Green tea consumption and risk of type 2 diabetes in Chinese adults: the Shanghai Women's Health Study and the Shanghai Men's Health Study.

Background: Epidemiological evidence on the association between tea consumption and the risk of type 2 diabetes (T2D) is inconsistent. This study prospectively investigated whether green tea drinking affects the risk of T2D. Methods: This study included participants from the Shanghai Women's Health Study (N = 67 058) and the Shanghai Men's Health Study (N = 52 315) without diabetes at study enrolment. Details of tea consumption, including types and amounts, were collected at the baseline and follow-up survey. Incident T2D was identified through follow-up surveys. Plasma level of caffeine metabolite was measured in a nested case-control study involving 592 diabetes case-control pairs. Cox regression analysis, with tea drinking as a time-dependent variable and covariates adjusted for by a propensity score, was applied to estimate the hazard ratio (HR) and 95% confidence interval (CI) for T2D risk. Logistic regression analysis was applied to evaluate the association between caffeine metabolites and T2D risk. Results: Current green tea drinkers had an increased risk of T2D compared with non-current drinkers [HR = 1.20 (95% CI = 1.14-1.27)], and a dose-response relationship was observed for duration of drinking tea and the amount of tea consumed [P for trend <0.001]. The increased risk associated with green tea drinking was observed in both women and men, across the entire period of follow-up, with HR (95% CI) of 1.08 (0.97-1.19) within 5 years of follow-up, 1.22 (1.12-1.32) during the period of 5-10 years of follow-up and 1.16 (1.03-1.30) after 10 years of follow-up. This association did not vary significantly by body mass index, waist-to-hip circumference ratio or smoking status. Plasma level of caffeine was also associated with increased diabetes risk (P = 0.03), confirming the results based on self-reported tea drinking. Conclusions: Green tea drinking was associated with an increased risk of T2D in Chinese adults. The mechanisms underlying the association need to be elucidated.

Metabolic Effects of Betaine: A Randomized Clinical Trial of Betaine Supplementation in Prediabetes.

Context: Plasma betaine correlates with insulin sensitivity in humans. Betaine supplementation improves metabolic effects in mice fed a high-fat diet. Objective: To assess metabolic effects of oral betaine in obese participants with prediabetes. Design: A 12-week, parallel arm, randomized, double-masked, placebo-controlled trial. Setting: University-affiliated hospital. Participants and Interventions: Persons with obesity and prediabetes (N = 27) were randomly assigned to receive betaine 3300 mg orally twice daily for 10 days, then 4950 mg twice daily for 12 weeks, or placebo. Main Outcome Measures: Changes from baseline in insulin sensitivity, glycemia, hepatic fat, and endothelial function. Results: There was a 16.5-fold increase in plasma dimethylglycine [dimethylglycine (DMG); P < 0.0001] levels, but modest 1.3- and 1.5-fold increases in downstream serine and methionine levels, respectively, in the betaine vs placebo arm. Betaine tended to reduce fasting glucose levels (P = 0.08 vs placebo) but had no other effect on glycemia. Insulin area under curve after oral glucose was reduced for betaine treatment compared with placebo (P = 0.038). Insulin sensitivity, assessed by euglycemic hyperinsulinemic clamp, was not improved. Serum total cholesterol levels increased after betaine treatment compared with placebo (P = 0.032). There were no differences in change in intrahepatic triglyceride or endothelial function between groups. Conclusion: DMG accumulation supports DMG dehydrogenase as rate limiting for betaine metabolism in persons with prediabetes. Betaine had little metabolic effect. Additional studies may elucidate mechanisms contributing to differences between preclinical and human responses to betaine, and whether supplementation of metabolites downstream of DMG improves metabolism.

Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice.

Identifying markers of human insulin resistance may permit development of new approaches for treatment and prevention of type 2 diabetes. To this end, we analyzed the fasting plasma metabolome in metabolically characterized human volunteers across a spectrum of insulin resistance. We demonstrate that plasma betaine levels are reduced in insulin-resistant humans and correlate closely with insulin sensitivity. Moreover, betaine administration to mice with diet-induced obesity prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating fibroblast growth factor (Fgf)21 levels. Betaine administration failed to improve glucose homeostasis and liver fat content in Fgf21(-/-) mice, demonstrating that Fgf21 is necessary for betaine's beneficial effects. Together, these data indicate that dietary betaine increases Fgf21 levels to improve metabolic health in mice and suggest that betaine supplementation merits further investigation as a supplement for treatment or prevention of type 2 diabetes in humans.

A pilot, short-term dietary manipulation of branched chain amino acids has modest influence on fasting levels of branched chain amino acids.

BACKGROUND: Elevated fasting levels of branched chain amino acids (BCAAs: valine, isoleucine, leucine) in venous blood are associated with a variety of metabolic impairments, including increased risk of type 2 diabetes (T2D). Fasting BCAA levels are influenced by non-dietary factors. However, it is unknown whether fasting BCAAs can be altered through manipulation of dietary intake alone. OBJECTIVE: To test whether a specific dietary intervention, using differences in BCAA intake, alters fasting BCAA levels independent of other factors. DESIGN: Five healthy male volunteers underwent 4 days of a low and 4 days of a high BCAA content dietary intervention (ClinicalTrials.gov [NCT02110602]). All food and supplements were provided. Fasting BCAAs were measured from venous blood samples by mass spectrometry at baseline and after each intervention. RESULTS: Diets were isocaloric; contained equal percentages of calories from carbohydrate, fats, and protein; and differed from each other in BCAA content (1.5±0.1 vs. 14.0±0.6 g for valine; 4.5±0.9 g vs. 13.8±0.5 g for isoleucine; 2.1±0.2 g vs. 27.1±1.0 g for leucine; p<0.0001 for all). Fasting valine was significantly lower (p=0.02) and fasting isoleucine and leucine were numerically lower following the low BCAA content vs. the high BCAA content diet levels. The inter-individual response to the dietary interventions was variable and not explained by adherence. CONCLUSION: Short-term dietary manipulation of BCAA intake led to modest changes in fasting levels of BCAAs. The approach from our pilot study can be expanded to test the metabolic implications of dietary BCAA manipulation.

Dimethylglycine Deficiency and the Development of Diabetes.

Experimental studies have suggested possible protective effects of dimethylglycine (DMG) on glucose metabolism. DMG is degraded to glycine through a DMG-dehydrogenase (DMGDH)-catalyzed reaction, and this is the only known pathway for the breakdown of DMG in mammals. In this study, we aimed to identify the strongest genetic determinant of circulating DMG concentration and to investigate its associations with metabolic traits and incident diabetes. In the cohort with full metabolomics data (n = 709), low plasma levels of DMG were significantly associated with higher blood glucose levels (P = 3.9E(-4)). In the genome-wide association study (GWAS) of the discovery cohort (n = 5,205), the strongest genetic signal of plasma DMG was conferred by rs2431332 at the DMGDH locus, where the major allele was associated with lower DMG levels (P = 2.5E(-15)). The same genetic variant (major allele of rs2431332) was also significantly associated with higher plasma insulin (P = 0.019), increased HOMA insulin resistance (P = 0.019), and an increased risk of incident diabetes (P = 0.001) in the pooled analysis of the discovery cohort together with the two replication cohorts (n = 20,698 and n = 7,995). These data are consistent with a possible causal role of DMG deficiency in diabetes development and encourage future studies examining if inhibition of DMGDH, or alternatively, supplementation of DMG, might prove useful for the treatment/prevention of diabetes.

Chemical and metabolomic screens identify novel biomarkers and antidotes for cyanide exposure.

Exposure to cyanide causes a spectrum of cardiac, neurological, and metabolic dysfunctions that can be fatal. Improved cyanide antidotes are needed, but the ideal biological pathways to target are not known. To understand better the metabolic effects of cyanide and to discover novel cyanide antidotes, we developed a zebrafish model of cyanide exposure and scaled it for high-throughput chemical screening. In a screen of 3120 small molecules, we discovered 4 novel antidotes that block cyanide toxicity. The most potent antidote was riboflavin. Metabolomic profiling of cyanide-treated zebrafish revealed changes in bile acid and purine metabolism, most notably by an increase in inosine levels. Riboflavin normalizes many of the cyanide-induced neurological and metabolic perturbations in zebrafish. The metabolic effects of cyanide observed in zebrafish were conserved in a rabbit model of cyanide toxicity. Further, humans treated with nitroprusside, a drug that releases nitric oxide and cyanide ions, display increased circulating bile acids and inosine. In summary, riboflavin may be a novel treatment for cyanide toxicity and prophylactic measure during nitroprusside treatment, inosine may serve as a biomarker of cyanide exposure, and metabolites in the bile acid and purine metabolism pathways may shed light on the pathways critical to reversing cyanide toxicity.

An in vivo zebrafish screen identifies organophosphate antidotes with diverse mechanisms of action.

Organophosphates are a class of highly toxic chemicals that includes many pesticides and chemical weapons. Exposure to organophosphates, either through accidents or acts of terrorism, poses a significant risk to human health and safety. Existing antidotes, in use for over 50 years, have modest efficacy and undesirable toxicities. Therefore, discovering new organophosphate antidotes is a high priority. Early life stage zebrafish exposed to organophosphates exhibit several phenotypes that parallel the human response to organophosphates, including behavioral deficits, paralysis, and eventual death. Here, we have developed a high-throughput zebrafish screen in a 96-well plate format to find new antidotes that counteract organophosphate-induced lethality. In a pilot screen of 1200 known drugs, we identified 16 compounds that suppress organophosphate toxicity in zebrafish. Several in vitro assays coupled with liquid chromatography/tandem mass spectrometry-based metabolite profiling enabled determination of mechanisms of action for several of the antidotes, including reversible acetylcholinesterase inhibition, cholinergic receptor antagonism, and inhibition of bioactivation. Therefore, the in vivo screen is capable of discovering organophosphate antidotes that intervene in distinct pathways. These findings suggest that zebrafish screens might be a broadly applicable approach for discovering compounds that counteract the toxic effects of accidental or malicious poisonous exposures.

Early detection and prediction of cardiotoxicity in chemotherapy-treated patients.

As breast cancer survival increases, cardiotoxicity associated with chemotherapeutic regimens such as anthracyclines and trastuzumab becomes a more significant issue. Assessment of the left ventricular (LV) ejection fraction fails to detect subtle alterations in LV function. The objective of this study was to evaluate whether more sensitive echocardiographic measurements and biomarkers could predict future cardiac dysfunction in chemotherapy-treated patients. Forty-three patients diagnosed with breast cancer who received anthracyclines and trastuzumab therapy underwent echocardiography and blood sampling at 3 time points (baseline and 3 and 6 months during the course of chemotherapy). The LV ejection fraction; peak systolic myocardial longitudinal, radial, and circumferential strain; echocardiographic markers of diastolic function; N-terminal pro-B-type natriuretic peptide; and high-sensitivity cardiac troponin I were measured. Nine patients (21%) developed cardiotoxicity (1 at 3 months and 8 at 6 months) as defined by the Cardiac Review and Evaluation Committee reviewing trastuzumab. A decrease in longitudinal strain from baseline to 3 months and detectable high-sensitivity cardiac troponin I at 3 months were independent predictors of the development of cardiotoxicity at 6 months. The LV ejection fraction, parameters of diastolic function, and N-terminal pro-B-type natriuretic peptide did not predict cardiotoxicity. In conclusion, cardiac troponin plasma concentrations and longitudinal strain predict the development of cardiotoxicity in patients treated with anthracyclines and trastuzumab. The 2 parameters may be useful to detect chemotherapy-treated patients who may benefit from alternative therapies, potentially decreasing the incidence of cardiotoxicity and its associated morbidity and mortality.

Bone marrow-derived lin(-)c-kit(+)Sca-1+ stem cells do not contribute to vasculogenesis in Lewis lung carcinoma.

The development of tumor vasculature is thought to occur through two complementary processes: sprouting angiogenesis from preexisting blood vessels of the host, and vasculogenesis, which involves the spontaneous development of vessels through specific recruitment, differentiation, and vascular incorporation of circulating endothelial cells (EC), endothelial progenitor cells (EPC), or potentially bone marrow-derived cells. Recent reports, however, have challenged the belief that bone marrow-derived cells contribute to tumor neovascularization, claiming an exclusive role for sprouting angiogenesis in tumor blood vessel development. In the present study, we explored the recruitment behavior of bone marrow-derived lin(-)c-kit(+)Sca-1+ stem cells to subcutaneously implanted Lewis lung carcinoma in a syngeneic bone marrow transplantation model. We observed that although lin(-)c-kit(+)Sca-1+ and their derived cells demonstrate significant recruitment to carcinomas in vivo, they do not appear to functionally contribute to tumor neovascularization. Furthermore, our results support the hypothesis that new vessel formation in carcinomas occurs primarily through endothelialization from adjacent and preexisting vasculature.