Refine
Has Fulltext
- yes (2)
Document Type
- Doctoral Thesis (2) (remove)
Language
- English (2) (remove)
Is part of the Bibliography
- yes (2)
Keywords
- nutrition (2) (remove)
Institute
- Institut für Ernährungswissenschaft (2) (remove)
Background: Consumption of whole-grain, coffee, and red meat were consistently related to the risk of developing type 2 diabetes in prospective cohort studies, but potentially underlying biological mechanisms are not well understood. Metabolomics profiles were shown to be sensitive to these dietary exposures, and at the same time to be informative with respect to the risk of type 2 diabetes. Moreover, graphical network-models were demonstrated to reflect the biological processes underlying high-dimensional metabolomics profiles.
Aim: The aim of this study was to infer hypotheses on the biological mechanisms that link consumption of whole-grain bread, coffee, and red meat, respectively, to the risk of developing type 2 diabetes. More specifically, it was aimed to consider network models of amino acid and lipid profiles as potential mediators of these risk-relations.
Study population: Analyses were conducted in the prospective EPIC-Potsdam cohort (n = 27,548), applying a nested case-cohort design (n = 2731, including 692 incident diabetes cases). Habitual diet was assessed with validated semiquantitative food-frequency questionnaires. Concentrations of 126 metabolites (acylcarnitines, phosphatidylcholines, sphingomyelins, amino acids) were determined in baseline-serum samples. Incident type 2 diabetes cases were assed and validated in an active follow-up procedure. The median follow-up time was 6.6 years.
Analytical design: The methodological approach was conceptually based on counterfactual causal inference theory. Observations on the network-encoded conditional independence structure restricted the space of possible causal explanations of observed metabolomics-data patterns. Given basic directionality assumptions (diet affects metabolism; metabolism affects future diabetes incidence), adjustment for a subset of direct neighbours was sufficient to consistently estimate network-independent direct effects. Further model-specification, however, was limited due to missing directionality information on the links between metabolites. Therefore, a multi-model approach was applied to infer the bounds of possible direct effects. All metabolite-exposure links and metabolite-outcome links, respectively, were classified into one of three categories: direct effect, ambiguous (some models indicated an effect others not), and no-effect.
Cross-sectional and longitudinal relations were evaluated in multivariable-adjusted linear regression and Cox proportional hazard regression models, respectively. Models were comprehensively adjusted for age, sex, body mass index, prevalence of hypertension, dietary and lifestyle factors, and medication.
Results: Consumption of whole-grain bread was related to lower levels of several lipid metabolites with saturated and monounsaturated fatty acids. Coffee was related to lower aromatic and branched-chain amino acids, and had potential effects on the fatty acid profile within lipid classes. Red meat was linked to lower glycine levels and was related to higher circulating concentrations of branched-chain amino acids. In addition, potential marked effects of red meat consumption on the fatty acid composition within the investigated lipid classes were identified.
Moreover, potential beneficial and adverse direct effects of metabolites on type 2 diabetes risk were detected. Aromatic amino acids and lipid metabolites with even-chain saturated (C14-C18) and with specific polyunsaturated fatty acids had adverse effects on type 2 diabetes risk. Glycine, glutamine, and lipid metabolites with monounsaturated fatty acids and with other species of polyunsaturated fatty acids were classified as having direct beneficial effects on type 2 diabetes risk.
Potential mediators of the diet-diabetes links were identified by graphically overlaying this information in network models. Mediation analyses revealed that effects on lipid metabolites could potentially explain about one fourth of the whole-grain bread effect on type 2 diabetes risk; and that effects of coffee and red meat consumption on amino acid and lipid profiles could potentially explain about two thirds of the altered type 2 diabetes risk linked to these dietary exposures.
Conclusion: An algorithm was developed that is capable to integrate single external variables (continuous exposures, survival time) and high-dimensional metabolomics-data in a joint graphical model. Application to the EPIC-Potsdam cohort study revealed that the observed conditional independence patterns were consistent with the a priori mediation hypothesis: Early effects on lipid and amino acid metabolism had the potential to explain large parts of the link between three of the most widely discussed diabetes-related dietary exposures and the risk of developing type 2 diabetes.
Dietary approaches contribute to the prevention and treatment of type 2 diabetes. High protein diets were shown to exert beneficial as well as adverse effects on metabolism. However, it is unclear whether the protein origin plays a role in these effects. The LeguAN study investigated in detail the effects of two high protein diets, either from plant or animal origin, in type 2 diabetic patients. Both diets contained 30 EN% protein, 40 EN% carbohydrates, and 30 EN% fat. Fiber content, glycemic index, and composition of dietary fats were similar in both diets. In comparison to previous dietary habits, the fat content was exchanged for protein, while the carbohydrate intake was not modified. Overall, both high protein diets led to improvements of glycemic control, insulin sensitivity, liver fat, and cardiovascular risk markers without remarkable differences between the protein types.
Fasting glucose together with indices of insulin resistance were ameliorated by both interventions to varying extents but without significant differences between protein types. The decline of HbA1c was more pronounced in the plant protein group, whereby the improvement of insulin sensitivity in the animal protein group. The high protein intake had only slight influence on postprandial metabolism seen for free fatty acids and indices of insulin secretion, sensitivity and degradation. Except for GIP release, ingestion of animal and plant meals did not provoke differential metabolic and hormonal responses despite diverse circulating amino acid levels.
The animal protein diets led to a selective increase of fat-free mass and decrease of total fat mass, which was not significantly different from the plant protein diet. Moreover, the high protein diets potently decreased liver fat content by 42% on average which was linked to significantly diminished lipogenesis, free fatty acids flux and lipolysis in adipose tissue. Moderate decline of circulating liver enzymes was induced by both interventions. The liver fat reduction was associated with improved glucose homeostasis and insulin sensitivity which underlines the protective effect of the diets.
Blood lipid profile improved in all subjects and was probably related to the lower fat intake. Reductions in uric acid and markers of inflammation further argued for metabolic benefits of both high protein diets. Systolic and diastolic blood pressure declined only in the PP group pointing a possible role of arginine.
Kidney function was not altered by high protein consumption over 6 weeks. The rapid decrease of serum creatinine in the PP group was noteworthy and should be further investigated. Protein type did not seem to play a role but long-term studies are warranted to fully elucidate safety of high protein regimen.
Varying the source of dietary proteins did not affect the mTOR pathway in adipose tissue and blood cells under neither acute nor chronic settings. Enhancement of whole-body insulin sensitivity suggested also no alteration of mTOR and no impairment of insulin sensitivity in skeletal muscle.
A remarkable outcome was the extensive reduction of FGF21, critical regulator of metabolic processes, by approximately 50% independently of protein type. Whether hepatic ER-stress, ammonia flux or rather macronutrient preferences is behind this paradoxical finding remains to be investigated in detail.
Unlike initial expectations and previous reports plant protein based diet had no clear advantage over animal proteins. The pronounced beneficial effect of animal protein on insulin homeostasis despite high BCAA and methionine intake was certainly unexpected assuming more complex metabolic adaptations occurring upon prolonged consumption. In addition, the reduced fat intake may have also contributed to the overall improvements in both groups.
Taking into account the above observed study results, a short-term diet containing 30 EN% protein (either from plant or animal origin), 40 EN% carbohydrates, and 30 EN% fat with lower SFA amount leads to metabolic improvements in diabetic patients, regardless of protein source.