A Molecular Cage Accessed by Threefold Click Reaction of a C3v-Symmetric Triazido-Functionalized Tribenzotriquinacene.

The hitherto unknown hexakis(halomethyl)-functionalized tribenzotriquinacenes (TBTQs) 9 and 10 were synthesized from the key 4b,8b,12b-tribromo-TBTQ derivative 6 by an improved route in 67% overall yield. Extension of the bowl-shaped framework of 9 or 10 by threefold condensation with propargylamine or 2-azidoethylamine afforded the corresponding TBTQ-trialkyne 11 and TBTQ-triazide 12, respectively. While attempts to construct bis-TBTQ cages, including homodimerization of 11 and heterocoupling of 11 with 12, were unsuccessful, triazide 12 was found to undergo threefold [3 + 2]-cycloaddition with 3-ethynylaniline and phloroglucinol tripropargyl ether under click chemistry conditions. The latter reaction enabled facile capping of the TBTQ bowl to give the novel cage compound 5 in 22% yield.

Ramulus Mori (Sangzhi) Alkaloids Alleviate High-Fat Diet-Induced Obesity and Nonalcoholic Fatty Liver Disease in Mice.

Nonalcoholic fatty liver disease (NAFLD), obesity, and type 2 diabetes mellitus (T2DM) have highly related mechanisms. Ramulus Mori (Sangzhi) alkaloids (SZ-A) from Morus alba L. were approved in 2020 for the treatment of T2DM. In this study, we examined the therapeutic effects and mechanism of SZ-A on obesity and NAFLD in mice. Mice (C57BL/6J) fed a high-fat diet (HFD) for 14 weeks were treated with SZ-A for another 6 weeks. HFD-induced weight gain was reduced by SZ-A in a dose-dependent manner. SZ-A treatment significantly stimulated adiponectin expression and secretion in adipose tissue and 3T3-L1 adipocytes. Additionally, SZ-A markedly reduced hepatic steatosis (triglyceride, total cholesterol) and expression of pro-inflammatory and pro-fibrotic genes. SZ-A regulated lipid metabolism and oxidative stress (malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH)) in the liver. Palmitic acid-induced insulin resistance and lipid accumulation in HepG2 cells were also repressed by SZ-A. Collectively, SZ-A protected mice from HFD-induced NAFLD through an indirect effect of improved systemic metabolism reducing bodyweight, and a direct effect by enhancing the lipid metabolism of HepG2 cells. The weight-loss effect of SZ-A in mice was partly due to improved fatty oxidation instead of influencing food consumption.

The Chinese patent medicine, Jin-tang-ning, ameliorates hyperglycemia through improving ß cell function in pre-diabetic KKAy mice.

Jin-tang-ning (JTN), a Chinese patent medicine, mainly comprised of Bombyx moriL., has been proved to show α-glucosidase inhibitory efficacy and clinically effective for the treatment of type 2 diabetes (T2DM). Recently, we have reported that JTN could ameliorate postprandial hyperglycemia and improved ß cell function in monosodium glutamate (MSG)-induced obese mice, suggesting that JTN might play a potential role in preventing the conversion of impaired glucose tolerance (IGT) to T2DM. In this study, we evaluated the effect of JTN on the progression of T2DM in the pre-diabetic KKAy mice. During the 10 weeks of treatment, blood biochemical analysis and oral glucose tolerance tests were performed to evaluate glucose and lipid profiles. The ß cell function was quantified using hyperglycemic clamp at the end of the study. JTN-treated groups exhibited slowly raised fasting and postprandial blood glucose levels, and also ameliorated lipid profile. JTN improved glucose intolerance after 8 weeks of treatment. Meanwhile, JTN restored glucose-stimulated first-phase of insulin secretion and induced higher maximum insulin levels in the hyperglycemic clamp. Thus, to investigate the underlying mechanisms of JTN in protecting ß cell function, the morphologic changes of the pancreatic islets were observed by optical microscope and immunofluorescence of hormones (insulin and glucagon). Pancreatic protein expression levels of key factors involving in insulin secretion-related pathway and ER stress were also detected by Western blot. Pre-diabetic KKAy mice exhibited a compensatory augment in ß cell mass and abnormal α cell distribution. Long-term treatment of JTN recovered islet morphology accompanied by reducing α cell area in KKAy mice. JTN upregulated expression levels of glucokinase (GCK), pyruvate carboxylase (PCB) and pancreas duodenum homeobox-1 (PDX-1), while down-regulating C/EBP homologous protein (Chop) expression in pancreas of the hyperglycemic clamp, which indicated the improvement of mitochondrial metabolism and relief of endoplasmic reticulum (ER) stress of ß cells after JTN treatment. These results will provide a new insight into exploring a novel strategy of JTN for protecting ß cell function and preventing the onset of pre-diabetes to T2DM.

Comprehensive proteomics and functional annotation of mouse brown adipose tissue.

Knowledge about the mouse brown adipose tissue (BAT) proteome can provide a deeper understanding of the function of mammalian BAT. Herein, a comprehensive analysis of interscapular BAT from C57BL/6J female mice was conducted by 2DLC and high-resolution mass spectrometry to construct a comprehensive proteome dataset of mouse BAT proteins. A total of 4949 nonredundant proteins were identified, and 4495 were quantified using the iBAQ method. According to the iBAQ values, the BAT proteome was divided into high-, middle- and low-abundance proteins. The functions of the high-abundance proteins were mainly related to glucose and fatty acid oxidation to produce heat for thermoregulation, while the functions of the middle- and low-abundance proteins were mainly related to protein synthesis and apoptosis, respectively. Additionally, 497 proteins were predicted to have signal peptides using SignalP4 software, and 75 were confirmed in previous studies. This study, for the first time, comprehensively profiled and functionally annotated the BAT proteome. This study will be helpful for future studies focused on biomarker identification and BAT molecular mechanisms.

Berberine combined with stachyose induces better glycometabolism than berberine alone through modulating gut microbiota and fecal metabolomics in diabetic mice.

Berberine (BBR), a small alkaloid, is used as a hypoglycemic agent in China. Stachyose (Sta), a Rehmannia glutinosa oligosaccharide, acts as a prebiotic. This study aimed to evaluate whether BBR combined with Sta produced better glycometabolism than BBR alone, and explored the effects on gut microbiota and metabolomics. Type-2 diabetic db/db mice were administered BBR (100 mg/kg), Sta (200 mg/kg), or both by gavage once daily. Glucose metabolism, the balance of α- and ß-cells, and mucin-2 expression were ameliorated by combined treatment of BBR and Sta, with stronger effects than upon treatment with BBR alone. The microbial diversity and richness were altered after combined treatment and after treatment with BBR alone. The abundance of Akkermansia muciniphila was increased by combined treatment compared to treatment with BBR alone, while the levels of the metabolite all-trans-heptaprenyl diphosphate were decreased and the levels of fumaric acid were increased, which both showed a strong correlation with A. muciniphila. In summary, BBR combined with Sta produced better glycometabolism than BBR alone through modulating gut microbiota and fecal metabolomics, and may aid in the development of a novel pharmaceutical strategy for treating Type 2 diabetes mellitus.

Effects of metformin on metabolism of white and brown adipose tissue in obese C57BL/6J mice.

BACKGROUND: To investigate effects of metformin on the regulation of proteins of white adipose tissue (WAT) and brown adipose tissue (BAT) in obesity and explore the underlying mechanisms on energy metabolism. METHODS: C57BL/6J mice were fed with normal diet (ND, n = 6) or high-fat diet (HFD, n = 12) for 22 weeks. HFD-induced obese mice were treated with metformin (MET, n = 6). After treatment for 8 weeks, oral glucose tolerance test (OGTT) and hyperinsulinemic-euglycemic clamp were performed to evaluate the improvement of glucose tolerance and insulin sensitivity. Protein expressions of WAT and BAT in mice among ND, HFD, and MET group were identified and quantified with isobaric tag for relative and absolute quantification (iTRAQ) coupled with 2D LC-MS/MS. The results were analyzed by MASCOT, Scaffold and IPA. RESULTS: The glucose infusion rate in MET group was increased significantly compared with HFD group. We identified 4388 and 3486 proteins in WAT and BAT, respectively. As compared MET to HFD, differential expressed proteins in WAT and BAT were mainly assigned to the pathways of EIF2 signaling and mitochondrial dysfunction, respectively. In the pathways, CPT1a in WAT, CPT1b and CPT2 in BAT were down-regulated by metformin significantly. CONCLUSIONS: Metformin improved the body weight and insulin sensitivity of obese mice. Meanwhile, metformin might ameliorate endoplasmic reticulum stress in WAT, and affect fatty acid metabolism in WAT and BAT. CPT1 might be a potential target of metformin in WAT and BAT.

Comprehensive map and functional annotation of the mouse white adipose tissue proteome.

White adipose tissue (WAT) plays a significant role in energy metabolism and the obesity epidemic. In this study, we sought to (1) profile the mouse WAT proteome with advanced 2DLC/MS/MS approach, (2) provide insight into WAT function based on protein functional annotation, and (3) predict potentially secreted proteins. A label-free 2DLC/MS/MS proteomic approach was used to identify the WAT proteome from female mouse WAT. A total of 6,039 proteins in WAT were identified, among which 5,160 were quantified (spanning a magnitude of 106) using an intensity-based absolute quantification algorithm, and 3,117 proteins were reported by proteomics technology for the first time in WAT. To comprehensively analyze the function of WAT, the proteins were divided into three quantiles based on abundance and we found that proteins of different abundance performed different functions. High-abundance proteins (the top 90%, 1,219 proteins) were involved in energy metabolism; middle-abundance proteins (90-99%, 2,273 proteins) were involved in the regulation of protein synthesis; and low-abundance proteins (99-100%, 1,668 proteins) were associated with lipid metabolism and WAT beiging. Furthermore, 800 proteins were predicted by SignalP4.0 to have signal peptides, 265 proteins had never been reported, and five have been reported as adipokines. The above results provide a large dataset of the normal mouse WAT proteome, which might be useful for WAT function research.

Metal-free oxidative coupling of quinoxalin-2(1H)-ones with arylaldehydes leading to 3-acylated quinoxalin-2(1H)-ones.

A facile TBHP-mediated direct oxidative coupling of quinoxalin-2(1H)-ones with arylaldehydes has been developed under metal-free conditions. This method provided a convenient and efficient approach to various 3-acylated quinoxalin-2(1H)-ones from readily available starting materials with excellent regioselectivity. This reaction proceeded efficiently under mild conditions over a broad range of substrates and with functional group tolerance.

Copper-catalysed difluoroalkylation of aromatic aldehydes via a decarboxylation/aldol reaction.

A copper-catalysed tandem decarboxylation/aldol reaction of simple aromatic aldehydes with 2,2-difluoro-3-oxo-3-arylpropanoic acid has been developed under mild conditions. This method provides a new route for the direct one-pot synthesis of difluorinated aldols in moderate to good yields from simple substrates.

The PI3K/Akt1-FoxO1 Translocation Pathway Mediates EXf Effects on NIT-1 Cell Survival.

EXf, a glucagon-like peptide 1 (GLP-1) receptor agonist, stimulates ß-cell proliferation and reduces apoptosis in diabetic animal models, but the underlying mechanisms are not fully understood. We constructed a FoxO1-GFP fusion protein expression plasmid and transiently transfected it into NIT-1 cells to investigate whether FoxO1 mediates EXf effects on NIT-1 cell survival. Our results showed that EXf could increase cell viability by inhibiting apoptosis and stimulating proliferation, and it could also promote the translocation of the FoxO1-GFP fusion protein from the nucleus to the cytoplasm in NIT-1 cells. However, the above effects of EXf were suppressed by the inhibitor of PI3K. Comparative transcription analysis showed up-regulation of igf-1r, irs-2, pI3k, akt1 and pdx-1 in NIT-1 cells after EXf treatment. Moreover, the up-regulation of PI3K and phosphorylation of Akt1 upon EXf treatment was confirmed by Western blot, both phenomena were abrogated by wortmannin, an inhibitor of PI3K. In summary, FoxO1 may mediate the effects of EXf on NIT-1 cell survival by activating the PI3K/Akt1 pathway.

Cyanogenetic glycosides and simple glycosides from the linseed meal.

Three new cyanogenetic triglycosides linustatins A-C (1-3), and two new simple glycosides linustatins D and E (4 and 5) were isolated from the 70% ethanol extract of flaxseed meal (Linum usitatissimum L.). Their structures were elucidated on the basis of spectroscopic analysis and chemical evidence. All of the isolates showed moderate activities against aldose reductase and weak activities against α-glucosidase, DPP-IV, and FBPase at the same concentrations as the positive control drugs.

Effects of Estrogen on Insulin Sensitivity and Adipokines in Mice.

OBJECTIVE: To study the potential mechanisms via which estrogen exerts its effects on the insulin sensitivity in mice. METHODS: Totally 36 female C57BL/6J mice aged 6 weeks were randomly divided into six groups:normal diet (NOR) group, normal diet with ovariectomy (NOR+OVX) group, normal diet with ovariectomy and estrogen replacement (NOR+OVX+E2) group,high-fat diet (HF) group, high-fat diet with ovariectomy (HF+OVX) group, and high-fat diet with ovariectomy and estrogen replacement (HF+OVX+E2) group. There were six mice in each group. After the ovariectomy based on the grouping, the mice were given normal diet or high-fat diet for 20 weeks. The intervention groups were given estrogen (5 µg/d,subcutaneous injection) for 20 days. Then,the body weight,visceral fat weight,oral glucose tolerance and insulin sensitivity (by euglycemic hyperinsulinemic clamp test), and serum leptin, adiponectin,and resistin levels were compared among these six groups. RESULTS: Compared with HF group, the HF+OVX group had significantly higher body weight and visceral fat weight and lower glucose tolerance, which were significantly improved after estrogen replacement therapy (all P<0.05). However, these indicators showed no significant differences among groups with normal diets (all P>0.05). The insulin sensitivity of ovariectomized mice was significantly decreased in both high-fat and normal diet groups and was also improved significantly after estrogen replacement (P<0.05). The serum leptin was increased and adiponectin was decreased significantly in ovariectomized mice, and the improvements of these two adipokines were also statistically significant after estrogen therapy (P<0.05): however,the serum resistin level was not significantly different among these 6 groups (P>0.05). CONCLUSIONS: Estrogen replacement therapy can improve insulin resistance by lowering body weight. In addition, it can exert its effect directly on adipose tissue,improve the levels of adipokines,reduce the amount of visceral fat, and improve insulin sensitivity in mice.

[Farnesoid X receptor regulates glucose and lipid metabolisms].

As a member of nuclear receptor superfamily, farnesoid X receptor (FXR) has been shown to regulate numerous metabolic pathways, which include playing an important role in bile acid metabolism, maintaining lipid and glucose homeostasis when FXR is activated. With the prevalence of the glucose and lipids disorder, FXR attracts increasing attention. It may be a potential target for the treatment of type 2 diabetes mellitus and lipid disorders.

Comparative proteome analysis of brown adipose tissue in obese C57BL/6J mice using iTRAQ-coupled 2D LC-MS/MS.

High-fat diet (HFD) leads to the development of obesity accompanied by insulin resistance, which increases the risk of type 2 diabetes mellitus and cardiovascular disease. Brown adipose tissue (BAT) plays an essential role in energy metabolism, thus it will give us promising treatment targets through elucidating underlying mechanisms of BAT in obesity. In this study, female C57BL/6J mice were fed HFD or normal diet (ND) for 22 weeks. Hyperinsulinemic-euglycemic clamp was performed to evaluate insulin sensitivity, which was independently correlated with obesity. Using isobaric tag for relative and absolute quantification (iTRAQ) coupled with 2D LC-MS/MS, we quantitated 3048 proteins in BAT. As compared HFD with ND, we obtained 727 differentially expressed proteins. Functional analysis found that those proteins were mainly assigned to the pathway of mitochondrial function. In this pathway, carnitine O-palmitoyltransferase 2 (CPT2), uncoupling protein 1 (UCP1) and apoptosis-inducing factor 1 (AIF1) were up-regulated significantly by HFD, and they were confirmed by western blotting. The results indicated that HFD might induce the apoptosis of brown adipocytes via the up-regulated AIF1. Meanwhile, HFD also stimulated fatty acid ß-oxidation and raised compensatory energy consuming through the increases of CPT2 and UCP1, respectively. However, the apoptosis of brown adipocytes might weaken the compensatory energy expenditure, and finally contribute to overweight/obesity. So, preventing the apoptosis of brown adipocytes may be the key target to treat obesity.

[Effect of Mudan Granule on islets beta cell function in monosodium glutamate induced obese mice with insulin resistance: an experimental study].

OBJECTIVE: To study the effect of Mudan Granule (MD) on the glucose metabolism and beta cell function in monosodium glutamate (MSG) induced obese mice with insulin resistance (IR). METHODS: MSG obese mice were induced by subcutaneous injecting MSG (4 g/kg for 7 successive days in neonatal ICR mice). Forty MSG mice with IR features were recruited and divided into four groups according to body weight, fasting blood glucose, triglyceride (TG), total cholesterol (TC), and the percentage of blood glucose decreased within 40 min in the IR test, i.e., the model group (Con), the low dose MD group, the high dose MD group, and the Metformin group (Met). Besides, another 10 ICR mice were recruited as the normal control group (Nor). The water solvent of 2.5 g/kg MD or 5 g/kg MD was respectively administered to mice in the low dose MD group and the high dose MD group. Metformin hydrochloride was given to mice in the Met group at 0.2 g/kg body weight. Equal dose solvent distilled water was administered to mice in the Nor group and the Con group by gastrogavage, once per day. All medication was lasted for 15 weeks. Insulin tolerance test (ITT) and oral glucose tolerance test (OGTT) were performed after 6 weeks of treatment. Beta cell function was assessed by hyperglycemic clamp technique. The morphological changes in the pancreas were evaluated by hematoxylin-eosin (HE) staining. Changes of iNOS, NF-kappaB p65, and p-NF-kappaB p65 in the pancreas were tested. RESULTS: Compared with the Nor group, the blood glucose level, AUC, and fasting blood insulin, ONOO-contents, iNOS activities, and the expression of iNOS, NF-kappaB p65 subunit, pNF-kappaB p65 subunit obviously increased; decreased percentage of blood glucose within 40 min in ITT, glucose infusion rate (GIR), Clamp 1 min insulin, and Max-Insulin obviously decreased in the Con group (P < 0.05, P < 0.01). Compared with the Con group, the aforesaid indices could be improved in the Met group (P < 0.05, P < 0.01). In the low dose MD group, AUC, iNOS activities, and the expression of iNOS and p-NF-kappaB p65 subunit obviously decreased; percentage of blood glucose within 40 min in ITT and GIR obviously increased (P < 0.05, P < 0.01). In the high dose MD group, AUC, ONOO-contents, iNOS activities, and the expression of iNOS, NF-kappaB p65 subunit, and p-NF-KB p65 subunit obviously decreased; percentage of blood glucose within 40 min in ITT, Max-Insulin, and GIR obviously increased (P < 0.05, P < 0.01). CONCLUSION: MD could significantly improve IR and functional disorder of 3 cells in MSG obese mice, which might be associated with lowering inflammatory reaction in the pancreas.

Atorvastatin helps preserve pancreatic ß cell function in obese C57BL/6 J mice and the effect is related to increased pancreas proliferation and amelioration of endoplasmic-reticulum stress.

BACKGROUND: 3-Hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitors or statins are competitive inhibitors of the rate-limiting enzyme in cholesterol biosynthesis. Currently, statins are used as first-line therapy in the treatment of diabetic dyslipidemia. However, effects of statins on ß cell function remains unclear. This study aims to examine effects of atorvastatin treatment on pancreatic ß cell function in obese C57BL/6 J mice and the possible mechanisms. METHODS: Diet-induced obesity (DIO) C57BL/6 J mice were treated with atorvastatin (30 mg/kg/day) for 58 days. ß cell function was assessed by hyperglycemic clamp and the area of insulin-positive ß cells was examined by immunofluorescence. Gene expression was assessed by RT-PCR, and endoplasmic reticulum (ER) stress related proteins were examined by Western blot. Additionally, cell viability and apoptosis of the cholesterol-loaded NIT-1 cells were investigated after atorvastatin treatment. RESULTS: Hyperglycemic clamp study revealed that glucose infusion rate (GIR) and insulin stimulation ratio in atorvastatin-treated DIO mice were markedly higher than control mice (P < 0.05, P < 0.01 vs. con), indicating preserved ß-cell sensitivity to glucose. Lipid profiles of plasma triglyceride (TG), pancreas TG and plasma cholesterol (CHO) were improved. Pancreas weight and weight index were improved significantly after atorvastatin treatment (P < 0.05 vs. con). Immunofluorescence results showed that atorvastatin-treated mice had significantly larger insulin-positive ß cell area (P < 0.05 vs. con). Furthermore, RT-PCR and western blot showed that the mRNA and protein expression of pancreatic and duodenal homeobox 1 (Pdx1) in the pancreas were upregulated (P < 0.001, P < 0.01 vs. con). Moreover, the expression level of ER stress markers of activating transcription factor 4 (ATF4), CCAAT-enhancer-binding protein homologous protein (CHOP) and phosphorylated eukaryotic initiation factor 2α (eIF2α) were downregulated in the pancreas of atorvastatin-treated mice (P < 0.001, P < 0.01, P < 0.01 vs. con). Besides, atorvastatin protected the pancreatic ß cell line of NIT-1 from cholesterol-induced apoptosis. Western blot showed increased expression of anti-apoptotic protein of B-cell lymphoma 2 (Bcl-2). CONCLUSION: Pancreatic ß cell function of obese C57BL/6 J mice was preserved after atorvastatin treatment, and this improvement may be attributed to enhanced pancreas proliferation and amelioration of pancreatic ER stress.

A refined-JinQi-JiangTang tablet ameliorates prediabetes by reducing insulin resistance and improving beta cell function in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Refined-JQ (JQ-R) is a mixture of refined extracts from three major herbal components of JinQi-JiangTang tablet: Coptis chinensis (Ranunculaceae), Astragalus membranaceus (Leguminosae), and Lonicera japonica (Caprifoliaceae). Our previous studies have indicated that JQ-R could decrease fasting blood glucose levels in diabetic mice and insulin resistance mice. Investigating the hypoglycemic effect of JQ-R on prediabetes has practical application value for preventing or delaying insulin resistance, impaired glucose tolerance and possibly the development of clinical diabetes. MATERIALS AND METHODS: The anti-diabetic potential of JQ-R was investigated using a high fat-diet (HFD)-induced obesity mouse model. C57BL/6J mice (HFD-C57 mice) were fed with high-fat diet for 4 months. HFD-C57 mice were treated with either JQ-R (administered intragastrically once daily for 4 weeks) or metformin (as positive control), and the effects of JQ-R on body weight, blood lipids, glucose metabolism, insulin sensitivity, and beta cell function were monitored. RESULTS: The body weight, serum cholesterol, and the Homeostasis Model Assessment ratio (insulin resistance index) were significantly reduced in JQ-R or metformin-treated mice, and the glucose tolerance was enhanced and insulin response was improved simultaneously. Moreover, both JQ-R and metformin could activate liver glycogen syntheses even under a relatively high glucose loading. Although glyconeogenesis was inhibited in the metformin treated mice, it was not observed in JQ-R treated mice. Similar to metformin, JQ-R could also improve the glucose infusion rate (GIR) in hyperglycemic clamp test. JQ-R was also shown to increase the levels of phosphorylated AMPKα and phosphorylated acetyl CoA carboxylase (ACC), similar to metformin. CONCLUSION: JQ-R could reduce HFD-induced insulin resistance by regulating glucose and lipid metabolism, increasing insulin sensitivity through activating the AMPK signaling pathway, and subsequently improving ß cell function. Therefore, JQ-R may offer an alternative in treating disorders associated with insulin resistance, such as prediabetes and T2DM.

[Metformin ameliorates ß-cell dysfunction by regulating inflammation production, ion and hormone homeostasis of pancreas in diabetic KKAy mice].

This study is to evaluate the effects of the metformin (Met) on ß cell function of diabetic KKAy mice. Female diabetic KKAy mice selected by insulin tolerance test (ITT) were divided randomly into two groups. Con group was orally administered by gavage with water, Met group with metformin hydrochloride at a dose of 0.2 g x kg(-1) for about 12 weeks. ITT and glucose tolerance tests (OGTT) were determined. Beta cell function was assessed by hyperglycemic clamp. Pancreatic biochemical indicators were tested. The changes of gene and protein expression in the pancreas and islets were also analyzed by Real-Time-PCR and immunostaining. Met significantly improved glucose intolerance and insulin resistance in KKAy mice. Fasting plasma glucose and insulin levels were also decreased. In addition, Met markedly increased glucose infusion rate (GIR) and elevated the Ist phase and maximum insulin secretion during clamp. It showed that Met decreased TG content and iNOS activities and increased Ca(2+) -Mg(2+)-ATPase activity in pancreas. Islets periphery was improved, and down-regulation of glucagon and up-regulated insulin protein expressions were found after Met treatment. Pancreatic mRNA expressions of inflammation factors including TLR4, NF-κB, JNK, IL-6 and TNF-α were down-regulated, p-NF-κB p65 protein levels also down-regulated by Met. And mRNA expressions of ion homeostasis involved in insulin secretion including SERCA2 and Kir6.2 were up-regulated by Met. Met increased SIRT5 expression level in pancreas of KKAy mice under the hyperglycemic clamp. These results indicated that chronic administration of Met regulated pancreatic inflammation generation, ion and hormone homeostasis and improved ß cell function of diabetic KKAy mice.

[Valibose, an alpha-glucosidase inhibitor, ameliorates the metabolic disorder of glucose and lipids and the nephropathy in streptozotocin-induced diabetic rats].

This study is to evaluate the anti-diabetic effects of the alpha-glucosidase inhibitor valibose in a streptozotocin (STZ)-induced type 1 diabetes rat model. Diabetes was induced by a single dose of STZ (58 mg x kg(-1), ip) in SD rats, rats with elevated fasting blood glucose levels (250-450 mg x dL(-1)) were selected and divided into five groups (n = 10 in each). Another ten normal SD rats were chosen as normal group. Valibose mixed with the high sucrose diets (0.4, 1.0 and 2.5 mg 100 g(-1) diets) or acarbose (30 mg x 100 g(-1) diets) was administrated in the diabetic rats for about 5 weeks. In all groups, fasting and postprandial plasma glucose, plasma lipids, glycosylated serum protein, N-acetyl-beta-D-glucosaminidase (NAG), creatinine (Cre), blood urea nitrogen (BUN) and urine sugar levels were determined during the treatment. At the end of the experiment, the morphological alterations in kidney were evaluated by hematoxylin-eosin (HE) staining. After 3-weeks administration, valibose significantly decreased postprandial and fasting blood glucose, urine glucose, and reduced the levels of serum fructosamine. Valibose also decreased plasma triglyceride and cholesterol levels after 4 weeks treatment. These results indicated that valibose ameliorated metabolic disturbance of glucose and lipids in STZ-induced diabetic rats. In addition, valibose markedly reduced level of serum NAG and BUN, and decreased the weight index of kidney. HE staining showed reduced kidney pathological changes after valibose treatment. The findings of the present study indicate that valibose may be a novel alpha-glucosidase inhibitor for the prevention from hyperglycemia in STZ-induced type 1 diabetes rats. And valibose might have a potential role for protecting against diabetic nephropathy during hyperglycemia.

[Salicylic acid derivatives as simplified and novel GK small molecule activators].

Glucokinase (GK) is a new target for the treatment of type II diabetes mellitus (T2DM). In order to find a structure-simplified small molecule GK activator, 19 salicylic acid derivatives were designed and synthesized based on new lead compound (1). Experimental results showed that the potency of compound 8h is superior to control RO-28-0450 in GK activation.