Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis.

Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury. Here, we examined the function of Treg cells in non-alcoholic steatohepatitis (NASH), a setting of chronic liver injury. Areg-producing Treg cells were enriched in the livers of mice and humans with NASH. Deletion of Areg in Treg cells, but not in myeloid cells, reduced NASH-induced liver fibrosis. Chronic liver damage induced transcriptional changes associated with Treg cell activation. Mechanistically, Treg cell-derived Areg activated pro-fibrotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling. Deletion of Areg in Treg cells protected mice from NASH-dependent glucose intolerance, which also was dependent on EGFR signaling on hepatic stellate cells. Areg from Treg cells promoted hepatocyte gluconeogenesis through hepatocyte detection of hepatic stellate cell-derived interleukin-6. Our findings reveal a maladaptive role for Treg cell-mediated tissue repair functions in chronic liver disease and link liver damage to NASH-dependent glucose intolerance.

Biomarker screening using integrated bioinformatics for the development of "normal-impaired glucose intolerance-type 2 diabetes mellitus".

Type 2 diabetes mellitus (T2DM) is a progressive disease. We utilized bioinformatics analysis and experimental research to identify biomarkers indicative of the progression of T2DM, aiming for early detection of the disease and timely clinical intervention. Integrating Mfuzz analysis with differential expression analysis, we identified 76 genes associated with the progression of T2DM, which were primarily enriched in signaling pathways such as apoptosis, p53 signaling, and necroptosis. Subsequently, using various analytical methods, including machine learning, we further narrowed down the hub genes to STK17A and CCT5. Based on the hub genes, we calculated the risk score for samples and interestingly found that the score correlated with multiple programmed cell death (PCD) pathways. Animal experiments revealed that the diabetes model exhibited higher levels of MDA and LDH, with lower expression of SOD, accompanied by islet cell apoptosis. In conclusion, our study suggests that during the progression of diabetes, STK17A and CCT5 may contribute to the advancement of the disease by regulating oxidative stress, programmed cell death pathways, and critical signaling pathways such as p53 and MAPK, thereby promoting the death of islet cells. This provides substantial evidence in support of further disease prevention and treatment strategies.

Mechanisms by which sheep milk consumption ameliorates insulin resistance in high-fat diet-fed mice.

Sheep milk is rich in fat, protein, vitamins and minerals and is also one of the most important sources of natural bioactives. Several biopeptides in sheep milk have been reported to possess antibacterial, antiviral and anti-inflammatory properties, and they may prevent type 2 diabetes (T2D), disease and cancer. However, the precise mechanism(s) underlying the protective role of sheep milk against T2D development remains unclear. Therefore, in the current study, we investigated the effect of sheep milk on insulin resistance and glucose intolerance in high-fat diet (HFD)-fed mice, by conducting intraperitoneal glucose tolerance tests, metabolic cage studies, genomic sequencing, polymerase chain reaction, and biochemical assays. Hyperinsulinemic-euglycemic clamp-based experiments revealed that mice consuming sheep milk exhibited lower hepatic glucose production than mice in the control group. These findings further elucidate the mechanism by which dietary supplementation with sheep milk alleviates HFD-induced systemic glucose intolerance.

KLF4 down-regulation underlies placental angiogenesis impairment induced by maternal glucose intolerance in late pregnancy.

Maternal glucose intolerance in late pregnancy can easily impair pregnancy outcomes and placental development. The impairment of placental angiogenesis is closely related to the occurrence of glucose intolerance during pregnancy, but the mechanism remains largely unknown. In this study, the pregnant mouse model of maternal high-fat diet and endothelial injury model of porcine vascular endothelial cells (PVECs) was used to investigate the effect of glucose intolerance on pregnancy outcomes and placental development. Feeding pregnant mice, a high-fat diet was shown to induce glucose intolerance in late pregnancy, and significantly increase the incidence of resorbed fetuses. Moreover, a decrease was observed in the proportion of blood sinusoids area and the expression level of CD31 in placenta, indicating that placental vascular development was impaired by high-fat diet. Considering that hyperglycemia is an important symptom of glucose intolerance, we exposed PVECs to high glucose (50 mM), which verified the negative effects of high glucose on endothelial function. Bioinformatics analysis further emphasized that high glucose exposure could significantly affect the angiogenesis-related functions of PVECs and predicted that Krüppel-like factor 4 (KLF4) may be a key mediator of these functional changes. The subsequent regulation of KLF4 expression confirmed that the inhibition of KLF4 expression was an important reason why high glucose impaired the endothelial function and angiogenesis of PVECs. These results indicate that high-fat diet can aggravate maternal glucose intolerance and damage pregnancy outcome and placental angiogenesis, and that regulating the expression of KLF4 may be a potential therapeutic strategy for maintaining normal placental angiogenesis.

LPS-Induced Modifications in Macrophage Transcript and Secretion Profiles Are Linked to Muscle Wasting and Glucose Intolerance.

Macrophages are versatile immune cells that play crucial roles in tissue repair, immune defense, and the regulation of immune responses. In the context of skeletal muscle, they are vital for maintaining muscle homeostasis but macrophage-induced chronic inflammation can lead to muscle dysfunction, resulting in skeletal muscle atrophy characterized by reduced muscle mass and impaired insulin regulation and glucose uptake. Although the involvement of macrophage-secreted factors in inflammation-induced muscle atrophy is well-established, the precise intracellular signaling pathways and secretion factors affecting skeletal muscle homeostasis require further investigation. This study aimed to explore the regulation of macrophage-secreted factors and their impact on muscle atrophy and glucose metabolism. By employing RNA sequencing (RNA-seq) and proteome array, we uncovered that factors secreted by lipopolysaccharide (LPS)-stimulated macrophages upregulated markers of muscle atrophy and pro-inflammatory cytokines, while concurrently reducing glucose uptake in muscle cells. The RNA-seq analysis identified alterations in gene expression patterns associated with immune system pathways and nutrient metabolism. The utilization of gene ontology (GO) analysis and proteome array with macrophage-conditioned media revealed the involvement of macrophage-secreted cytokines and chemokines associated with muscle atrophy. These findings offer valuable insights into the regulatory mechanisms of macrophage-secreted factors and their contributions to muscle-related diseases.

Periportal hepatocyte proliferation at midgestation governs maternal glucose homeostasis in mice.

The maternal liver is challenged by metabolic demands throughout pregnancy. However, hepatocyte dynamics and their physiological significance in pregnancy remain unclear. Here, we show in mice that hepatocyte proliferation is spatiotemporally regulated in each liver lobular zone during pregnancy, with transient proliferation of periportal and pericentral hepatocytes during mid and late gestation, respectively. Using adeno-associated virus (AAV)-8-mediated expression of the cell cycle inhibitor p21 in hepatocytes, we show that inhibition of hepatocyte proliferation during mid, but not late, gestation impairs liver growth. Transcriptionally, genes involved in glucose/glycogen metabolism are downregulated in late pregnancy when midgestational hepatocyte proliferation is attenuated. In addition, hepatic glycogen storage is abolished, with concomitant elevated blood glucose concentrations, glucose intolerance, placental glycogen deposition, and fetal overgrowth. Laser capture microdissection and RNA-seq analysis of each liver lobular zone show zone-specific changes in the transcriptome during pregnancy and identify genes that are periportally expressed at midgestation, including the hyaluronan-mediated motility receptor (Hmmr). Knockdown of Hmmr in hepatocytes by AAV8-shHmmr suppresses periportal hepatocyte proliferation at midgestation and induces impaired hepatic glycogen storage, glucose intolerance, placental glycogen deposition and fetal overgrowth. Our results suggest that periportal hepatocyte proliferation during midgestation is critical for maternal glycogen metabolism and fetal size.

Effect of (poly)phenol-rich 'Daux Belan' apple supplementation on diet-induced obesity and glucose intolerance in C57BL/6NCrl mice.

Obesity is a state of metabolic dysfunction that can lead to dyslipidemia and impaired glucose homeostasis. Apple polyphenols have been shown to ameliorate dyslipidemia/metabolic dysfunction in humans. The influence of apple (poly)phenols on energy metabolism in high-fat (HF) diet-induced obese mice remains controversial. This study examined the effect of dietary supplementation of (poly)phenol-rich 'Daux Belan' apple (DB; 6.2 mg gallic acid equivalence (GAE)/mouse/day; 0.15% (poly)phenol) in the form of freeze-dried powder on glucose and lipid metabolism in male HF-fed C57BL/6NCrl mice, in comparison to low-(poly)phenol-containing 'Zestar' apple (Z; 0.4 mg GAE/mouse/day). Obesity, glucose intolerance, hypertriglyceridemia, and hepatic lipid vacuolation were induced by HF feeding while circulating cholesterol levels remained unchanged. DB apple supplementation did not protect against HF-induced body weight gain, hyperglycemia, hepatic triglyceride level elevation, and hepatic lipid vacuolation at the tested dosage. Future studies should be conducted with increased DB dosage and employ apple (poly)phenols supplemented in the form of extracts or sugar-free powder.

Suppression of FOXO1 attenuates inflamm-aging and improves liver function during aging.

The liver is a key metabolic organ that maintains whole-body nutrient homeostasis. Aging-induced liver function alterations contribute to systemic susceptibility to aging-related diseases. However, the molecular mechanisms of liver aging remain insufficiently understood. In this study, we performed bulk RNA-Seq and single-cell RNA-Seq analyses to investigate the underlying mechanisms of the aging-induced liver function changes. We found that liver inflammation, glucose intolerance, and liver fat deposition were aggravated in old mice. Aging significantly increased pro-inflammation in hepatic macrophages. Furthermore, we found that Kupffer cells (KCs) were the major driver to induce pro-inflammation in hepatic macrophages during aging. In KCs, aging significantly increased pro-inflammatory levels; in monocyte-derived macrophages (MDMs), aging had a limited effect on pro-inflammation but led to a functional quiescence in antigen presentation and phagosome process. In addition, we identified an aging-responsive KC-specific (ARKC) gene set that potentially mediates aging-induced pro-inflammation in KCs. Interestingly, FOXO1 activity was significantly increased in the liver of old mice. FOXO1 inhibition by AS1842856 significantly alleviated glucose intolerance, hepatic steatosis, and systemic inflammation in old mice. FOXO1 inhibition significantly attenuated aging-induced pro-inflammation in KCs partially through downregulation of ARKC genes. However, FOXO1 inhibition had a limited effect on aging-induced functional quiescence in MDMs. These results indicate that aging induces pro-inflammation in liver mainly through targeting KCs and FOXO1 is a key player in aging-induced pro-inflammation in KCs. Thus, FOXO1 could be a potential therapeutic target for the treatment of age-associated chronic diseases.

Hepatoprotective and anti-hyperglycemic effects of ferulic acid in arsenic-exposed mice.

Arsenic is a toxic metalloid that increases the risk of hepatotoxicity and hyperglycemia. The objective of the present study was to assess the effect of ferulic acid (FA) in mitigating glucose intolerance and hepatotoxicity caused by sodium arsenite (SA). A total of six groups including control, FA 100 mg/kg, SA 10 mg/kg, and groups that received different doses of FA (10, 30, and 100 mg/kg), respectively just before SA (10 mg/kg) for 28 days were examined. Fasting blood sugar (FBS) and glucose tolerance tests were conducted on the 29th day. On day 30, mice were sacrificed and blood and tissues (liver and pancreas) were collected for further investigations. FA reduced FBS and improved glucose intolerance. Liver function and histopathological studies confirmed that FA preserved the structure of the liver in groups received SA. Furthermore, FA increased antioxidant defense and decreased lipid peroxidation and tumor necrosis factor-alpha level in SA-treated mice. FA, at the doses of 30 and 100 mg/kg, prevented the decrease in the expression of PPAR-γ and GLUT2 proteins in the liver of mice exposed to SA. In conclusion, FA prevented SA-induced glucose intolerance and hepatotoxicity by reducing oxidative stress, inflammation, and hepatic overexpression of PPAR-γ and GLUT2 proteins.

Plasma insulin is required for the increase in plasma angiopoietin-like protein 8 in response to nutrient ingestion.

BACKGROUND: Plasma levels of angiopoietin-like protein 8 (ANGPTL8) are regulated by feeding and they increase following glucose ingestion. Because both plasma glucose and insulin increase following food ingestion, we aimed to determine whether the increase in plasma insulin and glucose or both are responsible for the increase in ANGPTL8 levels. METHODS: ANGPTL8 levels were measured in 30 subjects, 14 with impaired fasting glucose (IFG), and 16 with normal fasting glucose (NFG); the subjects received 75g glucose oral Glucose tolerance test (OGTT), multistep euglycaemic hyperinsulinemic clamp and hyperglycaemic clamp with pancreatic clamp. RESULTS: Subjects with IFG had significantly higher ANGPTL8 than NGT subjects during the fasting state (p < 0.05). During the OGTT, plasma ANGPTL8 concentration increased by 62% above the fasting level (p < 0.0001), and the increase above fasting in ANGPTL8 levels was similar in NFG and IFG individuals. During the multistep insulin clamp, there was a dose-dependent increase in plasma ANGPTL8 concentration. During the 2-step hyperglycaemic clamp, the rise in plasma glucose concentration failed to cause any change in the plasma ANGPTL8 concentration from baseline. CONCLUSIONS: In response to nutrient ingestion, ANGPTL8 level increased due to increased plasma insulin concentration, not to the rise in plasma glucose. The incremental increase above baseline in plasma ANGLPTL8 during OGTT was comparable between people with normal glucose tolerance and IFG.

Hepatic leucine carboxyl methyltransferase 1 (LCMT1) contributes to high fat diet-induced glucose intolerance through regulation of glycogen metabolism.

Impaired glucose regulation is one of the most important risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which have become a major public health issue worldwide. Dysregulation of carbohydrate metabolism in liver has been shown to play a critical role in the development of glucose intolerance but the molecular mechanism has not yet been fully understood. In this study, we investigated the role of hepatic LCMT1 in the regulation of glucose homeostasis using a liver-specific LCMT1 knockout mouse model. The hepatocyte-specific deletion of LCMT1 significantly upregulated the hepatic glycogen synthesis and glycogen accumulation in liver. We found that the liver-specific knockout of LCMT1 improved high fat diet-induced glucose intolerance and insulin resistance. Consistently, the high fat diet-induced downregulation of glucokinase (GCK) and other important glycogen synthesis genes were reversed in LCMT1 knockout liver. In addition, the expression of GCK was significantly upregulated in MIHA cells treated with siRNA targeting LCMT1 and improved glycogen synthesis. In this study, we provided evidences to support the role of hepatic LCMT1 in the development of glucose intolerance induced by high fat diet and demonstrated that inhibiting LCMT1 could be a novel therapeutic strategy for the treatment of glucose metabolism disorders.

Association between tea consumption and glucose metabolism and insulin secretion in the Shanghai High-risk Diabetic Screen (SHiDS) study.

INTRODUCTION: The relationship between tea consumption and glucose metabolism remains controversial. This study investigated the associations of tea consumption with impaired glucose regulation, insulin secretion and sensitivity in Shanghai High-risk Diabetic Screen project. RESEARCH DESIGN AND METHODS: A total of 2337 Chinese subjects were enrolled in the study from 2014 to 2019. Each participant conducted a 75 g oral glucose tolerance test (OGTT) with five-point glucose and insulin level examined. They also completed a nurse-administered standard questionnaire including tea, coffee, and alcohol consumption, smoking habit, physical activity, education, sleep quality, etc. RESULTS: The result showed that tea consumption was positively associated with plasma glucose levels during OGTT after adjusting for confounder (Ps <0.05) and was associated with worsening glucose tolerance (OR 1.21, 95% CI 1.01-1.44; p=0.034). Strong tea consumption or long-term tea intake (>10 years) had an increased risk of glucose intolerance (all p<0.05). These associations did not vary in participants drinking green tea. In addition, insulin secretion indexes were decreased 7.0%-13.0% in tea consumption group. Logistic regression analysis showed that tea consumption was independently associated with lower insulin secretion (homeostasis model assessment of ß-cell function (HOMA-ß) (OR 0.81, 95% CI 0.68-0.97; p=0.021); Stumvoll first-phase index (OR 0.81, 95% CI 0.68-0.97; p=0.020)) in a fully adjusted model. Green tea consumption showed a negative association with insulin secretion (HOMA-ß (OR 0.77, 95% CI 0.62-0.96; p=0.019)). CONCLUSIONS: Tea intake is associated with an increased risk of glucose intolerance in a large high-risk diabetic Chinese population. Habitual tea consumption subjects might have lower pancreatic ß-cell function.

Epidermal Growth Factor Receptor in Hepatic Endothelial Cells Suppresses MCP-1-Dependent Monocyte Recruitment in Diabetes.

Insulin resistance is a compromised response to insulin in target tissues such as liver. Emerging evidence shows that vascular endothelial cells (ECs) are critical in mediating glucose metabolism. However, how liver ECs can regulate inflammation in the setting of insulin resistance is still unknown. Using genome-wide transcriptome analysis of ECs isolated from diabetic mice, we found enrichment of the genes involved in epidermal growth factor receptor (Egfr) signaling. In line with this, hepatic sinusoidal ECs in diabetic mice had elevated levels of Egfr expression. Interestingly, we found an increased number of hepatic myeloid cells, especially macrophages, and systemic glucose intolerance in Cdh5Cre/+Egfrfl/fl mice lacking Egfr in ECs compared with littermate control mice with type II diabetes. Egfr deficiency upregulated the expression of MCP-1 in hepatic sinusoidal ECs. This resulted in augmented monocyte recruitment and macrophage differentiation in Cdh5Cre/+Egfrfl/fl mice compared with littermate control mice as determined by a mouse model of parabiosis. Finally, MCP-1 neutralization and hepatic macrophage depletion in Cdh5Cre/+Egfrfl/fl mice resulted in a reduced number of hepatic macrophages and ameliorated glucose intolerance compared with the control groups. Collectively, these results demonstrate a protective endothelial Egfr signaling in reducing monocyte-mediated hepatic inflammation and glucose intolerance in type II diabetic mice.

Loss of Lkb1 in CD11c+ myeloid cells protects mice from diet-induced obesity while enhancing glucose intolerance and IL-17/IFN-γ imbalance.

Adipose tissue CD11c+ myeloid cell is an independent risk factor associated with obesity and metabolic disorders. However, the underlying molecular basis remains elusive. Here, we demonstrated that liver kinase B1 (Lkb1), a key bioenergetic sensor, is involved in CD11c+ cell-mediated immune responses in diet-induced obesity. Loss of Lkb1 in CD11c+ cells results in obesity resistance but lower glucose tolerance, which accompanies tissue-specific immune abnormalities. The accumulation and CD80's expression of Lkb1 deficient adipose-tissue specific dendritic cells but not macrophages is restrained. Additionally, the balance of IL-17A and IFN-γ remarkably tips towards the latter in fat T cells and CD11c- macrophages. Mechanistically, IFN-γ promotes apoptosis of preadipocytes and inhibits their adipogenesis while IL-17A promotes the adipogenesis in vitro, which might account in part for the fat gain resistant phenotype. In summary, these findings reveal that Lkb1 is essential for fat CD11c+ dendritic cells responding to HFD exposure and provides new insights into the IL-17A/IFN-γ balance in HFD-induced obesity.

Cotadutide effect in liver and adipose tissue in obese mice.

Obesity, adipose tissue inflammation, and nonalcoholic fatty liver disease (NAFLD) are associated with insulin resistance and type 2 diabetes (T2D). Cotadutide is a dual agonist GLP-1/glucagon, currently in a preclinical study phase 2 that presents an anti-obesity effect. Diet-induced obese (DIO) C57BL/6 mice were treated for 4 weeks with cotadutide (30 nm/kg once a day at 14:00 h). The study focused on epididymal white adipose tissue (eWAT), liver (NAFLD), inflammation, lipid metabolism, AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) pathways, and the endoplasmic reticulum (ER) stress. As a result, cotadutide controlled weight gain, glucose intolerance, and insulin resistance and showed beneficial effects on plasma markers in DIO mice (triacylglycerol, total cholesterol, alanine aminotransferase, and aspartate aminotransferase, leptin, adiponectin, monocyte chemoattractant protein-1, resistin, interleukin-6, tumor necrosis factor-alpha). Also, cotadutide lessened liver fat accumulation, eWAT proinflammatory markers, and ER stress. In addition, cotadutide improved lipid metabolism genes in eWAT, fatty acid synthase, peroxisome proliferator-activated receptor gamma and mitigates adipocyte hypertrophy and apoptosis. Furthermore, the effects of cotadutide were related to liver AMPK/mTOR pathway and ER stress. In conclusion, cotadutide induces weight loss and treats glucose intolerance and insulin resistance in DIO mice. In addition, cotadutide shows beneficial effects on liver lipid metabolism, mitigating steatosis, inflammation, and ER stress. Besides, in adipocytes, cotadutide decreases hypertrophy and reduces apoptosis. These actions rescuing the AMPK and mTOR pathway, improving lipid metabolism, and lessening NAFLD, inflammation, and ER stress in both eWAT and liver of DIO mice indicate cotadutide as a potentially new pharmacological treatment for T2D and associated obesity.

Loss of Hematopoietic Cell-Derived Oncostatin M Worsens Diet-Induced Dysmetabolism in Mice.

Innate immune cells infiltrate growing adipose tissue and propagate inflammatory clues to metabolically distant tissues, thereby promoting glucose intolerance and insulin resistance. Cytokines of the IL-6 family and gp130 ligands are among such signals. The role played by oncostatin M (OSM) in the metabolic consequences of overfeeding is debated, at least in part, because prior studies did not distinguish OSM sources and dynamics. Here, we explored the role of OSM in metabolic responses and used bone marrow transplantation to test the hypothesis that hematopoietic cells are major contributors to the metabolic effects of OSM. We show that OSM is required to adapt during the development of obesity because OSM concentrations are dynamically modulated during high-fat diet (HFD) and Osm-/- mice displayed early-onset glucose intolerance, impaired muscle glucose uptake, and worsened liver inflammation and damage. We found that OSM is mostly produced by blood cells and deletion of OSM in hematopoietic cells phenocopied glucose intolerance of whole-body Osm-/- mice fed a HFD and recapitulated liver damage with increased aminotransferase levels. We thus uncovered that modulation of OSM is involved in the metabolic response to overfeeding and that hematopoietic cell-derived OSM can regulate metabolism, likely via multiple effects in different tissues.

Betaine protects against sodium arsenite-induced diabetes and hepatotoxicity in mice.

Epidemiological evidence has associated chronic exposure to inorganic arsenic with an increased occurrence of glucose intolerance and diabetes mellitus. Furthermore, inorganic arsenic induces oxidative stress in organs such as the liver. Betaine, as a methyl donor, plays a pivotal role in homocysteine metabolism. Betaine has antioxidant and anti-inflammatory properties. Therefore, the aim of this study was to evaluate the effects of betaine against sodium arsenite-induced diabetes and hepatotoxicity in mice. Forty-eight male mice were divided into 6 groups of 8. Group 1, received distilled water every day for 4 weeks by gavage. Group 2 received 500 mg/kg betaine every day for 4 weeks by gavage. Group 3 was given 10 mg/kg NaAsO2 every day for 4 weeks by gavage. Groups 4, 5, and 6 were co-treated with 125, 250, and 500 mg/kg betaine half an hour before NaAsO2 (10 mg/kg), respectively, daily for up to 4 weeks by gavage. After 28 days of the study, the mice were fasted overnight and on day 29, fasting blood glucose was measured and glucose tolerance test was performed. On day 30, the mice were anesthetized and a blood sample was taken from the heart. Serum factors (alanine aminotransferase, aspartate transaminase, and alkaline phosphatase activities), oxidative stress factors (malondialdehyde and glutathione levels, and the activity of superoxide dismutase, glutathione peroxidase, and catalase enzymes) and hepatic inflammatory factors (nitric oxide and tumor necrosis factor α) were measured. Histopathological studies were also performed on the liver and pancreas. In this study, it was shown that arsenic causes glucose intolerance, and oxidative/inflammatory hepatic damage. Co-administration of betaine prevents hepatotoxicity and glucose intolerance induced by arsenic in mice. Co-treatment of betaine with arsenic improved glucose intolerance and protected the liver against arsenic induced-oxidative damage and inflammation. Betaine at the dose of 500 mg/kg showed better results than the other doses. Accordingly, betaine can be suggested as a therapeutic agent against diabetogenic and hepatotoxic effects of arsenic.

Hyperuricemia contributes to glucose intolerance of hepatic inflammatory macrophages and impairs the insulin signaling pathway via IRS2-proteasome degradation.

Aim: Numerous reports have demonstrated the key importance of macrophage-elicited metabolic inflammation in insulin resistance (IR). Our previous studies confirmed that hyperuricemia or high uric acid (HUA) treatment induced an IR state in several peripheral tissues to promote the development of type 2 diabetes mellitus (T2DM). However, the effect of HUA on glucose uptake and the insulin sensitivity of macrophages and its mechanism is unclear. Methods: To assess systemic IR, we generated hyperuricemic mice by urate oxidase knockout (UOX-KO). Then, glucose/insulin tolerance, the tissue uptake of 18F-fluorodeoxyglucose, body composition, and energy balance were assessed. Glucose uptake of circulating infiltrated macrophages in the liver was evaluated by glucose transporter type 4 (GLUT-4) staining. Insulin sensitivity and the insulin signaling pathway of macrophages were demonstrated using the 2-NBDG kit, immunoblotting, and immunofluorescence assays. The immunoprecipitation assay and LC-MS analysis were used to determine insulin receptor substrate 2 (IRS2) levels and its interacting protein enrichment under HUA conditions. Results: Compared to WT mice (10 weeks old), serum uric acid levels were higher in UOX-KO mice (WT, 182.3 ± 5.091 µM versus KO, 421.9 ± 45.47 µM). Hyperuricemic mice with metabolic disorders and systemic IR showed inflammatory macrophage recruitment and increased levels of circulating proinflammatory cytokines. HUA inhibited the nuclear translocation of GLUT-4 in hepatic macrophages, restrained insulin-induced glucose uptake and glucose tolerance, and blocked insulin IRS2/PI3K/AKT signaling. Meanwhile, HUA mediated the IRS2 protein degradation pathway and activated AMPK/mTOR in macrophages. LC-MS analysis showed that ubiquitination degradation could be involved in IRS2 and its interacting proteins to contribute to IR under HUA conditions. Conclusion: The data suggest that HUA-induced glucose intolerance in hepatic macrophages contributed to insulin resistance and impaired the insulin signaling pathway via IRS2-proteasome degradation.

New insights on hyperglycemia in 17-hydroxylase/17,20-lyase deficiency.

Objective: The adrenal glands of patients with 17-hydroxylase/17,20-lyase deficiency (17OHD) synthesize excessive 11-deoxycorticosterone(DOC) and progesterone, and produce less amount of sex steroid production. Mineralocorticoids and sex hormones play an important role in regulating glucose homeostasis. This study aimed to describe the glucose metabolism in 17OHD patients diagnosed at Peking Union Medical College Hospital (PUMCH). Design/methods: A total of 69 patients diagnosed with 17OHD after adolescence in PUMCH from 1995 to June in 2021. Among them 23 patients underwent a 3-hours oral glucose tolerance test (3hOGTT) after being diagnosed with 17OHD. Insulin response in patients with normal glucose tolerance (NGT) were further compared between the study two groups with different kalemia status. Another 19 patients were followed up to 30 years and older. All clinical data were obtained from the hospital information system of PUMCH. Results: Baseline: (1) The average body mass index(BMI) of all patients at baseline was 20.3 ± 3.7kg/m2. Twenty-three patients underwent 3hOGTT, of whom three were diagnosed with diabetes mellitus, and one with impaired glucose tolerance (IGT). Positive correlation between the ratio of progesterone to upper limit of normal range (P times) and hyperglycaemia was exist(r=0.707, P=0.005). (2) In 19 NGT patients, the insulin concentrations at 0 minute, results of the homeostasis model assessment for ß-cell function and insulin resistance were lower in the hypokalaemia group than in the normal kalemia group(7.0(5.8-13.2) vs 12.4(8.9-14.9) µIU/ml, P=0.017; 115.5(88.2-240.9) vs 253.1(177.2-305.8), P=0.048; 1.54(1.17-2.61) vs 2.47(1.91-2.98), P=0.022, respectively). Follow-up: Four patients had IGT, while seven patients had diabetes mellitus. Of the 19 patients,11 had hyperglycaemia. P times was significantly higher(7.6(5.0-11.0) vs 3.75(2.2-5.3), P=0.008) in hyperglycemia group than in the normal glucose group. Conclusions: Abnormal glucose metabolism was common in 17OHD patients, which was possibly associated with hypokalaemia and high progesterone levels. Routine monitoring on glucose metabolism in 17OHD patient should be conducted.

Exercise-Linked Skeletal Irisin Ameliorates Diabetes-Associated Osteoporosis by Inhibiting the Oxidative Damage-Dependent miR-150-FNDC5/Pyroptosis Axis.

Recent evidence suggests that physical exercise (EX) promotes skeletal development. However, the impact of EX on the progression of bone loss and deterioration of mechanical strength in mice with type 2 diabetic mellitus (T2DM) remains unexplored. In the current study, we investigated the effect of EX on bone mass and mechanical quality using a diabetic mouse model. The T2DM mouse model was established with a high-fat diet with two streptozotocin injections (50 mg/kg/body wt) in C57BL/6 female mice. The diabetic mice underwent treadmill exercises (5 days/week at 7-11 m/min for 60 min/day) for 8 weeks. The data showed that diabetes upregulated miR-150 expression through oxidative stress and suppressed FNDC5/Irisin by binding to its 3'-untranslated region. The decreased level of irisin further triggers the pyroptosis response in diabetic bone tissue. EX or N-acetyl cysteine or anti-miRNA-150 transfection in T2DM mice restored FNDC5/Irisin expression and bone formation. Furthermore, EX or recombinant irisin administration prevented T2DM-Induced hyperglycemia and improved glucose intolerance in diabetic mice. Furthermore, osteoblastic knockdown of Nlrp3 silencing (si-Nlrp3) or pyroptosis inhibitor (Ac-YVADCMK [AYC]) treatment restores bone mineralization in diabetic mice. Micro-computed tomography scans and mechanical testing revealed that trabecular bone microarchitecture and bone mechanical properties were improved after EX in diabetic mice. Irisin, either induced by skeleton or daily EX or directly administered, prevents bone loss by mitigating inflammasome-associated pyroptosis signaling in diabetic mice. This study demonstrates that EX-induced skeletal irisin ameliorates diabetes-associated glucose intolerance and bone loss and possibly provides a mechanism of its effects on metabolic osteoporosis.