Evaluation of Poorly-Bioavailable Cocoa Flavanols and Their Gut Microbial Metabolites in Potentiating Anti-diabetic Activities Through BTBR.Cg-Lepob/ob/WiscJ Mice

Abstract Objectives Cocoa (Theobroma cacao) is a concentrated dietary source of flavanols that have beneficial activities against type-2 diabetes. These compounds have limited small intestinal absorption and are metabolized by the microbiota to bioavailable metabolites that may exert anti-diabetic effects locally and in peripheral tissues. Our objectives were to 1) determine the role of the gut microbiome in facilitating protective effects of cocoa flavanols, and 2) evaluate these effects in a novel mouse model of progressive type-2 diabetes. Methods A small pilot study (n = 3) of male and female BTBR mice (wild-type and homozygous for the Lepob mutation) received either control or cocoa extract-supplemented diet for 10 weeks. Half the animals were administered antibiotics orally to knock down the commensal gut microbiota. Glucose and insulin tolerance tests were conducted at weeks 1 and 5 and 2 and 6, respectively. Weight gain and food intake were monitored weekly. Biomarkers of gut integrity and inflammation were assessed by ELISA. Results Baseline fasting blood glucose (FBG) levels in five-week-old homozygous males and females were measured at 211–271 mg/dL and 112–234 mg/dL, respectively. After five weeks, FBG measured at 281–438 mg/dL and 177–562 mg/dL, respectively. Cocoa provided moderate, yet not significant, protection against weight gain in homozygous males when compared to homozygous males fed control diet. Cocoa provided no significant protection against hypoglycemia in homozygous male or female mice when compared to homozygous controls. In treatment comparisons with and without antibiotics, knocking out the commensal gut microbiota appeared to have minimal effect on weight gain and glycemic control in both males and females. Conclusions Cocoa did provide a moderate level of protection for homozygous males when directly comparing weight gain and FBG across sex. While the microbiome has displayed a promising role in the bioavailability of large flavanols, in this particular model, the impact was minimal. Overall, cocoa was ineffective against the mediation of advanced diabetes and further work must be conducted to understand if this conclusion is isolated to this model of progressive type-2 diabetes. Funding Sources This work was supported by the US Department of Agriculture by AFRI grant 2020–67,017-30,846.

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PDB72 The Impact on Utilities of Weight Loss and Weight Gain Among Canadian Patients With Type 2 Diabetes

Value in Health ◽

10.1016/j.jval.2012.03.993 ◽

2012 ◽

Vol 15 (4) ◽

pp. A183 ◽

Cited By ~ 3

Author(s):

S. Lane ◽

A.R. Levy ◽

J. Sambrook ◽

J. Mukherjee ◽

M. Leahy ◽

...

Keyword(s):

Type 2 Diabetes ◽

Weight Loss ◽

Weight Gain ◽

The Impact

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Factors Associated With Weight Gain and Hypoglycaemia and The Impact Upon Hospitalisation in Type 2 Diabetes Patients Managed With Metformin Plus Sulphonylurea

Value in Health ◽

10.1016/j.jval.2014.08.783 ◽

2014 ◽

Vol 17 (7) ◽

pp. A360

Author(s):

P. McEwan ◽

J. Gordon ◽

M. Evans ◽

J. Puelles

Keyword(s):

Type 2 Diabetes ◽

Weight Gain ◽

Factors Associated ◽

The Impact ◽

Diabetes Patients

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The Impact of Weight Gain on Motivation, Compliance, and Metabolic Control in Patients with Type 2 Diabetes Mellitus

Postgraduate Medicine ◽

10.3810/pgm.2009.09.2056 ◽

2009 ◽

Vol 121 (5) ◽

pp. 94-107 ◽

Cited By ~ 53

Author(s):

F. Xavier Pi-Sunyer

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Weight Gain ◽

Metabolic Control ◽

The Impact

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Faecal virome transplantation decrease symptoms of type-2-diabetes and obesity in a murine model

10.1101/792556 ◽

2019 ◽

Cited By ~ 2

Author(s):

Torben Sølbeck Rasmussen ◽

Caroline M. Junker Mentzel ◽

Witold Kot ◽

Josué L. Castro-Mejía ◽

Simone Zuffa ◽

...

Keyword(s):

Type 2 Diabetes ◽

Weight Gain ◽

Glucose Tolerance ◽

Gut Microbiota ◽

List Type ◽

Proof Of Concept ◽

Viral Community ◽

Plasma Metabolome ◽

New Findings

ABSTRACTObjectiveDevelopment of obesity and type-2-diabetes (T2D) are associated with gut microbiota (GM) changes. The gut viral community is predominated by bacteriophages (phages), which are viruses that attack bacteria in a host-specific manner. As a proof-of-concept we demonstrate the efficacy of faecal virome transplantation (FVT) from lean donors for shifting the phenotype of obese mice into closer resemblance of lean mice.DesignThe FVT consisted of viromes extracted from the caecal content of mice fed a low-fat (LF) diet for fourteen weeks. Male C57BL/6NTac mice were divided into five groups: LF (as control), high-fat diet (HF), HF+Ampicillin (Amp), HF+Amp+FVT and HF+FVT. At week six and seven of the study the HF+FVT and HF+Amp+FVT mice were treated with FVT by oral gavage. The Amp groups were treated with ampicillin 24 h prior to first FVT treatment.ResultsSix weeks after first FVT the HF+FVT mice showed a significant decrease in weight gain compared to the HF group. Further, glucose tolerance was comparable between the lean LF and HF+FVT mice, while the other HF groups all had impaired glucose tolerance. These observations were supported by significant shifts in GM composition, blood plasma metabolome, and expression levels of genes involved in obesity and T2D development.ConclusionsTransfer of gut viral communities from mice with a lean phenotype into those with an obese phenotype reduce weight gain and normalise blood glucose parameters relative to lean mice. We hypothesise that this effect is mediated via FVT-induced GM changes.Significance of this studyWhat is already known about this subject?Obesity and type-2-diabetes (T2D) are associated with gut microbiota (GM) dysbiosis.Faecal microbiota transplant from lean donors has previously shown potential in treating obesity and T2D.Patients suffering from recurrent Clostridium difficile infections (rCDI) have been cured with sterile filtered donor faeces (containing enteric viruses and no bacteria), here defined as faecal virome transplantation (FVT).What are the new findings?FVT from lean donors lead to decreased weight gain and normalised blood sugar tolerance in a diet-induced obesity (DIO) mouse model.FVT significantly changed the bacterial and viral GM component, as well as the plasma metabolome and the expression profiles of obesity and T2D associated genes.Initial treatment with ampicillin prior FVT seems to counteract the beneficial effects associated with FVT.How might it impact on clinical practice in the foreseeable future?We here show a proof-of-concept, providing a solid base for designing a clinical study of FVT targeting obesity and T2D in humans. This is further augmented by the increased safety related to FVT, since bacteria and other microorganisms are removed from the donor faeces, and therefore minimises the risk of disease transmission.These findings highlight the potential application of FVT treatment of various diseases related to GM dysbiosis and further support the vital role of the viral community in maintaining and shaping the GM.

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Breast Cancer Endocrine Therapy Promotes Weight Gain With Distinct Adipose Tissue Effects in Lean and Obese Female Mice

Endocrinology ◽

10.1210/endocr/bqab174 ◽

2021 ◽

Vol 162 (11) ◽

Author(s):

Rebecca L Scalzo ◽

Rebecca M Foright ◽

Sara E Hull ◽

Leslie A Knaub ◽

Stevi Johnson-Murguia ◽

...

Keyword(s):

Breast Cancer ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Weight Gain ◽

Endocrine Therapy ◽

Female Mice ◽

Adipocyte Progenitors ◽

Adipocyte Hypertrophy ◽

The Impact

Abstract Breast cancer survivors treated with tamoxifen and aromatase inhibitors report weight gain and have an elevated risk of type 2 diabetes, especially if they have obesity. These patient experiences are inconsistent with, preclinical studies using high doses of tamoxifen which reported acute weight loss. We investigated the impact of breast cancer endocrine therapies in a preclinical model of obesity and in a small group of breast adipose tissue samples from women taking tamoxifen to understand the clinical findings. Mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in mesenchymal stem cells from adipose tissue, endocrine therapy was associated with adipose accumulation and more preadipocytes compared with estrogen-treated control mice but resulted in fewer adipocyte progenitors only in the context of HFHS. Analysis of subcutaneous adipose stromal cells revealed diet- and treatment-dependent effects of endocrine therapies on various cell types and genes, illustrating the complexity of adipose tissue estrogen receptor signaling. Breast cancer therapies supported adipocyte hypertrophy and associated with hepatic steatosis, hyperinsulinemia, and glucose intolerance, particularly in obese females. Current tamoxifen use associated with larger breast adipocyte diameter only in women with obesity. Our translational studies suggest that endocrine therapies may disrupt adipocyte progenitors and support adipocyte hypertrophy, potentially leading to ectopic lipid deposition that may be linked to a greater type 2 diabetes risk. Monitoring glucose tolerance and potential interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

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A Pilot Study on the Metabolic Impact of Mediterranean Diet in Type 2 Diabetes: Is Gut Microbiota the Key?

Nutrients ◽

10.3390/nu13041228 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1228

Author(s):

Shámila Ismael ◽

Marta P. Silvestre ◽

Miguel Vasques ◽

João R. Araújo ◽

Juliana Morais ◽

...

Keyword(s):

Type 2 Diabetes ◽

Pilot Study ◽

Gut Microbiota ◽

Mediterranean Diet ◽

Dietary Intervention ◽

Model Assessment ◽

Bacterial Richness ◽

Diabetes Outcome ◽

The Impact

The Mediterranean diet (MD) has been recommended for type 2 diabetes (T2D) treatment. The impact of diet in shaping the gut microbiota is well known, particularly for MD. However, the link between MD and diabetes outcome improvement is not completely clear. This study aims to evaluate the role of microbiota modulation by a nonpharmacological intervention in patients with T2D. In this 12-week single-arm pilot study, nine participants received individual nutritional counseling sessions promoting MD. Gut microbiota, biochemical parameters, body composition, and blood pressure were assessed at baseline, 4 weeks, and 12 weeks after the intervention. Adherence to MD [assessed by Mediterranean Diet Adherence Screener (MEDAS) score] increased after the intervention. Bacterial richness increased after 4 weeks of intervention and was negatively correlated with fasting glucose levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Prevotella to Bacteroides ratio also increased after 4 weeks. In contrast, glycated haemoglobin (HbA1c) and HOMA-IR were only decreased at the end of study. Alkaline phosphatase activity was assessed in fecal samples and was negatively correlated with HbA1c and positively correlated with bacterial diversity. The results of this study reinforce that MD adherence results in a better glycemic control in subjects with T2D. Changes in gut bacterial richness caused by MD adherence may be relevant in mediating the metabolic impact of this dietary intervention.

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Weight change and risk of cardiovascular disease among adults with type 2 diabetes: more than 14 years of follow-up in the Tehran Lipid and Glucose Study

Cardiovascular Diabetology ◽

10.1186/s12933-021-01326-2 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Seyyed Saeed Moazzeni ◽

Reyhane Hizomi Arani ◽

Niloofar Deravi ◽

Mitra Hasheminia ◽

Davood Khalili ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Weight Gain ◽

Weight Change ◽

P Value ◽

Increased Risk ◽

History Of ◽

The Impact

Abstract Background To examine the impact of weight change on incident cardiovascular disease and coronary heart disease (CVD/CHD) among an Iranian population with type 2 diabetes mellitus (T2DM). Methods The study population included 763 participants with T2DM aged ≥ 30 years without a history of CVD and cancer at baseline. Two weight measurements done at baseline and about 3 years later. Based on their weight change, they categorized into: > 5% loss, 3–5% loss, stable (± < 3%), 3–5% gain, > 5% gain. Participants were then followed for incident CVD/CHD annually up to 20 March 2018. Multivariable Cox proportional hazard models, adjusted for age, sex, body mass index, educational level, current smoking, glucose-lowering drug use, family history of CVD, hypertension, hypercholesterolemia, chronic kidney disease, and fasting plasma glucose (FPG) were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of weight change categories for incident CVD/CHD, considering stable weight as reference. Results After the weight change measurement, during a median follow-up of 14.4 years, 258 CVD and 214 CHD occurred. Over 5% weight gain was associated with reduced risks of CVD and CHD development by the HRs of 0.70 [95% CI 0.48–1.01; P-value: 0.058] and 0.61 [0.40–0.93], respectively, in multivariable analysis. After further adjustment for FPG change, the HRs of weight gain > 5% were attenuated to 0.75 [0.51–1.10; P-value: 0.138] and 0.66 [043–1.01; P-value: 0.053] for incident CVD and CHD, respectively. The effect of weight loss > 5% was in opposite direction among those older versus younger than 60 years; with suggestive increased risk (not statistically significant) of incident CHD/CVD for the older group. Moreover, weight gain > 5% significantly reduced the risk of CHD only among those older than 60 years (P-value for interaction < 0.2). Furthermore, weight gain > 5% had an association with lower risk of CVD and CHD among sulfonylurea users (0.56 [0.32–0.98] for CVD and 0.54 [0.29–0.99] for CHD). Conclusions Our results with a long-term follow-up showed that weight gain > 5% was associated with better CVD/CHD outcomes among Iranian participants with T2DM, especially older ones. Moreover, we did not find an unfavorable impact on incident CVD/CHD for sulfonylurea-induced weight gain.

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The Impact of Rhodiola Rosea On Biomarkers of Diabetes, Inflammation, and Gut Microbiota in a Leptin Receptor-Knockout Mouse Model

10.21203/rs.3.rs-1186409/v1 ◽

2022 ◽

Author(s):

Mahtab Jafari ◽

Jasmin Grace Juanson Arabit ◽

Robert Courville ◽

Dara Kiani ◽

John M. Chaston ◽

...

Keyword(s):

Type 2 Diabetes ◽

Mouse Model ◽

Gut Microbiota ◽

Leptin Receptor ◽

Insulin Response ◽

Rhodiola Rosea ◽

Root Extract ◽

Receptor Knockout Mouse ◽

The Impact

Abstract Type 2 diabetes is the most prevalent endocrine disease in the world, and recently the gut microbiota have become a potential target for its management. Recent studies have illustrated that this disease may predispose individuals to certain microbiome compositions, and treatments like metformin have been shown to change gut microbiota and their associated metabolic pathways. However, given the limitations and side effects associated with pharmaceuticals currently being used for therapy of diabetes, there is a significant need for alternative treatments. In this study, we investigated the effects of a root extract from Rhodiola rosea in a Leptin receptor knockout (db/db) mouse model of type 2 diabetes. Our previous work showed that Rhodiola rosea had anti-inflammatory and gut microbiome-modulating properties, while extending lifespan in several animal models. In this study, treatment with Rhodiola rosea improved the insulin response, and significantly decreased serum lipopolysaccharide and C-reactive protein levels. We hypothesize that these changes may in part reflect the modulation of the microbiota, resulting in improved gut barrier integrity and decreasing the translocation of inflammatory biomolecules into the bloodstream. These findings indicate that Rhodiola rosea is an attractive candidate for further research in the management of type 2 diabetes.

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