Impact of postprandial glucose control on diabetes-related complications: How is the evidence evolving?

Conflicting findings in the literature and lack of long-term definitive outcome studies have led to difficulty in drawing conclusions about the role of postprandial hyperglycemia in diabetes and its complications. Recent scientific publications support the role of postprandial glucose (PPG) as a key contributor to overall glucose control and a predictor of microvascular and macrovascular events. However, the need remains for definitive evidence to support the precise relationship between PPG excursions and the development and progression of cardiovascular complications of diabetes. Drawing firm conclusions on the relationship between PPG and microvascular and macrovascular complications is challenged by the absence of antidiabetic agents that can specifically exert their action on PPG alone, without a basal glucose-lowering effect. Areas under investigation include interventions that more closely approximate 'normal' physiological postprandial responses, as well as technologies that advance the mode of insulin delivery or optimize methods to sense glycemic levels and variation. In conclusion, the precise role of postprandial hyperglycemia in relation to development of diabetic complications is unclarified and is one of the remaining unanswered questions in diabetes. Nevertheless, current evidence supports PPG control as an important strategy to consider in the comprehensive management plan of individuals with diabetes.

J Diabetes Complications. 2016 Mar;30(2):374-85.

Delphinol® standardized maqui berry extract reduces postprandial blood glucose increase in individuals with impaired glucose regulation by novel mechanism of sodium glucose cotransporter inhibition.

AIM: The impetus of our study was to investigate the effects of a nutritional supplement Delphinol®, an extract of maqui berries (Aristotelia chilensis) standardised to ≥25% delphinidins and ≥35% total anthocyanins, on postprandial blood glucose and insulin levels and identify the physiologic mechanism involved. METHODS: Postprandial blood glucose and insulin were investigated in double-blind, placebo-controlled, cross-over fashion in ten volunteers with moderate glucose intolerance. Longer term effects on blood sugar levels were investigated in streptozotocin-diabetic rats over a four months period. Effects of maqui berry delphinidins on sodium-glucose symport were examined in rodent jejenum of the small intestine. RESULTS: Delphinol® intake prior to rice consumption statistical significantly lowered post prandial blood glucose and insulin as compared to placebo. We identified an inhibition of Na+-dependant glucose transport by delphinidin, the principal polyphenol to which Delphinol® is standardised. In a diabetic rat model the daily oral application of Delphinol® over a period of four months significantly lowered fasting blood glucose levels and reached values indistinguishable from healthy non-diabetic rats. CONCLUSION: Our results suggest a potential use of Delphinol® for naturally controlling post-prandial blood glucose owed to inhibition of sodium glucose co-transporter in small intestine.

Panminerva Med. 2014 Jun;56(2 Suppl 3):1-7.

Influence of insulin resistance, secretion, and clearance on serum cholesterol, triglycerides, lipoprotein cholesterol, and blood pressure in healthy men.

Relations between serum lipids, lipoproteins, blood pressure, and insulin metabolism were investigated in 158 healthy men aged 19-77 years and with body mass indexes (BMIs) of 19-41 kg.m-2. Mathematical modeling analysis of glucose, insulin, and C-peptide concentrations during an intravenous glucose tolerance test was used to measure parameters of insulin metabolism. In univariate analysis, both fasting and postglucose insulin concentrations showed significant positive associations with fasting serum triglyceride levels (r = 0.33 and 0.38, respectively) and systolic (r = 0.22 and 0.26) and diastolic (r = 0.21 and 0.24) blood pressure and negative associations with high density lipoprotein subfraction 2 cholesterol (HDL2; r = -0.21 and -0.25). In multivariate analysis, the associations between insulin and HDL2 cholesterol concentrations were found to depend on triglyceride levels. Insulin resistance and basal pancreatic insulin secretion showed significant positive associations with serum triglycerides, which were independent of the effects of age, BMI, and fat distribution. Hepatic insulin throughout was independently associated with HDL2 cholesterol. Associations of insulin-related variables with blood pressure were generally dependent on age and BMI. These results underline the importance of insulin sensitivity and insulin concentrations as determinants of triglyceride metabolism. They also indicate a close relation between hepatic insulin handling and HDL2 concentration that is independent of triglyceride metabolism.

Arterioscler Thromb. 1992 Sep;12(9):1030-5.

Serum Levels of sRAGE Are Associated with Body Measurements, but Not Glycemic Parameters in Patients with Prediabetes.

BACKGROUND: Our aim was to assess serum levels of the soluble receptor for advanced glycation end products (sRAGE) and to examine their association with anthropometric and metabolic parameters in patients with prediabetes and obese controls. METHODS: The two study groups were composed of 42 patients with prediabetes and diabetic neuropathy and 42 age-, gender-, body weight (BW)-, and body mass index (BMI)-matched obese adults as the control group. Prediabetes was diagnosed by the following criteria issued by the American Diabetes Association: impaired fasting glucose [fasting plasma glucose (FPG) level of 100-125 mg/dL], impaired glucose tolerance (2 hr plasma glucose level of 140-199 mg/dL after a 75 grams oral glucose challenge), or a glycated hemoglobin (HbA1C) level of 5.7%-6.4%. RESULTS: There were no differences between the groups in terms of age, gender distribution, BW, or BMI. Despite these similarities, patients with prediabetes had higher FPG, HbA1c, and 2-hr postchallenge glucose levels, higher systolic and diastolic blood pressure, and larger waist and hip circumferences compared with the obese controls. Lipid measurements, complete blood counts, kidney and liver function tests, high-sensitivity C-reactive protein, and sRAGE levels were similar between the two groups. We found significant negative correlations between sRAGE levels and BW, BMI, waist and hip circumferences, waist-to-hip ratios, and low-density lipoprotein (LDL) cholesterol levels. There were no significant correlations with other parameters, including demographic, metabolic, and blood pressure measurements. CONCLUSIONS: In contrast to glycemic parameters, serum levels of sRAGE were negatively correlated with body measurements indicative of obesity in the prediabetic state. In addition, the negative correlation with LDL cholesterol levels suggests that sRAGE has a more robust association with metabolic syndrome than with prediabetes.

Metab Syndr Relat Disord. 2016 Feb;14(1):33-9.

Plasma insulin, leptin, and soluble TNF receptors levels in relation to obesity-related atherogenic and thrombogenic cardiovascular disease risk factors among men.

Obesity is related to cardiovascular disease (CVD) morbidity and mortality, however, the mechanisms for the development of obesity-induced CVD risk remain unclear. Hyperinsulinemia and insulin resistance are considered key components in the metabolic cardiovascular syndrome and as independent risk factors for CVD. Plasma leptin and tumor necrosis factor-alpha (TNF-alpha), two adipocyte products, are also proposed to be associated with the development of CVD risk. The purpose of this study is to evaluate the association of plasma leptin, soluble TNF receptors (sTNF-R), and insulin levels as possible mediators of the effect of obesity on atherogenic and thrombogenic CVD risk factors among men. From the Health Professionals Follow-up Study (HPFS), we selected 268 men, aged 47--83 years, who were free of CVD, diabetes, and cancer (except non-melanoma skin cancer), and who had provided a fasting blood sample in 1994. We measured plasma insulin and leptin levels by radioimmunoassay and sTNF-R levels by ELISA. Men in the highest quintile of body mass index (BMI, mean=30.5 kg/m(2)) were less physically active and had a more adverse cardiovascular lipid and homeostatic profile, as indicated by levels of insulin, triglyceride (TG), tissue plasminogen activator (t-PA) antigen levels, and apolipoprotein A1 (Apo-A1). In a multivariate regression model controlling for age, smoking, alcohol intake, physical activity and diet, BMI was inversely associated with HDL-cholesterol (HDL-C) and Apo-A1 and positively associated with TG, Apo-B and t-PA antigen levels. The associations between BMI and these CVD risk factors were only slightly changed after adjusting for leptin and/or sTNF-R; but were substantially attenuated after controlling for insulin levels. These data suggest that the association between obesity and biological predictors of CVD may be mediated through changes in plasma insulin, rather than leptin or sTNF-R levels. However, plasma leptin may still play a role in CVD through independent effects on lipid metabolism.

Atherosclerosis. 2001 Aug;157(2):495-503.

Hyperinsulinemia is associated with the incidence of hypertension and dyslipidemia in middle-aged men.

Insulin resistance or compensatory hyperinsulinemia has been associated with hypertension and dyslipidemia in cross-sectional studies. In contrast, evidence from prospective population-based studies, which could establish the time order of the relationship, is sparse and inconsistent. Therefore, we investigated the associations of hyperinsulinemia with the incidence of hypertension and dyslipidemia in the Kuopio Ischemic Heart Disease Risk Factor Study, a population-based 4-year follow-up study of middle-aged men from eastern Finland. Out of 975 men who had no diabetes, 543 had resting systolic blood pressure (sBP) of < 165 mmHg and resting diastolic blood pressure (dBP) of < 95 mmHg at baseline and were not taking antihypertensive medication, and 764 had serum triglycerides of < 2.3 mmol/l and HDL cholesterol of > or =1.0 mmol/l at baseline. In logistic regression models adjusted for age, baseline resting blood pressure, baseline lipids, obesity, weight change, and other risk factors, men with hyperinsulinemia (fasting insulin in the highest quintile, > or =12.0 mU/l) at baseline had a 2.0-fold (95% CI 1.1-3.5, P = 0.025) incidence of hypertension (sBP of > or =165 or dBP of > or =95 mmHg), a 2.1-fold (95% CI 1.3-3.4, P = 0.002) incidence of dyslipidemia (serum HDL cholesterol of < 1.0 mmol/l or serum triglycerides of > or =2.3 mmol/l), and a 2.6-fold (95% CI 1.1-6.3, P = 0.028) incidence of the combination of these disorders in 4 years, compared with normoinsulinemic men. These findings demonstrate the role of hyperinsulinemia in incident hypertension and dyslipidemia and suggest that both hypertension and dyslipidemia are associated with insulin metabolism disturbance, independently of obesity and body weight.

Diabetes. 1998 Feb;47(2):270-5.

Mechanisms of insulin resistance in aging.

We have studied 17 elderly and 27 non-elderly, nonobese subjects (mean age 69+/-1 and 37+/-2 yr, respectively) to assess the mechanisms responsible for the abnormal carbohydrate tolerance associated with aging. Serum glucose and insulin levels were significantly elevated in the elderly subjects compared with the nonelderly subjects during a 75-g oral glucose tolerance test, suggesting an insulin resistant state. Peripheral insulin sensitivity was assessed in both groups using the euglycemic glucose clamp technique during an insulin infusion rate of 40 mU/m(2) per min. Similar steady-state serum insulin levels led to a peripheral glucose disposal rate of 151+/-17 mg/m(2) per min in the elderly compared with a value of 247+/-12 mg/m(2) per min in the nonelderly, thus documenting the presence of insulin resistance in the elderly subjects. Insulin binding to isolated adipocytes and monocytes was similar in the elderly and nonelderly groups (2.34+/-0.33 vs. 2.62+/-0.24% and 5.04+/-1.10 vs. 5.12+/-1.07%), respectively. Thus, insulin resistance in the presence of normal insulin binding suggests the presence of a postreceptor defect in insulin action. This was confirmed by performing additional euglycemic clamp studies using infusion rates of 15 and 1,200 mU/m(2) per min to assess the contours of the dose-response relationship. These studies revealed a 39 and 25% decrease in the glucose disposal rate in the elderly subjects, respectively. The results confirm the presence of a postreceptor defect as well as a rightward shift in the dose-response curve. Insulin's ability to suppress hepatic glucose output was less in the elderly subjects during the 15 mU/m(2) per min insulin infusion (77+/-5 vs. 89+/-4% suppression), but hepatic glucose output was fully and equally suppressed in both groups during the 40 and 1,200 mU/m(2) per min infusion. Finally, a significant inverse relationship was observed between the degree of glucose intolerance in the individual elderly subjects, as reflected by the 2-h serum glucose level during the oral glucose tolerance test, and the degree of peripheral insulin resistance as assessed by the glucose disposal rate during the 40 mU/m(2) per min insulin infusion (r = 0.59, P < 0.01).We conclude that carbohydrate intolerance develops as part of the aging process. This carbohydrate intolerance appears to be the consequence of peripheral insulin resistance caused by a postreceptor defect in target tissue insulin action, which causes both a decrease in the maximal rate of peripheral glucose disposal and a rightward shift in the insulin action dose-response curve. In elderly subjects, the severity of the abnormality in carbohydrate tolerance is directly correlated to the degree of peripheral insulin resistance.

J Clin Invest. 1983 Jun;71(6):1523-35.

Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: A randomized controlled trial and an updated meta-analysis.

BACKGROUND: Oxidative stress and inflammation have been proposed as emerging components of metabolic syndrome (MetS). Curcuminoids are natural polyphenols with strong antioxidant and anti-inflammatory properties. OBJECTIVE: To study the effectiveness of supplementation with a bioavailable curcuminoid preparation on measures of oxidative stress and inflammation in patients with MetS. Our secondary aim was to perform a meta-analysis of data from all randomized controlled trials in order to estimate the effect size of curcuminoids on plasma C-reactive protein (CRP) concentrations. METHODS: In this randomized double-blind placebo-controlled trial, 117 subjects with MetS (according to the NCEP-ATPIII diagnostic criteria) were randomly assigned to curcuminoids (n = 59; drop-outs = 9) or placebo (n = 58; drop-outs = 8) for eight weeks. Curcuminoids were administered at a daily dose of 1 g, and were co-supplemented with piperine (10 mg/day) in order to boost oral bioavailability. Serum activities of superoxide dismutase (SOD) and concentrations of malondialdehyde (MDA) and CRP were measured at baseline and at study end. Regarding the importance of CRP as a risk marker and risk factor of cardiovascular disease, a random-effects meta-analysis of clinical trials was performed to estimate the overall impact of curcuminoid therapy on circulating concentrations of CRP. The robustness of estimated effect size was evaluated using leave-one-out sensitivity analysis.RESULTS: Supplementation with curcuminoid-piperine combination significantly improved serum SOD activities (p < 0.001) and reduced MDA (p < 0.001) and CRP (p < 0.001) concentrations compared with placebo. Quantitative data synthesis revealed a significant effect of curcuminoids vs. placebo in reducing circulating CRP concentrations (weighed mean difference: -2.20 mg/L; 95% confidence interval [CI]: -3.96, -0.44; p = 0.01). This effect was robust in sensitivity analysis. CONCLUSIONS: Short-term supplementation with curcuminoid-piperine combination significantly improves oxidative and inflammatory status in patients with MetS. Curcuminoids could be regarded as natural, safe and effective CRP-lowering agents.

Clin Nutr. 2015 Dec;34(6):1101-8.

Curcumin as a potential candidate for treating hyperlipidemia: A review of cellular and metabolic mechanisms.

Curcumin is an herbal polyphenol extensively investigated for antioxidant, anti-inflammatory, and hypolipidaemic properties. In the present review, the efficacy of curcumin for improving a plasma lipid profile has been evaluated and compared with statins, a well-known class of medicines for treating hypercholesterolemia and hyperlipidaemia. Curcumin is presumably most effective in reducing triglyceride (TG), while statins are most efficient in lowering low-density lipoproteins-cholesterol (LDL-C). Additionally, various molecular and metabolic mediators of cholesterol and plasma lipid homeostasis are discussed in relation to how they are modulated by curcumin or statins. Overall, curcumin influences the same mediators of plasma lipid alteration as statins do. Almost all the pathways through which cholesterol trafficking takes place are affected by these agents. These include gastrointestinal absorption of dietary cholesterol, hepatocellular removal of plasma cholesterol, the mediators of reverse cholesterol transport, and removal of cholesterol from peripheral tissues. Moreover, the reactive oxygen species (ROS) scavenging potential of curcumin limits the risk of lipid peroxidation that triggers inflammatory responses causing cardiovascular diseases (CVD) and atherosclerosis. Taken together, curcumin could be used as a safe and well-tolerated adjunct to statins to control hyperlipidaemia more effectively than statins alone.

J Cell Physiol. 2016 Dec 24. doi: 10.

Lipid-modifying effects of adjunctive therapy with curcuminoids-piperine combination in patients with metabolic syndrome: results of a randomized controlled trial.

BACKGROUND: Dyslipidemia is an established feature of metabolic syndrome (MS) that is associated with an increased risk of atherosclerotic cardiovascular disease. Curcuminoids are natural products with anti-atherosclerotic and lipid-modifying effects but their efficacy in patients with MS has not yet been tested. OBJECTIVE: To investigate the effects of bioavailability-enhanced curcuminoids, as adjunctive to standard of care, on serum lipid concentrations in patients with MS. METHODS: Patients diagnosed with MS according to the NCEP-ATPIII criteria who were receiving standard of care were assigned to either curcuminoids (C3 complex®; 1000 mg/day; n=50) or placebo (n=50; matched with drug capsules in shape and color) for 8 weeks. In order to improve the oral bioavailability, curcuminoids were co-administered with piperine (bioperine®) in a ratio of 100:1. Serum concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, small dense LDL (sdLDL), lipoprotein(a) [Lp(a)], and non-HDL-C were determined at baseline and at the end of 8-week treatment period. RESULTS: Curcuminoids were more effective than placebo in reducing serum LDL-C, non-HDL-C, total cholesterol, triglycerides and Lp(a), and elevating HDL-C concentrations. However, changes in serum sdLDL levels were found to be comparable between the study groups. The effects of curcuminoids on triglycerides, non-HDL-C, total cholesterol and Lp(a) remained significant after adjustment for baseline values of lipids and body mass index. CONCLUSION: Curcuminoids-piperine combination is an efficacious adjunctive therapy in patients with MS and can modify serum lipid concentrations beyond what is achieved with sandard of care.

Complement Ther Med. 2014 Oct;22(5):851-7.

Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: A post-hoc analysis of a randomized controlled trial.

BACKGROUND: Cytokines are involved in the development of metabolic abnormalities that may result in metabolic syndrome (MetS). Since curcumin has shown anti-inflammatory properties, the aim of this study was to evaluate the effect of curcumin supplementation on serum cytokines concentrations in subjects with MetS. METHODS: This study was a post-hoc analysis of a randomized controlled trial in which males and females with diagnosis of MetS, according to the criteria defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines, were studied. Subjects who met the inclusion criteria were randomly assigned to either curcumin (daily dose of 1g/day) or a matched placebo for a period of 8 weeks. RESULTS: One hundred and seventeen subjects were assigned to either curcumin (n=59) or placebo (n=58) groups. Within-group analysis revealed significant reductions in serum concentrations of TNF-a, IL-6, TGF-b and MCP-1 following curcumin supplementation (p<0.001). In the placebo group, serum levels of TGF-b were decreased (p=0.003) but those of IL-6 (p=0.735), TNF-a (p=0.138) and MCP-1 (p=0.832) remained unaltered by the end of study. Between-group comparison suggested significantly greater reductions in serum concentrations of TNF-a, IL-6, TGF-b and MCP-1 in the curcumin versus placebo group (p<0.001). Apart from IL-6, changes in other parameters remained statistically significant after adjustment for potential confounders including changes in serum lipids and glucose levels, and baseline serum concentration of the cytokines. CONCLUSION: Results of the present study suggest that curcumin supplementation significantly decreases serum concentrations of pro-inflammatory cytokines in subjects with MetS.

Biomed Pharmacother. 2016 Aug;82:578-82.

Effects of curcumin on HDL functionality.

Curcumin, a bioactive polyphenol, is a yellow pigment of the Curcuma longa (turmeric) plant. Curcumin has many pharmacologic effects including antioxidant, anti-carcinogenic, anti-obesity, anti-angiogenic and anti-inflammatory properties. Recently, it has been found that curcumin affects lipid metabolism, and subsequently, may alleviate hyperlipidemia and atherosclerosis. Plasma HDL cholesterol (HDL-C) is an independent negative risk predictor of cardiovascular disease (CVD). However, numerous clinical and genetic studies have yielded disappointing results about the therapeutic benefit of raising plasma HDL-C levels. Therefore, research efforts are now focused on improving HDL functionality, independent of HDL-C levels. The quality of HDL particles can vary considerably due to heterogeneity in composition. Consistent with its complexity in composition and metabolism, a wide range of biological activities is reported for HDL, including antioxidant, anti-glycation, anti-inflammatory, anti-thrombotic, anti-apoptotic and immune modulatory activities. Protective properties of curcumin may influence HDL functionality; therefore, we reviewed the literature to determine whether curcumin can augment HDL function. In this review, we concluded that curcumin may modulate markers of HDL function, such as apo-AI, CETP, LCAT, PON1, MPO activities and levels. Curcumin may subsequently improve conditions in which HDL is dysfunctional and may have potential as a therapeutic drug in future. Further clinical trials with bioavailability-improved formulations of curcumin are warranted to examine its effects on lipid metabolism and HDL function.

Pharmacol Res. 2017 May;119:208-218.

Potential role of curcumin phytosome (Meriva) in controlling the evolution of diabetic microangiopathy. A pilot study.

AIM: The aim of the present study was to evaluate the improvement of diabetic microangiopathy in patients suffering from this condition since at least five years, and whose disease was managed without insulin. METHODS: Curcumin, the orange pigment of turmeric, has recently received increasing attention because of its antioxidant properties, mediated by both direct oxygen radical quenching and by induction of anti-oxidant responses via Nrf2 activation. This aspect, combined with the beneficial effects on endothelial function and on tissue and plasma inflammatory status, makes curcumin potentially useful for the management of diabetic microangiopathy. To further evaluate this, Meriva, a lecithinized formulation of curcumin, was administered at the dosage of two tablets/day (1 g Meriva/day) to 25 diabetic patients for four weeks. A comparable group of subjects followed the best possible management for this type of patients. RESULTS: All subjects in the treatment and control group completed the follow-up period; there were no dropouts. In the treatment group, at four weeks, microcirculatory and clinical evaluations indicated a decrease in skin flux (P<0.05) at the surface of the foot, a finding diagnostic of an improvement in microangiopathy, the flux being generally increased in patients affected by diabetic microangiopathy. Also, a significant decrease in the edema score (P<0.05) and a corresponding improvement in the venoarteriolar response (P<0.05) were observed. The PO2 increased at four weeks (P<0.05), as expected from a better oxygen diffusion into the skin due to the decreased edema. These findings were present in all subjects using Meriva, while no clinical or microcirculatory effects were observed in the control group. CONCLUSION: Meriva was, in general, well tolerated, and these preliminary findings suggest the usefulness of this curcumin formulation for the management of diabetic microangiopathy, opening a window of opportunities to be evaluated in more prolonged and larger studies. The molecular mechanisms involved in the beneficial effects of curcumin on microcirculation and edema are also worth investigation.

Panminerva Med. 2011 Sep;53(3 Suppl 1):43-9.

Curcumin attenuates cardiomyocyte hypertrophy induced by high glucose and insulin via the PPARγ/Akt/NO signaling pathway.

AIM: To investigate the potential effect of curcumin on cardiomyocyte hypertrophy and a possible mechanism involving the PPARg/Akt/NO signaling pathway in diabetes. METHODS: The cardiomyocyte hypertrophy induced by high glucose (25.5mmol/L) and insulin (0.1µmol/L) (HGI) and the antihypertrophic effect of curcumin were evaluated in primary culture by measuring the cell surface area, protein content and atrial natriuretic factor (ANF) mRNA expression. The mRNA and protein expressions were assayed by reverse transcription PCR and Western blotting, whereas the NO concentration and endothelial NO synthase (eNOS) activity were determined using nitrate reduction and ELISA methods, respectively. RESULTS: The cardiomyocyte hypertrophy induced by HGI was characterized by increasing ANF mRNA expression, total protein content, and cell surface area, with downregulated mRNA and protein expressions of both PPARγ and Akt, which paralleled the declining eNOS mRNA expression, eNOS content, and NO concentration. The effects of HGI were inhibited by curcumin (1, 3, 10µmol/L) in a concentration-dependent manner. GW9662 (10µmol/L), a selective PPARg antagonist, could abolish the effects of curcumin. LY294002 (20µmol/L), an Akt blocker, and N(G)-nitro-l-arginine-methyl ester (100µmol/L), a NOS inhibitor, could also diminish the effects of curcumin. CONCLUSIONS: The results suggested that curcumin supplementation can improve HGI-induced cardiomyocytes hypertrophy in vitro through the activation of PPARg/Akt/NO signaling pathway.

Diabetes Res Clin Pract. 2015 May;108(2):235-42.

Sugar Industry and Coronary Heart Disease Research: A Historical Analysis of Internal Industry Documents.

Early warning signals of the coronary heart disease (CHD) risk of sugar (sucrose) emerged in the 1950s. We examined Sugar Research Foundation (SRF) internal documents, historical reports, and statements relevant to early debates about the dietary causes of CHD and assembled findings chronologically into a narrative case study. The SRF sponsored its first CHD research project in 1965, a literature review published in the New England Journal of Medicine, which singled out fat and cholesterol as the dietary causes of CHD and downplayed evidence that sucrose consumption was also a risk factor. The SRF set the review's objective, contributed articles for inclusion, and received drafts. The SRF's funding and role was not disclosed. Together with other recent analyses of sugar industry documents, our findings suggest the industry sponsored a research program in the 1960s and 1970s that successfully cast doubt about the hazards of sucrose while promoting fat as the dietary culprit in CHD. Policymaking committees should consider giving less weight to food industry-funded studies and include mechanistic and animal studies as well as studies appraising the effect of added sugars on multiple CHD biomarkers and disease development.

JAMA Intern Med. 2016 Nov 1;176(11):1680-1685.

Sugar industry influence on the scientific agenda of the National Institute of Dental Research's 1971 National Caries Program: a historical analysis of internal documents.

BACKGROUND: In 1966, the National Institute of Dental Research (NIDR) began planning a targeted research program to identify interventions for widespread application to eradicate dental caries (tooth decay) within a decade. In 1971, the NIDR launched the National Caries Program (NCP). The objective of this paper is to explore the sugar industry's interaction with the NIDR to alter the research priorities of the NIDR NCP. METHODS AND FINDINGS: We used internal cane and beet sugar industry documents from 1959 to 1971 to analyze industry actions related to setting research priorities for the NCP. The sugar industry could not deny the role of sucrose in dental caries given the scientific evidence. They therefore adopted a strategy to deflect attention to public health interventions that would reduce the harms of sugar consumption rather than restricting intake. Industry tactics included the following: funding research in collaboration with allied food industries on enzymes to break up dental plaque and a vaccine against tooth decay with questionable potential for widespread application, cultivation of relationships with the NIDR leadership, consulting of members on an NIDR expert panel, and submission of a report to the NIDR that became the foundation of the first request for proposals issued for the NCP. Seventy-eight percent of the sugar industry submission was incorporated into the NIDR's call for research applications. Research that could have been harmful to sugar industry interests was omitted from priorities identified at the launch of the NCP. Limitations are that this analysis relies on one source of sugar industry documents and that we could not interview key actors. CONCLUSIONS: The NCP was a missed opportunity to develop a scientific understanding of how to restrict sugar consumption to prevent tooth decay. A key factor was the alignment of research agendas between the NIDR and the sugar industry. This historical example illustrates how industry protects itself from potentially damaging research, which can inform policy makers today. Industry opposition to current policy proposals-including a World Health Organization guideline on sugars proposed in 2014 and changes to the nutrition facts panel on packaged food in the US proposed in 2014 by the US Food and Drug Administration-should be carefully scrutinized to ensure that industry interests do not supersede public health goals.

PLoS Med. 2015 Mar 10;12(3):e1001798.

Global and regional mortality from ischaemic heart disease and stroke attributable to higher-than-optimum blood glucose concentration: comparative risk assessment.

Cardiovascular mortality risk increases continuously with blood glucose, from concentrations well below conventional thresholds used to define diabetes. We aimed to quantify population-level effects of all higher-than-optimum concentrations of blood glucose on mortality from ischaemic heart disease and stroke worldwide. METHODS: We used population distribution of fasting plasma glucose to measure exposure to higher-than-optimum blood glucose. We collated exposure data in 52 countries from individual-level records in population health surveys, systematic reviews, and data provided by investigators. Relative risks for ischaemic heart disease and stroke mortality were from a meta-analysis of more than 200,000 participants in the Asia-Pacific region, with adjustment for other cardiovascular risk factors. RESULTS: In addition to 959,000 deaths directly assigned to diabetes, 1,490,000 deaths from ischaemic heart disease and 709,000 from stroke were attributable to high blood glucose, accounting for 21% and 13% of all deaths from these conditions. 1.8 million of these 2.2 million cardiovascular deaths (84%) were in low-and-middle-income countries (1,224,000 for ischaemic heart disease, 623,000 for stroke). 792,000 (53%) of deaths from ischaemic heart disease and 345,000 (49%) from stroke that were attributable to high blood glucose were in men. Largest numbers of deaths attributable to this risk factor from ischaemic heart disease were in low-and-middle-income countries of South Asia (548,000) and Europe and Central Asia (313,000), and from stroke in South Asia (215,000) and East Asia and Pacific (190,000). INTERPRETATION: Higher-than-optimum blood glucose is a leading cause of cardiovascular mortality in most world regions. Programmes for cardiovascular risk and diabetes management and control at the population level need to be more closely integrated.

Lancet. 2006 Nov 11;368(9548):1651-9.

Chronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus.

BACKGROUND: We explored whether chronic hyperglycemia is associated with defects in endothelium-dependent vasodilatation in vivo and whether defects in the hemodynamic effects of insulin explain insulin resistance. METHODS AND RESULTS: Vasodilator responses to brachial artery infusions of acetylcholine, sodium nitroprusside, and NG-monomethyl-L-arginine and, on another occasion, in vivo insulin sensitivity (euglycemic insulin clamp combined with the forearm catheterization technique) were determined in 18 patients with insulin-dependent diabetes mellitus (IDDM) and 9 normal subjects. At identical glucose and insulin levels, insulin stimulation of whole-body and forearm glucose uptake was 57% reduced in the IDDM patients compared with normal subjects (P < .001). The defect in forearm glucose uptake was attributable to a defect in glucose extraction (glucose AV difference, 1.1 +/- 0.2 versus 1.9 +/- 0.2 mmol/L, P < .001, IDDM versus normal subjects), not blood flow. Within the group of IDDM patients, hemoglobin A1c was inversely correlated with forearm blood flow during administration of acetylcholine (r = -.50, P < .02) but not sodium nitroprusside (r = .07). The ratio of endothelium-dependent to endothelium-independent blood flow was approximately 40% lower in patients with poor glycemic control than in normal subjects or patients with good or moderate glycemic control. CONCLUSIONS: We conclude that chronic hyperglycemia is associated with impaired endothelium-dependent vasodilatation in vivo and with a glucose extraction defect during insulin stimulation. These data imply that chronic hyperglycemia impairs vascular function and insulin action via distinct mechanisms. The defect in endothelium-dependent vasodilatation could contribute to the increased cardiovascular risk in diabetes.

Circulation. 1996 Sep 15;94(6):1276-82.

Advances in biochemical mechanisms of diabetic retinopathy.

Diabetes mellitus is a major cause of blindness in the working population of the Western World. Numerous large, prospective, randomized clinical trials have delineated the current standard prevention and treatment protocols including intensive glycemic and blood pressure control as well as laser photocoagulation for clinically significant macular edema and/or proliferative retinopathy at a high risk for tractional retinal detachment. However, despite all these interventions, vision loss from diabetic retinopathy still occurs at an alarming rate and no data provide an adequate explanation for the serious and rapid involvement of the retinal microcirculation that may be observed in the disease despite a good metabolic control. In fact, there is now ample of evidence that the development of diabetic retinopathy is a multifactorial process where genetic, metabolic and growth factors play an important role. Some biochemical mechanisms, supposed to be involved in the pathogenesis of diabetic retinopathy, have been highlighted in this review.

Eur Rev Med Pharmacol Sci. 2007 May-Jun;11(3):155-63.

Advanced glycation endproducts in human diabetic and non-diabetic cataractous lenses.

BACKGROUND: Advanced glycation endproduct (AGE) formation is thought to contribute to aging and cataract formation in the lens. In this study, we evaluated AGE immunoreactivity in human diabetic (n=14) and nondiabetic (n=31) cataractous lenses in relation to high-molecular-weight (HMW) protein content, which is believed to contribute to the onset of cataract. METHODS: AGE immunoreactivity was detected in alkali-soluble individual lens samples. Competitive ELISA with polyclonal anti-AGE antibody was performed to estimate AGEs. SDS-PAGE was used to detect changes in lens protein composition on the basis of molecular size. RESULTS: Regression analysis of data from nondiabetic lenses showed a significant correlation between lens AGE content and patient age (r=0.665, P<0.001). The curve exhibited exponential regression ( y=0.272.e(0.025x)). The level of nonspecified AGEs measured in diabetic lenses showed an overall increase compared with nondiabetic lenses (4.03+/-1.85 vs 1.78+/-0.71 AU/mg protein, P<0.0078). SDS-PAGE showed the occurrence of HMW proteins in both diabetic and nondiabetic lens samples. However, in diabetic patients, who had a higher level of AGEs, a significantly higher proportion of HMW proteins was also observed. The levels of AGE and percent of HMW aggregates showed a very significant correlation ( r=0.68, P<0.007) in the diabetic group, whereas in nondiabetics the correlation, although positive, did not reach statistical significance.CONCLUSION: The AGE distribution, with a higher proportion in the samples of lenses rich in HMW aggregates, corroborates the hypothesis that the advanced glycation process might have a role in degenerative changes in eye lens, which in diabetic patients occur vigorously and much earlier than in those without diabetes.

Graefes Arch Clin Exp Ophthalmol. 2003 May;241(5):378-84.

Low to moderate sugar-sweetened beverage consumption impairs glucose and lipid metabolism and promotes inflammation in healthy young men: a randomized controlled trial.

BACKGROUND: Sugar-sweetened beverages (SSBs) have unfavorable effects on glucose and lipid metabolism if consumed in high quantities by obese subjects, but the effect of lower doses in normal-weight subjects is less clear. OBJECTIVE: The aim was to investigate the effects of SSBs consumed in small to moderate quantities for 3 wk on LDL particle distribution and on other parameters of glucose and lipid metabolism as well as on inflammatory markers in healthy young men. DESIGN: Twenty-nine subjects were studied in a prospective, randomized, controlled crossover trial. Six 3-wk interventions were assigned in random order as follows: 600 mL SSBs containing 1)40 g fructose/d [medium fructose (MF)], 2) 80 g fructose/d [high fructose (HF)], 3) 40 g glucose/d [medium glucose (MG)], 4) 80 g glucose/d [high glucose (HG)], 5) 80 g sucrose/d [high sucrose (HS)], or 6) dietary advice to consume low amounts of fructose. Outcome parameters were measured at baseline and after each intervention. RESULTS: LDL particle size was reduced after HF by -0.51 nm (95% CI: -0.19, -0.82 nm) and after HS by -0.43 nm (95% CI: -0.12, -0.74; P < 0.05 for both). Similarly, a more atherogenic LDL subclass distribution was seen when fructose-containing SSBs were consumed (MF, HF, and HS: P < 0.05). Fasting glucose and high-sensitivity C-reactive protein (hs-CRP) increased significantly after all interventions (by 4-9% and 60-109%, respectively; P < 0.05); leptin increased during interventions with SSBs containing glucose only (MG and HG: P < 0.05). CONCLUSION: The present data show potentially harmful effects of low to moderate consumption of SSBs on markers of cardiovascular risk such as LDL particles, fasting glucose, and hs-CRP within just 3 wk in healthy young men, which is of particular significance for young consumers.

Am J Clin Nutr. 2011 Aug;94(2):479-85.

Habitual coffee consumption and risk of cognitive decline/dementia: A systematic review and meta-analysis of prospective cohort studies.

OBJECTIVE: Findings from epidemiologic studies of coffee consumption and risk for cognitive decline or dementia are inconclusive. The aim of this study was to conduct a meta-analysis of prospective studies to assess the association between coffee consumption and the risk for cognitive decline and dementia. METHODS: Relevant studies were identified by searching PubMed and Embase databases between 1966 and December 2014. Prospective cohorts that reported relative risk (RRs) and 95% confidence intervals (CIs) for the association of coffee consumption with dementia incidence or cognitive changing were eligible. Study-specific RRs were combined by using a random-effects model. RESULTS: Eleven prospective studies, including 29,155 participants, were included in the meta-analysis. The combined RR indicated that high coffee consumption was not associated with the different measures of cognitive decline or dementia (summary RR, 0.97; 95% CI, 0.84-1.11). Subgroup analyses suggested a significant inverse association between highest coffee consumption and the risk for Alzheimer disease (summary RR, 0.73; 95% CI, 0.55-0.97). The dose-response analysis, including eight studies, did not show an association between the increment of coffee intake and cognitive decline or dementia risk (an increment of 1 cup/d of coffee consumed; summary RR, 1.00; 95% CI, 0.98-1.02). CONCLUSIONS: The present study suggests that higher coffee consumption is associated with reduced risk for Alzheimer disease. Further randomized controlled trials or well-designed cohort studies are needed to determine the association between coffee consumption and cognitive decline or dementia.

Nutrition. 2016 Jun;32(6):628-36.

Coffee consumption and prostate cancer risk: a meta-analysis of cohort studies.

This meta-analysis was conducted to assess the association between coffee consumption and prostate cancer risk. Thirteen cohort studies with 34,105 cases and 539,577 participants were included in the meta-analysis. The summary relative risks (RRs) with 95% confidence intervals (CIs) for different coffee intake levels were calculated. Dose-response relationship was assessed using generalized least square trend estimation. The pooled RR for the highest vs. lowest coffee intake was 0.90 (95% CI: 0.85-0.95), with no significant heterogeneity across studies (P = 0.267; I(2) = 17.5%). The dose-response analysis showed a lower cancer risk decreased by 2.5% (RR = 0.975; 95% CI: 0.957-0.995) for every 2 cups/day increment in coffee consumption. Stratifying by geographic region, there was a statistically significant protective influence of coffee on prostate cancer risk among European populations. In subgroup analysis of prostate cancer grade, the summary RRs were 0.89 (95% CI: 0.83-0.96) for nonadvanced, 0.82 (95% CI: 0.61-1.10) for advanced and 0.76 (95% CI: 0.55-1.06) for fatal diseases. Our findings suggest that coffee consumption may be associated with a reduced risk of prostate cancer and it also has an inverse association with nonadvanced prostate cancer. Because of the limited number of studies, more prospective studies with large sample size are needed to confirm this association.

Nutr Cancer. 2015;67(3):392-400.

Effects of chlorogenic acid on voltage-gated potassium channels of trigeminal ganglion neurons in an inflammatory environment.

Chlorogenic acid (CGA) composed of coffee acid and quinic acid is an effective ingredient of many foods and medicines and widely exhibits biological effects. Recently, it is reported to have analgesic effect. However, little is known about the analgesic mechanism of CGA. In this study, whole-cell patch-clamp recordings were performed on two main subtypes (IK,A and IK,V channels) of voltage-gated potassium (KV) channels in small-diameter(<30µm) trigemianl ganglion neurons to analyze the effects of CGA in an inflammatory environment created by Prostaglandin E2 (PGE2). On one hand, the activation and inactivation V1/2 values of IK,A and IK,V channels showed an elevation towards a depolarizing shift caused by PGE2. On the other hand, the activation and inactivation V1/2 values of the two channels had a reduction towards a hyperpolarizing shift caused by CGA under PGE2 pretreatment. Our results demonstrated that CGA may exhibited an analgesic effect by promoting KV channels activation and inactivation under inflammatory condition, which provided a novel molecular and ionic mechanism underlying anti-inflammatory pain of CGA.

Brain Res Bull. 2016 Oct;127:119-125.

Neuroprotection comparison of chlorogenic acid and its metabolites against mechanistically distinct cell death-inducing agents in cultured cerebellar granule neurons.

While the number of patients diagnosed with neurodegenerative disorders like Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease is increasing, there are currently no effective treatments that significantly limit the neuronal cell death underlying these diseases. Chlorogenic acid (CGA), a polyphenolic compound found in high concentration in coffee, is known to possess antioxidant and free radical scavenging activity. In this study, we investigated the neuroprotective effects of CGA and its major metabolites in primary cultures of rat cerebellar granule neurons. We show that CGA and caffeic acid displayed a dramatic protective effect against the nitric oxide donor, sodium nitroprusside. In marked contrast, ferulic acid and quinic acid had no protective effect against this nitrosative stress. While CGA and quinic acid had no protective effect against glutamate-induced cell death, caffeic acid and ferulic acid significantly protected neurons from excitotoxicity. Finally, caffeic acid was the only compound to display significant protective activity against hydrogen peroxide, proteasome inhibition, caspase-dependent intrinsic apoptosis, and endoplasmic reticulum stress. These results indicate that caffeic acid displays a much broader profile of neuroprotection against a diverse range of stressors than its parent polyphenol, CGA, or the other major metabolites, ferulic acid and quinic acid. We conclude that caffeic acid is a promising candidate for testing in pre-clinical models of neurodegeneration.

Brain Res. 2016 Oct 1;1648(Pt A):69-80.

Chronic coffee and caffeine ingestion effects on the cognitive function and antioxidant system of rat brains.

Coffee is a popular beverage consumed worldwide and its effect on health protection has been well studied throughout literature. This study investigates the effect of chronic coffee and caffeine ingestion on cognitive behavior and the antioxidant system of rat brains. The paradigms of open field and object recognition were used to assess locomotor and exploratory activities, as well as learning and memory. The antioxidant system was evaluated by determining the activities of glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD), as well as the lipid peroxidation and reduced glutathione content. Five groups of male rats were fed for approximately 80 days with different diets: control diet (CD), fed a control diet; 3% coffee diet (3%Co) and 6% coffee diet (6%Co), both fed a diet containing brewed coffee; 0.04% caffeine diet (0.04%Ca) and 0.08% caffeine diet (0.08%Ca), both fed a control diet supplemented with caffeine. The estimated caffeine intake was approximately 20 and 40 mg/kg per day, for the 3%Co-0.04%Ca and 6%Co-0.08%Ca treatments, respectively. At 90 days of life, the animals were subjected to the behavioral tasks and then sacrificed. The results indicated that the intake of coffee, similar to caffeine, improved long-term memory when tested with object recognition; however, this was not accompanied by an increase in locomotor and exploratory activities. In addition, chronic coffee and caffeine ingestion reduced the lipid peroxidation of brain membranes and increased the concentration of reduced-glutathione. The activities of the GR and SOD were similarly increased, but no change in GPx activity could be observed. Thus, besides improving cognitive function, our data show that chronic coffee consumption modulates the endogenous antioxidant system in the brain. Therefore, chronic coffee ingestion, through the protection of the antioxidant system, may play an important role in preventing age-associated decline in the cognitive function.

Pharmacol Biochem Behav. 2011 Oct;99(4): 659-64.

Protective Effects of Chlorogenic Acid and its Metabolites on Hydrogen Peroxide-Induced Alterations in Rat Brain Slices: A Comparative Study with Resveratrol.

The effectiveness of chlorogenic acid and its main metabolites, caffeic and quinic acids, against oxidative stress was investigated. Resveratrol, another natural phenolic compound, was also tested for comparison. Rat cortical slices were incubated with 200 µM H2O2 for 1 h, and alterations in oxidative stress parameters, such as 2, 3, 5-triphenyltetrazolium chloride (TTC) staining and the production of both malondialdehyde (MDA) and reactive oxygen species (ROS), were assayed in the absence or presence of phenolic compounds. Additionally, the effectiveness of chlorogenic acid and other compounds on H2O2-induced increases in fluorescence intensities were also compared in slice-free incubation medium. Although quinic acid failed, chlorogenic and caffeic acids significantly ameliorated the H2O2-induced decline in TTC staining intensities. Although resveratrol also caused an increase in staining intensity, its effect was not dose-dependent; the high concentrations of resveratrol tested in the present study (10 and 100 µM) further lessened the staining of the slices. Additionally, all phenolic compounds significantly attenuated the H2O2-induced increases in MDA and ROS levels in cortical slices. When the IC50 values were compared to H2O2-induced alterations, chlorogenic acid was more potent than either its metabolites or resveratrol for all parameters studied under these experimental conditions. In slice-free experimental conditions, on the other hand, chlorogenic and caffeic acids significantly attenuated the fluorescence emission enhanced by H2O2 with a similar order of potency to that obtained in slice-containing physiological medium. These results indicate that chlorogenic acid is a more potent phenolic compound than resveratrol and its main metabolites caffeic and quinic acids against H2O2-induced alterations in oxidative stress parameters in rat cortical slices.

Neurochem Res. 2016 Aug;41(8):2075-85.