Low-density lipoprotein receptor genotypes modify the sera metabolome of patients with homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is an extremely rare metabolism disorder usually caused by low-density lipoprotein receptor (LDLR) mutations. LDLR genotype is commonly known to determine blood concentrations of LDL cholesterol. However, effects of LDLR genotype on holistic metabolome remain unclear. Herein, we present metabolomic, genetic, and clinical datasets from a large multi-center panel of 142 patients with LDLR-mutated HoFH. We found that true homozygotes and compound heterozygotes showed few differences in clinical and metabolomic phenotypes. Compared with defective/defective mutation carriers, patients carrying one or two null mutation showed profound alterations in clinical laboratory lipids and serum cholesterol esters, lysophosphocholines, bile acids, and amino acids. Importantly, these altered metabolites are implicated in multiple biochemical reactions and associated with LDL cholesterol. This study extends the first map of different LDLR genotypes influencing the metabolome and suggests that the small-molecule metabolites serve as potential targets to mitigate the deleterious impact of LDLR mutations on HoFH.

Cyclocarya paliurus extract activates insulin signaling via Sirtuin1 in C2C12 myotubes and decreases blood glucose level in mice with impaired insulin secretion.

Diabetes is caused by the lack of release or action of insulin. Some foods and supplements can compensate for this deficiency; thus, they can aid in the prevention or treatment of diabetes. The aim of this study was to investigate the effects of Cyclocarya paliurus extract (CPE) on insulin signaling and its capacity to correct hyperglycemia in the absence of insulin. To investigate the hypoglycemic effects of CPE, C2C12 cells were exposed to CPE (50 and 100 µg/mL). CPE promoted 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2NBDG) uptake into the cells via translocation of glucose transporter 4 (Glut4) to the plasma membrane. In addition, CPE enhanced tyrosine phosphorylation of insulin receptor substrate and activated phosphatidylinositol 3-kinase and protein kinase B (Akt) via sirtuin1 in C2C12 cells. Moreover, we found that oral administration of CPE (1 g/kg) to streptozotocin-induced hyperglycemic mice produced a progressive decrease in plasma glucose levels at 1 h after single dosing. At that point, CPE significantly increased the expression of skeletal muscle membrane Glut4 and enhanced the phosphorylation of Akt. These results suggest that CPE exerts antidiabetic effects similar to those of insulin, and may be an oral therapeutic alternative for the management of diabetes.

Tangnaikang improves insulin resistance and ß-cell apoptosis by ameliorating metabolic inflammation in SHR.Cg-Leprcp/NDmcr rats.

OBJECTIVE: To investigate the effects of Tangnaikang (TNK), a mixture of five herbal plant extracts, on inflammation-mediated insulin resistance and B-cell apoptosis in SHR.Cg-Leprcp/NDmcr (SHR-cp) rats. METHODS: Seven-week-old SHR-cp rats were randomly divided into a control (CON) group and a TNK (3.24 g/kg) group. Wistar-Kyoto rats at the same age were used as the normal control group. After 7 weeks of continuous intragastric administration of TNK, the glucose metabolic status and insulin sensitivity of the rats were evaluated by assessing fasting serum glucose (FBG), the oral glucose tolerance test (OGTT), fasting serum insulin (FINS), and the insulin sensitivity index (ISI). Serum tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), C-reactive protein (CRP) and adiponectin were measured via enzyme-linked immunosorbent assays. Macrophage infiltration and apoptosis in adipose tissues were detected through F4/80 immunohistochemistry and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Islet morphology and B-cell apoptosis were investigated using double immunofluorescence staining and the TUNEL assay. The expression of cytokine genes in adipose tissue, the liver, and the pancreas was detected in real-time polymerase chain reaction assays. The expression and phosphorylation levels of insulin signaling-, inflammation-, and B-cell survival-related proteins in the liver and pancreas of SHR-cp rats were detected by western blotting. RESULTS: TNK (3.24 g/kg) treatment significantly decreased body weight, FBG and FINS; improved impaired glucose tolerance; increased the ISI; reduced serum levels of TNF-a, CRP and IL-6; and increased serum adiponectin. The mRNA expression of inflammatory markers was markedly reduced in the liver, pancreas, and adipose tissue. F4/80- and TUNEL-positive cells in adipose tissues were decreased, as was the number of TUNEL-positive B-cells. The phosphorylation of c-Jun N-terminal kinase and that of insulin receptor substrate-1 at serines 307 and 1101 was significantly decreased. In the pancreas, the expression of nuclear factor kappa-light chain-enhancer of activated B cells-p65 was significantly decreased, and phosphoinositide 3-kinase and IRS-2 were significantly increased. CONCLUSION: TNK was able to improve insulin resistance and B-cell apoptosis in SHR-cp rats, which might be associated with its ability to relieve the overall and local metabolic inflammatory responses observed in SHR-cp rats.

Mixture of five herbal extracts ameliorates pioglitazone-induced aggravation of hepatic steatosis via activating the adiponectin receptor 2/AMP-activated protein kinase signal pathway in diabetic KKAy mice.

OBJECTIVE: To assess the effect of a mixture of five herbal extracts (FT-5) on insulin resistance, glucose/lipid metabolism, hepatic steatosis, and to investigate whether the combination of FT-5 and pioglitazone would provide a robust effect on diabetes treatment, while may minimize undesirable side-effects of pioglitazone in diabetic Ay gene (KKAy) mice. METHODS: Seven-week-old KKAy mice were randomly divided into five groups: control (CON) group, FT-5 (2.0 g/kg) group, pioglitazone (20 mg/kg) (PIO) group, pioglitazone (20 mg/kg) + FT-5 (2.0 g/kg) (P + F) group. Age-matched C57BL/6J mice were used as the control group. After seven weeks of continuous intragastric administration of medication, the glucose metabolism, insulin sensitivity and lipid metabolism of KKAy mice were evaluated by assessing the fasting blood glucose (FBG), oral glucose tolerance test (OGTT), fasting serum insulin (FINS), insulin tolerance test (ITT), homeostasis model of assessment-insulin resistance index (HOMA-IR), total cholesterol (TC), total triglycerides (TG), and free fatty acids (FFA) in plasma and liver. Plasma and hepatic adiponectin were measured via enzyme-linked immunosorbent assays. Genes related to adipogenesis and lipolysis in white adipose tissues (WAT) and liver were examined by real-time polymerase chain reaction. Lipid metabolism-related protein expression in the liver of KKAy mice were detected by Western blotting. RESULTS: PIO treatment remarkably improved insulin resistance. However, it also showed substantial side effects. FT-5 group exhibited no significant decrease in serum glucose. However, it reduced fasting plasma TG levels and improved hepatic steatosis of KKAy mice. P + F group showed improved insulin resistance and similar body weight gain, as compared with control group. The mRNA expression of genes related to fatty acid oxidation was markedly up-regulated in the liver of P + F group. Pioglitazone administration markedly decreased the phosphorylation levels of AMPK, as compared with all other groups. Besides, even though plasma adiponectin increased in PIO, FT-5, P + F group, adipoR2 gene expression significantly decreased in the liver of PIO group. CONCLUSION: FT-5 decreased plasma TG and alleviated aggravating hepatic steatosis induced by pioglitazone in KKAy mice. FT-5's mechanism might be associated with its ability to activate the AdipoR2/AMPK pathway.

Qiwei granules alleviates podocyte lesion in kidney of diabetic KK-Ay mice.

BACKGROUND: Chinese medicine comprised of all natural herbs is widespread used in the treatment of diabetic nephropathy (DN). Podocyte contributes to the integrity of glomerular filtration barrier whose injury plays an important role in the initiation and progression of DN. Our study aimed to investigate the effect of Qiwei granules on podocyte lesion in diabetic KK-A(y) mice kidney and its underlying mechanism. METHODS: Twelve-week-old male KK-A(y) mice were randomly divided in vehicle group and Qiwei granules group, while C57BL/6J mice were used as normal control. The mice were gavage with 1.37 g/kg/day Qiwei granules or water for 10 weeks. We measured water, food intake and body weight (BW) and fasting blood glucose (FBG) every 2 weeks, and urine protein every 4 weeks. At the end of the experiment, all surviving mice were sacrificed. The kidney weight and serum renal parameters were measured, and the renal morphology was observed. To search the underlying mechanism, we examined the podocyte positive marker, slit diaphragm protein expression and some involved cell signal pathway. RESULTS: Qiwei granules treatment significantly improved the metabolic parameters, alleviated the urinary protein, and protected renal function in KK-A(y) mice. In addition, the glomerular injuries and podocyte lesions were mitigated with Qiwei granules treatment. Furthermore, Qiwei granules increased expression of nephrin, CD2AP, and integrin alpha3beta1 in the podocytes of KK-A(y) mice. Qiwei granules improved the phosphoration of Akt and inhibited cleaved caspase-3 protein expression. CONCLUSION: These finding suggest that Qiwei granules protects the podocyte from the development of DN via improving slit diaphragm (SD) molecules expression and likely activating Akt signaling pathway in KK-A(y) mice.

Tang-Nai-Kang alleviates pre-diabetes and metabolic disorders and induces a gene expression switch toward fatty acid oxidation in SHR.Cg-Leprcp/NDmcr rats.

Increased energy intake and reduced physical activity can lead to obesity, diabetes and metabolic syndrome. Transcriptional modulation of metabolic networks has become a focus of current drug discovery research into the prevention and treatment of metabolic disorders associated with energy surplus and obesity. Tang-Nai-Kang (TNK), a mixture of five herbal plant extracts, has been shown to improve abnormal glucose metabolism in patients with pre-diabetes. Here, we report the metabolic phenotype of SHR.Cg-Leprcp/NDmcr (SHR/cp) rats treated with TNK. Pre-diabetic SHR/cp rats were randomly divided into control, TNK low-dose (1.67 g/kg) and TNK high-dose (3.24 g/kg) groups. After high-dose treatment for 2 weeks, the serum triglycerides and free fatty acids in SHR/cp rats were markedly reduced compared to controls. After 3 weeks of administration, the high dose of TNK significantly reduced the body weight and fat mass of SHR/cp rats without affecting food consumption. Serum fasting glucose and insulin levels in the TNK-treated groups decreased after 6 weeks of treatment. Furthermore, TNK-treated rats exhibited obvious improvements in glucose intolerance and insulin resistance. The improved glucose metabolism may be caused by the substantial reduction in serum lipids and body weight observed in SHR/cp rats starting at 3 weeks of TNK treatment. The mRNA expression of NAD+-dependent deacetylase sirtuin 1 (SIRT1) and genes related to fatty acid oxidation was markedly up-regulated in the muscle, liver and adipose tissue after TNK treatment. Furthermore, TNK promoted the deacetylation of two well-established SIRT1 targets, PPARγ coactivator 1α (PGC1α) and forkhead transcription factor 1 (FOXO1), and induced the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in different tissues. These observations suggested that TNK may be an alternative treatment for pre-diabetes and metabolic syndrome by inducing a gene expression switch toward fat oxidation through the activation of SIRT1 and AMPK signaling.

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.