Sodium­glucose cotransporter­2 inhibitors in obesity and associated cardiometabolic disorders: where do we stand?

As the tide of obesity and its complications are on the rise, there is an urgent need for new drugs with weight­lowering and beneficial metabolic properties. Obesity­related disorders, such as metabolic syndrome, prediabetes, type 2 diabetes (T2D), cardiovascular disease, and nonalcoholic fatty liver disease (NAFLD) make this need more than mandatory. Sodium­glucose cotransporter­2 (SGLT­2) inhibitors (empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin) are the latest class of agents to receive approval for the treatment of T2D. Not long after their marketing, a wide spectrum of target organ­protective and overall beneficial health effects associated with their use began to unveil. An increasing bulk of evidence indicates that these actions are to a great degree independent of glucose lowering, which has led to the broadening of the indications for SGLT­2 inhibitors outside the frame of antihyperglycemic therapy. Additionally, their unique mode of action including increased renal glucose excretion, and hence net energy loss, could render SGLT­2 inhibitors attractive candidates for the treatment of obesity. Very few reviews in the literature have holistically appraised the therapeutic potential of SGLT­2 inhibitors in obesity and its associated complications. Herein, we summarize the currently available evidence regarding the effects of drugs of this class on body adiposity, together with considerations on their potential use as weight loss agents. Furthermore, we attempt to overview their actions and future perspectives of their use with respect to a range of obesity­related disorders, which include cardiovascular, renal, and ovarian dysfunctions, as well as NAFLD and malignancy.

Therapeutic Potential of GLP-2 Analogs in Gastrointestinal Disorders: Current Knowledge, Nutritional Aspects, and Future Perspectives.

PURPOSE OF REVIEW: Although Glucagon-like peptide (GLP)-1 receptor agonists have been used for almost two decades in the treatment of diabetes mellitus type 2 and, lately, in obesity, recent years have seen an increasing interest in the pharmacological agonism of other proglucagon-derived peptides, including GLP-2. Herein, we aimed to review the available evidence on the effects of GLP-2 agonism from animal and clinical studies. Furthermore, we summarize the current clinical applications of GLP-2 agonists among patients with intestinal failure associated with short bowel syndrome (SBS-IF) as well as potential future expansion of their indications to other intestinal disorders. RECENT FINDINGS: Evidence from preclinical studies has highlighted the cellular trophic and functional beneficial actions of GLP-2 on small intestinal and colonic mucosa. Subsequently, pharmacologic agonism of GLP-2 has gathered interest for the treatment of patients with conditions pertaining to the loss of intestinal anatomical and/or functional integrity to a degree requiring parenteral support, collectively referred to as intestinal failure. GLP-2 analogs positively influence nutrient absorption in animal models and humans, although continued therapy is likely needed for sustained effects. The degradation-resistant GLP-2-analog teduglutide has received approval for the treatment of SBS-IF, in which it may decisively reduce patient dependency on parenteral support and improve quality of life. Another two longer-acting analogs, glepaglutide and apraglutide, are currently undergoing phase III clinical trials. The use of GLP-2 analogs is effective in the management of SBS-IF and may show promise in the treatment of other severe gastrointestinal disorders associated with loss of effective intestinal resorptive surface area.

Obesity, Hypovitaminosis D, and COVID-19: the Bermuda Triangle in Public Health.

PURPOSE OF REVIEW: The COVID-19 pandemic has challenged public health to a significant extent by markedly increasing morbidity and mortality. Evidence suggests that obesity and hypovitaminosis D constitute important risk factors for SARS-CoV-2 infection, severity of disease, and poor outcomes. Due to their high prevalence globally, obesity and hypovitaminosis D are considered pandemics. This review presents current epidemiologic and genetic data linking obesity, hypovitaminosis D, and COVID-19, highlighting the importance of the convergence of three pandemics and their impact on public health. We also briefly summarize potential mechanisms that could explain these links. RECENT FINDINGS: Epidemiologic data have shown that obesity is an independent risk factor for COVID-19, severe disease and death, and genetic evidence has suggested a causal association between obesity-related traits and COVID-19 susceptibility and severity. Additionally, obesity is independently associated with hypovitaminosis D, which is highly prevalent in subjects with obesity. Hypovitaminosis D is independently associated with a higher risk for COVID-19, severity, hospitalization, infectious complications, acute respiratory distress syndrome, and poor outcomes. However, genome-wide association studies have not revealed any causal association between vitamin D levels and the risk for COVID-19, while there is no robust evidence for a beneficial role of vitamin D supplementation in the prevention and treatment of COVID-19. In the context of the ongoing COVID-19 pandemic, the epidemiologic impact of obesity and hypovitaminosis D is emphasized. Efforts to increase public awareness and reinforce preventive and therapeutic measures against obesity and hypovitaminosis D are strongly required.

Vitamin D and Obesity: Current Evidence and Controversies.

PURPOSE OF REVIEW: Evidence from observational studies suggests that obesity is associated with low vitamin D. As both obesity and hypovitaminosis D present an alarmingly increased prevalence worldwide, there is an intense research interest to clarify all aspects of this association. This review summarizes current evidence from meta-analyses investigating vitamin D status in obesity, including the effects of weight loss and bariatric surgery on vitamin D status and the outcomes of vitamin D supplementation on body weight. We also discuss potential pathophysiologic mechanisms and important controversies. RECENT FINDINGS: Data from meta-analyses consistently support an inverse association of vitamin D levels with body weight. However, the impact of weight loss on improving vitamin D status is small, while studies on the supplementation with vitamin D after bariatric surgery have shown conflicting results regarding vitamin D status. Moreover, interventional studies do not support a beneficial effect of vitamin D supplementation on body weight. These findings warrant a cautious interpretation due to important methodological limitations and confounding factors, such as high heterogeneity of studies, variable methods of determination of vitamin D and definition of deficiency/insufficiency, use of various adiposity measures and definitions of obesity, and inadequate adjustment for confounding variables influencing vitamin D levels. The underlying pathogenetic mechanisms associating low vitamin D in obesity include volumetric dilution, sequestration into adipose tissue, limited sunlight exposure, and decreased vitamin D synthesis in the adipose tissue and liver. Experimental studies have demonstrated that low vitamin D may be implicated in adipose tissue differentiation and growth leading to obesity either by regulation of gene expression or through modulation of parathyroid hormone, calcium, and leptin. Obesity is associated with low vitamin D status but weight loss has little effect on improving this; vitamin D supplementation is also not associated with weight loss. Evidence regarding vitamin D status after bariatric surgery is contradicting. The link between vitamin D and obesity remains controversial due to important limitations and confounding of studies. More research is needed to clarify the complex interplay between vitamin D and adiposity.

Probiotics, Prebiotics, Synbiotics, Postbiotics, and Obesity: Current Evidence, Controversies, and Perspectives.

PURPOSE OF REVIEW: In this review, we summarize current evidence on gut microbiome and obesity; we discuss the role of probiotics, prebiotics, synbiotics, and postbiotics in obesity prevention and management; and we highlight and analyze main limitations, challenges, and controversies of their use. RECENT FINDINGS: Overall, the majority of animal studies and meta-analyses of human studies examining the use of probiotics and synbiotics in obesity has shown their beneficial effects on weight reduction and other metabolic parameters via their involvement in gut microbiota modulation. Bifidobacterium and Lactobacillus strains are still the most widely used probiotics in functional foods and dietary supplements, but next generation probiotics, such as Faecalibacterium prausnitzii, Akkermansia muciniphila, or Clostridia strains, have demonstrated promising results. On the contrary, meta-analyses of human studies on the use of prebiotics in obesity have yielded contradictory results. In animal studies, postbiotics, mainly short-chain fatty acids, may increase energy expenditure through induction of thermogenesis in brown adipose tissue as well as browning of the white adipose tissue. The main limitations of studies on biotics in obesity include the paucity of human studies; heterogeneity among the studied subgroups regarding age, gender, and lifestyle; and use of different agents with potential therapeutic effects in different formulations, doses, ratio and different pharmacodynamics/pharmacokinetics. In terms of safety, the supplementation with prebiotics, probiotics, and synbiotics has not been associated with serious adverse effects among immune-competent individuals, with the exception of the use of probiotics and synbiotics in immunocompromised patients. Further large-scale Randomized Controlled Trials (RCTs) in humans are required to evaluate the beneficial properties of probiotics, prebiotics, synbiotics, and postbiotics; their ideal dose; the duration of supplementation; and the durability of their beneficial effects as well as their safety profile in the prevention and management of obesity.

Persistent hypokalemia due to a rare mutation in gitelman's syndrome.

Chronic hypokalemia is the main finding in patients with Gitelman's syndrome (GS). GS, a variant of Bartter's syndrome, is an autosomal recessive renal disorder characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. GS is caused by inactivating mutations in the thiazide-sensitive sodium-chloride cotransporter gene. It is also called the "milder" form of Bartter's syndrome, as patients with GS are usually diagnosed in adulthood during routine investigation. Our objective is to highlight the impact of correct distinction between the causes of hypokalemia on management and the need of long-term follow- up after the restoration of normokalemic status. Herein, we report an asymptomatic 40-year-old male, whose persistent hypokalemia was due to GS. The diagnosis was first established by laboratory tests, and he was treated with low-dose aldosterone antagonists (spironolactone), angiotensin-converting enzyme inhibitors, and potassium and magnesium supplements. Genetic testing confirmed the diagnosis of GS and revealed a rare mutation. We conclude that GS is a rare and real diagnostic and therapeutic challenge, for which a close collaboration between endocrinologists and nephrologists is mandatory, as also the thorough genetic investigation of the mutations associated with this syndrome.

The effect of Nigella sativa L. supplementation on serum C-reactive protein: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Evidence on the efficacy ofNigella sativa supplementation is equivocal, thus the aim of this systematic review and meta-analysis of randomized clinical trials (RCTs) was to examine the effect of Nigella sativa (N. sativa) supplementation on plasma C-reactive protein (CRP) concentrations. METHODS: PubMed, Scopus, ISI Web of Science, Cochrane library, and Google Scholar databases were searched (up to April 2019) to identify RCTs investigating the effects of N. sativa seed and seed oil supplementation on CRP. Weighted mean differences (WMD) was pooled using a random-effects model. Standard methods were also used for assessment of heterogeneity, sensitivity analysis, and publication bias. RESULTS: Eventually only five articles which reported data of interest entered for data analysis. The meta-analysis showed a significant reduction in serum CRP (WMD: -0.55 mg/L, 95% CI: -1.02, -0.08, P = 0.02), with significant heterogeneity between selected studies (I2 = 77.3%). Between-study heterogeneity disappeared following subgroup analysis, stratified by baseline BMI (≥30 kg/m2: I2 = 2.8%). However, the effect of N. sativa seed and seed oil supplementation on CRP was only significant in studies that were conducted on participants with BMI ≥ 30 kg/m2 (WMD: -0.50 mg/L, 95% CI: -0.85, -0.15). CONCLUSIONS: This meta-analysis suggests thatN. sativa seed and seed oil supplementation can significantly reduce serum CRP level. However, RCTs with a larger sample size and longer follow-up periods should be conducted for future investigations to confirm the veracity of these results.

Effect of cinnamon (Cinnamomum Zeylanicum) supplementation on serum C-reactive protein concentrations: A meta-analysis and systematic review.

OBJECTIVE: The effect of cinnamon (Cinnamomum Zeylanicum) on serum C-reactive protein (CRP), an acute phase protein commonly used as a marker of inflammation, is uncertain. Therefore, the objective of the present study was to conduct a systematic review and meta-analysis of published randomised controlled trials (RCTs) of cinnamon to determine the effect on levels of serum CRP, relative to controls. DESIGN: Studies were identified by a search of electronic databases including PubMed, Cochrane Library, Google Scholar and Scopus before August 2018. Combined and stratified analyses were used. Weighted mean differences (WMD) and its 95% confidence interval were estimated for net change in serum CRP by using random-effects model. The heterogeneity of meta-analysis was assessed by χ2 and I2 test. RESULTS: Six studies were identified, and data from 285 participants were included. Pooled analysis showed significant reductions in serum CRP (WMD: -0.81 mg/L, 95% CI: -1.36 to -0.26, p = 0.004), with significant heterogeneity between selected studies. Improvements in sub-group analysis were observed when baseline CRP levels were greater than 3 mg/dL, and in trials of >12 weeks duration. Doses <1500 mg/day and ≥1500 mg/day were effective in lowering serum CRP (WMD: -0.56 mg/dL, 95% CI: -1.01 to -0.10, p = 0.02 and WMD: -2.13 mg/dL, 95% CI: -4.08 to -0.19, p = 0.03), respectively, with significantly reduced heterogeneity in trials with lower doses of cinnamon <1500 mg/day (test for heterogeneity: P = 0.22 and I2 = 33%). No changes were found in controls. CONCLUSION: Cinnamon supplementation improves levels of serum CRP, particularly in chronic conditions, where basal CRP levels are raised. Further well-designed studies are warranted to confirm or not the above-mentioned findings.

The therapeutic potential of milk thistle in diabetes.

Milk thistle has been known for more than 2.000 years as a herbal remedy for a variety of disorders. It has mainly been used to treat liver and gallbladder diseases. Silibum marianum, the Latin term for the plant, and its seeds contain a whole family of natural compounds, called flavonolignans. Silimarin is a dry mixture of these compounds; it is extracted after processing with ethanol, methanol, and acetone. Silimarin contains mainly silibin A, silibin B, taxifolin, isosilibin A, isosilibin B, silichristin A, silidianin, and other compounds in smaller concentrations. Apart from its use in liver and gallbladder disorders, milk thistle has recently gained attention due to its hypoglycemic and hypolipidemic properties. Recently, a substance from milk thistle has been shown to possess peroxisome proliferator-activated receptor γ (PPARγ) agonist properties. PPARγ is the molecular target of thiazolidinediones, which are used clinically as insulin sensitizers to lower blood glucose levels in diabetes type 2 patients. The thiazolidinedione type of PPARγ ligands is an agonist with a very high binding affinity. However, this ligand type demonstrates a range of undesirable side effects, thus necessitating the search for new effective PPARγ agonists. Interestingly, studies indicate that partial agonism of PPARγ induces promising activity patterns by retaining the positive effects attributed to the full agonists, with reduced side effects. In this review, the therapeutic potential of milk thistle in the management of diabetes and its complications are discussed.

Resveratrol and diabetes.

Resveratrol is a stilbene compound, and a phytoalexin, synthesized by plants in response to stressful stimuli, usually caused by infection. It is abundantly present in red wine, ports and sherries, red grapes, blueberries, peanuts, itadori tea, as well as hops, pistachios, and in grape and cranberry juices. The anti-hyperglycemic effects of resveratrol seem to be the result of an increased action of the glucose transporter in the cytoplasmic membrane. Studies on rats with streptozotocin-induced diabetes have demonstrated that the expression of the insulin-dependent glucose transporter, GLUT4, is increased after resveratrol ingestion. Also, resveratrol enhances adiponectin levels, which could be one of the potential mechanisms by which it improves insulin sensitivity. Another important observation is that resveratrol induces the secretion of the gut incretin hormone, glucagon-like peptide-1. Resveratrol is also reported to activate Sir2 (silent information regulatory 2), a SIRT1 homolog, thus mimicking the benefits of calorie restriction. It produces a wide variety of effects in mammalian cells, including activation of AMP-activated protein kinase, which is involved in some of the same metabolic pathways as SIRT1, which may influence other mechanisms via the involvement of nuclear factor kappa B (NF-κB). In the near future, resveratrol-based therapies with either resveratrol or its analogs that have better bioavailability could be useful in the treatment of diabetes and its complications, either alone or in combination with other anti-diabetic drugs.