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Not all very-low-carbohydrate diets are created equal. Reply to Conte C, Camajani E, Lai A, Caprio M [letter].
Reynolds, AN, Kahleova, H, Uusitupa, M, Hermansen, K, Aas, AM, Schwab, U, Lean, MEJ, Pfeiffer, A, Salas-Salvadó, J, Mann, JI
Diabetologia. 2023;(9):1754-1755
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Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial.
Kahl, S, Gancheva, S, Straßburger, K, Herder, C, Machann, J, Katsuyama, H, Kabisch, S, Henkel, E, Kopf, S, Lagerpusch, M, et al
Diabetes care. 2020;(2):298-305
Abstract
OBJECTIVE To evaluate whether the sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (LFC) in recent-onset and metabolically well-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Patients with T2D (n = 84) (HbA1c 6.6 ± 0.5% [49 ± 10 mmol/mol], known disease duration 39 ± 27 months) were randomly assigned to 24 weeks of treatment with 25 mg daily EMPA or placebo. The primary end point was the difference of the change in LFC as measured with magnetic resonance methods from 0 (baseline) to 24 weeks between groups. Tissue-specific insulin sensitivity (secondary outcome) was assessed by two-step clamps using an isotope dilution technique. Exploratory analysis comprised circulating surrogate markers of insulin sensitivity and liver function. Statistical comparison was done by ANCOVA adjusted for respective baseline values, age, sex, and BMI. RESULTS EMPA treatment resulted in a placebo-corrected absolute change of -1.8% (95% CI -3.4, -0.2; P = 0.02) and relative change in LFC of -22% (-36, -7; P = 0.009) from baseline to end of treatment, corresponding to a 2.3-fold greater reduction. Weight loss occurred only with EMPA (placebo-corrected change -2.5 kg [-3.7, -1.4]; P < 0.001), while no placebo-corrected change in tissue-specific insulin sensitivity was observed. EMPA treatment also led to placebo-corrected changes in uric acid (-74 mol/L [-108, -42]; P < 0.001) and high-molecular-weight adiponectin (36% [16, 60]; P < 0.001) levels from 0 to 24 weeks. CONCLUSIONS EMPA effectively reduces hepatic fat in patients with T2D with excellent glycemic control and short known disease duration. Interestingly, EMPA also decreases circulating uric acid and raises adiponectin levels despite unchanged insulin sensitivity. EMPA could therefore contribute to the early treatment of nonalcoholic fatty liver disease in T2D.
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Prevention of Type 2 Diabetes by Lifestyle Changes: A Systematic Review and Meta-Analysis.
Uusitupa, M, Khan, TA, Viguiliouk, E, Kahleova, H, Rivellese, AA, Hermansen, K, Pfeiffer, A, Thanopoulou, A, Salas-Salvadó, J, Schwab, U, et al
Nutrients. 2019;11(11)
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With Type 2 Diabetes growing globally this paper analyses whether T2D is preventable with lifestyle measures including diet. Seven RCTs were included for review with a total of 4090 participants, and 2466 incidents of T2D, and were chosen on the basis that the lifestyle interventions included both physical exercise and diet (typically Mediterranean Diet). They found that diet and lifestyle intervention reduced the risk of T2D by 47%. Sustained risk reduction was also found in follow-up studies up to 10 years later with participants maintaining improved blood glucose control. Lifestyle interventions may also reduce risk factors for cardiovascular disease. Weight reduction was considered a cornerstone of preventing T2D and adherence to lifestyle changes a key element in long term prevention. Dietary foods reviewed include processed meats, white rice and sugars which correlated highly with T2D whilst leafy greens, berries, wholegrains, legumes, dietary fibre and yoghurt correlate with a lower risk of T2D. Dietary patterns of skipping breakfast and snacking correlate higher with T2D. Different criteria for evaluating physical activity estimate that it reduces risk factors by 50%. In conclusion there is high evidence that lifestyle factors which optimise diet, increase physical activity and promote weight reduction are preventative factors for T2D and can be sustained long term.
Abstract
Prevention of type 2 diabetes (T2D) is a great challenge worldwide. The aim of this evidence synthesis was to summarize the available evidence in order to update the European Association for the Study of Diabetes (EASD) clinical practice guidelines for nutrition therapy. We conducted a systematic review and, where appropriate, meta-analyses of randomized controlled trials (RCTs) carried out in people with impaired glucose tolerance (IGT) (six studies) or dysmetabolism (one study) to answer the following questions: What is the evidence that T2D is preventable by lifestyle changes? What is the optimal diet (with a particular focus on diet quality) for prevention, and does the prevention of T2D result in a lower risk of late complications of T2D? The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was applied to assess the certainty of the trial evidence. Altogether seven RCTs (N = 4090) fulfilled the eligibility criteria and were included in the meta-analysis. The diagnosis of incident diabetes was based on an oral glucose tolerance test (OGTT). The overall risk reduction of T2D by the lifestyle interventions was 0.53 (95% CI 0.41; 0.67). Most of the trials aimed to reduce weight, increase physical activity, and apply a diet relatively low in saturated fat and high in fiber. The PREDIMED trial that did not meet eligibility criteria for inclusion in the meta-analysis was used in the final assessment of diet quality. We conclude that T2D is preventable by changing lifestyle and the risk reduction is sustained for many years after the active intervention (high certainty of evidence). Healthy dietary changes based on the current recommendations and the Mediterranean dietary pattern can be recommended for the long-term prevention of diabetes. There is limited or insufficient data to show that prevention of T2D by lifestyle changes results in a lower risk of cardiovascular and microvascular complications.
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Renal function is independently associated with circulating betatrophin.
Maurer, L, Schwarz, F, Fischer-Rosinsky, A, Schlueter, N, Brachs, S, Möhlig, M, Pfeiffer, A, Mai, K, Spranger, J, Bobbert, T
PloS one. 2017;(3):e0173197
Abstract
OBJECTIVE Betatrophin has been identified as a marker linking liver with beta cell function and lipid metabolism in murine models. Until now, the regulation of circulating betatrophin in humans is not entirely clear. We here analyzed the relation of betatrophin levels to phenotypes of the metabolic syndrome and speculated that renal function might influence circulating betatrophin levels and explain age-dependent changes of betatrophin. SUBJECTS We analyzed blood samples from 535 individuals participating in the Metabolic Syndrome Berlin Potsdam study. RESULTS In a crude analysis we found a positive correlation between betatrophin levels and HbA1c (r = 0.24; p < 0.001), fasting glucose (r = 0.20; p < 0.001) and triglycerides (r = 0.12; p = 0.007). Furthermore betatrophin was positively correlated with age (r = 0.47; p <0.001), systolic blood pressure (r = 0.17; p < 0.001), intima media thickness (r = 0.26; p < 0.001) and negatively correlated with CKD-EPI eGFR (r = -0.33; p < 0.001) as an estimate of renal function. Notably, eGFR remained highly associated with betatrophin after adjustment for age, waist circumference, gender, HbA1c and lipid parameters in a multivariate linear regression model (β = -0.197, p< 0.001). CONCLUSIONS Our data suggest that circulating levels of betatrophin depend on age, gender, waist circumference, total/HDL cholesterol ratio and renal function. Especially the association to eGFR highlights the importance for future studies to address renal function as possible influence on betatrophin regulation and consider eGFR as potential confounder when analyzing the role of betatrophin in humans.
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Weight loss maintenance in overweight subjects on ad libitum diets with high or low protein content and glycemic index: the DIOGENES trial 12-month results.
Aller, EE, Larsen, TM, Claus, H, Lindroos, AK, Kafatos, A, Pfeiffer, A, Martinez, JA, Handjieva-Darlenska, T, Kunesova, M, Stender, S, et al
International journal of obesity (2005). 2014;(12):1511-7
Abstract
BACKGROUND A high dietary protein (P) content and low glycemic index (LGI) have been suggested to be beneficial for weight management, but long-term studies are scarce. OBJECTIVE The DIOGENES randomized clinical trial investigated the effect of P and GI on weight loss maintenance in overweight or obese adults in eight centers across Europe. This study reports the 1-year results in two of the centers that extended the intervention to 1 year. METHOD After an 8-week low-calorie diet (LCD), 256 adults (body mass index >27 kg m(-)(2)) were randomized to five ad libitum diets for 12 months: high P/LGI (HP/LGI), HP/high GI (HP/HGI), low P/LGI (LP/LGI), LP/HGI and a control diet. During the first 6 months, foods were provided for free through a shop system and during the whole 12-month period, subjects received guidance by a dietician. Primary outcome variable was the change in body weight over the 12-month intervention period. RESULTS During the LCD period, subjects lost 11.2 (10.8, 12.0) kg (mean (95% confidence interval (CI))). Average weight regain over the 12-month intervention period was 3.9 (95% CI 3.0-4.8) kg. Subjects on the HP diets regained less weight than subjects on the LP diets. The difference in weight regain after 1 year was 2.0 (0.4, 3.6) kg (P=0.017) (completers analysis, N=139) or 2.8 (1.4, 4.1) kg (P<0.001) (intention-to-treat analysis, N=256). No consistent effect of GI on weight regain was found. There were no clinically relevant differences in changes in cardiometabolic risk factors among diet groups. CONCLUSION A higher protein content of an ad libitum diet improves weight loss maintenance in overweight and obese adults over 12 months.
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Application of the Theory of Planned Behaviour to weight control in an overweight cohort. Results from a pan-European dietary intervention trial (DiOGenes).
McConnon, A, Raats, M, Astrup, A, Bajzová, M, Handjieva-Darlenska, T, Lindroos, AK, Martinez, JA, Larson, TM, Papadaki, A, Pfeiffer, A, et al
Appetite. 2012;(1):313-8
Abstract
Using the Theory of Planned Behaviour (TPB), this study investigates weight control in overweight and obese participants (27 kg/m(2)≤BMI<45 kg/m(2)) taking part in a dietary intervention trial targeted at weight loss maintenance (n=932). Respondents completed TPB measures investigating "weight gain prevention" at three time points. Correlation and regression analyses were used to investigate the relationship between TPB variables and weight regain. The TPB explained up to 27% variance in expectation, 14% in intention and 20% in desire scores. No relationship was established between intention, expectation or desire and behaviour at Time 1 or Time 2. Perceived need and subjective norm were found to be significantly related to weight regain, however, the model explained a maximum of 11% of the variation in weight regain. Better understanding of overweight individuals' trajectories of weight control is needed to help inform studies investigating people's weight regain behaviours. Future research using the TPB model to explain weight control should consider the likely behaviours being sought by individuals.
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In vivo activity of 11β-hydroxysteroid dehydrogenase type 1 in man: effects of prednisolone and chenodesoxycholic acid.
Diederich, S, Quinkler, M, Mai, K, Schöneshöfer, M, Baehr, V, Pfeiffer, A, Oelkers, W, Eigendorff, E
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2011;(1):66-71
Abstract
The 11β-hydroxysteroid dehydrogenases (11β-HSDs) play a pivotal role in glucocorticoid (GC) action. 11β-HSD1 is a predominant reductase, activating GCs from inert metabolites, whereas 11β-HSD2 is a potent dehydrogenase inactivating GCs. Knowing the metabolic effects of GCs, a selective inhibition of 11β-HSD1 represents a potential target for therapy of impaired glucose tolerance, insulin insensitivity and central obesity. In vitro, 11β-HSD1 is selectively inhibited by chenodesoxycholic acid (CDCA) and upregulated under GC exposure. Therefore, we aimed to investigate the effects of CDCA and prednisolone on hepatic 11β-HSD1 activity in vivo by measuring 11-reduction of orally given cortisone (E) acetate to cortisol (F). CDCA or placebo was given to 5 male healthy volunteers within a randomised cross-over trial before and after oral administration of 12.5 mg E acetate at 8:00 h. For measurement of in vivo effects of GCs on 11β-HSD1 activity, hepatic reduction of 25 mg E acetate before and after treatment with prednisolone (30 mg for 6 days) was determined in 7 healthy males. Serum GC levels were determined using a fully automated liquid chromatographic system. CDCA had no effect on the activity of 11β-HSD1 in vivo. Prednisolone therapy leads to a marked rise in serum F concentrations and an elevated F/E serum ratio. This proves GC-induced activation of hepatic 11β-HSD1, which could not be extinguished by a parallel increase of IGF-1 under prednisolone. CDCA does not affect in vivo activity of 11β-HSD1 when given in therapeutic dosages. During GC treatment, increased hepatic activation of E to F may aggravate metabolic side effects of GCs such as seen in the metabolic syndrome.
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Effects of different protein content and glycaemic index of ad libitum diets on diabetes risk factors in overweight adults: the DIOGenes multicentre, randomized, dietary intervention trial.
Goyenechea, E, Holst, C, van Baak, MA, Saris, WH, Jebb, S, Kafatos, A, Pfeiffer, A, Handjiev, S, Hlavaty, P, Stender, S, et al
Diabetes/metabolism research and reviews. 2011;(7):705-16
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Abstract
BACKGROUND Dietary regimens providing different levels of protein and glycemic index (GI) foods when prescribed for weight management may also influence insulin sensitivity. PROCEDURES AND OUTCOMES Overweight/obese adults in 8 European countries who lost ≥ 8% of initial body-weight (BW) after following a low calorie diet (LCD) were later randomly assigned with a 2x2 factorial design into 4 ad libitum dietary groups with two different protein content levels and dissimilar glycemic index, which were compared to a healthy reference diet. Specific markers assessing insulin resistance were measured. The LCD was initially applied to 932 adults and 773 were randomised to the 5 ad libitum diets. The 6-months programme was completed by 548 participants. The assignment to the Low Protein /High Glycemic Index diet induced a statistically higher HOMA-IR increase during the 6 months period as compared to the control. Contrariwise, the insulin response was lower in the High Protein/Low Glycemic Index diet after 60 and 90 min of an Oral Glucose Tolerance test subsequently carried out after the 6-months intervention. The Low Glycemic Index diets (either with high or low protein content) also lead to a decrease in fructosamine levels during the trial. CONCLUSION/INTERPRETATION After a weight loss period, an increase in the dietary protein proportions and a decrease in the consumption of foods with a high Glycemic Index within an ad libitum dietary intervention aiming to weight maintenance produced favorable effects on glycaemic control and insulin sensitivity in overweight/obese subjects.
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The Diet, Obesity and Genes (Diogenes) Dietary Study in eight European countries - a comprehensive design for long-term intervention.
Larsen, TM, Dalskov, S, van Baak, M, Jebb, S, Kafatos, A, Pfeiffer, A, Martinez, JA, Handjieva-Darlenska, T, Kunesová, M, Holst, C, et al
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2010;(1):76-91
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Diogenes is a Pan-European, randomized, controlled dietary intervention study investigating the effects of dietary protein and glycaemic index on weight (re)gain, metabolic and cardiovascular risk factors in obese and overweight families in eight European centres. The article is methodological in character, and the presentation of 'results' will be limited to baseline characteristics of the study populations included. A total of 891 families with at least one overweight/obese parent underwent screening. The parents started an initial 8-week low-calorie diet and families with minimum one parent attaining a weight loss of > or = 8%, were randomized to one of five energy ad libitum, low-fat (25-30 E%) diets for 6 or 12 months: low protein/low glycaemic index, low protein/high glycaemic index, high protein/low glycaemic index, high protein/high glycaemic index or control (national dietary guidelines). At two centres the families were provided dietary instruction plus free foods for 6 months followed by 6-month dietary instruction only. At the remaining six centres the families received dietary instruction only for 6 months. The median weight loss during the low-calorie diet was 10.3 kg (inter-quartile range: 8.7-12.8 kg, n = 775). A total of 773 adults and 784 children were randomized to the 6-month weight (re)gain prevention phase. Despite major cultural and dietary regional differences in Europe, interventions addressing effects of dietary factors are feasible with a reasonable attrition.
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Genetic variation in GPR133 is associated with height: genome wide association study in the self-contained population of Sorbs.
Tönjes, A, Koriath, M, Schleinitz, D, Dietrich, K, Böttcher, Y, Rayner, NW, Almgren, P, Enigk, B, Richter, O, Rohm, S, et al
Human molecular genetics. 2009;(23):4662-8
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Recently, associations of several common genetic variants with height have been reported in different populations. We attempted to identify further variants associated with adult height in a self-contained population (the Sorbs in Eastern Germany) as discovery set. We performed a genome wide association study (GWAS) (approximately 390,000 genetic polymorphisms, Affymetrix gene arrays) on adult height in 929 Sorbian individuals. Subsequently, the best SNPs (P < 0.001) were taken forward to a meta-analysis together with two independent cohorts [Diabetes Genetics Initiative, British 1958 Birth Cohort, (58BC, publicly available)]. Furthermore, we genotyped our best signal for replication in two additional German cohorts (Leipzig, n = 1044 and Berlin, n = 1728). In the primary Sorbian GWAS, we identified 5 loci with a P-value < 10(-5) and 455 SNPs with P-value < 0.001. In the meta-analysis on those 455 SNPs, only two variants in GPR133 (rs1569019 and rs1976930; in LD with each other) retained a P-value at or below 10(-6) and were associated with height in the three cohorts individually. Upon replication, the SNP rs1569019 showed significant effects on height in the Leipzig cohort (P = 0.004, beta = 1.166) and in 577 men of the Berlin cohort (P = 0.049, beta = 1.127) though not in women. The combined analysis of all five cohorts (n = 6,687) resulted in a P-value of 4.7 x 10(-8) (beta = 0.949). In conclusion, our GWAS suggests novel loci influencing height. In view of the robust replication in five different cohorts, we propose GPR133 to be a novel gene associated with adult height.