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Effects of a Dulaglutide plus Calorie-Restricted Diet versus a Calorie-Restricted Diet on Visceral Fat and Metabolic Profiles in Women with Polycystic Ovary Syndrome: A Randomized Controlled Trial.
Zhang, Y, Qu, Z, Lu, T, Shao, X, Cai, M, Dilimulati, D, Gao, X, Mao, W, Hu, F, Su, L, et al
Nutrients. 2023;15(3)
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Polycystic ovary syndrome (PCOS) is a unification of reproductive endocrine and metabolic disorders. Lifestyle and weight management, particularly dietary intake aimed at weight loss, are initial treatment strategies for PCOS. A calorie-restricted diet (CRD) seems to be the optimal dietary pattern for weight management in the PCOS population. The aim of this study was to evaluate modifications in fat distribution, the androgenic state, and metabolic profiles in the overweight and obese PCOS-affected population, who obtained modest and equivalent weight loss induced by a CRD regimen with or without Dulaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist (RA). This study was a randomised controlled trial which enrolled 68 females diagnosed with PCOS. Participants were randomly assigned to receive to one of the two groups: a GLP-1 RA combined with CRD or CRD alone. Results showed that participants in the GLP-1 RA + CRD group took a shorter time to achieve a 7% weight loss goal than those in the CRD group. Furthermore, both interventions had similar positive effects in improving menstrual frequency and reducing levels of blood pressure, insulin, aminotransferases, lipids, total fat mass, total lean mass, and abdominal subcutaneous adipose tissue mass after equivalent weight loss. Authors conclude that their findings support the importance of dietary intervention as a first-line treatment in women with PCOS, and that GLP-1 RA therapy offers an effective and generally tolerable adjunct therapy to aid in achieving weight targets based on dietary therapy in overweight and obese women with PCOS.
Abstract
The effects of dulaglutide and a calorie-restricted diet (CRD) on visceral adipose tissue (VAT) and metabolic profiles in polycystic ovary syndrome (PCOS) have not been extensively investigated. In this study, we investigated whether dulaglutide combined with CRD could further reduce VAT and promote clinical benefits as compared with a CRD regimen alone in overweight or obese PCOS-affected women. Between May 2021 and May 2022, this single-center, randomized, controlled, open-label clinical trial was conducted. Overall, 243 participants with PCOS were screened, of which 68 overweight or obese individuals were randomly randomized to undergo dulaglutide combined with CRD treatment (n = 35) or CRD treatment alone (n = 33). The duration of intervention was set as the time taken to achieve a 7% weight loss goal from baseline body weight, which was restricted to 6 months. The primary endpoint was the difference in the change in VAT area reduction between the groups. The secondary endpoints contained changes in menstrual frequency, metabolic profiles, hormonal parameters, liver fat, and body composition. As compared with the CRD group, the dulaglutide + CRD group had a considerably shorter median time to achieve 7% weight loss. There was no significant between-group difference in area change of VAT reduction (-0.97 cm2, 95% confidence interval from -14.36 to 12.42, p = 0.884). As compared with CRD alone, dulaglutide + CRD had significant advantages in reducing glycated hemoglobin A1c and postprandial plasma glucose levels. The results of the analyses showed different changes in menstruation frequency, additional metabolic profiles, hormonal markers, liver fat, and body composition between the two groups did not differ significantly. Nausea, vomiting, constipation, and loss of appetite were the main adverse events of dulaglutide. These results emphasize the value of dietary intervention as the first line of treatment for PCOS-affected women, while glucagon-like peptide 1 receptor agonist therapy provides an efficient and typically well tolerated adjuvant therapy to aid in reaching weight targets based on dietary therapy in the population of overweight/obese PCOS-affected women.
2.
Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study.
Wang, S, Ren, H, Zhong, H, Zhao, X, Li, C, Ma, J, Gu, X, Xue, Y, Huang, S, Yang, J, et al
Gut microbes. 2022;14(1):2003176
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Hyperlipidaemia is a major risk factor for atherosclerotic cardiovascular diseases particularly when combined with hyperglycaemia and type 2 diabetes (T2D). Current diagnostic criteria and treatment targets are based on evaluating fasting lipidaemia (FL). However, increasing evidence has supported that a high level of non-fasting lipidaemia, mainly constituted by post-prandial lipidaemia (PL), is also an important CVD risk factor. The aim of this study was to investigate how the combination treatment of berberine (BBR) and probiotics (Prob), or either one could exert benefit on lowering PL, and whether their impact on gut microbiota could contribute to this effect. This study is based on the PREMOTE trial, which was a randomised, double-blind, placebo-controlled clinical trial in 20 medical centres in China and enrolled newly diagnosed T2D patients. This lipidomic study included 365 of the 409 participants enrolled for the PREMOTE trial. Results showed that: - Prob+BBR combined therapy exerted a similar effect on reducing fasting lipidaemia with BBR alone but a superior effect on the levels of postprandial plasma total cholesterol and post-prandial low-density lipoprotein cholesterol compared to either BBR or Prob alone. - a substantial decrease in various lipid species after Prob+BBR treatment. Authors conclude that their findings proved the therapeutic effect of a combined treatment of oral administration of probiotics with berberine on improving PL in patients newly diagnosed with T2D and proposed a new gut microbiome related remedy for managing dyslipidaemia, covering both PL and FL, in patients with T2D.
Abstract
Non-fasting lipidemia (nFL), mainly contributed by postprandial lipidemia (PL), has recently been recognized as an important cardiovascular disease (CVD) risk as fasting lipidemia (FL). PL serves as a common feature of dyslipidemia in Type 2 Diabetes (T2D), albeit effective therapies targeting on PL were limited. In this study, we aimed to evaluate whether the therapy combining probiotics (Prob) and berberine (BBR), a proven antidiabetic and hypolipidemic regimen via altering gut microbiome, could effectively reduce PL in T2D and to explore the underlying mechanism. Blood PL (120 min after taking 100 g standard carbohydrate meal) was examined in 365 participants with T2D from the Probiotics and BBR on the Efficacy and Change of Gut Microbiota in Patients with Newly Diagnosed Type 2 Diabetes (PREMOTE study), a random, placebo-controlled, and multicenter clinical trial. Prob+BBR was superior to BBR or Prob alone in improving postprandial total cholesterol (pTC) and low-density lipoprotein cholesterol (pLDLc) levels with decrement of multiple species of postprandial lipidomic metabolites after 3 months follow-up. This effect was linked to the changes of fecal Bifidobacterium breve level responding to BBR alone or Prob+BBR treatment. Four fadD genes encoding long-chain acyl-CoA synthetase were identified in the genome of this B. breve strain, and transcriptionally activated by BBR. In vitro BBR treatment further decreased the concentration of FFA in the culture medium of B. breve compared to vehicle. Thus, the activation of fadD by BBR could enhance FFA import and mobilization in B. breve and diliminish the intraluminal lipids for absorption to mediate the effect of Prob+BBR on PL. Our study confirmed that BBR and Prob (B. breve) could exert a synergistic hypolipidemic effect on PL, acting as a gut lipid sink to achieve better lipidemia and CVD risk control in T2D.
3.
Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study).
Zhang, Y, Gu, Y, Ren, H, Wang, S, Zhong, H, Zhao, X, Ma, J, Gu, X, Xue, Y, Huang, S, et al
Nature communications. 2020;11(1):5015
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Berberine, which is a naturally occurring alkaloid found in plants, has been traditionally used as a remedy to protect against Type 2 diabetes and other metabolic disorders. It is important to study how berberine affects the human gut microbiome, specifically in regard to its impact on short-chain fatty acid and bile acid metabolism, due to its low oral bioavailability. The PREMOTE study investigated the glycaemic lowering effects of individual and combination of berberine and probiotics in newly diagnosed Type 2 Diabetes patients. This randomised, double-blinded, placebo-controlled trial included four hundred and nine Type 2 diabetic patients and randomly assigned them (1:1:1:1 ratio) to receive berberine alone, berberine combined with probiotics, probiotics alone or a placebo for twelve weeks. A combination of berberine plus probiotics and berberine alone significantly improved glycated haemoglobin levels compared to the placebo and probiotics alone treatment. The antidiabetic effects of berberine could be due to the Ruminococcus bromii abundance followed by the berberine treatment and its ability to inhibit deoxycholic acid biotransformation. Further robust studies are required to consider the therapeutic application of berberine and probiotics in a general population due to the limitations of the present study. However, healthcare professionals can use the results of this trial to understand the mechanism behind the anti-diabetic effects of berberine and probiotics.
Expert Review
Conflicts of interest:
None
Take Home Message:
- The use of berberine, as a specific antimicrobial agent, along with high strength probiotics may be beneficial for managing blood glucose and potentially other metabolic health markers alongside diet and lifestyle modifications
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
Dysbiosis of the human gut microbiome has been associated with the development of type 2 diabetes (T2D). Research has found that, in part, mechanisms of action for the antidiabetic medications, Metformin and Acarbose, include alterations in the gut microbiome as well as the inhibition of bile acid (BA) metabolism and signalling. Remedies targeting the gut microbiota for treatment of T2D and other metabolic diseases have therefore been investigated.
Berberine (BBR) has been used in Indian Ayurvedic and Traditional Chinese Medicine to treat metabolic conditions for hundreds of years. Probiotics have also been extensively researched for their potential metabolic benefits. This randomised, double-blind, placebo-controlled trial aimed to investigate whether BBR and probiotics may be effective in managing T2D.
Methods
A total of 409 participants aged 42-61 years were recruited from 20 medical centres in China. All patients were newly diagnosed (<12 months) with T2D and had no previous antidiabetic medication history. Participants were randomised into 4 groups; Probiotics and BBR, BBR only, probiotics only or a placebo for 12 weeks. Subgroup analysis was also completed for those aged >50 and >54.
Dosage of BBR was 0.6 g prior to a meal, twice daily. 4 g of powdered multi-strain probiotics including 9 strains of lactic acid bacteria were taken at bedtime. All participants were given a 7-day broad-spectrum antibiotic treatment immediately prior to baseline. 391 people completed the trial. The primary outcome measurement was glycaemic haemoglobin (HbA1c). Secondary evaluations of additional metabolic markers included fasting and post-load plasma glucose (FPG, PPG), homeostasis assessment model index for insulin resistance (HOMA-IR), total cholesterol (TC), high density lipoprotein cholesterol (HDL-c), low density lipoprotein cholesterol (LDL-c) and serum triglycerides (TG).
Results
Results showed a reduction in glycaemic haemoglobin (HbA1c) for both the BBR plus probiotics group (least squares mean [95% CI] -1.04 [-1-19, -0.89]% ) and the BBR only group (-.99 [-1.16, 0.83]%). The results for these groups were significantly greater than the probiotics alone (-0.53 {-068, -0.37]%) and the placebo groups (0.59 [-0.75, -0.44]%).
Secondary metabolic evaluations for FPG and PPG, TC, LDL -c and TGs also showed similar improvements in the BBR and BBR plus probiotic groups only. Additionally, in the >50 and >54 subgroups BBR and probiotics marginally improved the HOMA-IR.
Metagenomic and metabolomic analysis of the gut microbiome was also undertaken after a one-week pre-treatment with antibiotics immediately prior to the trial and at week 13. These results showed that the blood glucose lowering effects of BBR may be due to decreased deoxycholic acid species (DCA) biotransformation by ruminococcus bromii.
Higher levels of adverse gastrointestinal side effects were reported in the BBR treatment groups, however, the authors reported that this did not affect glycemic control outcomes.
Conclusion
This study found that BBR had an antidiabetic effect through microbial alterations in the human gut microbiome
The authors declare no conflicts of interest.
Clinical practice applications:
- 600mg of BBR twice daily prior to a meal plus a multi-strain (lactic acid) probiotic of >50 billion colony forming units (CFU) for 12 weeks may be effective in lowering HbA1c in T2D clients diagnosed within the previous 12 months
- Further research is needed for clients with longer term T2D diagnosis
- Insulin resistance may be marginally improved in clients >50
- Practitioners should be aware that in this study, adverse gastrointestinal side effects were more likely to be be experienced with the use of BBR
Considerations for future research:
The authors reported several limitations to this study:
- A population of Chinese people living in China may not be generalisable to other ethnic/racial populations
- The study was over a short duration. Longer studies are needed to confirm the results
- Participants had newly diagnosed T2D and had not received any previous medications. Future studies should include patients with a longer diagnosis time
- Records should be kept of any additional lifestyle changes made by the participants
- Adverse reactions were experienced in the BBR groups, in this study. It was reported that the gut microbiome and anti-diabetic effects were not affected, however, this may be something to be considered in longer trials.
Abstract
Human gut microbiome is a promising target for managing type 2 diabetes (T2D). Measures altering gut microbiota like oral intake of probiotics or berberine (BBR), a bacteriostatic agent, merit metabolic homoeostasis. We hence conducted a randomized, double-blind, placebo-controlled trial with newly diagnosed T2D patients from 20 centres in China. Four-hundred-nine eligible participants were enroled, randomly assigned (1:1:1:1) and completed a 12-week treatment of either BBR-alone, probiotics+BBR, probiotics-alone, or placebo, after a one-week run-in of gentamycin pretreatment. The changes in glycated haemoglobin, as the primary outcome, in the probiotics+BBR (least-squares mean [95% CI], -1.04[-1.19, -0.89]%) and BBR-alone group (-0.99[-1.16, -0.83]%) were significantly greater than that in the placebo and probiotics-alone groups (-0.59[-0.75, -0.44]%, -0.53[-0.68, -0.37]%, P < 0.001). BBR treatment induced more gastrointestinal side effects. Further metagenomics and metabolomic studies found that the hypoglycaemic effect of BBR is mediated by the inhibition of DCA biotransformation by Ruminococcus bromii. Therefore, our study reports a human microbial related mechanism underlying the antidiabetic effect of BBR on T2D. (Clinicaltrial.gov Identifier: NCT02861261).
4.
Spexin peptide is expressed in human endocrine and epithelial tissues and reduced after glucose load in type 2 diabetes.
Gu, L, Ma, Y, Gu, M, Zhang, Y, Yan, S, Li, N, Wang, Y, Ding, X, Yin, J, Fan, N, et al
Peptides. 2015;71:232-9
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Little is known about the functions of the peptide spexin. Recent studies have shown a relationship between spexin and body weight regulation. It is thought that spexin might be related to glucose control and fat metabolism in type 2 diabetes mellitus (T2DM). The aim of this study was to examine the location of spexin in human tissue and measure spexin levels after a glucose load in T2DM patients. First, the researchers examined human tissue samples. Blood samples were then collected from 121 adults with T2DM and 105 healthy individuals. Additionally, an oral glucose tolerance test (OGTT) was performed on 12 healthy volunteers. In human tissue samples, the levels of spexin were highest in the adrenal gland, skin, stomach, small intestine, liver, thyroid, pancreatic islets, visceral fat, lung, colon, and kidney, and lowest in muscle and connective tissue. Blood levels of spexin were significantly lower in T2DM patients compared to healthy controls. Spexin levels were found to be inversely related to fasting blood glucose and lipids. During the OGTT, spexin levels were also inversely correlated with blood glucose levels. The authors concluded that spexin is highly expressed among endocrine and epithelial tissues. Changes in the blood levels of spexin could represent an adaptation to the rise of glucose and lipids associated with T2DM. However, the exact role of spexin in endocrine diseases is still to be discovered.
Abstract
Spexin mRNA and protein are widely expressed in rat tissues and associate with weight loss in rodents of diet-induced obesity. Its location in endocrine and epithelial cells has also been suggested. Spexin is a novel peptide that involves weight loss in rodents of diet-induced obesity. Therefore, we aimed to examine its expression in human tissues and test whether spexin could have a role in glucose and lipid metabolism in type 2 diabetes mellitus (T2DM). The expression of the spexin gene and immunoreactivity in the adrenal gland, skin, stomach, small intestine, liver, thyroid, pancreatic islets, visceral fat, lung, colon, and kidney was higher than that in the muscle and connective tissue. Immunoreactive serum spexin levels were reduced in T2DM patients and correlated with fasting blood glucose (FBG, r=-0.686, P<0.001), hemoglobin A1c (HbA1c, r=-0.632, P<0.001), triglyceride (TG, r=-0.236, P<0.001) and low density lipoprotein-cholesterol (LDL-C, r=-0.382, P<0.001). A negative correlation of blood glucose with spexin was observed during oral glucose tolerance test (OGTT). Spexin is intensely expressed in normal human endocrine and epithelial tissues, indicating that spexin may be involved in physiological functions of endocrine and in several other tissues. Circulating spexin levels are low in T2DM patients and negatively related to blood glucose and lipids suggesting that the peptide may play a role in glucose and lipid metabolism in T2DM.