The role of mindfulness training in sustaining weight reduction: retrospective cohort analysis.

BACKGROUND: Psychological stress has an established bi-directional relationship with obesity. Mindfulness techniques reduce stress and improve eating behaviours, but their long-term impact remains untested. CALMPOD (Compassionate Approach to Living Mindfully for Prevention of Disease) is a psychoeducational mindfulness-based course evidenced to improve eating patterns across a 6-month period, possibly by reducing stress. However, no long-term evaluation of impact exists. AIMS: This study retrospectively evaluates 2-year outcomes of CALMPOD on patient engagement, weight and metabolic markers. METHOD: All adults with a body mass index >35 kg/m2 attending an UK obesity service during 2016-2020 were offered CALMPOD. Those who refused CALMPOD were offered standard lifestyle advice. Routine clinic data over 2 years, including age, gender, 6-monthly appointment attendance, weight, haemoglobin A1C and total cholesterol, were pooled and analysed to evaluate CALMPOD. RESULTS: Of 289 patients, 163 participated in the CALMPOD course and 126 did not. No baseline demographic differences existed between the participating and non-participating groups. The CALMPOD group had improved attendance across all 6-monthly appointments compared with the non-CALMPOD group (P < 0.05). Mean body weight reduction at 2 years was 5.6 kg (s.d. 11.2, P < 0.001) for the CALMPOD group compared with 3.9 kg (s.d. 10.5, P < 0.001) for the non-CALMPOD group. No differences in haemoglobin A1C and fasting serum total cholesterol were identified between the groups. CONCLUSIONS: The retrospective evaluation of CALMPOD suggests potential for mindfulness and compassion-based group educational techniques to improve longer-term patient and clinical outcomes. Prospective large-scale studies are needed to evaluate the impact of stress on obesity and the true impact of CALMPOD.

Changes in 24-h energy expenditure, substrate oxidation, and body composition following resistance exercise and a high protein diet via whey protein supplementation in healthy older men.

PURPOSE: To investigate changes in 24-h energy expenditure (EE), substrate oxidation, and body composition following resistance exercise (RE) and a high protein diet via whey protein supplementation (alone and combined) in healthy older men. METHODS: In a pooled groups analysis, 33 healthy older men [(mean ± SE) age: 67 ± 1 years; BMI: 25.4 ± 0.4 kg/m2] were randomized to either RE (2×/week; n = 17) or non-exercise (n = 16) and either a high protein diet via whey protein supplementation (PRO, 2 × 25 g whey protein isolate/d; n = 17) or control (CON, 2 × 23.75 g maltodextrin/d; n = 16). An exploratory sub-analysis was also conducted between RE+CON (n = 8) and RE+PRO (n = 9). At baseline and 12 weeks, participants resided in respiration chambers for measurement of 24-h EE and substrate oxidation and wore an accelerometer for 7 days for estimation of free-living EE. RESULTS: Resistance exercise resulted in greater increases in fat-free mass (1.0 ± 0.3 kg), resting metabolic rate [(RMR) 36 ± 14 kcal/d], sedentary EE (60 ± 33 kcal/d), and sleeping metabolic rate [(SMR) 45 ± 7 kcal/d] compared to non-exercise (p < 0.05); however, RE decreased activity energy expenditure in free-living (-90 ± 25 kcal/d; p = 0.049) and non-exercise activity inside the respiration chamber (-1.9 ± 1.1%; p = 0.049). PRO decreased fat mass [(FM) -0.5 ± 0.3 kg], increased overnight protein oxidation (30 ± 6 g/d), and decreased 24-h protein balance (-20 ± 4 g/d) greater than CON (p < 0.05). RE+PRO decreased FM (-1.0 ± 0.5 kg) greater than RE+CON (p = 0.04). CONCLUSION: Resistance exercise significantly increased RMR, SMR, and sedentary EE in healthy older men, but not total EE. PRO alone and combined with RE decreased FM and aided body weight maintenance. This study was registered at clinicaltrials.gov as NCT03299972.

Effects of resistance exercise and whey protein supplementation on skeletal muscle strength, mass, physical function, and hormonal and inflammatory biomarkers in healthy active older men: a randomised, double-blind, placebo-controlled trial.

PURPOSE: To determine the individual and combined effects of 12 weeks of resistance exercise (RE) and whey protein supplementation on skeletal muscle strength (primary outcome), mass and physical function, and hormonal and inflammatory biomarkers in older adults. METHODS: Thirty-six healthy older men [(mean±SE) age: 67±1 y; BMI: 25.5±0.4 kg/m2] were randomised to either control (CON; n=9), whey protein (PRO; n=9), RE+control (EX+CON; n=9), or RE+whey protein (EX+PRO; n=9) in a double-blinded fashion. Whole-body RE (2 sets of 8 repetitions and 1 set to volitional failure at 80% 1RM) was performed twice weekly. Supplements (PRO, 25 g whey protein isolate; CON, 23.75 g maltodextrin) were consumed twice daily. RESULTS: EX+CON and EX+PRO increased leg extension (+19±3 kg and +20±3 kg, respectively) and leg press 1RM (+27±3 kg and +39±2 kg, respectively) greater than the CON and PRO groups (P<0.001, Cohen's d=1.50-1.90). RE (EX+CON and EX+PRO groups pooled) also increased fat-free mass (FFM) (+0.9±0.3 kg) and 6-min walk test distance (+21±5 m) and decreased fat mass (-0.4±0.4 kg), and interleukin-6 (-1.0±0.4 pg/mL) and tumor necrosis factor-alpha concentration (-0.7±0.3 pg/mL) greater than non-exercise (CON and PRO groups pooled; P<0.05, Cohen's f=0.37-0.45). Whey protein supplementation (PRO and EX+PRO groups pooled) increased 4-m gait speed greater than control (CON and EX+CON groups pooled) (+0.08±0.03 m/s; P=0.007, f=0.51). CONCLUSION: RE increased muscle strength, FFM and physical function, and decreased markers of systemic inflammation in healthy active older men. Whey protein supplementation alone increased gait speed. No synergistic effects were observed. This study was registered at clinicaltrials.gov as NCT03299972.

Reversal of Insulin Resistance in Overweight and Obese Subjects by trans-Resveratrol and Hesperetin Combination-Link to Dysglycemia, Blood Pressure, Dyslipidemia, and Low-Grade Inflammation.

The dietary supplement, trans-resveratrol and hesperetin combination (tRES-HESP), induces expression of glyoxalase 1, countering the accumulation of reactive dicarbonyl glycating agent, methylglyoxal (MG), in overweight and obese subjects. tRES-HESP produced reversal of insulin resistance, improving dysglycemia and low-grade inflammation in a randomized, double-blind, placebo-controlled crossover study. Herein, we report further analysis of study variables. MG metabolism-related variables correlated with BMI, dysglycemia, vascular inflammation, blood pressure, and dyslipidemia. With tRES-HESP treatment, plasma MG correlated negatively with endothelial independent arterial dilatation (r = -0.48, p < 0.05) and negatively with peripheral blood mononuclear cell (PBMC) quinone reductase activity (r = -0.68, p < 0.05)-a marker of the activation status of transcription factor Nrf2. For change from baseline of PBMC gene expression with tRES-HESP treatment, Glo1 expression correlated negatively with change in the oral glucose tolerance test area-under-the-curve plasma glucose (ΔAUGg) (r = -0.56, p < 0.05) and thioredoxin interacting protein (TXNIP) correlated positively with ΔAUGg (r = 0.59, p < 0.05). Tumor necrosis factor-α (TNFα) correlated positively with change in fasting plasma glucose (r = 0.70, p < 0.001) and negatively with change in insulin sensitivity (r = -0.68, p < 0.01). These correlations were not present with placebo. tRES-HESP decreased low-grade inflammation, characterized by decreased expression of CCL2, COX-2, IL-8, and RAGE. Changes in CCL2, IL-8, and RAGE were intercorrelated and all correlated positively with changes in MLXIP, MAFF, MAFG, NCF1, and FTH1, and negatively with changes in HMOX1 and TKT; changes in IL-8 also correlated positively with change in COX-2. Total urinary excretion of tRES and HESP metabolites were strongly correlated. These findings suggest tRES-HESP counters MG accumulation and protein glycation, decreasing activation of the unfolded protein response and expression of TXNIP and TNFα, producing reversal of insulin resistance. tRES-HESP is suitable for further evaluation for treatment of insulin resistance and related disorders.

Effects of Insoluble Cereal Fibre on Body Fat Distribution in the Optimal Fibre Trial.

SCOPE: The Optimal Fibre Trial (OptiFiT) investigates metabolic effects of insoluble cereal fibre in subjects with impaired glucose tolerance (IGT), showing moderate glycemic and anti-inflammatory benefits, especially in subjects with an obesity-related phenotype. An OptiFiT sub-group is analysed for effects on body fat distribution. METHODS AND RESULTS: 180 participants with IGT receive a blinded, randomized supplementation with insoluble cereal fibre or placebo for 2 years. Once a year, all subjects undergo fasting blood sampling, oral glucose tolerance test, and anthropometric measurements. A subgroup (n=47) also received magnetic resonance imaging and spectroscopy for quantification of adipose tissue distribution and liver fat content. We compared MR, metabolic and inflammatory outcomes between fibre and placebo group metabolism and inflammation. Visceral and non-visceral fat, fasting glucose, HbA1c, fasting insulin, insulin resistance, and uric acid decrease only in the fibre group, mirroring effects of the entire cohort. However, after adjustment for weight loss, there are no significant between-group differences. There is a statistical trend for fibre-driven liver fat reduction in subjects with confirmed non-alcoholic fatty liver disease (NAFLD; n = 19). CONCLUSIONS: Data and evidence on beneficial effects of insoluble cereal fibre on visceral and hepatic fatstorage is limited, but warrants further research. Targeted trials are required.

Supplementation of Vitamin D Deficiency in Patients with Neuroendocrine Tumors Using Over-the-Counter Vitamin D3 Preparations.

Vitamin D (vit-D) deficiency is highly prevalent in patients with gastro-entero-pancreatic neuroendocrine tumors (GEP-NET) and has been linked to reduced overall survival. We here assessed the vit-D status in 183 patients with GEP-NET at the time of their first presentation in the ARDEN NET Centre. We further examined the effect of simple advice to increase vit-D intake using over-the-counter vit-D preparations [colecalciferol (Vit-D3), 1,000-2,000 units/day], over a prospective observation period of 24 mo. At baseline, only 33.3% of patients showed vit-D sufficiency (25-OH-vit-D; >50 nmol/L), the remainder was insufficient (31.3%; 25-OH-vit-D; 25-50 nmol/L) or deficient (35.5%; 25-OH-vit-D; <25 nmol/L). Repeated advice to increase vit-D intake at routine 6-monthly follow-up appointments was associated with increased 25-OH-vit-D from 37.8 ± 3.5 nmol/L at baseline to 60.4 ± 5.6 nmol/L (P < 0.0001) and 56.8 ± 7.0 nmol/L (P = 0.039) after 12 and 24 mo. Percentage of vit-D insufficiency decreased from 66.6% at baseline to 44.9% and 46.2% after 12 and 24 months, respectively. Previous abdominal surgery, but not treatment with somatostatin analogues predicted 25-OH-vit-D levels in bootstrapped linear regression analyses (P = 0.037). In summary, simple advice to increase vit-D intake using over-the-counter preparations was associated with significant improvement of vit-D deficiency/insufficiency, although, 15% of GEP-NET patients remained deficient and may benefit from additional measures of vit-D replacement.

Fibre supplementation for the prevention of type 2 diabetes and improvement of glucose metabolism: the randomised controlled Optimal Fibre Trial (OptiFiT).

AIMS/HYPOTHESIS: Insoluble cereal fibres have been shown in large prospective cohort studies to be highly effective in preventing type 2 diabetes, but there is a lack of interventional data. Our 2 year randomised double-blind prospective intervention study compared the effect of an insoluble oat fibre extract with that of placebo on glucose metabolism and incidence of diabetes. METHODS: A total of 180 participants with impaired glucose tolerance underwent a modified version of the 1 year lifestyle training programme PREvention of DIAbetes Self-management (PREDIAS) and were randomised to receive a fibre supplement (n = 89; 7.5 g of insoluble fibre per serving) or placebo (n = 91; 0.8 g of insoluble fibre per serving) twice daily for 2 years. Eligible participants were men and women, were at least 18 years old and did not report corticosteroid or other intensive anti-inflammatory treatment, fibre intolerance or any of the following disorders: overt diabetes, chronic or malignant disease, or severe cardiopulmonary, endocrine, psychiatric, gastrointestinal, autoimmune or eating disorder. Participants were recruited at two clinical wards in Berlin and Nuthetal. The allocation was blinded to participants and study caregivers (physicians, dietitians, study nurses). Randomisation was conducted by non-clinical staff, providing neutrally numbered supplement tins. Both supplements were similar in their visual, olfactory and gustatory appearance. Intention-to-treat analysis was applied to all individuals. RESULTS: After 1 year, 2 h OGTT levels decreased significantly in both groups but without a significant difference between the groups (fibre -0.78 ± 1.88 mmol/l [p ≤ 0.001] vs placebo -0.46 ± 1.80 mmol/l [p = 0.020]; total difference 0.32 ± 0.29 mmol/l; not significant). The 2 year incidence of diabetes was 9/89 (fibre group) compared with 16/91 (placebo group; difference not significant). As secondary outcomes, the change in HbA1c level was significantly different between the two groups (-0.2 ± 4.6 mmol/mol [-0.0 ± 0.0%; not significant] vs +1.2 ± 5.2 mmol/mol [+0.1 ± 0.0%; not significant]; total difference 1.4 ± 0.7 mmol/mol [0.1 + 0.0%]); p = 0.018); insulin sensitivity and hepatic insulin clearance increased in both groups. After 2 years, improved insulin sensitivity was still present in both groups, although the effect size had diminished. Separate analysis of the sexes revealed a significantly greater reduction in 2 h glucose levels for women in the fibre group (-0.88 ± 1.59 mmol/l [p ≤ 0.001] vs -0.22 ± 1.52 mmol/l [p = 0.311]; total difference 0.67 ± 0.31 mmol/l; p = 0.015). Levels of fasting glucose, adipokines and inflammatory markers remained unchanged in the two groups. Significantly increased fibre intake was restricted to the fibre group, despite dietary counselling for both groups. No severe side effects occurred. CONCLUSIONS/INTERPRETATION: We cannot currently provide strong evidence for a beneficial effect of insoluble cereal fibre on glycaemic metabolism, although further studies may support minor effects of fibre supplementation in reducing glucose levels, insulin resistance and the incidence of type 2 diabetes. TRIAL REGISTRATION: clinicaltrials.gov NCT01681173 Funding: German Diabetes Foundation (grant no. 232/11/08).

Modulation of circulating vasoactive peptides and extracellular matrix proteins are two novel mechanisms in the cardioprotective action of acarbose.

BACKGROUND: Acarbose, an alpha-glucosidase inhibitor, unexpectedly reduced the incidence of hypertension and cardiovascular endpoints in the STOP-NIDDM study. Based on the growing evidence of a link between vasoregulatory peptides and metabolic traits, we hypothesized that changes of the Glycemic Index by acarbose may modulate vasoregulatory peptide levels via regulation of postprandial metabolism. METHODS: Subjects with type 2 diabetes and with metabolic syndrome were treated with acarbose (12 weeks, 300mg/d) in a double-blind, placebo-controlled, cross-over intervention. Changes in fasting and postprandial levels of midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1) and midregional pro-adrenomedullin (MR-proADM), WNT1 Inducible Signaling Pathway Protein 1 (WISP1) as well as fasting and postprandial glucose/insulin levels in the liquid meal test were assessed. RESULTS: Acarbose strongly decreased postprandial insulin concentrations in subjects with metabolic syndrome (P=0.004), and postprandial glucose excursions in both groups. Postprandial MR-proANP and CT-proET-1 levels increased after acarbose treatment (P<0.01 and P<0.05, respectively) in subjects with metabolic syndrome only. No effect of acarbose treatment on MR-prADM was observed in both groups. All three peptides were correlated with each over, but neither with insulin sensitivity in euglycemic clamps, nor with adiponectin levels. WISP1 decreased after acarbose treatment in subjects with metabolic syndrome. CONCLUSIONS: Plasma MR- proANP and CT-proET-1 concentrations, but not MR-prADM concentrations, were affected by treatment with acarbose over 12 weeks. Our findings provide new possible mechanisms of acarbose action in diabetes and metabolic syndrome.

Modulation of amino acid metabolic signatures by supplemented isoenergetic diets differing in protein and cereal fiber content.

CONTEXT: Amino-acid (AA) metabolic signatures differ in insulin-resistant (IR) obese vs normal-weight subjects, improve after weight loss, and seem to predict the risk of type 2 diabetes. It is unknown whether weight-maintaining dietary measures aimed at influencing IR alter AA signatures of high-risk subjects. SETTING AND DESIGN: In the randomized controlled Protein, Fiber and Metabolic Syndrome (ProFiMet) trial we investigated effects of four isoenergetic, moderately fat-reduced diets varying in protein and cereal-fiber contents on complete AA metabolic signatures in 76 group-matched overweight or obese high-risk subjects. We analyzed the relation of whole-body and hepatic IR with AA signatures, body fat composition and liver fat, after 0, 6, and 18 weeks of dietary intervention. Discrimination between diets was further enhanced by providing tailored dietary supplements for twice-daily consumption over 18 weeks in all groups. RESULTS: Baseline AA, including branched-chain signatures significantly related to IR, liver fat, and visceral fat mass. Isoenergetic variation of protein and cereal-fiber dietary contents, but not fat restriction, significantly influenced IR, whereas the relation of AA with IR changed with all diets. The tryptophan ratio was significantly suppressed in obese vs overweight participants, but increased after 6 weeks of high cereal-fiber intake to a nonobese phenotype. Modeling analyses revealed diet-induced alterations of complex AA profiles to relate to 70% and 62% of changes in whole-body and hepatic IR. CONCLUSIONS: We demonstrate that relatively short-term isoenergetic changes in the diet significantly alter the relation of AA signatures with IR, with possible implications on the determination and treatment of diabetes risk.

Effects of supplemented isoenergetic diets differing in cereal fiber and protein content on insulin sensitivity in overweight humans.

BACKGROUND: Despite their beneficial effects on weight loss and blood lipids, high-protein (HP) diets have been shown to increase insulin resistance and diabetes risk, whereas high-cereal-fiber (HCF) diets have shown the opposite effects on these outcomes. OBJECTIVE: We compared the effects of isoenergetic HP and HCF diets and a diet with moderate increases in both cereal fibers and dietary protein (Mix diet) on insulin sensitivity, as measured by using euglycemic-hyperinsulinemic clamps with infusion of [6,6-(2)H(2)]glucose. DESIGN: We randomly assigned 111 overweight adults with features of the metabolic syndrome to 1 of 4 two-phased, 18-wk isoenergetic diets by group-matching. Per 3-d food protocols, the percentages of energy derived from protein and carbohydrates and the intake of cereal fiber per day, respectively, were as follows-after 6 wk: 17%, 52%, and 14 g (control); 17%, 52%, and 43 g (HCF); 28%, 43%, and 13 g (HP); 23%, 44%, and 26 g (Mix); after 18 wk: 17%, 51%, and 15 g (control); 17%, 51%, and 41 g (HCF); 26%, 45%, and 14 g (HP); and 22%, 46%, and 26 g (Mix). Eighty-four participants completed the study successfully and were included in the final analyses. Adherence was supported by the provision of tailored dietary supplements twice daily in all groups. RESULTS: Insulin sensitivity expressed as an M value was 25% higher after 6 wk of the HCF diet than after 6 wk of the HP diet (subgroup analysis: 4.61 ± 0.38 compared with 3.71 ± 0.36 mg · kg(-1) · min(-1), P = 0.008; treatment × time interaction: P = 0.005). Effects were attenuated after 18 wk (treatment × time interaction: P = 0.054), which was likely explained by lower adherence to the HP diet. HP intake was associated with a tendency to increased protein expression in adipose tissue of the translation initiation factor serine-kinase-6-1, which is known to mediate amino acid-induced insulin resistance. Biomarkers of protein intake indicated interference of cereal fibers with dietary protein absorption. CONCLUSION: Greater changes in insulin sensitivity after intake of an isoenergetic HCF than after intake of an HP diet might help to explain the diverse effects of these diets on diabetes risk. This trial is registered at clinicaltrials.gov as NCT00579657.

Effects of acarbose treatment on markers of insulin sensitivity and systemic inflammation.

BACKGROUND: This study assessed the effect of postprandial glucose reduction by acarbose on insulin sensitivity and biomarkers of systemic inflammation. METHODS: This was a single-center, double-blind, randomized, placebo-controlled, crossover study <40 weeks in duration, involving 66 subjects with varying degrees of glucose tolerance. Eligible patients completed a 3-week run-in period and were randomized to receive either 100 mg of acarbose three times daily followed by placebo, or vice versa, lasting 12 weeks each with a 12-week washout between interventions. Liquid meal challenges and hyperinsulinemic-euglycemic glucose clamp were performed at weeks 0, 12, 24, and 36. RESULTS: Fasting proinsulin levels and proinsulin-to-adiponectin ratios but not fasting adiponectin levels were significantly lower during acarbose versus placebo treatment. Clamp-derived insulin sensitivity index and body weight were unchanged by the intervention. Levels of fasting insulin, fasting glucose, monocyte chemoattractant protein-1, interleukin-6, and interleukin-1ß were comparable between treatments. In the liquid meal challenge tests, postprandial glucose and insulin responses were significantly lower during acarbose versus placebo treatment. The effects of acarbose on the reduction of fasting proinsulin was most pronounced in subjects with impaired fasting glucose/impaired glucose tolerance (n = 24). CONCLUSIONS: Reduction of the glycemic load by acarbose decreased fasting levels of proinsulin but had no effect on adiponectin and whole-body insulin sensitivity as well as biomarkers reflecting inflammation. The preventive effects of acarbose on type 2 diabetes mellitus and cardiovascular risk need further investigation and cannot be explained by changes of insulin resistance and inflammatory biomarkers.

Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21.

OBJECTIVE: Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator-activator receptor (PPAR) alpha-dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARalpha, might modify FGF-21 levels. RESEARCH DESIGN AND METHODS: The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARgamma activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks. RESULTS: Oleate and linoleate increased FGF-21 expression and secretion in a PPARalpha-dependent fashion, as demonstrated by small-interfering RNA-induced PPARalpha knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect. CONCLUSIONS: The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity.