"Ficus johannis Boiss. leaves ethanolic extract ameliorate streptozotocin-induced diabetes in rats by upregulating the expressions of GCK, GLUT4, and IGF and downregulating G6P".

The leaves of Ficus johannis Boiss (F. johannis), commonly known as Fig tree, Anjir, and Teen, are used by the folk medicinal practitioners in Iran for controlling hyperglycemia in diabetic patients. This study investigated the pharmacological basis for antidiabetic effect of the ethanolic extract of F. johannis leaves using in vitro and in vivo experimental models. Qualitative screening of phytochemicals, estimation of total phenolic and flavonoid contents, and in vitro antioxidant and α-amylase inhibition assays were performed. Moreover, the High-performance liquid chromatography (HPLC) quantification, acute toxicity, glucose tolerance, and in vivo antidiabetic effect along with the evaluation of gene expressions involved in diabetes mellitus were carried out. Significant quantities of phenolic (71.208 ± 2.89 mgg-1 GAE) and flavonoid (26.38 ± 3.53 mgg-1 QE) were present. Inhibitory concentration (IC50) of the plant extract exhibited an excellent in vitro antioxidant (IC50 = 33.81 µg/mL) and α-amylase (IC50 = 12.18 µg/mL) inhibitory potential. The HPLC analysis confirmed the gallic acid (257.79 mgg-1) as main constituent of the extract followed by kaempferol (22.86 mgg-1), myricetin (0.16 mgg-1), and quercetin (3.22 mgg-1). Ethanolic extract displayed glucose tolerance in normo-glycemic rats. Streptozotocin-induced hyperglycemia declined dose dependently in the extract treated rats with improvement in lipid profile and liver and renal function biomarkers. The F. johannis-treated groups showed an increase in mRNA expressions of glucose transporter 4 (GLUT-4), glucokinase, insulin growth like factor 1 and peroxisomal proliferator activating receptor gamma in pancreas. However, the Glucose-6-phosphatase was downregulated. Present study suggests that the ethanolic extract of F. johannis leaves demonstrates a good anti-diabetic profile by improving insulin sensitivity, GLUT-4 translocation, and carbohydrate metabolism while inhibiting lipogenesis.

Dapagliflozin attenuates renal gluconeogenic enzyme expression in obese rats.

The kidneys release glucose into the systemic circulation through glucose reabsorption and renal gluconeogenesis. Currently, the significance of renal glucose release in pathological conditions has become a subject of interest. We examined the effect of sodium-dependent glucose cotransporter 2 inhibitor (SGLT2i) on renal gluconeogenic enzyme expression in obese rats. Male Wistar rats (180-200 g) were fed either a normal diet (ND, n = 6) or a high-fat diet. At 16 weeks, after confirming the degree of glucose intolerance, high-fat diet-fed rats were randomly subdivided into three groups (n = 6/group): untreated group (HF), treated with dapagliflozin 1 mg/kg/day (HFSG) and treated with metformin 30 mg/kg/day (HFM). The treatment was continued for 4 weeks. We observed that dapagliflozin or metformin mitigated the enhanced expression of renal gluconeogenic enzymes, PEPCK, G6Pase and FBPase, as well as improved glucose tolerance and renal function in obese rats. Dapagliflozin downregulated the elevated expression of gluconeogenic transcription factors p-GSK3ß, p-CREB and coactivator PGC1α in the renal cortical tissue. Metformin reduced the expression levels of renal cortical FOXO1 and CREB. Furthermore, reduced renal insulin signaling was improved and renal oxidative stress was attenuated by either dapagliflozin or metformin treatment in obese rats. We concluded that glucose tolerance was improved by dapagliflozin in obese prediabetic rats by suppressing renal glucose release from not only glucose reabsorption but also renal gluconeogenesis through improving renal cortical insulin signaling and oxidative stress. The efficacy of dapagliflozin in improving renal insulin signaling, oxidative stress and renal function was greater than that of metformin.

Circular RNA HIPK3 contributes to hyperglycemia and insulin homeostasis by sponging miR-192-5p and upregulating transcription factor forkhead box O1.

It has been shown that circular RNAs, a class of non-coding RNA molecules, play an important role in the regulation of glucose and lipid homeostasis. In the present study, we sought to investigate the function of circular RNA HIPK3 (circHIPK3) in diabetes-associated metabolic disorders, including hyperglycemia and insulin resistance. Results show that oleate stimulated circHIPK3 increase, and that circHIPK3 enhanced the stimulatory effect of oleate on adipose deposition, triglyceride (TG) content, and cellular glucose content in HepG2 cells. MiR-192-5p was the potential target of circHIPK3, since circHIPK3 significantly decreased miR-192-5p mRNA level, whereas anti-circHIPK3 significantly increased miR-192-5p mRNA level. Further study shows that transcription factor forkhead box O1 (FOXO1) was a downstream regulator of miR-192-5p, since miR-192-5p significantly decreased FOXO1 expression, whereas circHIPK3 significantly increased FOXO1 expression. Notably, the inhibitory effect of miR-192-5p was significantly reversed by circHIPK3. In vivo study shows that anti-miR-192-5p significantly increased blood glucose content, which was significantly inhibited by FOXO1 shRNA. MiR-192-5p significantly decreased adipose deposition and TG content in HepG2 cells, which was significantly reversed by the co-treatment with circHIPK3. Forskolin/dexamethasone (FSK/DEX) significantly increased cellular glucose, mRNA level of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), and this stimulatory effect of FSK/DEX was significantly inhibited by miR-192-5p. In the presence of circHIPK3, however, the inhibitory effect of miR-192-5p was totally lost. In summary, the present study demonstrated that circHIPK3 contributes to hyperglycemia and insulin resistance by sponging miR-192-5p and up-regulating FOXO1.

Lupinus albus Conglutin Gamma Modifies the Gene Expressions of Enzymes Involved in Glucose Hepatic Production In Vivo.

Lupinus albus seeds contain conglutin gamma (Cγ) protein, which exerts a hypoglycemic effect and positively modifies proteins involved in glucose homeostasis. Cγ could potentially be used to manage patients with impaired glucose metabolism, but there remains a need to evaluate its effects on hepatic glucose production. The present study aimed to analyze G6pc, Fbp1, and Pck1 gene expressions in two experimental animal models of impaired glucose metabolism. We also evaluated hepatic and renal tissue integrity following Cγ treatment. To generate an insulin resistance model, male Wistar rats were provided 30% sucrose solution ad libitum for 20 weeks. To generate a type 2 diabetes model (STZ), five-day-old rats were intraperitoneally injected with streptozotocin (150 mg/kg). Each animal model was randomized into three subgroups that received the following oral treatments daily for one week: 0.9% w/v NaCl (vehicle; IR-Ctrl and STZ-Ctrl); metformin 300 mg/kg (IR-Met and STZ-Met); and Cγ 150 mg/kg (IR-Cγ and STZ-Cγ). Biochemical parameters were assessed pre- and post-treatment using colorimetric or enzymatic methods. We also performed histological analysis of hepatic and renal tissue. G6pc, Fbp1, and Pck1 gene expressions were quantified using real-time PCR. No histological changes were observed in any group. Post-treatment G6pc gene expression was decreased in the IR-Cγ and STZ-Cγ groups. Post-treatment Fbp1 and Pck1 gene expressions were reduced in the IR-Cγ group but increased in STZ-Cγ animals. Overall, these findings suggest that Cγ is involved in reducing hepatic glucose production, mainly through G6pc inhibition in impaired glucose metabolism disorders.

Porphyromonas gingivalis lipopolysaccharide upregulates insulin secretion from pancreatic ß cell line MIN6.

BACKGROUND: A close association between periodontitis and diabetes has been demonstrated in human cross-sectional studies, but an exact relationship between periodontitis and prediabetes has not been established. Previous studies using animal model systems consistently have shown that hyperinsulinemia occurs in animals with periodontitis compared to animals with healthy periodontium (while maintaining normoglycemia). Because bacterial lipopolysaccharide (LPS) plays an important role in the pathogenesis of periodontitis, we hypothesized that LPS may stimulate insulin secretion through a direct effect on ß cell function. To test this hypothesis, pancreatic ß cell line MIN6 cells were used to determine the effect of Porphyromonas gingivalis (Pg) LPS on insulin secretion. Furthermore, expression of genes altered by Pg LPS in innate immunity and insulin-signaling pathways was determined. METHODS: MIN6 cells were grown in medium with glucose concentration of normoglycemia (5.5 mM). Pg LPS was added to each well at final concentrations of 50, 200, and 500 ng/mL. Insulin secretion was measured using enzyme-linked immunosorbent assay. Gene expression levels altered by Pg LPS were determined by polymerase chain reaction (PCR) array for mouse innate and adaptive immunity response and mouse insulin-signaling pathways, and results were confirmed for specific genes of interest by quantitative PCR. RESULTS: Pg LPS stimulated insulin secretion in the normoglycemic condition by ≈1.5- to 3.0-fold depending on the concentration of LPS. Pg LPS treatment altered the expression of several genes involved in innate and adaptive immune response and insulin-signaling pathway. Pg LPS upregulated the expression of the immune response-related genes cluster of differentiation 8a (Cd8a), Cd14, and intercellular adhesion molecule-1 (Icam1) by about two-fold. LPS also increased the expression of two insulin signaling-related genes, glucose-6-phosphatase catalytic subunit (G6pc) and insulin-like 3 (Insl3), by three- to four-fold. CONCLUSIONS: We have demonstrated for the first time that Pg LPS stimulates insulin secretion by pancreatic ß cell line MIN cells. Pg LPS may have significant implications on the development of ß cell compensation and insulin resistance in prediabetes in individuals with periodontitis.

Methazolamide is a new hepatic insulin sensitizer that lowers blood glucose in vivo.

We previously used Gene Expression Signature technology to identify methazolamide (MTZ) and related compounds with insulin sensitizing activity in vitro. The effects of these compounds were investigated in diabetic db/db mice, insulin-resistant diet-induced obese (DIO) mice, and rats with streptozotocin (STZ)-induced diabetes. MTZ reduced fasting blood glucose and HbA(1c) levels in db/db mice, improved glucose tolerance in DIO mice, and enhanced the glucose-lowering effects of exogenous insulin administration in rats with STZ-induced diabetes. Hyperinsulinemic-euglycemic clamps in DIO mice revealed that MTZ increased glucose infusion rate and suppressed endogenous glucose production. Whole-body or cellular oxygen consumption rate was not altered, suggesting MTZ may inhibit glucose production by different mechanism(s) to metformin. In support of this, MTZ enhanced the glucose-lowering effects of metformin in db/db mice. MTZ is known to be a carbonic anhydrase inhibitor (CAI); however, CAIs acetazolamide, ethoxyzolamide, dichlorphenamide, chlorthalidone, and furosemide were not effective in vivo. Our results demonstrate that MTZ acts as an insulin sensitizer that suppresses hepatic glucose production in vivo. The antidiabetic effect of MTZ does not appear to be a function of its known activity as a CAI. The additive glucose-lowering effect of MTZ together with metformin highlights the potential utility for the management of type 2 diabetes.

Gluconeogenic enzymes are differentially regulated by fatty acid cocktails in Madin-Darby bovine kidney cells.

Expression of mRNA for pyruvate carboxylase (PC) is elevated at calving and during other physiological states when plasma NEFA concentrations are increased. The objective of this study was to determine the direct effects of fatty acids on expression of PC, cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), mitochondrial PEPCK (PEPCK-M), and glucose-6-phosphatase (G6Pase) mRNA in Madin-Darby bovine kidney (MDBK) cells. Combinations of C14:0, C16:0, C18:0, C18:1n-6 cis, C18:2n-6 cis, and C18:3n-3 cis were created to mimic the profiles and concentrations in serum from far-off dry cows and late postcalving intervals (PRPT), the profile at calving (CALV), and the profile observed in cows induced to express fatty liver at calving (IFL). The MDBK cells were exposed to fatty acid mixtures for 24h at the following concentrations: 0.25 and 0.5mM for PRPT; 0.25, 0.5, and 1.0mM for CALV; and 0.5 and 1.0mM for IFL. Cells exposed to PRPT had greater PEPCK-C and tended to have greater G6Pase mRNA than control cells. Exposure of cells to 0.25mM PRPT increased expression of PEPCK-C compared with cells exposed to 0.5mM PRPT. Expression of PC and PEPCK-M did not differ with exposure to PRPT. Expression of PEPCK-C was decreased and that of PEPCK-M and G6Pase mRNA increased linearly in response to CALV. The ratio of PC:PEPCK-C mRNA was increased by the IFL mixture and in response to increasing amounts of the CALV fatty acid mixture. Treatment of cells with CALV or IFL increased the sum of PC 5' untranslated region (UTR) variants A, B, C, and F but did not alter PC 5' UTR D and E expression. The changes in PEPCK-C, G6Pase, and PC mRNA and the ratio of PC:PEPCK-C observed in MDBK cells in response to fatty acids suggests a role for fatty acid concentration and profile in mediating the expression of key gluconeogenic enzymes.

Antidiabetic activity of alcoholic stem extract of Gymnema montanum in streptozotocin-induced diabetic rats.

In the present study, the effect of alcoholic stem extract of Gymnema montanum (GMSt) on blood glucose, plasma insulin, and carbohydrate metabolic enzymes were studied in experimental diabetes. Diabetes mellitus was induced by a single intraperitoneal injection of STZ (60 mg/kg bw). Five days after STZ induction, diabetic rats received GMSt orally at the doses of 25, 50, 100 and 200mg/kg daily for 3 weeks. Graded doses of stem extract showed a significant reduction in blood glucose levels and improvement in plasma insulin levels. The effect was more pronounced in 100 and 200mg/kg than 50mg/kg. GMSt showed significant increase in hexokinase, Glucose-6-phosphate dehydrogenase and glycogen content in liver of diabetic rats while there was significant reduction in the levels of glucose-6-phosphatase and fructose-1,6-bisphosphatase. The present study clearly indicated significant antidiabetic effect with the stem extract of G. montanum and lends support for its traditional usage.

Impact of a glycogen phosphorylase inhibitor and metformin on basal and glucagon-stimulated hepatic glucose flux in conscious dogs.

The effects of a glycogen phosphorylase inhibitor (GPI) and metformin (MT) on hepatic glucose fluxes (µmol · kg(-1) · min(-1)) in the presence of basal and 4-fold basal levels of plasma glucagon were investigated in 18-h fasted conscious dogs. Compared with the vehicle treatment, GPI infusion suppressed net hepatic glucose output (NHGO) completely (-3.8 ± 1.3 versus 9.9 ± 2.8) despite increased glucose 6-phosphate (G-6-P) neogenesis from gluconeogenic precursors (8.1 ± 1.1 versus 5.5 ± 1.1). MT infusion did not alter those parameters. In response to a 4-fold rise in plasma glucagon levels, in the vehicle group, plasma glucose levels were increased 2-fold, and NHGO was increased (43.9 ± 5.7 at 10 min and 22.7 ± 3.4 at steady state) without altering G-6-P neogenesis (3.7 ± 1.5 and 5.5 ± 0.5, respectively). In the GPI group, there was no increase in NHGO due to decreased glucose-6-phosphatase flux associated with reduced G-6-P concentration. A lower G-6-P concentration was the result of increased net glycogenesis without altering G-6-P neogenesis. In the MT group, the increment in NHGO (22.2 ± 4.4 at 10 min and 12.1 ± 3.6 at steady state) was approximately half of that of the vehicle group. The lesser NHGO was associated with reduced glucose-6-phosphatase flux but a rise in G-6-P concentration and only a small incorporation of plasma glucose into glycogen. In conclusion, the inhibition of glycogen phosphorylase a activity decreases basal and glucagon-induced NHGO via redirecting glucose 6-phosphate flux from glucose toward glycogen, and MT decreases glucagon-induced NHGO by inhibiting glucose-6-phosphatase flux and thereby reducing glycogen breakdown.

Central nervous system delivery of the antipsychotic olanzapine induces hepatic insulin resistance.

OBJECTIVE: Olanzapine (OLZ) is an atypical antipsychotic whose clinical efficacy is hampered by side effects including weight gain and diabetes. Recent evidence shows that OLZ alters insulin sensitivity independent of changes in body weight and composition. The present study addresses whether OLZ-induced insulin resistance is driven by its central actions. RESEARCH DESIGN AND METHODS: Sprague-Dawley rats received an intravenous (OLZ-IV group) or intracerebroventricular (OLZ-ICV group) infusion of OLZ or vehicle. Glucose kinetics were assessed before (basal period) and during euglycemic-hyperinsulinemic clamp studies. RESULTS: OLZ-IV caused a transient increase in glycemia and a higher rate of glucose appearance (R(a)) in the basal period. During the hyperinsulinemic clamp, the glucose infusion rate (GIR) required to maintain euglycemia and the rate of glucose utilization (R(d)) were decreased in OLZ-IV, whereas endogenous glucose production (EGP) rate was increased compared with vehicle-IV. Consistent with an elevation in EGP, the OLZ-IV group had higher hepatic mRNA levels for the enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Phosphorylation of hypothalamic AMP-activated protein kinase (AMPK) was increased in OLZ-IV rats compared with controls. Similarly, an intracerebroventricular infusion of OLZ resulted in a transient increase in glycemia as well as a higher R(a) in the basal period. During the hyperinsulinemic period, OLZ-ICV caused a decreased GIR, an increased EGP, but no change in R(d). Furthermore, OLZ-ICV rats had increased hepatic gluconeogenic enzymes and elevated hypothalamic neuropeptide-Y and agouti-related protein mRNA levels. CONCLUSIONS: Acute central nervous system exposure to OLZ induces hypothalamic AMPK and hepatic insulin resistance, pointing to a hypothalamic site of action for the metabolic dysregulation of atypical antipsychotics.

Anti-diabetic effects of lemon balm ( Melissa officinalis) essential oil on glucose- and lipid-regulating enzymes in type 2 diabetic mice.

The antioxidant activity of lemon balm (Melissa officinalis) essential oil (LBEO) on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and its hypoglycaemic effect in db/db mice were investigated. LBEO scavenged 97 % of DPPH radicals at a 270-fold dilution. Mice administered LBEO (0.015 mg/d) for 6 weeks showed significantly reduced blood glucose (65 %; P < 0.05) and TAG concentrations, improved glucose tolerance, as assessed by an oral glucose tolerance test, and significantly higher serum insulin levels, compared with the control group. The hypoglycaemic mechanism of LBEO was further explored via gene and protein expression analyses using RT-PCR and Western blotting, respectively. Among all glucose metabolism-related genes studied, hepatic glucokinase and GLUT4, as well as adipocyte GLUT4, PPAR-gamma, PPAR-alpha and SREBP-1c expression, were significantly up-regulated, whereas glucose-6-phosphatase and phosphoenolpyruvate carboxykinase expression was down-regulated in the livers of the LBEO group. The results further suggest that LBEO administered at low concentrations is an efficient hypoglycaemic agent, probably due to enhanced glucose uptake and metabolism in the liver and adipose tissue and the inhibition of gluconeogenesis in the liver.

Phenolic extract of soybean (Glycine max) attenuates cisplatin-induced nephrotoxicity in rats.

The present study investigated the modulatory role of phenolic extract of soybean (PESB) in a rat model of nephrotoxic acute renal failure induced by cisplatin. Cisplatin (2 mg/kg/day) was administered to the rats for 5 days and the animals were pretreated with PESB (250-1000 mg/kg). Blood urea nitrogen reduced by 49.8% and 59.0%, serum creatinine by 34.7% and 62.1% and urinary N-acetyl-beta-D-glucosaminidase also decreased by 37.7% and 49.2% following treatment with 250- and 500-mg/kg doses of the extract respectively in the cisplatin-treated rats. The extract also significantly increased renal myeloperoxidase activity by 26.8% and 40.6% at these doses. PESB also decreased renal xanthine oxidase activity and serum nitrate/nitrite in the cisplatin-treated rats. In addition, PESB significantly attenuated the marked renal oxidative damage that accompanied cisplatin treatment. The extract improved liver histology and significantly increased the activities of the antioxidant enzymes measured [superoxide dismutase, catalase, glutathione-S-transferase], prevented glutathione depletion and decreased malondialdehyde level following cisplatin treatment. Furthermore, cisplatin-induced decrease in the activities of glucose-6-phosphatase and 5'-nucleotidase in these rats was attenuated only at 250 mg/kg dose of the extract. We concluded therefore that PESB via antioxidant and possibly anti-inflammatory actions offered protective benefit against cisplatin-mediated acute toxic injury to the kidney.

Apigenin (4',5,7-trihydroxyflavone) regulates hyperglycaemia, thyroid dysfunction and lipid peroxidation in alloxan-induced diabetic mice.

The potential of apigenin (4',5,7-trihydroxyflavone) in regulating hyperglycaemia, thyroid dysfunction and lipid peroxidation (LPO) has been revealed. While in alloxan-treated diabetic animals, a significant decrease in the concentrations of serum insulin, thyroxine (T(4)) and triiodothyronine (T(3)), with a parallel increase in serum glucose and hepatic glucose-6-phospatase (G-6-Pase) activity, was observed, administration of 0.78 mg kg(-1) of apigenin for 10 consecutive days increased the levels of serum insulin and thyroid hormones with a parallel decrease in glucose concentration and hepatic G-6-Pase activity. Alloxan-induced elevation in serum cholesterol was also reduced by the compound. With respect to LPO, while in alloxan-treated animals an increase in hepatic LPO and a decrease in the activity of cellular antioxidants, such as catalase (CAT) and superoxide dismutase (SOD), and in glutathione (GSH) content was observed, administration of apigenin to alloxan-treated mice reversed all these changes, suggesting its hepatoprotective potential. Similar effects of apigenin were also observed in most of the parameters in normoglycaemic animals. It appears that apigenin has a potential to regulate diabetes mellitus, as well as disease-induced thyroid dysfunction and lipid peroxidation.

Convenient synthesis of 3- and 6-deoxy-D-myo-inositol phosphate analogues from (+)-epi- and (-)-vibo-quercitols.

Starting from (+)-epi- and (-)-vibo-quercitols readily produced by bioconversion of myo-inositol, some biologically interesting phosphate and polyphosphate analogues, including the Ins(1,4,5)P(3) derivatives of 3-deoxy- and 6-deoxy-D-myo-inositol, could be readily prepared in a conventional manner. In addition, chemical modification at C-2 of the 3-deoxy Ins(1,4,5)P(3) provided 2-epimer, and 2-deoxy and 2-deoxy-2-fluoro forms. Eight polyphosphate analogues obtained were assayed for biological activity against PDH-Pase and PDH-K, and G6Pase, but none proved positive.

Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome.

AMP-activated protein kinase (AMPK) is a key sensor and regulator of intracellular and whole-body energy metabolism. We have identified a thienopyridone family of AMPK activators. A-769662 directly stimulated partially purified rat liver AMPK (EC50 = 0.8 microM) and inhibited fatty acid synthesis in primary rat hepatocytes (IC50 = 3.2 microM). Short-term treatment of normal Sprague Dawley rats with A-769662 decreased liver malonyl CoA levels and the respiratory exchange ratio, VCO2/VO2, indicating an increased rate of whole-body fatty acid oxidation. Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662 decreased hepatic expression of PEPCK, G6Pase, and FAS, lowered plasma glucose by 40%, reduced body weight gain and significantly decreased both plasma and liver triglyceride levels. These results demonstrate that small molecule-mediated activation of AMPK in vivo is feasible and represents a promising approach for the treatment of type 2 diabetes and the metabolic syndrome.

Inhibition of hepatic neoglucogenesis and glucose-6-phosphatase by quercetin 3-O-alpha(2''-galloyl)rhamnoside isolated from Bauhinia megalandra leaves.

In intact microsomes, quercetin 3-O-alpha-(2''-galloyl)rhamnoside (QGR) inhibits glucose-6-phosphatase (G-6-Pase) in a concentration-dependent manner. QGR increased the G-6-Pase K(m) for glucose-6-phosphate without change in the V(max). The flavonol did not change the kinetic parameters of disrupted microsomal G-6-Pase or intact or disrupted microsomal G-6-Pase pyrophosphatase (PPase) activity. This result allowed the conclusion that QGR competitively inhibits the glucose-6-phosphate (G-6-P) transporter (T1) without affecting the catalytic subunit or the phosphate/pyrophosphate transporter (T2) of the G-6-Pase system.QGR strongly inhibits the neoglucogenic capacity of rat liver slices incubated in a Krebs-Ringer bicarbonate buffer, supplemented with lactate and oleate saturated albumin. The QGR G-6-Pase inhibition might explain the decrease in the liver slice neoglucogenic capacity and, in turn, could reduce glucose levels in diabetic patients.

Effects of green tea on gene expression of hepatic gluconeogenic enzymes in vivo.

It has recently been reported that the major green tea polyphenolic constituent, epigallocatechin 3-gallate (EGCG), mimics the cellular effects of insulin including the reductive effect on the gene expression of rate-limiting gluconeogenic enzymes in a cell culture system. We show that administration of green tea that contains EGCG caused a reduction in the level of mRNAs for gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the mouse liver. EGCG alone was also found to down-regulate the gene expression of these enzymes but not so curcumin or quercetin. The results of this study support the idea that green tea intake may be beneficial in the prevention of diabetes mellitus.

Effect of estradiol and progesterone treatment on carbohydrate metabolizing enzymes in tissues of aging female rats.

The aim of this study was to determine the effect of administration of estradiol (E2), progesterone (P4), and combination of estradiol and progesterone (EP) in aging female rats. The changes in the activities of hexokinase (HK), glucose-6-phosphatase (G6P'tase) and glucose-6-phosphate dehydrogenase (G6PDH) enzymes, and in protein levels in tissues of rats namely brain (cerebral hemisphere), heart, liver, kidney and uterus have been measured in different age groups. The random blood sugar level was measured in serum and liver. The different age groups of rats were given 0.1 microg/g body weight estradiol, 2.5 microg/g body weight progesterone and a similar concentration of both in a combined treatment for 1 month. This dose was selected after determining estrogen and progesterone levels in 3 month adult female animals so that the aging female animals had circulating hormone levels nearly the same as those of young female animals. The random sugar level was determined in serum and liver cytosolic fractions, and it was increased by combination treatment. The protein content in tissues showed significant changes only with combined hormone administration when compared with age-matched controls. The activity of HK decreased in aged animals and significantly increased by hormone treatments in all the tissues of the aged rats studied. The activity of G6P'tase increased with age up to 1.5 years and decreased in 2 years. Treatment with E2 and EP further decreased the activity significantly in all the tissues. G6PDH showed a similar pattern as was observed in HK in all the age groups. Therefore, the E2 and EP treatments caused an entire series of growth-related responses, including an increased uptake of glucose, increased the protein level in the tissues of aging rats, thereby reducing the risk factors associated with aging by normalizing hormone levels which decreased with aging and resulted in diseases such as Alzheimer's diseases and diabetes.

Piperine lowers the serum concentrations of thyroid hormones, glucose and hepatic 5'D activity in adult male mice.

Piperine, the main alkaloid of Piper nigrum fruits, was evaluated for its thyroid hormone and glucose regulatory efficacy in adult male Swiss albino mice. Its daily oral administration (2.50 mg/kg) for 15 days lowered the serum levels of both the thyroid hormones, thyroxin (T (4)) and triiodothyronine (T (3)) as well as glucose concentrations with a concomitant decrease in hepatic 5'D enzyme and glucose-6-phospatase (G-6-Pase) activity. However, no significant alterations were observed in animals treated with 0.25 mg/kg of piperine in any of the activities studied except an inhibition in serum T (3) concentration. The decrease in T (4), T (3) concentrations and in G-6-Pase were comparable to that of a standard antithyroid drug, Proylthiouracil (PTU). The hepatic lipid-peroxidation (LPO) and the activity of endogenous antioxidants, superoxide dismutase (SOD), and catalase (CAT) were not significantly altered in either of the doses. It appears that the action of P. nigrum on thyroid functions is mediated through its active alkaloid, piperine. We also suggest that a higher dose of piperine may inhibit thyroid function and serum glucose concentration in euthyroid individuals.