Glucose Metabolism In Diabetic Mice Research Articles

Molecular mechanism of microRNA-mediated hypoglycemic effect of whole grain highland barley

As a non-coding RNA, microRNA (miRNA) has been proven to play an important role in the development and progression of type 2 diabetes mellitus (T2DM). Highland barley is a whole grain from the Tibetan areas of China. Our previous studies have demonstrated its hypoglycemic effect. To further explore the underlining molecular mechanism, we investigated the effect of highland barley intervention on liver miRNA expression profiles in diabetic mice. Our results showed that ten differentially expressed miRNA among different groups were identified and their target genes were predicted. Remarkably, many glycometabolism-associated genes, including Foxo3, Nras, Rptor, Igf1r, Tsc2 and Braf, were negatively regulated by miR-122-5p, miR-503-5p, miR-455-5p and miR-210-3p, respectively. Pathway enrichment analysis revealed these target genes were mainly involved in AMPK, MAPK and FOXO signaling pathways. Thereby, these miRNA and mRNA were validated using qRT-PCR, and the results were consistent with the small RNA-seq and expectations. Highland barley could regulate the MAPK, AMPK, and FOXO signaling pathways by regulating critical miRNA-mRNA pairs, e.x. miR-210-3p-Tsc2/Braf, miR-122-5p-Foxo3, and miR-455-5p-Igf1r, thereby improving blood glucose metabolism in diabetic mice. The present study preliminarily explored the hypoglycaemic effects of highland barley based on transcriptomics, and more detailed and in-depth studies on this topic are needed in the future.

Effects of Cinnamon Powder on Glucose Metabolism in Diabetic Mice and the Molecular Mechanisms.

The liver is the primary organ regulating glucose metabolism. In our recent study, cinnamon improved liver function in diabetic mice. However, it is not clear whether cinnamon can reduce the glycemia of diabetic animals by regulating liver glucose metabolism. The purpose of this study was to investigate the hypoglycemic mechanism of cinnamon powder (CP) from the perspective of regulating liver glucose metabolism. To achieve this, different doses of CP (200, 400, or 800 mg/kg body weight) were given to diabetic mice by gavage once per day for 8 weeks. These mice were compared with healthy controls, untreated diabetic mice, and diabetic mice treated with metformin (the main first-line drug for type 2 diabetes). CP treatment effectively reduced fasting blood glucose levels and food intake, improved glucose tolerance and fasting serum insulin levels, and decreased glycated serum protein levels in diabetic mice. Furthermore, treatment with CP increased liver glycogen content and reduced the level of the gluconeogenesis precursor pyruvate in the liver. Data obtained by qPCR and western blotting suggested that CP improved glucose metabolism disorders by regulating AMPKα/PGC1α-mediated hepatic gluconeogenesis and PI3K/AKT-mediated hepatic glycogen synthesis. CP exhibits good hypoglycemic effects by improving hepatic glycogen synthesis and controlling hepatic gluconeogenesis. Therefore, CP may be applied as a functional food to decrease blood glucose.

Enhancement of the SESN2-SHP cascade by melatonin ameliorates hepatic gluconeogenesis by inhibiting the CRBN-BTG2-CREBH signaling pathway

Melatonin is involved in the regulation of various biological functions. Here, we explored a novel molecular mechanism by which the melatonin-induced sestrin2 (SESN2)-small heterodimer partner (SHP) signaling pathway protects against fasting- and diabetes-mediated hepatic glucose metabolism. Various key gene expression analyses were performed and multiple metabolic changes were assessed in liver specimens and primary hepatocytes of mice and human participants. The expression of the hepatic cereblon (CRBN) and b-cell translocation gene 2 (BTG2) genes was significantly increased in fasting mice, diabetic mice, and patients with diabetes. Overexpression of Crbn and Btg2 increased hepatic gluconeogenesis by enhancing cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH), whereas this phenomenon was prominently ablated in Crbn null mice and Btg2-silenced mice. Interestingly, melatonin-induced SESN2 and SHP markedly reduced hepatic glucose metabolism in diabetic mice and primary hepatocytes, and this protective effect of melatonin was strikingly reversed by silencing Sesn2 and Shp. Finally, the melatonin-induced SESN2-SHP signaling pathway inhibited CRBN- and BTG2-mediated hepatic gluconeogenic gene transcription via the competition of BTG2 and the interaction of CREBH. Mitigation of the CRBN-BTG2-CREBH axis by the melatonin-SESN2-SHP signaling network may provide a novel therapeutic strategy to treat metabolic dysfunction due to diabetes.

Effects of Chuju Polysaccharides on Glucose Metabolism in Diabetic Mice

Chuju is a special Chinese flower tea with extensive health benefits. In this study, we have examined the effects of crude Chuju polysaccharides on alloxan-induced diabetic mice by measuring fasting blood glucose, insulin-related index, activities of superoxide dismutase, glutathione peroxidase, and content of malondialdehyde in the serum and liver. The results show that the treatment led to increased insulin sensitivity and decreased fasting glucose. The blood and liver levels of malondialdehyde decreased, whereas superoxide dismutase and glutathione peroxidase levels were elevated by crude Chuju polysaccharides in alloxan-induced diabetic mice. These data support a basis for clinical investigations on crude Chuju polysaccharides in diabetic human subjects.

Antidiabetic activity of a Flavonoid-Rich extract from flowers of Wisteria sinensis in type 2 diabetic mice via activation of the IRS-1/PI3K/Akt/GLUT4 pathway

• WS-FRE ameliorated a series of diabetes-related indices. • WS-FRE promoted GLUT4 translocation and expression by activating PI3K/Akt pathway. • WS-FRE ameliorated pathological changes of insulin-sensitive tissues. • WS-FRE regulated glucose metabolism through IRS-1/PI3K/Akt/GLUT4 pathway. The present study aimed to investigate anti-diabetic activities of a flavonoid-rich extract from Wisteria sinensis (WS-FRE). In vitro , WS-FRE significantly promote the translocation of GLUT4 (Glucose transporter 4) to the plasma membrane. Mechanisms analysis revealed that WS-FRE enhanced glucose uptake via activation of Akt and GLUT4. In vivo , 4-week treatment of WS-FRE alleviated the typical symptoms including hyperglycemia, glucose intolerance, hyperinsulinemia and dyslipidemia. Histopathological examinations revealed that WS-FRE relieved hepatic steatosis, adipocyte hypertrophy and pancreatic islet lesion to a certain extent in diabetic mice. Western blot analysis indicated that WS-FRE resulted in the suppression of IRS-1 serine phosphorylation and an elevation of PI3K p85, Akt phosphorylation and GLUT4 expression in insulin target tissues, which contributes to improving insulin sensitivity in peripheral tissues and thereby ameliorating glucose metabolism in diabetic mice. Diverse anti-diabetic effects of WS-FRE may be attributed to regulation of GLUT4, IRS-1 serine phosphorylation, PI3K phosphorylation and Akt phosphorylation.

Effects of D-Chiro-Inositol on Glucose Metabolism in db/db Mice and the Associated Underlying Mechanisms.

In this study, we observed the effect of D-chiro-inositol (DCI) on glucose consumption in type 2 diabetic db/db mice, and investigated the relevant mechanism. We discovered that the stability of 24-h blood glucose under the nonfasting condition and decreased glucose tolerance were both alleviated after treatment with DCI. Moreover, the content of glycosylated protein and advanced glycation end products in the serum was reduced, the damage in the liver tissue was alleviated, and the synthesis of liver glycogen was significantly promoted. In addition, DCI increased the expression of insulin receptor substrate 2 (IRS2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), glucose transporters 4 (GLUT4), and phospho-AKT (S473) protein. In contrast, DCI decreased the expression level of glycogen synthase kinase 3β (GSK3β) protein in liver tissue to various degrees, as shown by immunohistochemistry and western blotting. Furthermore, DCI increased the mRNA expression of IRS2, PI3K, AKT, and GLUT4, and reduced that of GSK3β in liver tissue, as demonstrated by polymerase chain reaction. Finally, DCI promoted glucose consumption in high glucose-stimulating HepG2 cells and increased the expression of IRS2 protein in HepG2 cells, as revealed by fluorescence staining and flow cytometry. Our results indicate that DCI can significantly improve glucose metabolism in diabetic mice and HepG2 cells. This effect may be associated with the upregulation of IRS2, PI3K, AKT, and GLUT4 and downregulation of GSK3β.

A siRNA mediated hepatic dpp4 knockdown affects lipid, but not glucose metabolism in diabetic mice.

Systemic inhibition of dipeptidyl peptidase 4 (dpp4) represents an effective and established treatment option for type 2 diabetes (T2D). The current study investigated in mice if a liver selective knock-down of dpp4 by therapeutic siRNAs could be a novel, similarly effective treatment option for T2D. Furthermore, the potential effects on hepatic steatosis, inflammation and lipid metabolism were investigated after hepato-selective knock-down of dpp4. The knock-down efficiency and IC50 values of siRNAs targeting dpp4 were analyzed in PC3 cells. In two independent studies, either db/db mice or C57BL/6J mice were injected intravenously with a liposomal formulation of siRNAs targeting either dpp4 or a non-targeting control, followed by metabolically characterization. In comparator groups, additional cohorts of mice were treated with an oral dpp4 inhibitor. In both animal studies, we observed a robust knock-down (~75%) of hepatic dpp4 with a potent siRNA. Hepatic dpp4 knockdown did not significantly affect glucose metabolism or circulating incretin concentrations in both animal studies. However, in obese and diabetic db/db mice hepatic steatosis was reduced and hepatic mRNA expression of acaca, scd1, fasn and pparg was significantly lower after siRNA treatment. Systemic inhibition of the enzymatic dpp4 activity by an oral dpp4 inhibitor significantly improved glucose handling in db/db mice but did not affect hepatic endpoints. These data demonstrate that a targeted reduction of dpp4 expression in the liver may not be sufficient to improve whole-body glucose metabolism in obese and diabetic mice but may improve hepatic lipid metabolism.

Dendrobium officinale polysaccharide ameliorates diabetic hepatic glucose metabolism via glucagon-mediated signaling pathways and modifying liver-glycogen structure.

Dendrobium officinale polysaccharide (DOP) is the main active ingredient of Dendrobium officinale Kimura & Migo, which is a precious traditional Chinese medicine and often used in treatment of hepatitis, diabetes, obesity and rheumatoid arthritis. DOP exhibits significant hypoglycemic activity, while its mechanism remains unclear. The present study aims to investigate the hypoglycemic mechanisms of DOP based on the glucagon-mediated signaling pathways and the liver glycogen structure, which catalyze hepatic glucose metabolism, and provide new knowledge about the antidiabetic mechanism of DOP and further evidence for its clinical use for diabetes. DOP were obtained from the dry stems of Dendrobium officinale by water extraction and alcohol precipitation method. T2DM mice model was established by high-fat diet combined with streptozotocin. Liver histopathological changes were observed by H&E and PAS straining. Pancreatic histology was studied by H&E staining and immunofluorescence analysis. The levels of glucagon and insulin were detected by Elisa Kit and the hepatic glycogen content was detected by GOPOD. The expressions of the hepatic glycogen-related metabolism enzymes, hepatic gluconeogenesis enzymes, and the related protein in cAMP-PKA and Akt/FoxO1 signaling pathways were detected by western blots. Liver glycogen was extracted from the liver tissues by sucrose density gradient centrifugation, and size exclusion chromatography (SEC) was used to analyze the structure of liver glycogen. DOP could significantly affect the glucagon-mediated signaling pathways, cAMP-PKA and Akt/FoxO1, to further promote hepatic glycogen synthesis, inhibit hepatic glycogen degradation and hepatic gluconeogenesis. Moreover, DOP could reverse the instability of the liver glycogen structure and thus probably suppressed glycogen degradation. Thus, DOP finally would ameliorate hepatic glucose metabolism via glucagon-mediated signaling pathways and modifying liver-glycogen structure in diabetic mice. The hypoglycemic mechanism of DOP might be associated with the regulation of glucagon-mediated hepatic glycogen metabolism and gluconeogenesis, and of liver glycogen structure, contributing to improved hepatic glucose metabolism in diabetic mice.

Chronotherapeutic effect of orexin antagonists on glucose metabolism in diabetic mice.

Disrupted sleep is associated with increased risk of type 2 diabetes. Central actions of orexin, mediated by orexin-1 and orexin-2 receptors, play a crucial role in the maintenance of wakefulness; accordingly, excessive activation of the orexin system causes insomnia. Resting-phase administration of dual orexin receptor antagonist (DORA) has been shown to improve sleep abnormalities and glucose intolerance in type 2 diabetic db/db mice, although the mechanism remains unknown. In the present study, to investigate the presence of functional link between sleep and glucose metabolism, the influences of orexin antagonists with or without sleep-promoting effects were compared on glucose metabolism in diabetic mice. In db/db mice, 2-SORA-MK1064 (an orexin-2 receptor antagonist) and DORA-12 (a DORA) acutely improved non-rapid eye movement sleep, whereas 1-SORA-1 (an orexin-1 receptor antagonist) had no effect. Chronic resting-phase administration of these drugs improved glucose intolerance, without affecting body weight, food intake, locomotor activity, and energy expenditure calculated from O2 consumption and CO2 production. The expression levels of pro-inflammatory factors in the liver were reduced by 2-SORA-MK1064 and DORA-12, but not 1-SORA-1, whereas those in the white adipose tissue were reduced by 1-SORA-1 and DORA-12 more efficiently than 2-SORA-MK1064. When administered chronically at awake phase, these drugs caused no effect. In streptozotocin-induced type 1-like diabetic mice, neither abnormality in sleep-wake behavior nor improvement of glucose intolerance by these drugs were observed. These results suggest that both 1-SORA-type (sleep-independent) and 2-SORA-type (possibly sleep-dependent) mechanisms can provide chronotherapeutic effects against type 2 diabetes associated with sleep disturbances in db/db mice.

Effects of nanoparticles of hydroxy-aluminum phthalocyanine on markers of liver injury and glucose metabolism in diabetic mice.

Photodynamic therapy, by reducing pain and inflammation and promoting the proliferation of healthy cells, can be used to treat recurrent lesions, such as diabetic foot ulcers. Studies using the photosensitizer phthalocyanine, together with the nanostructured copolymeric matrix of Pluronic® and Carbopol® for the treatment of diabetic foot ulcers and leishmaniosis lesions, are showing promising outcomes. Despite their topical or subcutaneous administration, these molecules are absorbed and their systemic effects are unknown. Therefore, we investigated the effect of the subcutaneous administration of the hydroxy-aluminum phthalocyanine hydrogel without illumination on systemic parameters, markers of liver injury, and liver energy metabolism in type 1 diabetic Swiss mice. Both the hydrogel and the different doses of phthalocyanine changed the levels of injury markers and the liver glucose release, sometimes aggravating the alterations caused by the diabetic condition itself. However, the dose of 2.23 µg/mL caused less marked plasmatic and metabolic changes and did not change glucose tolerance or insulin sensitivity of the diabetic mice. These results are indicative that the use of hydroxy-aluminum phthalocyanine hydrogel for the treatment of cutaneous ulcers in diabetic patients is systemically safe.

Beta-Cell Glucotoxicity in KATP-Induced Diabetes Is Alleviated by Genetic Reduction of Glucose Metabolism

Glucotoxicity, reduced β-cell function and mass are key events in the pathogenesis and progression of diabetes. We previously generated an insulin secretory-deficient mouse model of human KATP-induced diabetes. As predicted, KATP-GOF (gain-of-function) mice demonstrate severe diabetes due to low circulating insulin levels, reiterating the human disease. However, as diabetes progresses, KATP-GOF mice show reduction of insulin content and β-cell mass, consequences of glucotoxicity. Islets from diabetic mice also show increased glucose metabolism (NAD(P)H autofluorescence) and oxygen consumption rate (Seahorse analysis), and augmented mitochondrial membrane potential. Strikingly, they also demonstrate increased glucokinase (GK, first enzyme in glucose metabolism) and GLUT2 gene transcripts and proteins. We hypothesized that augmented glucose metabolism in diabetic mice will contribute to the glucotoxic reduction in in insulin content, β-cell function and mass; and that these consequences will be alleviated by reducing glucose metabolism. To test this in vivo, we crossed KATP-GOF mice with mildly glucose-intolerant heterozygous GK+/- knockout mice (with reduced glucose metabolism), to generate double-transgenic GK+/-/KATP-GOF mice. Progression of diabetes, assessed by blood glucose levels overtime, is slower in GK+/-/KATP-GOF mice, compared with KATP-GOF mice. Importantly also, glucose tolerance is enhanced in GK+/-/KATP-GOF mice 12 days after disease onset, with respect to KATP-GOF mice, without significant changes in insulin sensitivity. Insulin gene expression, insulin content and β-cell mass are partially preserved in GK+/-/KATP-GOF mice. Together, these results demonstrate that hyperglycemia induce accelerated metabolism in KATP-GOF mice damaging the islets, and that deceleration of metabolism by reducing GK activity delays/prevent hypermetabolism induced-glucotoxicity in KATP-GOF mice. Disclosure M. Fortunato: None. Z. Yan: None. Z.A. Shyr: None. H.E. Conway: None. M.S. Remedi: None.

Ocimum basilicum but not Ocimum gratissimum present cytotoxic effects on human breast cancer cell line MCF-7, inducing apoptosis and triggering mTOR/Akt/p70S6K pathway.

Breast cancer is the major cause of death by cancer in women worldwide and in spite of the many drugs for its treatment, there is still the need for novel therapies for its control. Ocimum species have been used by traditional medicine to control several diseases, including cancer. We have previously characterized the antidiabetic properties of the unfractionated aqueous leaf extracts of Ocimum basilicum (OB) and Ocimum gratissimum (OG), modulating glucose metabolism in diabetic mice. Since glucose metabolism is primordial for cancer cells survival, we hypothesized that these extracts are effective against cancer cells. The unfractionated aqueous leaf extracts of OB and OG were chemically characterized and tested for their cytotoxic, cytostatic and anti-proliferative properties against the human breast cancer cell line MCF-7. Both extracts presented cytostatic effects with an 80% decrease in MCF-7 cell growth at 1mg/mL. However, only OB promoted cytotoxic effects, interfering with the cell viability even after interruption of the treatment. Moreover, OB but not OG affected the cell proliferation and metabolism, evaluated in terms of lactate production and intracellular ATP content. After 24h of treatment, OB treated cells presented an apoptotic profile, while OG treated cells were more necrotic. The treatment with both extracts also activated AMPK, but OB was much more efficient than OG in promoting this. The activation of mTOR signaling, another survival pathway was promoted by OB, whereas OG failed to activate it. In the end, we conclude that OB extract is efficient against the human breast cancer cell line.

ID: 1072 Increasing dose of intravenous human adipose-derived stem cells improves the pancreatic function of diabetic mice

Mesenchymal tem cell transplantation is a novel treatment for diabetes mellitus, especially type 1 diabetes. Many publications have proved the effect of MSC therapy on reducing blood glucose and improving insulin production in type 1 diabetic animal as well as in clinic trials. However, there is no conclusion that how many cells are effective for diabetes. Thus, this study has investigated that different adipose-derived MSC doses affected glucose metabolism in diabetic mice. STZ-induced diabetic mice were intravenous transfused with human MSCs with dose either 106 (treated group A) or 2x106 cells/mouse (treated group B). Both treated and untreated mice were monitored the blood glucose levels, glucose and insulin tolerance test, pancreatic structure change and insulin production every week until 56 days after transplantation. The results showed that the higher dose of MSC could reduce death rate (66% vs. 0% death in group A vs. group B after 56 days of treatment, respectively) and remarkably lower blood glucose levels while the mice treated with 1x106 cells/dose remaining hyperglycemia. Moreover, the glucose tolerance and insulin tolerance as well as insulin production were improved in group B at 28 days after transplantation. The histochemical imaging further demonstrated the decrease of inflammatory cells in the islets and the restoration of pancreatic structures in higher-dose-MSCs-treated mice. Thus, the dose 2x106 cells of MSCs may be an effective strategy for diabetes mellitus concerning hyperglycemia, impaired glucose metabolism and islet destruction.

A Human Glucagon-Like Peptide-1-albumin Recombinant Protein with Prolonged Hypoglycemic Effect Provides Efficient and Beneficial Control of Glucose Metabolism in Diabetic Mice.

GW002 is a recombinant protein engineered by fusing the C-terminal region of human glucagon-like peptide-1 (GLP-1) to the N-terminal region of human serum albumin (HSA) with a peptide linker. This study aims to evaluate its anti-diabetic effects both in vitro and in vivo. The GLP-1 receptor-dependent luciferase reporter plasmid was transiently transfected in NIT-1 cells to calculate the half-maximal concentration (EC50) for GLP-1 receptor activation, and normal ICR mice and diabetic KKAy mice were acutely injected with GW002 (1, 3, 9 mg/kg) subcutaneously to evaluate the hypoglycemic action, while the diabetic KKAy and db/db mice were treated with GW002 once daily for 7 weeks to evaluate the effects on glucose metabolism. The results showed that GW002 activated GLP-1 receptor in NIT-1 cells with higher EC50 versus exendin-4 (46.7 vs. 7.89 nM), and single subcutaneous injection of GW002 at doses of 1, 3 and 9 mg/kg efficiently restrained the glycemia variation after oral glucose loading in ICR mice for at least 4 d, as well as reducing the non-fasting blood glucose in KKAy mice for about 2 d, while repeated injections of GW002 significantly improved abnormal glycaemia, hemoglobin (Hb)A1c levels, oral glucose intolerance and β-cell function in diabetic db/db mice. These results suggested that GW002 showed prolonged hypoglycemic action by activating its cognate receptor and provided efficient control of glucose metabolism. Thus GW002 may be a potential treatment for the management of type 2 diabetes.

Jiang Tang Xiao Ke Granule, a Classic Chinese Herbal Formula, Improves the Effect of Metformin on Lipid and Glucose Metabolism in Diabetic Mice.

In the present study, the hypoglycemic, hypolipidemic, and antioxidative effects of metformin (MET) combined with Jiang Tang Xiao Ke (JTXK) granule derived from the “Di Huang Tang” were evaluated in mice with type 2 diabetes mellitus (DM) induced by high-fat diet/streptozotocin. DM mice were orally treated with MET (0.19 g/kg) either alone or combined with different doses (1.75, 3.5, or 7 g/kg) of JTXK for 4 weeks. Results showed that the serum and hepatic glucose, lipids, and oxidative stress levels were elevated in DM mice, when compared with the normal mice. MET treatment decreased FBG and serum glucagon levels of DM mice. Combination treatment with MET and JTXK 3.5 g/kg increased the hypoglycemia and insulin sensitivity at 4 weeks when compared with the DM mice treated with MET alone. However, neither MET nor MET/JTXK treatment could completely reverse the hyperglycemia in DM mice. JTXK enhanced the serum triglyceride (TG) and hepatic lipid-lowering effect of MET in a dose-dependent manner in DM mice. JTXK 1.75 and 3.5 g/kg improved the hepatoprotective effect of MET in DM mice. Synergistic effect of combination treatment with MET and JTXK on antioxidant stress was also found in DM mice compared with MET alone.

Hepatic Overexpression of ATP Synthase β Subunit Activates PI3K/Akt Pathway to Ameliorate Hyperglycemia of Diabetic Mice

ATP synthase β subunit (ATPSβ) had been previously shown to play an important role in controlling ATP synthesis in pancreatic β-cells. This study aimed to investigate the role of ATPSβ in regulation of hepatic ATP content and glucose metabolism in diabetic mice. ATPSβ expression and ATP content were both reduced in the livers of type 1 and type 2 diabetic mice. Hepatic overexpression of ATPSβ elevated cellular ATP content and ameliorated hyperglycemia of streptozocin-induced diabetic mice and db/db mice. ATPSβ overexpression increased phosphorylated Akt (pAkt) levels and reduced PEPCK and G6pase expression levels in the livers. Consistently, ATPSβ overexpression repressed hepatic glucose production in db/db mice. In cultured hepatocytes, ATPSβ overexpression increased intracellular and extracellular ATP content, elevated the cytosolic free calcium level, and activated Akt independent of insulin. The ATPSβ-induced increase in cytosolic free calcium and pAkt levels was attenuated by inhibition of P2 receptors. Notably, inhibition of calmodulin (CaM) completely abolished ATPSβ-induced Akt activation in liver cells. Inhibition of P2 receptors or CaM blocked ATPSβ-induced nuclear exclusion of forkhead box O1 in liver cells. In conclusion, a decrease in hepatic ATPSβ expression in the liver, leading to the attenuation of ATP-P2 receptor-CaM-Akt pathway, may play an important role in the progression of diabetes.

Evaluation of Chios Mastic Gum on Lipid and Glucose Metabolism in Diabetic Mice

Chios mastic gum (MG), a resin produced from Pistacia lentiscus var. Chia, is reported to possess beneficial cardiovascular and hepatoprotective properties. This study investigated the effect of crude Chios MG on metabolic parameters in diabetic mice. Streptozotocin-induced diabetic 12-week-old male C57bl/6 mice were assigned to three groups: NC (n=9) control; LdM (n=9) animals receiving low dose mastic for 8 weeks (20 mg/kg body weight [BW]); and HdM (n=9) animals receiving high dose mastic (500 mg/kg BW) for the same period. Serum lipid and glucose levels were determined at baseline, at 4 and 8 weeks. Serum total protein, adiponectin, and resistin levels were also measured at the end of the experiment. Histopathological examination for liver, kidney, aorta, and heart lesions was performed. After 4 weeks, MG administration resulted in decreased serum glucose and triglyceride levels in both LdM and HdM, whereas BW levels were reduced in LdM group compared with controls. At the end of the experiment, LdM presented significantly lower serum glucose, cholesterol, low-density lipoprotein cholesterol, and triglyceride levels and improved high-density lipoprotein cholesterol levels compared with control group. HdM group had ameliorated serum triglyceride levels. Hepatic steatosis observed in control group was partially reversed in LdM and HdM groups. MG administered in low dosages improves glucose and lipid disturbances in diabetic mice while alleviating hepatic damage.

Hepatic mechanisms of the Walnut antidiabetic effect in mice

AbstractThe present study was designed to explore the mechanism of action of walnut (the seed of Juglans regia) leaf and ridge on hepatic glucose metabolism in diabetic mice. Experimental diabetes was induced by intravenous administration of streptozotocin (60 mg/kg)and confirmed with an increase of blood glucose, 90–100% of the control, 72 hours later. Isolated extracts from walnut leaf and ridges were administered in a single effective dose of 400 mg/kg orally. Firstly, blood glucose was determined every 1 hour until 5 hours post administration of extracts. In the second experiment, the liver was surgically removed, 2 hours post treatment of diabetic animals with extracts, homogenized and used for measurement of key enzymes of glycogenolysis (glycogen phosphorylase, GP) and gluconeogenesis (phosphoenolpyruvate carboxykinase, PEPCK). Treatment by both leaf and ridge extracts decreased blood glucose and liver PEPCK activity and increased blood insulin and liver GP activity. It is concluded that walnut is able to lower blood glucose through inhibition of hepatic gluconeogenesis and secretion of pancreatic insulin.

Caveolin gene transfer improves glucose metabolism in diabetic mice

Caveolin, a member of the membrane-anchoring protein family, accumulates various growth receptors in caveolae and inhibits their function. Upregulation of caveolin attenuates cellular proliferation and growth. However, the role of caveolin in regulating insulin signals remains controversial. Here, we demonstrate that caveolin potently enhances insulin receptor (IR) signaling when overexpressed in the liver in vivo. Adenovirus-mediated gene transfer was used to overexpress caveolin specifically in the liver of diabetic obese mice, which were generated with a high-fat diet. Expression of molecules involved in IR signaling, such as IR or Akt, remained unchanged after gene transfer. However, hepatic glycogen synthesis was markedly increased with a decrease in phosphoenolpyruvate carboxykinase protein expression. Insulin sensitivity was increased after caveolin gene transfer as determined by decreased blood glucose levels in response to insulin injection and fasting blood glucose levels. Glucose tolerant test performance was also improved. Similar improvements were obtained in KKA(y) genetically diabetic mice. Adenovirus-mediated overexpression of caveolin-3 in hepatic cells also enhanced IR signaling, as shown by increased phosphorylation of IR in response to insulin stimulation and higher glycogen synthesis at baseline. These effects were attributed mostly to increased insulin receptor activity and caveolin-mediated, direct inhibition of protein tyrosine phosphatase 1B, which was increased in obese mouse livers. In conclusion, our results suggest that caveolin is an important regulator of glucose metabolism that can enhance insulin signals.

ACE2 gene therapy leads to Ang‐(1‐7)‐mediated restoration of glucose metabolism in diabetic mice

We previously demonstrated that pancreatic ACE2 overexpression is able to improve glucose tolerance and reduce fasting blood glucose in diabetic mice. We hypothesized that ACE2 overexpression improves glucose homeostasis by enhancing pancreatic beta cell function. Diabetic db/db and lean mice (n=10/group) were infected with Ad‐hACE2 or a control adenovirus (Ad‐eGFP) and glucose homeostasis assessed after 7 days. Insulin sensitivity (area under the curve, AUC) was not different between Ad‐hACE2‐ and Ad‐eGFP‐treated db/db (50 ±3 vs. 54 ±4) and lean (31 ±9 vs. 35 ±9) mice, respectively. Ad‐hACE2 increased islet insulin content (arbitrary units) in db/db mice (92 ±7 vs. 49 ±6, P<0.01) but had no effect on lean mice (109 ±17 vs. 124 ±9) compared to Ad‐eGFP. Infusion with an Ang‐(1‐7) receptor antagonist [D‐Ala7‐Ang‐(1‐7), 600 ng/kg/min, 7 days sc], prevented Ad‐hACE2‐mediated normalization of fasting blood glucose (247 ±31 vs. 135 ±11 mg/dl, P<0.01) but had no effect on Ad‐eGFP‐treated diabetic mice (224 ±26 vs. 191 ±12 mg/dl). D‐Ala7‐Ang‐(1‐7) also prevented the Ad‐hACE2‐mediated improvement in glucose tolerance (AUC: 67 ±2 vs. 51 ±5; P<0.05) but did not affect Ad‐eGFP‐treated db/db mice (AUC: 68 ±3 vs. 72 ±2). These data indicate that ACE2 gene therapy improves pancreatic beta cell function and restores glucose homeostasis by increasing Ang‐(1‐7) receptor‐mediated signaling pathways. (NIH NS052479 and RR018766)