Search Results (123)

Insulin resistance (IR) describes impaired hormone signaling that triggers compensatory homeostatic responses resulting in hyperinsulinemia, increased accumulation of fatty substrates, lipotoxicity, oxidative stress, inflammation, cell death and fibrosis in target tissues. These processes ultimately lead to organ dysfunction and predispose certain individuals to various types of cancer. In this context, we will review the molecular pathogenesis and clinical significance of IR, its role in ‘metaflammation’, and the damage caused by IR in the pancreas, cardiovascular system, liver, and kidneys. Additionally, we will discuss principles of drug treatment for IR and outline a research agenda in this field. Full article

The prevalence of chronic diseases, including obesity and related endocrine disorders, has risen significantly in recent decades. As a result, there has been growing interest in fermented foods with probiotic properties, such as kefir, which have potential health benefits. This study aimed to evaluate the hepatoprotective and antioxidant effects of kefir milk (KM) in a high-fat diet (HFD)-induced obesity rat model, complemented by in silico molecular docking studies with antioxidant enzymes. Twenty-four adult rats were divided into four groups: control (1 mL/100 g bw semi-skimmed cow milk), KM (1 mL/100 g bw kefir milk), HFD (1 mL/100 g bw semi-skimmed cow milk + high-fat diet), and KM/HFD (1 mL/100 g bw kefir milk + high-fat diet). After 60 days of treatment, biochemical assays and histological examinations were performed to assess the effects on lipid profiles and organ health. Kefir milk demonstrated significant antioxidant activity, with increased total phenolic content and enhanced DPPH, ABTS, and FRAP radical scavenging activities compared to commercial milk. Furthermore, KM administration protected against liver metabolic disruptions (ALT, AST, and LDH) induced by the high-fat diet and reduced lipid peroxidation in liver and testis tissues. KM supplementation also increased the activity of key antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Additionally, KM improved the fatty acid composition and decreased the de novo lipogenesis (DNL) index, as well as enzyme activities (SCD and Elovl6) associated with the high-fat diet. Histological analysis of liver, pancreas, and heart tissues revealed that kefir milk attenuated structural damage caused by the high-fat diet, suggesting its protective role in oxidative stress regulation and organ function. These findings underscore the potential of kefir milk as a functional food for preventing metabolic disturbances and liver damage associated with obesity. Full article

Background/Objectives: Developing and implementing clinical trials for rare diseases is complicated by the incomplete understanding of the varied genotype and subsequent phenotypic differences of a condition, particularly when low numbers of subjects are enrolled in a study. Moreover, a small-scale clinical study may indicate a positive outcome but have too small of a sampling population to adequately evaluate unwanted outcomes. Prader–Willi syndrome (PWS) is one such genetic disorder with varied subtypes and heterogeneity, where little progress has been made in treatment discoveries. Recently, the FDA approved diazoxide choline for treating key features of hyperphagia and obesity associated with PWS based on clinical trial experience. Diazoxide choline activates the ATP-sensitive potassium channel (KATP) of pancreatic beta cells, inhibiting the release of insulin. One of the subunits of KATP is the protein Kir6.2, the gene product of KCNJ11. Methods: Web-based programs and datasets were used to study the gene and protein functional enrichments of Kir6.2 and KCNJ11, including shared gene and/or protein–protein interactions, and biological processes and functions. Results: Four essential domains of related functions were identified: (1) apoptosis, protein degradation, and inflammation; (2) the coupling of G proteins needed for KATP channel activation; (3) glucose metabolism and control; and (4) the maintenance of intracellular ionic homeostasis. Conclusions: Cellular metabolism in the pancreas is linked to membrane excitability by KATP, which regulates insulin production, energy production and storage, appetite regulation, and fatty acid synthesis. As such, diazoxide choline may influence several biological systems beyond pancreatic and metabolic functions. Full article

Genetic background, the “Western diet”, and environment may all contribute to hyperinsulinemia. Hyperinsulinemia can precede and cause insulin resistance. In situations of fuel overload, insulin resistance limits the amount fuel (glucose and fatty acids) entering insulin-sensitive tissues. When energy intake is chronically greater than energy expenditure, the capacity of the subcutaneous fat tissues to store fat can be overpowered. If subcutaneous fat tissues are no longer able to accommodate excess energy, there will be spillover of lipids. Excess calories will be stored as ectopic fat (triglycerides) in the liver, pancreas, and skeletal muscle. Growing evidence suggests that ectopic fat deposition directly causes insulin resistance and pancreatic beta cell dysfunction. Overnutrition and ectopic fat increase diacylglycerol (DAG) accumulation in fat cells, hepatocytes, and skeletal muscle cells. A unifying hypothesis proposes that translocated DAG into the plasma membrane induces insulin resistance in all these three cell types. In addition, ectopic fat accumulation in the pancreas induces beta-cell dysfunction. Introducing a negative energy balance by bariatric surgery or a very low-calorie diet (VLCD) reduces ectopic fat depositions from the liver and pancreas and decreases intracellular DAG content: both are effective treatments to restore insulin sensitivity, normalize metabolism, and put type 2 diabetes in remission. Full article

Background: The dysregulation of both glucose and lipid metabolism is the main clinical features of type 2 diabetes. Qihua Tongtiao Formula (QHTTF) is our team’s current clinical empirical formula, and the related patent has been granted. It is composed of Astragalus membranaceus, Atractylodes macrocephala koidz, Aurantii Fructus Immaturus, Radix Bupleuri, Ligusticum chuanxiong hort, Angelicae sinensis radix, Raphanus sativus, and Polyporus umbellatus. It can alleviate tissue pathological damage in type 2 diabetic rats by improving glycolipid metabolism disorders. Nevertheless, the specific mechanisms of QHTTF in the treatment of type 2 diabetes remain unclear. Purpose: This research aims to explore the fundamental effect and underlying mechanism of the QHTTF formula in ZDF rats via network pharmacology, biological validation, and metabolomics technology. Methods: The chemical compounds of QHTTF were initially identified via UHPLC-MS/MS analysis. Meanwhile, drug targets, genes, related diseases, and differential metabolites of QHTTF in the treatment of T2DM were obtained through network pharmacology, molecular docking, and metabolomics. Then, we conducted animal experiments to further explore the therapeutic molecular mechanism of QHTTF in ZDF rats. Results: A total of 39 main chemical components were recognized through LC-MS/MS technology, and 22 remained after the second screening. Network pharmacology and molecular docking results revealed that 59 intersection targets were involved in the treatment of glycolipid metabolic disorders, and the PPARα, PPARγ, and TNF proteins were identified as crucial targets through PPI network analysis. Additionally, serum metabolomics analysis of ZDF rats showed that QHTTF could regulate linoleic acid metabolism, fructose and mannose metabolism, galactose metabolism, fatty acid biosynthesis, and other related signaling pathways. The results of biological experiments proved that QHTTF effectively lowered blood glucose and lipid levels, alleviated hepatic and pancreatic pathological damage, increased the expression of IRS-1 and GLUT4 in the pancreas, and improved insulin resistance, while inhibiting the inflammatory response and oxidative stress, as well as enhancing the expression of liver PPARα, PPARγ, and AMPK proteins in ZDF rats. Conclusions: In summary, QHTTF exerted a significant effect in improving glycolipid metabolism disorders of ZDF rats, which might show therapeutic effects by relieving insulin resistance, mitigating inflammation and oxidative damage, regulating related glucose, fatty acid, and amino acid metabolism, and increasing the expression of PPARα, PPARγ, and AMPK proteins by combining network analysis, metabolomics, and biological research. Full article

Type 2 diabetes (T2D) is a complex metabolic disease characterized by chronic hyperglycemia due to insulin resistance and inadequate insulin secretion. Beyond the classically implicated organs, emerging evidence highlights the gut as a central player in T2D pathophysiology through its interactions with metabolic organs. The gut hosts trillions of microbes and enteroendocrine cells that influence inflammation, energy homeostasis, and hormone regulation. Disruptions in gut homeostasis (dysbiosis and increased permeability) have been linked to obesity, insulin resistance, and β-cell dysfunction, suggesting multifaceted “Gut-X axes” contribute to T2D development. We aimed to comprehensively review the evidence for gut-mediated crosstalk with the pancreas, endocrine system, liver, and kidneys in T2D. Key molecular mechanisms (incretins, bile acids, short-chain fatty acids, endotoxins, etc.) were examined to construct an integrated model of how gut-derived signals modulate metabolic and inflammatory pathways across organs. We also discuss clinical implications of targeting Gut-X axes and identify knowledge gaps and future research directions. A literature search (2015–2025) was conducted in PubMed, Scopus, and Web of Science, following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews). Over 150 high-impact publications (original research and review articles from Nature, Cell, Gut, Diabetologia, Lancet Diabetes & Endocrinology, etc.) were screened. Data on gut microbiota, enteroendocrine hormones, inflammatory mediators, and organ-specific outcomes in T2D were extracted. The GRADE framework was used informally to prioritize high-quality evidence (e.g., human trials and meta-analyses) in formulating conclusions. T2D involves perturbations in multiple Gut-X axes. This review first outlines gut homeostasis and T2D pathogenesis, then dissects each axis: (1) Gut–Pancreas Axis: how incretin hormones (GLP-1 and GIP) and microbial metabolites affect insulin/glucagon secretion and β-cell health; (2) Gut–Endocrine Axis: enteroendocrine signals (e.g., PYY and ghrelin) and neural pathways that link the gut with appetite regulation, adipose tissue, and systemic metabolism; (3) Gut–Liver Axis: the role of microbiota-modified bile acids (FXR/TGR5 pathways) and bacterial endotoxins in non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance; (4) Gut–Kidney Axis: how gut-derived toxins and nutrient handling intersect with diabetic kidney disease and how incretin-based and SGLT2 inhibitor therapies leverage gut–kidney communication. Shared mechanisms (microbial SCFAs improving insulin sensitivity, LPS driving inflammation via TLR4, and aryl hydrocarbon receptor ligands modulating immunity) are synthesized into a unified model. An integrated understanding of Gut-X axes reveals new opportunities for treating and preventing T2D. Modulating the gut microbiome and its metabolites (through diet, pharmaceuticals, or microbiota therapies) can improve glycemic control and ameliorate complications by simultaneously influencing pancreatic islet function, hepatic metabolism, and systemic inflammation. However, translating these insights into clinical practice requires addressing gaps with robust human studies. This review provides a state-of-the-art synthesis for researchers and clinicians, underlining the gut as a nexus for multi-organ metabolic regulation in T2D and a fertile target for next-generation therapies. Full article

The meat quality of sheep and goats differs even within the same age, gender, and farming systems. Intramuscular fat (IMF) content is an important factor affecting the quality of livestock meat because it affects muscle color, tenderness, juiciness, water-holding capacity, and flavor. This study evaluates the differences in IMF deposition characteristics between Longdong cashmere goats and Tan sheep, and also explores the correlations between these variations and the gut microbiota. The results revealed that the IMF contents in shoulder and rump meat, as well as the blood lipid levels, of Longdong cashmere goats were higher than those of Tan sheep (p < 0.05). The content of fatty acid synthase (FAS) in the duodenum of the goats was lower, but the content of hormone-sensitive lipase (HSL) in both the pancreas and duodenum was greater (p < 0.05). The Chao1 and β diversity showed differences between the two breeds, observed not only in the abomasum but also in the colon. The specific microbiota identified from the goats were involved in the lipid metabolism pathway. The concentrations of acetic acid and propionic acid in the colonic and abomasal chyme were decreased in the goats when compared to the sheep (p < 0.05). The contents of FAS in the colonic chyme of the goats were significantly lower, while HSL in the abomasal chyme was significantly higher than that of the sheep. The correlation analysis of IMF deposition with gut microbiota showed that Acetobacter and UBA1711 in the abomasum, as well as Faecousia, WQUU01, UBA5905, and GCA-900066495 in the colon, were positively correlated with the IMF content in shoulder meat and the level of LDL (except for UBA1711), but negatively associated with the content of propionic acid (|r| > 0.45, p < 0.05). This preliminary study has demonstrated that some specific bacteria in the abomasum and colon were associated with IMF deposition, while also providing an indicative reference range for further investigation into the effects of microbes on IMF deposition. Full article

With the increasing use of imaging modalities such as ultrasonography, computed tomography, and magnetic resonance imaging, incidental findings of pancreatic abnormalities, including pancreatic cysts and fatty pancreas (FP), have become more common. FP, also referred to as pancreatic steatosis, intra-pancreatic fat deposition, or fatty pancreas disease, is characterized by the accumulation of fat in the pancreas. Although FP has been associated with metabolic syndromes such as obesity and diabetes, its clinical significance remains unclear. Recent evidence suggests that FP may play a role in pancreatic carcinogenesis. Metabolic disorders, including obesity, insulin resistance, and diabetes, have been implicated in the development of FP. Additionally, FP has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), possibly due to chronic inflammation, lipotoxicity, and an altered pancreatic microenvironment. While early detection of PDAC remains challenging, surveillance strategies for high-risk individuals, such as those with pancreatic cysts, new-onset diabetes, or a genetic predisposition, may be crucial. In this context, FP may be incorporated into this surveillance of high-risk individuals. Some pharmacological interventions, including glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors, have shown potential in reducing pancreatic fat accumulation, although further studies are needed to confirm their efficacy. Full article

Geese (Anser cygnoides) are popular worldwide with consumers for their unique meat quality, egg production, foie gras, and goose down; however, the key genes that influence geese growth remain elusive. To explore the mechanism of geese growth, a total of 500 Zhedong White geese were raised; four high-weight (HW) and four low-weight (LW) male geese were selected to collect carcass traits and for further transcriptomic and metabolomic analysis. The body weight and average daily gain of HW geese were significantly higher than those of the LW geese (p-value < 0.05), and the yields of the liver, gizzard, glandular stomach, and pancreas showed no significant difference between the HW and the LW group (p-value > 0.05). Compared with the LW geese, 19 differentially expressed genes (DEGs) (i.e., COL11A2, COL22A1, and TF) were detected in the breast muscle from the HW geese, which were involved in the PPAR signaling pathway, adipocytokine signaling pathway, fatty acid biosynthesis, and ferroptosis. A total of 59 differential accumulation metabolites (DAMs), which influence the pathways of glutathione metabolism and vitamin B6 metabolism, were detected in the breast muscle between the HW and LW geese. In the liver, 106 DEGs (i.e., THSD4, CREB3L3, and CNST) and 202 DAMs were found in the livers of the HW and LW groups, respectively. DEGs regulated the pathways of the TGF-beta signaling pathway, pyruvate metabolism, and adipocytokine signaling pathway; DAMs were involved in pyrimidine metabolism, nitrogen metabolism, and phenylalanine metabolism. Correlation analysis between the top DEGs and DAMs revealed that in the breast muscle, the expression levels of COL11A2 and COL22A1 were positively correlated with the content of S-(2-Hydroxy-3-buten-1-yl)glutathione. In the liver, the expression of THSD4 was positively correlated with the content of 2-Hydroxyhexadecanoic acid. In addition, one DEG (LOC106049048) and four DAMs (mogrol, brassidic acid, flabelline, and L-Leucyl-L-alanine) were shared in the breast muscle and liver. These important results contribute to improving the knowledge of goose growth and exploring the effective molecular markers that could be adopted for Zhedong White goose breeding. Full article

Type 2 Diabetes (T2D) is a complex metabolic disorder that affects multiple organs, leading to severe complications in the pancreas, kidneys, liver, and heart. Prolonged hyperglycemia, along with oxidative stress and chronic inflammation, plays a crucial role in accelerating tissue damage, significantly increasing the risk of diabetic complications such as nephropathy, hepatopathy, and cardiovascular disease. This review evaluates the protective effects of various antidiabetic treatments on organ tissues affected by T2D, based on findings from experimental animal models. Metformin, a first-line antidiabetic agent, has been widely recognized for its ability to reduce inflammation and oxidative stress, thereby mitigating diabetes-induced organ damage. Its protective role extends beyond glucose regulation, offering benefits such as improved mitochondrial function and reduced fibrosis in affected tissues. In addition to traditional therapies, new classes of antidiabetic drugs, including sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists not only improve glycemic control but also exhibit nephroprotective and cardioprotective properties by reducing glomerular hyperfiltration, oxidative stress, and inflammation. Similarly, GLP-1 receptor agonists have been associated with reduced hepatic steatosis and enhanced cardiovascular function. Preclinical studies suggest that tirzepatide, a dual GLP-1/gastric inhibitory polypeptide receptor agonist may offer superior metabolic benefits compared to conventional GLP-1 agonists by improving β-cell function, enhancing insulin sensitivity, and reducing fatty liver progression. Despite promising preclinical results, differences between animal models and human physiology pose a challenge. Further clinical research is needed to confirm these effects and refine treatment strategies. Future T2D management aims to go beyond glycemic control, emphasizing organ protection and long-term disease prevention. Full article

Type 2 diabetes mellites (T2DM) is the most common form of diabetes and affects a significant portion of the population. Obesity-related increases in free fatty acids and glucose in the diet contribute to β-cell dysfunction and loss, ultimately leading to the onset of T2DM. The endocannabinoid system, which is present throughout the body, plays a vital role in regulating various physiological processes, including those in the pancreas. This system has been implicated in metabolic disorders like obesity and diabetes, as it helps to regulate appetite, food intake, and fat production. Phytocannabinoids from Cannabis sativa have the potential to influence the endocannabinoid system, offering a promising therapeutic approach for diabetes and its complications. Using high-glucose–high-lipid (HGHL)-induced INS-1 β-cells, we investigated the protective effects of two major (THC and CBD) and three minor (THCV, CBC, and CBG) phytocannabinoids on high glucose–high lipid (HGHL)-induced apoptosis, cell cycle disruption, and impaired function of beta-cells. Our results showed that all five phytocannabinoids reduced HGHL-induced apoptosis, likely by decreasing TXNIP protein levels. Additionally, THC and all three minor phytocannabinoids provided protective effects against functional impairments caused by HGHL exposure. Full article

Digestive enzymes, such as proteases and lipases, are widely recognized for their crucial roles in the ripening and production of fermented foods. Digestive enzymes are also used as supplements in nonruminant livestock to enhance feed digestion and promote animal growth. However, information on the effects of exogenous digestive enzymes on gut health and disease remains limited. Notably, recent studies show that consuming proteases and lipases can increase the levels of beneficial bacteria and short-chain fatty acids in rodent gut. These findings led us to hypothesize that intestinal proteases and lipases play beneficial roles by enriching beneficial bacteria. To examine this hypothesis, we reviewed recent studies on the potential effects of exogenous digestive enzymes on gut microbiota composition and overall health. Consistent with the hypothesis, all 13 studies in this review reported significant improvements in animal gut microbiota composition with the dietary supplementation of proteases and lipases. Additionally, the possible mechanisms of the prebiotic-like effects of the enzymes through increased nutrient digestion were discussed. This review explores how exogenous proteases and lipases influence gut microbiota composition and overall health. This is the first review to provide insights into the potential roles of exogenous digestive enzymes as prebiotics. Full article

An association between gut microbiota and the development of pancreatic ductal adenocarcinoma (PDAC) has been previously described. To better understand the bacterial microbiota changes accompanying PDAC promotion and progression stimulated by inflammation and fecal microbiota transplantation (FMT), we investigated stool and pancreatic microbiota by 16s RNA-based metagenomic analysis in mice with inducible acinar transgenic expressions of KrasG12D, and age- and sex-matched control mice that were exposed to inflammatory stimuli and fecal microbiota obtained from mice with PDAC. Time- and inflammatory-dependent stool and pancreatic bacterial composition alterations and stool alpha microbiota diversity reduction were observed only in mice with a Kras mutation that developed advanced pancreatic changes. Stool Actinobacteriota abundance and pancreatic Actinobacteriota and Bifidobacterium abundances increased. In contrast, stool abundance of Firmicutes, Verrucomicrobiota, Spirochaetota, Desulfobacterota, Butyricicoccus, Roseburia, Lachnospiraceae A2, Lachnospiraceae unclassified, and Oscillospiraceae unclassified decreased, and pancreatic detection of Alloprevotella and Oscillospiraceae uncultured was not observed. Furthermore, FMT accelerated tumorigenesis, gradually decreased the stool alpha diversity, and changed the pancreatic and stool microbial composition in mice with a Kras mutation. Specifically, the abundance of Actinobacteriota, Bifidobacterium and Faecalibaculum increased, while the abundance of genera such as Lachnospiraceace A2 and ASF356, Desulfovibrionaceace uncultured, and Roseburia has decreased. In conclusion, pancreatic carcinogenesis in the presence of an oncogenic Kras mutation stimulated by chronic inflammation and FMT dynamically changes the stool and pancreas microbiota. In particular, a decrease in stool microbiota diversity and abundance of bacteria known to be involved in short-fatty acids production were observed. PDAC mouse model can be used for further research on microbiota–PDAC interactions and towards more personalized and effective cancer therapies. Full article

Background: Type 1 diabetes (T1D) is a severe chronic T-cell mediated autoimmune disease that attacks the insulin-producing beta cells of the pancreas. The multifactorial nature of T1D involves both genetic and environmental components, with recent research focusing on the gut microbiome as a crucial environmental factor in T1D pathogenesis. The gut microbiome and its metabolites play an important role in modulating immunity and autoimmunity. In recent years, studies have revealed significant alterations in the taxonomic and functional composition of the gut microbiome associated with the development of islet autoimmunity and T1D. These changes include reduced production of short-chain fatty acids, altered bile acid and tryptophan metabolism, and increased intestinal permeability with consequent perturbations of host (auto)immune responses. Methods/Results: In this review, we summarize and discuss recent observational, mechanistic and etiological studies investigating the gut microbiome in T1D and elucidating the intricate role of gut microbes in T1D pathogenesis. Moreover, we highlight the recent advances in intervention studies targeting the microbiota for the prevention or treatment of human T1D. Conclusions: A deeper understanding of the evolution of the gut microbiome before and after T1D onset and of the microbial signals conditioning host immunity may provide us with essential insights for exploiting the microbiome as a prognostic and therapeutic tool. Full article

Background/Objectives: It has been shown that the use of statins in patients with type 2 diabetes mellitus (T2DM) worsens hyperglycemia and hemoglobin A1c levels but may help in the preservation of pancreatic β-cell function. The potential role of a high pancreatic fat fraction (PFF) in this process has not yet been clarified. This study aimed to investigate whether the liver fat fraction (LFF) and PFF in T2DM patients is affected by statin therapy. Methods: This cross-sectional study involved a total of 140 T2DM patients, including both those who were receiving (n = 70) and those who were not receiving (n = 70) statin therapy. The mapping of the LFF and PFF utilizing the IDEAL-IQ sequence was conducted in magnetic resonance imaging. Results: In T2DM patients who used statins, the median PFF was higher compared to those who did not use statins (8.4 vs. 6.2%, p = 0.021), while the median LFF was found to be similar (8.4 vs. 8.9, p = 0.572). Variations in PFF were associated with the use of various statins (non-statin group: 6.2 vs. atovastatin: 8.7 vs. rosuvastatin: 3.2 vs. pitavastatin: 9.2, p = 0.004). The multivariable regression analysis indicated that insulin usage decreased log(LFF) by a factor of 0.16-fold (ꞵ ± SE = −0.16 ± 0.05, p = 0.010), and rosuvastatin usage reduced log(PFF) by 0.16-fold (ꞵ ± SE = −0.16 ± 0.07, p = 0.025), irrespective of other risk factors. Furthermore, the use of atorvastatin (ꞵ ± SE = 0.17 ± 0.06, p = 0.011) and pitavastatin (ꞵ ± SE = 0.19 ± 0.07, p = 0.008) were independently associated with an increase in log(PFF). Conclusions: In patients with T2DM, statin use did not show a significant effect on the liver fat fraction, but it caused differences in the pancreatic fat fraction. The observation of a lower pancreatic fat fraction in patients taking a rosuvastatin and atorvastatin dose of 40 mg/day suggests that different types and doses of statins may have varying effects on pancreatic fat accumulation. Full article