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A Double-Blind, Placebo-Controlled Randomized Phase IIa Study: Evaluating the Effect of Curcumin for Treatment of Cancer Anorexia-Cachexia Syndrome in Solid Cancer Patients.
Chaiworramukkul, A, Seetalarom, K, Saichamchan, S, Prasongsook, N
Asian Pacific journal of cancer prevention : APJCP. 2022;23(7):2333-2340
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Cancer anorexia–cachexia syndrome (CACS) is usually found in advanced cancer patients. CACS is a multifactorial process which comprises skeletal muscle and adipose tissue loss which may be compounded by anorexia and a dysregulated metabolic state. The hypothesis of this study was that curcumin will increase body compositions and body weight in patients with solid malignancy and CACS when compared to placebo after adjusting by age, gender, primary site of cancer, stage of cancer, performance status, and supplementary nutrition support. This study was a double-blind, placebo-controlled randomised phase lla study. A total of 46 patients were enrolled, of whom 33 underwent 1:1 block of four randomisations. Seventeen patients were randomly assigned to receive curcumin at dose of 800 mg twice daily orally and sixteen patients were randomly assigned to received placebo. Results show that curcumin supplementation: (1) did not statistically significantly improve body compositions and body weight when compared to placebo; (2) may cause clinical benefit in term of hand grip muscle strength and slow progress of CACS by decreasing in basal metabolic rate and preventing the decline in serum albumin; and (3) administered orally for two months at a dose of up to 2 grams daily appeared safe and no serious adverse events were reported. Authors conclude that curcumin inhibited process of CACS via reduction of basal metabolic rate and slowed down the progression of hand-grip muscle strength loss. Furthermore, nuclear factor kappa B [regulator of gene expression] levels merit further exploration as potentially suitable predictive biomarker for CACS treatment with curcumin.
Abstract
OBJECTIVE We aim to investigate the effect of curcumin on preventing cancer anorexia-cachexia syndrome (CACS) via through mechanism of inhibition on NF-kB signal pathway. Outcome measurement for primary end point was improvement of body tissue composition, and the secondary end points were body weight and body mass index, hand grip muscle strengthening, and safety. METHODS This is randomized, double-blind, placebo-controlled phase ll a study, 33 patients with CACS in solid malignancy were enrolled and randomized in 1:1 to receive oral curcumin (at a dose of 800 mg twice daily) or placebo for 8 weeks. RESULTS All parameters of body compositions were not statistically significant different between two groups, which were consist body fat mass [-1.25(SEM 0.87) vs. +0.63(SEM 0.55); p=0.119], skeletal muscle mass [-0.35(SEM 0.60) vs.+0.33(SEM 0.42); p=0.408] and percent body fat [-0.47(SEM 0.95) vs. -0.29(SEM 0.82); p=0.893] including with basal metabolic rate [-13.47(SEM 21.94) vs. +15.30(13.76); p=0.336]. The average of weight loss was also not statistically significant different between two groups. [-1.4 kg(SEM 0.89) in curcumin vs-1.12 kg(SEM 0.73), p=0.810]. Notably, patient with curcumin had less reduction of hand-grip muscle strength on both hands [Rt. handed: -2.47 in curcumin vs. -5.36 in placebo; p=0.318] [Lt. handed: -1.98 vs. -5.43; p=0.317], and basal metabolic rate than placebo group. Most adverse events were grade 1 on both groups similarly. CONCLUSION Curcumin was not shown to be superior to placebo with regard to increasing the body composition in cancer patients with CACS. However, curcumin might show some clinical benefits, including slow progression of hand-grip muscle strength loss, and basal metabolic rate. Further investigations should be explored.
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Diet-induced weight loss alters hepatic glucocorticoid metabolism in type 2 diabetes mellitus.
Stomby, A, Otten, J, Ryberg, M, Andrew, R, Walker, BR, Olsson, T
European journal of endocrinology. 2020;182(4):447-457
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Cushing syndrome is caused by an overexposure to cortisol and associated with abdominal adiposity, hypertension, dyslipidaemia, insulin resistance and type 2 diabetes mellitus (T2DM), and therefore bears similarities with metabolic syndrome and obesity. Whilst circulating cortisol levels are normal or slightly decreased in obese individuals, they tend to be increased in T2DM. The aim of this study was to investigate associations between obesity and T2DM measures and glucocorticoid metabolism, and any possible effects of a palaeolithic diet (PD) with or without exercise. In this single-blind study (investigators examining patients were blind to intervention), 28 patients with overweight or obesity and T2DM were randomised to either a PD alone or combined with a structured resistance and aerobic exercise programme for 12 weeks. The PD was based on a high intake of vegetables, fruit, lean meat, nuts, egg, fish and seafood, whilst grains, sugar, salt, dairy products and refined fats were reduced. Body mass index, waist circumference, glycaemic control, liver and systemic insulin sensitivity improved in both groups with no statistically significant difference between groups. There was no association between insulin sensitivity and indices of tissue specific glucocorticoid metabolism. PD with and without exercise was associated with increased conversion of the inactive cortisone to the active cortisol through increased activity of the conversion enzyme in the liver, but not with increased urinary excretion of glucocorticoid metabolites. The authors concluded that the results suggests that dysregulation of liver glucocorticoid metabolism in these patients is a consequence rather than a cause of metabolic dysfunction.
Abstract
CONTEXT Altered tissue-specific glucocorticoid metabolism has been described in uncomplicated obesity and type 2 diabetes. We hypothesized that weight loss induced by diet and exercise, which has previously been shown to reverse abnormal cortisol metabolism in uncomplicated obesity, also normalizes cortisol metabolism in patients with type 2 diabetes. OBJECTIVE Test the effects of a diet intervention with added exercise on glucocorticoid metabolism. DESIGN Two groups followed a Paleolithic diet (PD) for 12 weeks with added 180 min of structured aerobic and resistance exercise per week in one randomized group (PDEX). SETTING Umeå University Hospital. PARTICIPANTS Men and women with type 2 diabetes treated with lifestyle modification ± metformin were included. Twenty-eight participants (PD, n = 15; PDEX, n = 13) completed measurements of glucocorticoid metabolism. MAIN OUTCOME MEASURES Changes in glucocorticoid metabolite levels in 24-h urine samples, expression of HSD11B1 mRNA in s.c. adipose tissue and conversion of orally administered cortisone to cortisol measured in plasma. Body composition and insulin sensitivity were measured using a hyperinsulinemic-euglycemic clamp, and liver fat was measured by magnetic resonance spectroscopy. RESULTS Both groups lost weight and improved insulin sensitivity. Conversion of orally taken cortisone to plasma cortisol and the ratio of 5α-THF + 5β-THF/THE in urine increased in both groups. CONCLUSIONS These interventions caused weight loss and improved insulin sensitivity with concomitant increases in the conversion of cortisone to cortisol, which is an estimate of hepatic HSD11B1 activity. This suggests that dysregulation of liver glucocorticoid metabolism in these patients is a consequence rather than a cause of metabolic dysfunction.
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Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: a randomised cross-over trial.
Roager, HM, Vogt, JK, Kristensen, M, Hansen, LBS, Ibrügger, S, Mærkedahl, RB, Bahl, MI, Lind, MV, Nielsen, RL, Frøkiær, H, et al
Gut. 2019;68(1):83-93
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Whole grain consumption has been linked with decreased risk of lifestyle-related diseases. While animal studies have shown the gut microbiome to be a mediator of metabolic health, human studies examining the effect of whole grain intake of the gut remain inconclusive. The aim of this study was to investigate the effects of a whole grain diet on the gut microbiome, gut functionality and biomarkers of metabolic health. In this randomised, controlled, crossover study, 50 participants completed two 8-week dietary intervention periods comprising of a whole grain diet and a refined grain diet with a 6-week washout period. Examinations were done at the beginning and end of each intervention period to assess anthropometry and various plasma and gut markers. This study found that a whole grain diet as compared with a refined grain diet reduced energy intake and body weight as well as circulating markers of inflammation. Contrary to the hypothesis, these benefits were all observed independent of changes in the gut microbiome. Based on these results, the authors conclude higher intake of whole grains should be recommended to those at risk of inflammation-related disease.
Abstract
OBJECTIVE To investigate whether a whole grain diet alters the gut microbiome and insulin sensitivity, as well as biomarkers of metabolic health and gut functionality. DESIGN 60 Danish adults at risk of developing metabolic syndrome were included in a randomised cross-over trial with two 8-week dietary intervention periods comprising whole grain diet and refined grain diet, separated by a washout period of ≥6 weeks. The response to the interventions on the gut microbiome composition and insulin sensitivity as well on measures of glucose and lipid metabolism, gut functionality, inflammatory markers, anthropometry and urine metabolomics were assessed. RESULTS 50 participants completed both periods with a whole grain intake of 179±50 g/day and 13±10 g/day in the whole grain and refined grain period, respectively. Compliance was confirmed by a difference in plasma alkylresorcinols (p<0.0001). Compared with refined grain, whole grain did not significantly alter glucose homeostasis and did not induce major changes in the faecal microbiome. Also, breath hydrogen levels, plasma short-chain fatty acids, intestinal integrity and intestinal transit time were not affected. The whole grain diet did, however, compared with the refined grain diet, decrease body weight (p<0.0001), serum inflammatory markers, interleukin (IL)-6 (p=0.009) and C-reactive protein (p=0.003). The reduction in body weight was consistent with a reduction in energy intake, and IL-6 reduction was associated with the amount of whole grain consumed, in particular with intake of rye. CONCLUSION Compared with refined grain diet, whole grain diet did not alter insulin sensitivity and gut microbiome but reduced body weight and systemic low-grade inflammation. TRIAL REGISTRATION NUMBER NCT01731366; Results.
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A Pecan-Rich Diet Improves Cardiometabolic Risk Factors in Overweight and Obese Adults: A Randomized Controlled Trial.
McKay, DL, Eliasziw, M, Chen, CYO, Blumberg, JB
Nutrients. 2018;10(3)
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There has been a global rise in cardiovascular disease (CVD) and type 2 diabetes mellitus (TD2M) and dietary risk factors are a known contributor. While evidence has shown that an increased intake of tree nuts is associated with a reduced risk of disease indicators, there is limited research specifically on the effects of pecans. The aim of this randomised crossover trial was to assess the impact of pecan consumption on biomarkers related to CVD and T2DM risk in 26 overweight or obese women. Participants consumed a pecan-rich diet with an iso-caloric control diet of similar fat and fibre content, but absent in nuts, for four weeks with a two-week washout period. This trial demonstrated that displacing a portion of saturated fat in the typical American diet with pecans has a protective effect for CVD and TD2M. Based on these results, the authors recommend using dietary change as a first-line approach to disease prevention and management and suggest further studies be done to better understand potential benefits and associated mechanisms.
Abstract
Evidence from observational and intervention studies has shown a high intake of tree nuts is associated with a reduced risk of cardiovascular disease (CVD), mortality from type 2 diabetes (T2DM), and all-cause mortality. However, there is limited data regarding their effects on indicators of cardiometabolic risk other than hypercholesterolemia, and little is known about the demonstrable health benefits of pecans (Carya illinoensis (Wangenh.) K.Koch). We conducted a randomized, controlled feeding trial to compare the effects of a pecan-rich diet with an isocaloric control diet similar in total fat and fiber content, but absent nuts, on biomarkers related to CVD and T2DM risk in healthy middle-aged and older adults who are overweight or obese with central adiposity. After 4 weeks on a pecan-rich diet, changes in serum insulin, insulin resistance (HOMA-IR) and beta cell function (HOMA-β) were significantly greater than after the control diet (p < 0.05). Pecan consumption also lowered the risk of cardiometabolic disease as indicated by a composite score reflecting changes in clinically relevant markers. Thus, compared to the control diet, the pecan intervention had a concurrent and clinically significant effect on several relevant markers of cardiometabolic risk.
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A whole-grain diet reduces peripheral insulin resistance and improves glucose kinetics in obese adults: A randomized-controlled trial.
Malin, SK, Kullman, EL, Scelsi, AR, Haus, JM, Filion, J, Pagadala, MR, Godin, JP, Kochhar, S, Ross, AB, Kirwan, JP
Metabolism: clinical and experimental. 2018;82:111-117
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Literature shows that dietary whole-grain intake is associated with a lower incidence of type 2 diabetes. The aim of the study was to investigate the association between a whole-grain diet and insulin resistance and glucose use in individuals at risk for type 2 diabetes. The study was a randomized, double-blind, controlled crossover trial involving fourteen middle-aged, obese adults at risk for diabetes. Randomisation was carried out prior to metabolic testing. Results indicate that whole-grain intake as part of a mixed-meal diet significantly improved post-prandial (after a meal) glucose metabolism in middle-aged obese adults. Furthermore, both whole-grain and refined-grain interventions induced about 3–6% weight and fat loss. Authors conclude that whole-grain intake effectively promotes glycaemic control by improving insulin action.
Abstract
BACKGROUND Whole-grain intake is associated with lower risk of type 2 diabetes but the mechanisms are unclear. PURPOSE We tested the hypothesis that a WG diet reduces insulin resistance and improves glucose use in individuals at risk for type 2 diabetes compared with an isocaloric-matched refined-grain diet. METHODS A double-blind, randomized, controlled, crossover trial of 14 moderately obese adults (Age, 38 ± 2 y; BMI, 34.0 ± 1.1 kg/m2). Insulin resistance and glucose metabolism was assessed using an oral glucose tolerance test combined with isotopic tracers of [6,6-2H2]-glucose and [U-13C]-glucose, and indirect calorimetry. Peripheral and hepatic insulin resistance was assessed as 1/(rate of disposal/insulin), and endogenous glucose rates of appearance (Ra) iAUC60-240 × insulin iAUC60-240, respectively. Both diets met ADA nutritional guidelines and contained either whole-grain (50 g per 1000 kcal) or equivalent refined-grain. All food was provided for 8 wk. with an 8-10 wk. washout period between diets. RESULTS Post-prandial glucose tolerance, peripheral insulin sensitivity, and metabolic flexibility (insulin-stimulated - fasting carbohydrate oxidation) improvements were greater after whole-grain compared to the refined-grain diet (P < 0.05). Compared to baseline, body fat (~2 kg) and hepatic Ra insulin resistance was reduced by both diets, while fasting glucose and exogenous glucose-meal were unchanged after both interventions. Changes in peripheral insulin resistance and metabolic flexibility correlated with improved glucose tolerance (P < 0.05). CONCLUSION Whole-grains reduced diabetes risk and the mechanisms appear to work through reduced post-prandial blood glucose and peripheral insulin resistance that were statistically linked to enhanced metabolic flexibility.
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Favourable effects of consuming a Palaeolithic-type diet on characteristics of the metabolic syndrome: a randomized controlled pilot-study.
Boers, I, Muskiet, FA, Berkelaar, E, Schut, E, Penders, R, Hoenderdos, K, Wichers, HJ, Jong, MC
Lipids in health and disease. 2014;13:160
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The prevalence of metabolic syndrome (MetS) is increasing rapidly worldwide and is a major risk factor for type 2 diabetes (DM2) and cardiovascular disease (CVD). Modern lifestyle-induced insulin resistance and chronic systemic low grade inflammation are considered at the root of the MetS. Therefore, dietary patterns of our Palaeolithic ancestors may be ideal for prevention and treatment of metabolic disorders since they are thought to be in line with the evolution of human physiology and metabolism. The aim of this randomized controlled pilot study was to assess the efficacy of a Palaeolithic-type diet in improving the characteristics of MetS, compared to a diet based on healthy eating guidelines. The study included 34 participants with MetS who consumed their allocated diets for two weeks. Efforts were made to prevent weight loss so that any favourable effects could be explained by the dietary intervention and not by the positive health effects of weight loss. The findings of this study showed that the Palaeolithic-type diet significantly lowered blood pressure, total cholesterol and triglycerides, as well as improved HDL-cholesterol, compared to the reference diet. The participants in the Palaeolithic diet intervention also had fewer characteristics of MetS and a tendency to higher insulin sensitivity at the end of the study. Despite efforts to keep body-weight stable, more weight was lost by the participants in the Palaeolithic group. No changes were observed in the secondary outcomes of inflammation, intestinal permeability and salivary cortisol, which the authors explain by the short duration of the intervention and the attempt to prevent weight loss. The authors conclude that future studies should take full additional advantage of the greater weight loss with the Palaeolithic diet, which may be more satiating than other diets, hence allowing weight loss to happen.
Abstract
BACKGROUND The main goal of this randomized controlled single-blinded pilot study was to study whether, independent of weight loss, a Palaeolithic-type diet alters characteristics of the metabolic syndrome. Next we searched for outcome variables that might become favourably influenced by a Paleolithic-type diet and may provide new insights in the pathophysiological mechanisms underlying the metabolic syndrome. In addition, more information on feasibility and designing an innovative dietary research program on the basis of a Palaeolithic-type diet was obtained. METHODS Thirty-four subjects, with at least two characteristics of the metabolic syndrome, were randomized to a two weeks Palaeolithic-type diet (n = 18) or an isoenergetic healthy reference diet, based on the guidelines of the Dutch Health Council (n = 14). Thirty-two subjects completed the study. Measures were taken to keep bodyweight stable. As primary outcomes oral glucose tolerance and characteristics of the metabolic syndrome (abdominal circumference, blood pressure, glucose, lipids) were measured. Secondary outcomes were intestinal permeability, inflammation and salivary cortisol. Data were collected at baseline and after the intervention. RESULTS Subjects were 53.5 (SD9.7) year old men (n = 9) and women (n = 25) with mean BMI of 31.8 (SD5.7) kg/m2. The Palaeolithic-type diet resulted in lower systolic blood pressure (-9.1 mmHg; P = 0.015), diastolic blood pressure (-5.2 mmHg; P = 0.038), total cholesterol (-0.52 mmol/l; P = 0.037), triglycerides (-0.89 mmol/l; P = 0.001) and higher HDL-cholesterol (+0.15 mmol/l; P = 0.013), compared to reference. The number of characteristics of the metabolic syndrome decreased with 1.07 (P = 0.010) upon the Palaeolithic-type diet, compared to reference. Despite efforts to keep bodyweight stable, it decreased in the Palaeolithic group compared to reference (-1.32 kg; P = 0.012). However, favourable effects remained after post-hoc adjustments for this unintended weight loss. No changes were observed for intestinal permeability, inflammation and salivary cortisol. CONCLUSIONS We conclude that consuming a Palaeolithic-type diet for two weeks improved several cardiovascular risk factors compared to a healthy reference diet in subjects with the metabolic syndrome. TRIAL REGISTRATION Nederlands Trial Register NTR3002.