Liver Stiffness Measurement is Useful in Predicting Type 2 Diabetes Mellitus Among Nonalcohol Fatty Liver Disease Patients.

Background: Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are closely related conditions. Aim: This study investigated a group of individuals with NAFLD to evaluate if liver fibrosis, identified by FibroScan, correlated with T2DM. Methods: 154 NAFLD patients obtained FibroScan, liver ultrasonography (US), and a thorough assessment of clinical implications and chemical biomarkers. Results: In comparison to the NAFLD without T2DM group, the hemoglobin A1c(HBA1c)(mmol/mol%), homeostasis model of assessment for insulin resistance index (HOMA-IR), gamma-glutamyl transferase (GGT), fibrosis indices, and liver stiffness measurement (LSM) values were all considerably higher in the NAFLD with T2DM group. Patients with NAFLD and T2DM had considerably lower serum uric acid(SUA) levels than those with NAFLD alone.Those with severe fibrosis (79.3%, 23/29) in the NAFLD group showed a greater frequency of T2DM than those with mild fibrosis (45.6%, 21/46) or no fibrosis (27.85%, 22/79) (P=0.000). LSM value and elements of the metabolic syndrome (MetS) were independent risk factors for incident T2DM among NAFLD patients (OR=1.466, 95% CI [1.139-1.888], P=0.003; and OR=0.273, 95% CI [0.081-0.916], P=0.036). Conclusion: FibroScan can identify significant fibrosis, which is independently linked to a higher prevalence of T2DM. As a result, it is crucial to make use of this technology to predict T2DM in NAFLD patients.

Clinical Classification of Obesity and Implications for Metabolic Dysfunction-Associated Fatty Liver Disease and Treatment.

Obesity,and metabolic dysfunction-associated fatty liver disease (MAFLD) have reached epidemic proportions globally. Obesity and MAFLD frequently coexist and act synergistically to increase the risk of adverse clinical outcomes (both hepatic and extrahepatic). Type 2 diabetes mellitus (T2DM) is the most important risk factor for rapid progression of steatohepatitis and advanced fibrosis. Conversely, the later stages of MAFLD are associated with an increased risk of T2DM incident. According to the proposed criteria, MAFLD is diagnosed in patients with liver steatosis and in at least one in three: overweight or obese, T2DM, or signs of metabolic dysregulation if they are of normal weight. However, the clinical classification and correlation between obesity and MAFLD is more complex than expected. In addition, treatment for obesity and MAFLD are associated with a reduced risk of T2DM, suggesting that liver-based treatments could reduce the risk of developing T2DM. This review describes the clinical classification of obesity and MAFLD, discusses the clinical features of various types of obesity and MAFLD, emphasizes the role of visceral obesity and insulin resistance (IR) in the development of MAFLD,and summarizes the existing treatments for obesity and MAFLD that reduce the risk of developing T2DM.

FIB-4 is closer to FibroScan screen results to detecting advanced liver fibrosis and maybe facilitates NAFLD warning.

To assess the relationship between clinical biochemical characteristics and steatosis or fibrosis by Fibroscan in non-alcoholic fatty liver disease (NAFLD) patients in order to seek the simple effective screening method closed to the results of the fibroScan measurement. A cross-sectional study was conducted on 188 patients with NAFLD who underwent FibroScan examinations. Demographic data and clinical biochemical characteristics were collected and analyzed. The result showed elevated serum uric acid (SUA) (P = .023, odds ratio [OR = 1.005, 95% CI (1.001-1.009) and metabolic syndrome (MetS) (P = .000, OR = 4.549, 95%CI (1.974-10.484) were associated with severe steatosis (controlled attenuation parameter, CAP ≥ 300 dB/m). The magnitude of liver stiffness measured using FibroScan was positively correlated with aspartate transaminase/alanine aminotransferase (AST/ALT) ratio (R = 0.419, P = .000), AST to platelet ratio index (APRI) score (R = 0.309, P = .000), and Fibrosis-4 score (FIB-4) (R = 0.507, P = .000). The areas under the receiver operating curve (ROC) of AST/ALT, APRI, and FIB-4 for mild or severe fibrosis were 0.563, 0.696, and 0.728, respectively, and those for advanced fibrosis were 0.648, 0.750, and 0.821, respectively. The FIB-4 index cutoff value was 1.65 with a sensitivity of 68.3% and specificity of 89.8% during the diagnosis of advanced fibrosis. MetS and elevated SUA are associated with severe steatosis according to the CAP value screen, whereas FIB-4, as the fibrosis score method, is closer to the liver stiffness measurement results from FibroScan, which may facilitate early warning of NAFLD in the community or in remote areas.

Boosting Water Evaporation by Construction of Photothermal Materials with a Biomimetic Black Soil Aggregate Structure.

Solar-driven interfacial evaporation is considered an efficient way to get fresh water from seawater. However, the low evaporation rate, surface salt crystallization, and low energy collection of the photothermal evaporation layer limit its further application in an outdoor freshwater field. And the aggregate structure design of the material itself is often ignored in solar-driven water evaporation. Black soil (BS), with a unique soil aggregate structure, is rich in tubular pores, which can be used for multilevel sunlight utilization and good capillary water transport. Based on the extraordinary photothermal properties and pumping capacity of BS, a reasonable unidirectional salt-collecting device is designed, which can realize long-term collection of mineral salts and continuous evaporation of seawater and generate electric energy in the continuous evaporation. Inspired by the unique aggregate structure, the photothermal material doping of halloysite and nigrosin will simulate the generation of this aggregate structure and retain a good water transport effect while obtaining multistage utilization of sunlight. The solar-driven evaporation rate of a nigrosin-halloysite solar steam generator is 1.75 kg m-2 h-1 under 1 kW m-2 mimic solar radiation; it can achieve stable salt leaching-induced voltage generation of 240 mV. This work demonstrates not only a solar evaporator that can continuously achieve desalination but also the design strategy of BS-like aggregate photothermal materials, which promotes the development of low-cost resource recovery and energy generation for practical outdoor seawater desalination.

Emulsified isoflurane protects beta cells against high glucose-induced apoptosis via inhibiting endoplasmic reticulum stress.

BACKGROUND: Pancreatic beta cell damage induced by glucose toxicity is an important factor in type 2 diabetes mellitus (T2DM). It has become evident that endoplasmic reticulum stress (ERS)-induced apoptosis was contributed to beta cell dysfunction and insulin resistance. Our previous work showed that emulsified isoflurane (EIso) could alleviate ERS in lung reperfusion injury. This study aimed to elucidate whether EIso could alleviate apoptosis induced by glucose in rat islet RIN-m5F beta cells via inhibiting ERS. METHODS: RIN-m5F cells were divided into five groups: the control group; the 0.1G group, cultured in 0.1M glucose for 24 h; the 0.3G group, cultured in 0.3M glucose for 24 h; the 0.3G + 57E group, cultured in 0.3M glucose with 57 µM EIso for 24 h, and the 0.3G + 76E group, cultured in 0.3M glucose with 76 µM EIso for 24 h. First, cell proliferation was measured by MTT assay, and the level of insulin secretion was measured with enzyme-linked immunosorbent assay (ELISA) kit. Second, the expression of B cell leukemia/lymphoma 2 (Bcl-2) associated X (Bax) and Bcl-2 were detected by Western blotting. The level of caspase-3 activity was assessed by colorimetric method. Finally, the ERS marker CHOP and GRP78 expression were detected by Western blotting. The levels of activating transcription factor-6 (ATF6), X-box-binding protein 1 (Xbp1), and eukaryotic translation initiation factor-2α (eIF2α) mRNA were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) after being treated with EIso for 24 h. RESULTS: We found that exposure to high glucose reduced RIN-m5F cell viability, stimulated the secretion of insulin, activated caspase-3, improved the expression of Bax, and down-regulated Bcl-2. EIso improved the survival and protected the function of RIN-m5F. Compared to the 0.3G group, treatment with EIso inhibited the activity of caspase-3, and decreased the expression of Bax. The expression of CHOP and GRP78 were significantly suppressed by EIso at 24 h in a dose-dependent manner. The level of ATF6, Xbp1, and eIF2α mRNA of RIN-m5F were enhanced by high glucose, but only eIF2α mRNA was significantly decreased by EIso treatment. CONCLUSIONS: The present study suggests that high glucose induces rat islet beta cell RIN-m5F apoptosis and aggravates the function of beta cells. EIso protects beta cells against high glucose through the ERS-dependent apoptotic pathway and might serve as a potential therapy for diabetes.

Excitatory regulation of angiotensin II on gastric motility and its mechanism in guinea pig.

In the present study, we investigated the effect of Ang II on gastric smooth muscle motility and its mechanism using intracellular recording and whole-cell patch clamp techniques. Ang II dose-dependently increased the tonic contraction and the frequency of spontaneous contraction in the gastric antral circular smooth muscles of guinea pig. ZD7155, an Ang II type 1 receptor (AT(1)R) blocker, completely blocked the effect of Ang II on the spontaneous contraction of gastric smooth muscle. In contrast, TTX, a sodium channel blocker, failed to block the effect. Furthermore, nicardipine, a voltage-gated Ca(2+)-channel antagonist, did not block the effect of Ang II on the tonic contraction of gastric smooth muscle, but external free-calcium almost completely blocked this effect. Both ryanodine, an inhibitor of calcium-induced Ca(2+) release (CICR) from ryanodine-sensitive calcium stores, and thapsigargin, which depletes calcium in calcium stores, almost completely blocked the effect of Ang II on tonic contraction. However, 2-APB, an inositol trisphosphate (IP(3)) receptor blocker, significantly, but not completely, blocked the Ang II effect on tonic contraction. We also determined that Ang II depolarized membrane potential and increased slow wave frequency in a dose-dependent manner. It also inhibited delayed rectifying potassium currents in a dose-dependent manner, but did not affect L-type calcium currents or calcium-activated potassium currents. These results suggest that Ang II plays an excitatory regulation in gastric motility via AT(1)R-IP(3) and the CICR signaling pathway. The Ang II-induced inhibition of delayed rectifying potassium currents that depolarize membrane potential is also involved in the potentiation of tonic contraction and the frequency of spontaneous contraction in the gastric smooth muscle of guinea pig.

The properties of spontaneous transient inward currents of interstitial cells in rabbit portal vein.

The present study was designed to investigate the properties of spontaneous transient inward currents generated by interstitial cells (ICs) in the rabbit portal vein. Single ICs were freshly isolated from smooth muscle of the rabbit portal vein enzymetically. Using whole-cell patch clamp techniques, the spontaneous transient inward currents (STICs) were recorded at -60 mV of holding potential in freshly dispersed ICs. Both gadolinium, a non-selective cation channel inhibitor, and niflumic acid, a calcium-activated chloride channel blocker, abolished the inward currents. Replacement of external Na(+) with N-methyl-d-glucamine (NMDG(+)) also blocked the inward currents. The inward currents were abolished by caffeine, carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), thapsigargin and ryanodine, but were partly inhibited by 2-aminoethoxydiphenyl borate (2-APB). W-7, a calmodulin inhibitor, increased the amplitude of the inward currents. These results suggest that non-selective cation channels are involved in the generation of the spontaneous transient inward currents recorded from ICs. The currents are regulated by intracellular calcium and calmodulin. But in the present study, the involvement of the calcium-activated chloride channels in the generation of the currents cannot be excluded.

Spontaneous rhythmic inward currents recorded in interstitial cells of rabbit portal vein.

It is now well established that smooth muscle of the portal vein exhibits spontaneous rhythmic contraction in vitro. The present study was designed to investigate the pacemaking mechanism(s) underlying the spontaneous rhythmic contractions in the rabbit portal vein (RPV). Using whole-cell patch clamp techniques, spontaneous inward currents were recorded at -60 mV of holding potential in freshly dispersed c-Kit immunopositive interstitial cells (ICs) isolated from sections of RPV. The inward currents were abolished by caffeine, FCCP, thapsigargin, and ryanodine, but were partially inhibited by 2-APB. Both gadolinium, a non-selective cation channel inhibitor, and niflumic acid, a chloride channel blocker, inhibited the inward currents completely. Replacement of external Na(+) with NMDG(+) also blocked the inward currents. W-7, a calmodulin inhibitor, increased both the amplitude and frequency of the inward currents. Taken together, these results indicate that non-selective cationic channels are involved in the generation of spontaneous inward currents recorded from ICs. Intracellular calcium concentration and calmodulin regulate the spontaneous inward currents, which may account for spontaneous rhythmic contraction in the RPV, but a role of chloride channels may not be excluded in the present study.

[Preliminary study on the mechanism of spontaneous rhythmic contraction in rabbit portal vein].

This study sought to probe into the mechanism of spontaneous contraction of portal vein. The morphological and electrophysiological characteristics of the freshly isolated interstitial cells (ICs) of rabbit portal vein were investigated by using immunohistochemical and conventional whole-cell patch clamp techniques. The isolated interstitial cells exhibited stellate-shaped or spindle-shaped bodies with a variable number of thin processes projecting from cell bodies, and these cells were noted to be c-Kit immunopositive. Under conventional whole-cell patch clamp configuration, the membrane potential was held at -60 mV, the spontaneous rhythmic inward currents were recorded in ICs, and the frequencies of which were similar to those of spontaneous contraction of portal vein. The inward currents were insensitive to nicardipine (an L-type calcium channel blocker) but could be abolished by gadolinium (a non-selective cation channel blocker). The results suggested that the spontaneous rhythmic inward currents recorded in freshly isolated ICs may be pacemaker currents which elicit the spontaneous contraction of portal vein.

Atrial natriuretic peptide signal pathway upregulated in stomach of streptozotocin-induced diabetic mice.

AIM: To investigate atrial natriuretic peptide (ANP) secretion from gastric mucosa and the relationship between the ANP/natriuretic peptide receptor type A (NPR-A) pathway and diabetic gastroparesis. METHODS: Male imprinting control region (ICR) mice (4 wk old) were divided into two groups: control mice, and streptozotocin-induced diabetic mice. Eight weeks after injection, spontaneous gastric contraction was recorded by using physiography in control and streptozotocin-induced diabetic mice. The ANP-positive cells in gastric mucosa and among dispersed gastric epithelial cells were detected by using immunohistochemistry and flow cytometry, respectively. ANP and natriuretic peptide receptor type A (NPR-A) gene expression in gastric tissue was observed by using the reverse transcriptase polymerase chain reaction. RESULTS: The frequency of spontaneous gastric contraction was reduced from 12.9 +/- 0.8 cycles/min in the control group to 8.4 +/- 0.6 cycles/min in the diabetic mice (n = 8, P < 0.05). However, the amplitude of contraction was not significantly affected in the diabetic group. The depletion of interstitial cells of Cajal in the gastric muscle layer was observed in the diabetic mice. ANP-positive cells were distributed in the gastric mucosal layer and the density index of ANP-positive cells was increased from 20.9 +/- 2.2 cells/field in control mice to 51.8 +/- 2.9 cells/field in diabetic mice (n = 8, P < 0.05). The percentage of ANP-positive cells among the dispersed gastric epithelial cells was increased from 10.0% +/- 0.9% in the control mice to 41.2% +/- 1.0% in the diabetic mice (n = 3, P < 0.05). ANP and NPR-A genes were both expressed in mouse stomach, and the expression was significantly increased in the diabetic mice. CONCLUSION: These results suggest that the ANP/NPR-A signaling pathway is upregulated in streptozotocin-induced diabetic mice, and contributes to the development of diabetic gastroparesis.

Dual effect of exogenous hydrogen sulfide on the spontaneous contraction of gastric smooth muscle in guinea-pig.

Hydrogen sulfide (H(2)S) is produced endogenously in mammalian tissues and is important in both physiological and pathological processes. Despite its importance, little is known regarding the effect of H(2)S on gastrointestinal motility. We evaluated the effect of H(2)S on the spontaneous contraction of gastric antrum smooth muscle in the guinea pig (Cavia porcellus) using a physiograph. In addition, we investigated whether the effect of H(2)S was mediated by ionic channels by recording membrane currents in freshly dispersed gastric antrum myocytes using a whole-cell patch clamp. Sodium hydrogen sulfide (NaHS), an H(2)S donor, had a dual effect on the spontaneous contraction of gastric antrum muscle strips. At high concentrations (0.3-1.0 mM), NaHS suppressed the amplitude of spontaneous contraction. At low concentrations (0.1-0.3 mM), NaHS enhanced the resting tension of muscle strips while slightly reducing the contractile amplitude. The excitatory effect on spontaneous contraction, caused by low concentrations of NaHS, was abolished when the muscle strips were pretreated with 10 mM tetraethylammonium (TEA), a nonselective potassium channel blocker, or 0.5 mM 4-Aminopyridine (4-AP), a voltage-gated K(+) channel blocker. However, the excitatory effect of NaHS was not completely blocked by low concentrations of TEA (1 mM). Pretreatment with both TEA (1 mM) and 4-AP (0.5 mM) completely abolished the excitatory effect. The dose-response curve for the inhibitory effect of NaHS on the spontaneous contraction of gastric smooth muscle was shifted significantly to the left by TEA and 4-AP. Both Pinacidil, a K(ATP) channel opener, and NaHS significantly inhibited TEA-potentiated spontaneous contraction. Glibenclamide, a K(ATP) channel blocker, partially, but significantly, reversed the reduction in amplitude. NaHS enhanced the amplitude of the K(ATP) current, but inhibited the voltage-gated K(+) channel current (IK(V)) in a dose-dependent manner. NaHS had no effect on STOC at low concentrations (0.1-1.0 mM) but significantly inhibited STOC at high concentrations (4-10 mM). Our results suggest that H(2)S has multiple actions during the regulation of gastric motility in the guinea-pig. An excitatory effect is mediated via inhibition of the voltage-gated K(+) channel and an inhibitory effect is mediated via activation of the K(ATP) channel.

Role of calcium-activated potassium currents in CNP-induced relaxation of gastric antral circular smooth muscle in guinea pigs.

AIM: To investigate ion channel mechanism in CNP-induced relaxation of gastric circular smooth muscle in guinea pigs. METHODS: Spontaneous contraction of gastric smooth muscle was recorded by a four -channel physiograph. The whole cell patch-clamp technique was used to record calcium-activated potassium currents and membrane potential in the gastric myocytes isolated by collagenase. RESULTS: C-type natriuretic peptide (CNP) markedly inhibited the spontaneous contraction in a dose-dependent manner in gastric circular smooth muscle in guinea pigs. Ly83583, an inhibitor of guanylate cyclase, weakened CNP-induced inhibition on spontaneous contraction but Zaparinast, an inhibitor of cGMP sensitive phosphoesterase, potentiated CNP-induced inhibition in gastric circular smooth muscles. The inhibitory effects of CNP on spontaneous contraction were blocked by tetrathylammonium (TEA), a nonselective potassium channel blocker. CNP hyperpolarized membrane potential from -60.0 mV+/-2.0 mV to -68.3 mV+/-3.0 mV in a single gastric myocyte. CNP increased calcium-activated potassium currents (I(K(ca))) in a dose-dependent manner in gastric circular myocytes. CNP also increased the spontaneously transient outward currents (STOCs). Ly83583 partly blocked CNP-induced increase of calcium-activated potassium currents, but Zaparinast potented the effect. CONCLUSION: CNP inhibits spontaneous contraction, and potassium channel may be involved in the process in gastric circular smooth muscle of guinea pigs. CNP-induced increase of I(K(ca)) is mediated by a cGMP dependent pathway.

Role of actin microfilament in hyposmotic membrane stretch-induced increase in muscarinic current of guinea-pig gastric myocytes.

To investigate the relationship between cytoskeleton and hyposmotic membrane stretch-induced increase in muscarinic current, the role of actin microfilament in hyposmotic membrane stretch-induced increase in muscarinic current was studied with the whole-cell patch clamp technique in guinea-pig gastric myocytes. In this study, the muscarinic current was induced by carbachol (50 micromol/L) or GTPgammaS (0.5 mmol/L). The results showed that hyposmotic superfusate (202 mOsmol/L) increased carbachol-induced current (I(CCh)) by 145+/-27% and increased GTPgammaS-induced current by 183+/-30%; but in the presence of cytochalasin-B (Cyt-B, 20 micromol/L), an actin cytoskeleton disruptor, hyposmotic membrane stretch increased I(CCh) by 70+/-6%. However, hyposmotic membrane stretch induced increase in I(CCh) was potentiated to 545+/-81% by phalloidin (20 micromol/L), an actin microfilament stabilizer. The results demonstrated that hyposmotic membrane stretch increased the muscarinic currents induced by carbachol or GTPgammaS and that the actin microfilament is involved in the process in guinea-pig gastric myocytes.

Comparative study in the effect of C-type natriuretic peptide on gastric motility in various animals.

AIM: To investigate the effect of natriuretic peptides on gastric motility in various animals, and the effect of C-type natriuretic peptide (CNP) on spontaneous contraction of gastric smooth muscle in rat, guinea-pig and human in vitro was compared. METHODS: Spontaneous contraction of gastric smooth muscle was recorded by four channel physiograph. RESULTS: In the guinea-pig and rat gastric antral circular smooth muscle, CNP markedly decreased the amplitude of spontaneous contraction but it didn't affect the frequency, however, the contractile activity was completely inhibited by CNP in gastric antral longitudinal smooth muscle. In the human gastric antral circular and longitudinal smooth musle, CNP completely inhibited spontaneous contraction. In the circular smooth muscle of guinea-pig and rat gastric fundus, CNP obviously decreased the amplitude of spontaneous contraction but it didn't affect the frequency, however, the contractile activity was completely inhibited by CNP in smooth muscle of fundus longitudinal. In the circular and longitudinal smooth muscle of guinea-pig gastric body, CNP at first induced a relaxation and then an increase in amplitude of spontaneous contraction (rebound contraction), but the frequency was not changed. After the circular smooth muscle of gastric body was pretreated with atropine, an M receptor blocker, the rebound contraction was abolished; In circular and longitudinal smooth muscle of rat gastric body, CNP induced a transient and slight relaxation and successively followed by the recovery in amplitude of spontaneous contraction but it also didn't affect the frequency. After the smooth muscle was pretreated with atropine, the transient and slight relaxation was replaced by long term and complete inhibition; The percentage of CNP-induced inhibition was 76.77+/-6.21 % (fundus), 67.21+/-5.32 % (body) and 58.23+/- 6.21 % (antral) in the gastric circular muscle, however, the inhibitory percentage was 100+/-0.00 % (fundus), 68.66+/- 3.55 % (body) and 100+/-0.00 % (antrum) in the gastric longitudinal smooth muscle of guinea-pigs; In the rat, the percentage of CNP-induced inhibition was 95.87+/-4.12 % (fundus), 94.91+/-5.08 % (body) and 66.32+/-7.32 % (antrum)in the gastric circular smooth muscle, but in the longitudinal smooth muscle, CNP completely inhibited the spontaneous contraction. Using LY83583, a guanylate cyclase inhibitor, and zaparinast as a phosphoesterase inhibitor to inhibit the generation of cGMP, the effect of CNP on the spontaneous contraction was markedly weakened by LY83583, however, the inhibitory effect was enhanced by zaparinast. CONCLUSION: (1) CNP can obviously inhibit the spontaneous contraction of gastric antral circular and longitudinal smooth muscle in the rat, guinea-pig and human. The order of inhibitory potency is human >rat> guinea-pig. (2) In the same animals, the inhibitory effect of CNP on spontaneous contraction is the most powerful in fundus and the weakest in antrum, in the same position, the inhibitory effect on the circular smooth muscle is more powerful than that on longitudinal smooth muscle. (3) The inhibitory effect of CNP on spontaneous contraction in the gastric smooth muscle is mediated by a cGMP dependent pathway.