat/high-fructose fed + small dose streptozotocin-treated e HFHFS) male Wistar rats were treated with 4-PBA (1g/kg/day) by oral gavage for 6 weeks. At the end of the treatment period, [8, 9-3H]-palmitate was infused during an euglycemic ehyperinsulinemic clamp followed by an i.v. bolus of [1-14C]-2bromopalmitate at steady-state to determine oxidative and non-oxidative nonesterified fatty acid (NEFA) metabolism in tissues. Results: HFHFS-fed rats displayed insulin resistance with high levels of fasting glucose and insulin. Increased NEFA fractional uptake by the gastrocnemius and reduced myocardial NEFA nonoxidative disposal was observed. Animals treated with 4-PBA displayed greater plasmatic NEFA rate of appearance and clearance. 4-PBA normalized gastrocnemius fractional uptake and increased NEFA oxidation and fractional uptake by the liver. SCAT of treated rats are characterized larger SC adipocytes with greater fractional and net NEFA uptake. In vitro, 4-PBA inhibits differentiation of adipocytes precursors but stimulates fatty acids uptake by mature adipocytes. Conclusions: Redistribution of NEFA fluxes by 4-PBA treatment does not restore insulin sensitivity in a nutritional model of T2D but reduced fasting glucose.