Search Results (82)

Obesity is a complex chronic inflammatory condition that results from excess fat accumulation. It increases the risk of developing numerous co-morbidities such as Type 2 diabetes mellitus, cardiovascular disease, hypertension, and stroke. The adipose tissue is itself a vital endocrine organ that secretes numerous adipokines, cytokines, and exosomes, which are collectively known as the adipose-derived secretome (ADS). This ADS has been shown to influence and modulate many physiological processes. During obesity, the composition of ADS is altered, which may contribute to the development of obesity-associated diseases. Type-2 diabetes mellitus is one of the most common complications of obesity due to alterations in glucose homeostasis. Glucose absorption occurs via Na-glucose co-transport via SGLT1 at the brush border membrane (BBM) of small intestinal villus cells. This process of transepithelial glucose uptake is the primary method of glucose absorption from diet. However, how ADS mediates the function of SGLT1 is not yet known. This study aims to determine the mechanism of regulation of SGLT1 by ADS in intestinal epithelial cells. We show that ADS from OZR (but not LZR) stimulates SGLT1 in IEC-18 cells. OZR-ADS treatment diminished Na/K-ATPase activity in IEC-18 cells. Kinetic studies indicated that the mechanism of stimulation for SGLT1 during OZR-ADS treatment was secondary to an increase in the affinity (1/K_m) of the co-transporter for glucose without a change in co-transporter number. Western blot studies revealed that SGLT1 protein expression was unaltered in the two groups, confirming our kinetic studies. Immunoprecipitation demonstrated that an increase in the affinity of the SGLT1 protein was mediated by altered phosphorylation. In conclusion, during obesity, the adipose tissue secretome stimulates SGLT1 in intestinal epithelial cells, leading to an increase in affinity for glucose. The affinity change is due to alterations in SGLT1 phosphorylation. Together, these results may provide important insight into the mechanisms underlying altered glucose homeostasis in obesity and how this may lead to the development of Type 2 diabetes mellitus. Full article

After the first release of synthalin B (dodecamethylenbiguanide) in 1928 and its later retraction in the 1940s in Germany, the retraction of phenformin (N-Phenethylbiguanide) and of Buformin in the USA (but not outside) because of the lethal complication of acidosis seemed to have put an end to the era of the biguanides as oral antidiabetics. The strongly hygroscopic metformin (1-1-dimethylbiguanide), first synthesized 1922 and resuscitated as an oral antidiabetic (type 2 of the elderly) compound first released in 1959 in France and in other European countries, was used in the first large multicenter prospective long-term trial in England in the UKPDS (1977–1997). It was then released in the USA after a short-term prospective trial in healthy overweight “young” type 2 diabetics (mean age 53 years) in 1995 for oral treatment of type 2 diabetes. It was, however, prescribed to mostly multimorbid older patients (above 60–65 years of age). Metformin is now the most used oral drug for type 2 diabetes worldwide. While intravenous administration of biguanides does not have any glucose-lowering effect, their oral administration leads to enormous increase in their intestinal concentration (up to 300-fold compared to that measured in the blood), to reduced absorption of glucose from the diet, to increased excretion of glucose through the stool, and to decrease in insulin serum level through increased hepatic uptake and decreased production. Intravenously injected F18-labeled glucose in metformin-treated type 2 diabetics accumulates in the small and even more in the large intestine. The densitometry picture observed in metformin-treated overweight diabetics is like that observed in patients after bowel-cleansing or chronically taking different types of laxatives, where the accumulated radioactivity can even reach values observed in colon cancer. The glucose-lowering mechanism of action of metformin is therefore not only due to inhibition of glucose uptake in the small intestine but also to “attraction” of glucose from the hepatocyte into the intestine, possibly through the insulin-mediated uptake in the hepatocyte and its secretion into the bile. Furthermore, these compounds have also a diuretic effect (loss of sodium and water in the urine) Acute gastrointestinal side effects accompanied by fluid loss often lead to the drugs’ dose reduction and strongly limit adherence to therapy. Main long-term consequences are “chronic” dehydration, deficiency of vitamin B12 and of iron, and, as observed for all the biguanides, to “chronic” increase in fasting and postprandial lactate plasma level as a laboratory marker of a clinical condition characterized by hypotension, oliguria, adynamia, and evident lactic acidosis. Metformin is not different from the other biguanides: synthalin B, buformin, and phenformin. The mechanism of action of the biguanides as antihyperglycemic substances and their side effects are comparable if not even stronger (abdominal pain, nausea, vomiting, diarrhea, fluid loss) to those of laxatives. Full article

Background: Whether intestinal epithelial cells can regulate distant adipose tissue remains a mystery. Methods: Cold-stimulated intestinal epithelial cell-derived exosomes (Cold IEC-Exo) play a pivotal role in enhancing adipose thermogenesis and metabolic homeostasis, as demonstrated in this study. Results: IEC-Exo can accumulate in adipose tissue. Compared with IEC-Exo derived from room temperature mice (RT IEC-Exo), Cold IEC-Exo significantly enhanced the thermogenesis of adipose. In vitro, Cold IEC-Exo directly stimulated thermogenesis in primary adipocytes by elevating oxygen consumption rate, proton leak, and fatty acid uptake, with no effect on glucose uptake. Small RNA sequencing identified miR-674-3p as a key mediator enriched in Cold IEC-Exo. miR-674-3p mimicry replicated Cold IEC-Exo effects, augmenting Ucp1 expression, mitochondrial uncoupling, and fatty acid utilization in adipocytes. Local overexpression of miR-674-3p in BAT and sWAT via AAV in vivo enhanced thermogenesis and attenuated diet-induced glucose intolerance. Conclusions: These findings establish that Cold IEC-Exo, via miR-674-3p transfer, drive adipose thermogenic activation and mitigate metabolic dysfunction, highlighting their therapeutic potential in obesity-related disorders. Full article

Background/Objectives: Athletic performance matters for athletes and fitness enthusiasts. Scientific dietary intervention may boost athletic performance alongside training. Intermittent fasting, like time-restricted fasting (TF), may enhance metabolic health. NAD⁺ supplement nicotinamide mononucleotide (NMN) improves mitochondrial activity. Both potentially boost athletic performance. However, whether TF combined with NMN treatment can further enhance athletic ability is unclear. Methods: Healthy Kunming mice were utilized to test the effects of NMN and TF on the athletic performance of mice. To simulate the in vivo state and further verify the role of TF and NMN, low glucose combined with NMN was used to intervene in C2C12 cells. The exercise capacity of mice was evaluated through motor behavior experiments. At the same time, blood gas analysis and kit tests were used to assess oxygen uptake capacity and post-exercise oxidative stress levels. Muscle development and mitochondrial function were examined through gene expression, protein analysis, and enzyme activity tests, and the distribution of intestinal microbiota and short-chain fatty acid content were also analyzed. Results: The results show that TF combined with NMN improved mitochondrial dynamics and biosynthesis, mitochondrial respiratory function, and oxidative metabolism. Then, the intervention enhanced mice’s endurance, limb strength, motor coordination, and balance and reduced oxidative damage after exercise. Moreover, TF combined with NMN significantly increased the gut microbiota diversity and upregulated Ruminococcus, Roseburia, and Akkermansia in intestinal bacteria and short-chain fatty acids, which are associated with athletic performance. Conclusion: TF combined with NMN enhanced mitochondrial function, improved energy metabolism, modulated the gut microbiota and short-chain fatty acids, and affected muscle fiber transformation, ultimately leading to an overall improvement in exercise performance. These findings provide a theoretical framework for expanding the application of NMN and TF in kinesiology. Full article

Background/Objectives: Obesity impairs intestinal glucose uptake (GU) (intestinal uptake of circulating glucose from blood) and alters gut microbiome. Exercise improves intestinal insulin-stimulated GU and alters microbiome. Genetics influence the risk of obesity and gut microbiome. However, the role of genetics on the effects of exercise on intestinal GU and microbiome is unclear. Methods: Twelve monozygotic twin pairs discordant for BMI (age 40.4 ± 4.5 years, BMI heavier 36.7 ± 6.0, leaner 29.1 ± 5.7, 8 female pairs) performed a six-month-long training intervention. Small intestine and colonic insulin-stimulated GU was studied using [¹⁸F]FDG-PET and microbiota from fecal samples with 16s rRNA. Results: Ten pairs completed the intervention. At baseline, heavier twins had lower small intestine and colonic GU (p < 0.05). Response to exercise differed between twins (p = 0.05), with leaner twins increasing colonic GU. Alpha and beta diversity did not differ at baseline. During the intervention, beta diversity changed significantly, most prominently at the mid-point (p < 0.01). Beta diversity changes were only significant in the leaner twins when the twin groups were analyzed separately. Exercise was associated with changes at the phylum level, mainly at the mid-point (pFDR < 0.05); at the genus level, several microbes increased, such as Lactobacillus and Sellimonas (pFDR < 0.05). In type 1 analyses, many genera changes were associated with exercise, and fewer, such as Lactobacillus, were also associated with dietary sugar consumption (p < 0.05). Conclusions: Obesity impairs insulin-stimulated intestinal GU independent of genetics. Though both twin groups exhibited some microbiota changes, most changes in insulin-stimulated colon GU and microbiota were significant in the leaner twins. Full article

In the small intestine, sodium (Na) absorption occurs primarily via two apical transporters, Na-hydrogen exchanger 3 (NHE3) and Na-glucose cotransporter 1 (SGLT1). The two primary Na-absorptive pathways were previously shown to compensatorily regulate each other in rabbit and rat intestinal epithelial cells. However, whether NHE3 and SGLT1 regulate one another in normal human enterocytes is unknown, mainly due to a lack of appropriate experimental models. To investigate this, we generated 2D enterocyte monolayers from human jejunal 3D organoids and used small interfering RNAs (siRNAs) to knock down NHE3 or SGLT1. Molecular and uptake studies were performed to determine the effects on NHE3 and SGLT1 expression and activity. Knockdown of NHE3 by siRNA in enterocyte monolayers was verified by qPCR and Western blot analysis and resulted in reduced NHE3 activity. However, in NHE3 siRNA-transfected cells, SGLT1 activity was significantly increased. siRNA knockdown of SGLT1 was confirmed by qPCR and Western blot analysis and resulted in reduced SGLT1 activity. However, in SGLT1 siRNA-transfected cells, NHE3 activity was significantly increased. These results demonstrate for the first time the functionality of siRNA in patient-derived organoid monolayers. Furthermore, they show that the two primary Na absorptive pathways in human enterocytes reciprocally regulate one another. Full article

In the small intestine, nutrients from ingested food are absorbed and broken down by enterocytes, which constitute over 95% of the intestinal epithelium. Enterocytes demonstrate diet- and segment-dependent metabolic flexibility, enabling them to take up large amounts of glutamine and glucose to meet their energy needs and transfer these nutrients into the bloodstream. During glycolysis, ATP, lactate, and H⁺ ions are produced within the enterocytes. Based on extensive but incomplete glutamine oxidation large amounts of alanine or lactate are produced. Lactate, in turn, promotes hypoxia-inducible factor-1α (Hif-1α) activation and Hif-1α-dependent transcription of various proton channels and exchangers, which extrude cytoplasmic H⁺-ions into the intestinal lumen. In parallel, the vitamin C-dependent and duodenal cytochrome b-mediated conversion of ferric iron into ferrous iron progresses. Finally, the generated electrochemical gradient is utilized by the divalent metal transporter 1 for H⁺-coupled uptake of non-heme Fe²⁺-ions. Iron efflux from enterocytes, subsequent binding to the plasma protein transferrin, and systemic distribution supply a wide range of cells with iron, including erythroid precursors essential for erythropoiesis. In this review, we discuss the impact of vitamin C on the redox capacity of human erythrocytes and connect enterocyte function with iron metabolism, highlighting its effects on erythropoiesis. Full article

For early hominids, frequent encounters with plant foods necessitated the ability to discern bitter poisons and adjust the activity of the gastrointestinal system in anticipation of carbohydrate-rich meals. Plants bitters were also used historically to manage a variety of metabolic and digestive disorders despite an immense structural diversity of bitter phytochemicals without a common molecular target. Our study confirms these observations in a standardized C57BL/6J prediabetic mouse model using 24 model compounds by demonstrating acute lower peak blood glucose values and improved glucose tolerance following intragastric, but not intraperitoneal, treatment. The administration of the synthetic bitter compound denatonium benzoate yielded similar results that were attenuated by co-application of the allosteric inhibitor of the bitter TAS2R receptors. We also show that these effects occur dose-dependently; associate with reduced glucose uptake, increased intracellular [Ca²⁺] fluxes, and enhanced GLP-1 expression; and are attenuated by the TAS2R inhibitor in the neuroendocrine STC-1 intestinal cells. These findings support the view that inhibition of glucose transport from the intestinal lumen to the blood by TAS2R bitter receptor signaling in the gut may represent a common mechanism in the acute response to oral ingestion of bitter phytochemicals. Full article

Diabetes mellitus (DM) is a global health concern characterized by a deficiency in insulin production. Considering the systemic toxicity and limited efficacy associated with current antidiabetic medications, there is the utmost need for natural, plant-based alternatives. Herbal medicines have experienced exponential growth in popularity globally in recent years for their natural origins and minimal side effects. Ecuador has a rich cultural history in ethnobotany that plays a crucial role in its people’s lives. This study identifies 27 Ecuadorian medicinal plants that are traditionally used for diabetes treatment and are prepared through infusion, decoction, or juice, or are ingested in their raw forms. Among them, 22 plants have demonstrated hypoglycemic or anti-hyperglycemic properties that are rich with bioactive phytochemicals, which was confirmed in several in vitro and in vivo studies. However, Bryophyllum gastonis-bonnieri, Costus villosissimus, Juglans neotropica, Pithecellobium excelsum, and Myroxylon peruiferum, which were extensively used in traditional medicine preparation in Ecuador for many decades to treat diabetes, are lacking in pharmacological elucidation. The Ecuadorian medicinal plants used to treat diabetes have been found to have several bioactive compounds such as flavonoids, phenolics, fatty acids, aldehydes, and terpenoids that are mainly responsible for reducing blood sugar levels and oxidative stress, regulating intestinal function, improving insulin resistance, inhibiting α-amylase and α-glucosidase, lowering gluconeogenic enzymes, stimulating glucose uptake mechanisms, and playing an important role in glucose and lipid metabolism. However, there is a substantial lack of integrated approaches between the existing ethnomedicinal practices and pharmacological research. Therefore, this review aims to discuss and explore the traditional medicinal plants used in Ecuador for treating DM and their bioactive phytochemicals, which are mainly responsible for their antidiabetic properties. We believe that the use of Ecuadorian herbal medicine in a scientifically sound way can substantially benefit the local economy and industries seeking natural products. Full article

The reabsorption of uric acid (UA) is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys. Dotinurad inhibits URAT1 but does not inhibit other UA transporters, such as GLUT9, ATP-binding cassette transporter G2 (ABCG2), and organic anion transporter 1/3 (OAT1/3). We found that dotinurad ameliorated the metabolic parameters and renal function in hyperuricemic patients. We consider the significance of the highly selective inhibition of URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). The selective inhibition of URAT1 by dotinurad increases urinary UA in the proximal tubules, and this un-reabsorbed UA may compete with urinary glucose for GLUT9, reducing glucose reabsorption. The inhibition by dotinurad of UA entry via URAT1 into the liver and adipose tissues increased energy expenditure and decreased lipid synthesis and inflammation in rats. Such effects may improve metabolic parameters. CKD patients accumulate uremic toxins, including indoxyl sulfate (IS), in the body. ABCG2 regulates the renal and intestinal excretion of IS, which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into the kidneys, thereby increasing plasma IS, which produces oxidative stress and induces vascular endothelial dysfunction in CKD patients. The highly selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD, and CVD. Full article

This study aimed to evaluate the effects of a complex comprising formic acid, benzoic acid, and essential oils (AO3) on the growth performance of weaned piglets and explore the underlying mechanism. Dietary AO3 supplementation significantly enhanced the average daily gain (ADG) and average daily feed intake (ADFI), while decreasing the feed conversion rate (FCR) and diarrhea rate (p < 0.05). Additionally, AO3 addition altered the fecal microflora composition with increased abundance of f_Prevotellaceae. LPS challenges were further conducted to investigate the detailed mechanism underlying the benefits of AO3 supplementation. The piglets fed with AO3 exhibited a significant increase in villus height and decrease in crypt depth within the jejunum, along with upregulation of ZO-1, occludin, and claudin-1 (p < 0.05) compared with those piglets subjected to LPS. Furthermore, AO3 supplementation significantly ameliorated redox disturbances (T-AOC, SOD, and GSH) and inflammation (TNF-α, IL-1β, IL-6, and IL-12) in both the serum and jejunum of piglets induced by LPS, accompanied by suppressed activation of the MAPK signaling pathway (ERK, JNK, P38) and NF-κB. The LPS challenge downregulated the activation of the AMPK signaling pathway, mRNA levels of electron transport chain complexes, and key enzymes involved in ATP synthesis, which were significantly restored by the AO3 supplementation. Additionally, AO3 supplementation restored the reduced transport of amino acids, glucose, and fatty acids induced by LPS back to the levels observed in the control group. In conclusion, dietary AO3 supplementation positively affected growth performance and gut microbiota composition, also enhancing intestinal barrier integrity, nutrient uptake, and energy metabolism, as well as alleviating oxidative stress and inflammation under LPS stimulation. Full article

Diabetes is caused by abnormal glucose metabolism, and muscle, the largest tissue in the human body, is largely involved. Urolithin A (UroA) is a major intestinal and microbial metabolite of ellagic acid and ellagitannins and is found in fruits such as strawberry and pomegranate. In this present study, we investigated the antidiabetic effects of UroA in L6 myotubes and in KK-A^y/Ta, a mouse model of type 2 diabetes (T2D). UroA treatment elevated the glucose uptake (GU) of L6 myotubes in the absence of insulin. This elevation in GU by UroA treatment was partially inhibited by the concurrent addition of LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K) which activates Akt (PKB: protein kinase B) or Compound C, an inhibitor of 5′-adenosine monophosphate-activated protein kinase (AMPK). Moreover, UroA was found to activate both pathways of Akt and AMPK, and then to promote translocation of glucose transporter 4 (GLUT4) from the cytosol to the plasma membrane in L6 myotubes. Based on these in vitro findings, an intraperitoneal glucose tolerance test (IPGTT) was performed after the oral administration of UroA for 3 weeks to KK-A^y/Ta mice with glucose intolerance. UroA was demonstrated to alleviate glucose intolerance. These results suggest that UroA is a biofactor with antihyperglycemic effects in the T2D state. Full article

In piglets, it is observed that early weaning can lead to poor weight gain due to an underdeveloped gastrointestinal (GI) tract, which is unsuitable for an efficient absorption of nutrients. Short-chain fatty acids (SCFAs) such as butyrate have demonstrated their ability to improve intestinal development by increasing cell proliferation, which is vital during this transition period when the small and large intestinal tracts are rapidly growing. Previous reports on butyrate inclusion in feed demonstrated significantly increased feed intakes (FIs) and average daily gains (ADGs) during piglet weaning. Similar benefits in piglet performance have been observed with the inclusion of yeast cell wall in diets. A proprietary mix of yeast cell wall, SCFAs, and zinc proteinate (YSM) was assessed here in vitro to determine its impact on cellular growth, metabolism and appetite-associated hormones in ex vivo small intestinal pig cells and STC-1 mouse intestinal neuroendocrine cells. Intestinal cells demonstrated greater cell densities with the addition of YSM (150 ppm) compared to the control and butyrate (150 ppm) at 24 h. This coincided with the higher utilisation of both protein and glucose from the media of intestinal cells receiving YSM. Ghrelin (an appetite-inducing hormone) demonstrated elevated levels in the YSM-treated cells on a protein and gene expression level compared to the cells receiving butyrate and the control, while satiety hormone peptide YY protein levels were lower in the cells receiving YSM compared to the control and butyrate-treated cells across each time point. Higher levels of ghrelin and lower PYY secretion in cells receiving YSM may drive the uptake of protein and glucose, which is potentially facilitated by elevated gene transporters for protein and glucose. Greater ghrelin levels observed with the inclusion of YSM may contribute to higher cell densities that could support pig performance to a greater extent than butyrate alone. Full article

Sweet cherry (Prunus avium L.) is among the most valued fruits due to its organoleptic properties and nutritional worth. Cherry stems are rich in bioactive compounds, known for their anti-inflammatory and antioxidant properties. Innumerable studies have indicated that some bioactive compounds can modulate sugar absorption in the small intestine. In this study, the phenolic profile of a cherry stem infusion was investigated, as well as its capacity to modulate intestinal glucose and fructose transport in Caco-2 cells. Long-term (24 h) exposure to cherry stem infusion (25%, v/v) significantly reduced glucose (³H-DG) and fructose (¹⁴C-FRU) apical uptake, reduced the apical-to-basolateral P_app to ³H-DG, and decreased mRNA expression levels of the sugar transporters SGLT1, GLUT2 and GLUT5. Oxidative stress (induced by tert-butyl hydroperoxide) caused an increase in ³H-DG uptake, which was abolished by the cherry stem infusion. These findings suggest that cherry stem infusion can reduce the intestinal absorption of both glucose and fructose by decreasing the gene expression of their membrane transporters. Moreover, this infusion also appears to be able to counteract the stimulatory effect of oxidative stress upon glucose intestinal uptake. Therefore, it can be a potentially useful compound for controlling hyperglycemia, especially in the presence of increased intestinal oxidative stress levels. Full article

Type 2 diabetes (T2D) is a global health challenge with increased morbidity and mortality rates yearly. Herbal medicine has provided an alternative approach to treating T2D with limited access to formal healthcare. Tectona grandis is being used traditionally in the treatment of diabetes. The present study investigated the antidiabetic potential of T. grandis leaves in different solvent extractions, and the crude extract that demonstrated the best activity was further fractionated through solvent–solvent partitioning. The ethyl acetate fraction of the ethanol crude extract showed the best antidiabetic activity in inhibiting α-glucosidase, delaying glucose absorption at the small intestine’s lumen, and enhancing the muscle’s postprandial glucose uptake. The ethyl acetate fraction was further elucidated for its ability to reduce hyperglycemia in diabetic rats. The ethyl acetate fraction significantly reduced high blood glucose levels in diabetic rats with concomitant modulation in stimulated insulin secretions through improved pancreatic β-cell function, insulin sensitivity by increasing liver glycogen content, and reduced elevated levels of liver glucose-6-phosphatase activity. These activities could be attributed to the phytochemical constituents of the plant. Full article