The Anti-Diabetic Potential of Baicalin: Evidence from Rodent Studies.

Baicalin is a biologically active flavonoid compound that benefits the organism in various pathological conditions. Rodent studies have shown that this compound effectively alleviates diabetes-related disturbances in models of type 1 and type 2 diabetes. Baicalin supplementation limited hyperglycemia and improved insulin sensitivity. The anti-diabetic effects of baicalin covered the main insulin-sensitive tissues, i.e., the skeletal muscle, the adipose tissue, and the liver. In the muscle tissue, baicalin limited lipid accumulation and improved glucose transport. Baicalin therapy was associated with diminished adipose tissue content and increased mitochondrial biogenesis. Hepatic lipid accumulation and glucose output were also decreased as a result of baicalin supplementation. The molecular mechanism of the anti-diabetic action of this compound is pleiotropic and is associated with changes in the expression/action of pivotal enzymes and signaling molecules. Baicalin positively affected, among others, the tissue insulin receptor, glucose transporter, AMP-activated protein kinase, protein kinase B, carnitine palmitoyltransferase, acetyl-CoA carboxylase, and fatty acid synthase. Moreover, this compound ameliorated diabetes-related oxidative and inflammatory stress and reduced epigenetic modifications. Importantly, baicalin supplementation at the effective doses did not induce any side effects. Results of rodent studies imply that baicalin may be tested as an anti-diabetic agent in humans.

Regulatory Effects of Metformin, an Antidiabetic Biguanide Drug, on the Metabolism of Primary Rat Adipocytes.

Metformin is a biguanide compound commonly applied in humans with type 2 diabetes. The drug affects different tissues, including fat tissue. The direct influence of metformin on cells of fat tissue, i.e., adipocytes, is poorly elucidated. In the present study, the short-term (4-h) effects of metformin on lipogenesis, glucose transport, lipolysis, and lactate release in primary rat adipocytes were explored. It was demonstrated that metformin reduced insulin-induced lipogenesis and increased glucose transport into adipocytes. The tested compound also decreased lactate release from fat cells. It was shown that metformin substantially limited lipolysis stimulated by epinephrine (adrenergic receptor agonist) and dibutyryl-cAMP (direct activator of protein kinase A). Moreover, metformin decreased the lipolytic process triggered by DPCPX (adenosine A1 receptor antagonist). In the case of each lipolytic stimulator, the drug evoked a similar inhibitory effect in the presence of 3 and 12 mM glucose. The lipolytic response of adipocytes to epinephrine was also found to be reduced by metformin when glucose was replaced by alanine. It was demonstrated that the tested compound limits the release of both glycerol and fatty acids from fat cells. The results of the present study provided evidence that metformin significantly affects the metabolism of primary rat adipocytes. Its action covers processes related to lipid accumulation and release and occurs after relatively short-term exposure.

Resveratrol Affects Insulin Signaling in Type 2 Diabetic Goto-Kakizaki Rats.

Resveratrol is a biologically active diphenolic compound exerting multiple beneficial effects in the organism, including anti-diabetic properties. This action is, however, not fully elucidated. In the present study, we examined effects of resveratrol on some parameters related to insulin signaling, and also on diabetes-associated dysregulation in Goto-Kakizaki (GK) rats with congenital type 2 diabetes. Resveratrol was given at the dose of 20 mg/kg b.w. for 10 weeks. It was shown that the expression and phosphorylation levels of insulin receptor in the skeletal muscle of GK rats were significantly decreased, compared with control animals. However, these changes were totally prevented by resveratrol. Liver expression of the insulin receptor was also reduced, but in this case, resveratrol was ineffective. Resveratrol was also demonstrated to significantly influence parameters of insulin binding (dissociation constant and binding capacity) in the skeletal muscle and liver. Moreover, it was shown that the expression levels of proteins related to intracellular glucose transport (GLUT4 and TUG) in adipose tissue of GK rats were significantly decreased. However, treatment with resveratrol completely abolished these changes. Resveratrol was found to induce normalization of TUG expression in the skeletal muscle. Blood levels of insulin and GIP were elevated, whereas proinsulin and GLP-1 diminished in GK rats. However, concentrations of these hormones were not affected by resveratrol. These results indicate that resveratrol partially ameliorates diabetes-associated dysregulation in GK rats. The most relevant finding covers the normalization of the insulin receptor expression in the skeletal muscle and also GLUT4 and TUG in adipose tissue.

Resveratrol and diabetes: from animal to human studies.

Diabetes mellitus is a serious disease affecting about 5% of people worldwide. Diabetes is characterized by hyperglycemia and impairment in insulin secretion and/or action. Moreover, diabetes is associated with metabolic abnormalities and serious complications. Resveratrol is a natural, biologically active polyphenol present in different plant species and known to have numerous health-promoting effects in both animals and humans. Anti-diabetic action of resveratrol has been extensively studied in animal models and in diabetic humans. In animals with experimental diabetes, resveratrol has been demonstrated to induce beneficial effects that ameliorate diabetes. Resveratrol, among others, improves glucose homeostasis, decreases insulin resistance, protects pancreatic ß-cells, improves insulin secretion and ameliorates metabolic disorders. Effects induced by resveratrol are strongly related to the capability of this compound to increase expression/activity of AMPK and SIRT1 in various tissues of diabetic subjects. Moreover, anti-oxidant and anti-inflammatory effects of resveratrol were shown to be also involved in its action in diabetic animals. Preliminary clinical trials show that resveratrol is also effective in type 2 diabetic patients. Resveratrol may, among others, improve glycemic control and decrease insulin resistance. These results show that resveratrol holds great potential to treat diabetes and would be useful to support conventional therapy. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clincial findigns to improved patient outcomes.

Adipocyte dysfunction in rats with streptozotocin-nicotinamide-induced diabetes.

Administration of streptozotocin (STZ) and nicotinamide (NA) to adult rats allows for the induction of mild diabetes. However, this experimental model has not been fully characterized. This study was undertaken to determine the metabolic and secretory activity of adipose tissue in rats with STZ-NA-induced diabetes. Experiments were performed using epididymal adipocytes isolated from control and mildly diabetic rats. Lipogenesis, glucose transport as well as glucose and alanine oxidation, lipolysis, anti-lipolysis, cAMP levels and adipokine secretion were compared in cells isolated from the control and diabetic rats. Lipogenesis, glucose transport and oxidation were diminished in the adipocytes of diabetic rats compared with the fat cells of control animals. However, alanine oxidation appeared to be similar in the cells of non-diabetic and diabetic animals. Lipolytic response to low epinephrine concentrations was slightly increased in the adipocytes of diabetic rats; however, at higher concentrations of the hormone, lipolysis was similar in both groups of cells. The epinephrine-induced rise in cAMP levels was higher in the adipocytes of STZ-NA-induced diabetic rats, even in the presence of insulin. Lipolysis stimulated by dibutyryl-cAMP did not significantly differ, whereas anti-lipolytic effects of insulin were mildly decreased in the cells of diabetic rats. Secretion of adiponectin and leptin was substantially diminished in the adipocytes of diabetic rats compared with the cells of control animals. Our studies demonstrated that the balance between lipogenesis and lipolysis in the adipose tissue of rats with mild diabetes induced by STZ and NA is slightly shifted towards reduced lipid accumulation. Simultaneously, adiponectin and leptin secretion is significantly impaired.

The anti-diabetic potential of betaine. Mechanisms of action in rodent models of type 2 diabetes.

Betaine (N, N, N-trimethylglycine) is an amino-acid derivative exerting numerous beneficial effects on the organism. This compound is found in human and animal diets but is also endogenously generated. However, its synthesis may be insufficient to maintain or improve health. Moreover, the tissue content of betaine reduces under some pathological conditions, such as type 2 diabetes. This decrease may be, however, easily alleviated by dietary betaine supplementation. Rodent studies provided evidence that betaine effectively limits many diabetes-related disturbances. Betaine therapy improves glucose tolerance and insulin action, which is strongly associated with changes in insulin-sensitive tissues, such as skeletal muscle, adipose tissue, and liver. Betaine supplementation positively affects multiple genes, which expression is dysregulated in diabetes. AMP-activated protein kinase is thought to play a central role in the mechanism underlying the anti-diabetic betaine action. Moreover, studies with animal models of type 2 diabetes have shown that betaine exerts anti-inflammatory and anti-oxidant effects, and also alleviates endoplasmic reticulum stress. These changes contribute to improved insulin sensitivity and better blood glucose clearance. The results of animal studies encourage the exploration of the therapeutic betaine efficacy in humans with type 2 diabetes.

Methylglyoxal impairs ß-adrenergic signalling in primary rat adipocytes.

Methylglyoxal (MG) is dicarbonyl aldehyde generated intracellularly from glucose and from some other compounds. Its increased formation is associated with several harmful consequences. In the present study, short-term effects of MG on metabolism of isolated rat adipocytes were determined. Insulin-induced lipogenesis was unchanged by MG. However, epinephrine-stimulated lipolysis was shown to be significantly reduced in adipocytes exposed to 200 µM MG. This inhibitory effect was similar in the presence of low and high concentrations of glucose, and also in the presence of alanine. However, MG failed to affect lipolysis induced by forskolin (activator of adenylate cyclase), dibutyryl-cAMP (activator of PKA) and DPCPX (adenosine A1 receptor antagonist). It was also revealed that lipolysis was unchanged by MG in fat cells pre-incubated with this compound, and then stimulated with epinephrine alone. Our results suggest that MG may impair ß-adrenergic signalling in rat adipocytes due to interaction with epinephrine, and thereby disturbs lipolysis.

Effects of short-term fasting and pharmacological activation of AMPK on metabolism of rat adipocytes.

AMP-activated protein kinase (AMPK) is a key intracellular energy sensor and regulates processes associated with energy metabolism. In the present study, effects of AICAR, a pharmacological activator of AMPK, on metabolism of adipocytes of non-fasted and 12-h fasted rats were compared. It was shown that in fat cells of control rats, epinephrine- and dibutyryl-cAMP-induced lipolysis was markedly reduced in the presence of AICAR. However, in adipocytes of fasted animals, the lipolytic response was not significantly affected by AICAR. Moreover, in cells of control rats, the inhibitory effect of insulin on epinephrine-induced lipolysis was markedly deepened in the presence of AICAR. However, this effect was not shown in fat cells of fasted rats. This indicates that pharmacological activation of AMPK by AICAR influences metabolism of adipocytes of non-fasted rats, however, AICAR fails to affect metabolism of these cells under conditions of fasting.

Hemin attenuates response of primary rat adipocytes to adrenergic stimulation.

Hemin is an activator of heme oxygenase-1 (HO-1), an enzyme catalyzing heme degradation. Up-regulation of HO-1 is observed in response to various pathological conditions. Moreover, pharmacological activation of HO-1 is associated with numerous beneficial effects in the organism. Hemin was shown to exert, among other, anti-diabetic and anti-obesity properties. These effects are strongly linked with adipose tissue. However, the direct influence of hemin on metabolism of the fat cells have not been explored. The present study aimed to determine the short-term effects of hemin on metabolism of the primary rat adipocytes. We focused on processes directly related to lipid accumulation, such as lipogenesis and lipolysis. For this purpose, the isolated cells were subjected for 2 h to 40 µM hemin, and effects of this compound on insulin-stimulated glucose conversion to lipids, lactate release, lipolysis induced by various stimuli, and also on the antilipolytic action of insulin were determined. It was shown that hemin did not affect insulin-induced lipogenesis and lactate release. However, hemin significantly decreased lipolysis stimulated by epinephrine. The inhibitory effect of hemin on epinephrine-induced lipolysis was not abolished in the presence of SnMP, an inhibitor of HO-1, which suggests hemin action irrespective of this enzyme. Similar inhibitory effects on epinephrine-induced lipolysis were observed in the presence of 3 and 12 mM glucose. Moreover, hemin was shown to reduce epinephrine-induced lipolysis also when glucose was replaced by alanine or by succinate. Apart from changes in epinephrine action, it was found that the lipolytic response of the adipocytes to isoproterenol was also diminished by hemin. However, hemin failed to affect lipolysis stimulated by dibutyryl-cAMP (a direct activator of protein kinase A), forskolin (an activator of adenylate cyclase), and also by DPCPX (an adenosine A1 receptor antagonist). Additionally, epinephrine-induced lipolysis was shown to be decreased by insulin, and this effect was deepened in the presence of hemin. These results indicate that short-term exposure of the adipocytes to hemin does not affect processes related to glucose metabolism, such as lipogenesis and lactate release. However, hemin was found to decrease the lipolytic response to adrenergic stimulation, which is associated with reduced lipid release from adipocytes. Moreover, our results indicate that hemin is also capable of diminishing the exaggerated lipolysis, which occurs in the presence of supraphysiological concentrations of glucose.

Bisphenol A disturbs metabolism of primary rat adipocytes without affecting adipokine secretion.

Bisphenol A (BPA) is an ubiquitous synthetic chemical exerting numerous adverse effects. Results of rodent studies show that BPA negatively affects adipose tissue. However, the short-term influence of this compound addressing adipocyte metabolism and adipokine secretion is unknown. In the present study, isolated rat adipocytes were exposed for 2 h to 1 and 10 nM BPA. Insulin-induced glucose conversion to lipids along with glucose transport was significantly increased in the presence of BPA. However, basal glucose conversion to lipids, glucose oxidation, and formation of lipids from acetate were unchanged in adipocytes incubated with BPA. It was also shown that BPA significantly increases lipolytic response of adipocytes to epinephrine. However, lipolysis stimulated by dibutyryl-cAMP (a direct activator of protein kinase A) and the antilipolytic action of insulin were not affected by BPA. Moreover, BPA did not influence leptin and adiponectin secretion from adipocytes. Our new results show that BPA is capable of disturbing processes related to lipid accumulation in isolated rat adipocytes. This is associated with the potentiation of insulin and epinephrine action. The effects of BPA appear already after short-term exposure to low doses of this compound. However, BPA fails to change adipokine secretion.

Resveratrol ameliorates inflammatory and oxidative stress in type 2 diabetic Goto-Kakizaki rats.

Type 2 diabetes is associated with inflammatory and oxidative stress. Resveratrol, a naturally occurring diphenolic compound, was shown to improve glycemic control and alleviate metabolic disturbances in Goto-Kakizaki (GK) rats, a non-obese model of type 2 diabetes. However, in GK rats effects of resveratrol addressing inflammatory and oxidative stress were not explored. The present study aimed to determine anti-inflammatory and anti-oxidative properties of resveratrol in these rats. GK and Sprague-Dawley (SD) rats were divided into 4 groups: GK control, GK treated with resveratrol, SD control and SD treated with resveratrol. Resveratrol (20 mg/kg b.w.) was given once a day for 10 weeks. It was shown that contents of inflammatory markers, interleukin 6 (IL-6), interleukin 1 ß (IL-1ß), tumor necrosis factor α (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), were increased in the skeletal muscle of diabetic rats, but these effects were prevented by resveratrol therapy. Similarly, amounts of IL-1ß and TNF-α were elevated in livers of GK rats; however, this rise was alleviated in resveratrol-treated animals. Moreover, the contents of inflammation-related factors (IL-6, IL-1ß, TNF-α and NF-κB) were augmented in adipose tissue of GK rats; nevertheless, in this tissue resveratrol was ineffective. Resveratrol reduced also lipid peroxidation in the skeletal muscle, reduced activities of glutathione peroxidase in blood serum and catalase in the livers of GK rats. Our new findings show that resveratrol therapy results in relieving inflammatory and oxidative stress in GK rats, which may be largely associated with the alleviation of metabolic disturbances in this model of diabetes. Nevertheless, it was demonstrated that the efficacy of resveratrol action is tissue-specific.

Resveratrol, a naturally occurring diphenolic compound, affects lipogenesis, lipolysis and the antilipolytic action of insulin in isolated rat adipocytes.

Resveratrol is a naturally occurring diphenolic compound exerting numerous beneficial effects in the organism. The present study demonstrated its short-term, direct influence on lipogenesis, lipolysis and the antilipolytic action of insulin in freshly isolated rat adipocytes. In fat cells incubated for 90 min with 125 and 250 microM resveratrol (but not with 62.5 microM resveratrol), basal and insulin-induced lipogenesis from glucose was significantly reduced. The antilipogenic effect was accompanied by a significant diminution of CO(2) release and enhanced production of lactate. The inhibition of glucose conversion to lipids found in the presence of resveratrol was not attenuated by activator of protein kinase C. However, acetate conversion to lipids appeared to be insensitive to resveratrol. In adipocytes incubated for 90 min with epinephrine, 10 and 100 microM resveratrol significantly enhanced lipolysis, especially at lower concentrations of the hormone. However, the lipolytic response to dibutyryl-cAMP, a direct activator of protein kinase A, was unchanged. Further studies demonstrated that, in cells stimulated with epinephrine, 1, 10 and 100 microM resveratrol significantly enhanced glycerol release despite the presence of insulin or H-89, an inhibitor of protein kinase A. The influence of resveratrol on epinephrine-induced lipolysis and on the antilipolytic action of insulin was not abated by the blocking of estrogen receptor and was accompanied by a significant (with the exception of 1 microM resveratrol in experiment with insulin) increase in cAMP in adipocytes. It was also revealed that resveratrol did not change the proportion between glycerol and fatty acids released from adipocytes exposed to epinephrine. Results of the present study revealed that resveratrol reduced glucose conversion to lipids in adipocytes, probably due to disturbed mitochondrial metabolism of the sugar. Moreover, resveratrol increased epinephrine-induced lipolysis. This effect was found also in the presence of insulin and resulted from the synergistic action of resveratrol and epinephrine. The obtained results provided evidence that resveratrol affects lipogenesis and lipolysis in adipocytes contributing to reduced lipid accumulation in these cells.

The relevance of AMP-activated protein kinase in insulin-secreting ß cells: a potential target for improving ß cell function?

AMP-activated protein kinase (AMPK) is present in different kinds of metabolically active cells. AMPK is an important intracellular energy sensor and plays a relevant role in whole-body energy homeostasis. AMPK is activated, among others, in response to glucose deprivation, caloric restriction and increased physical activity. Upon activation, AMPK affects metabolic pathways leading to increased formation of ATP and simultaneously reducing ATP-consuming processes. AMPK is also expressed in pancreatic ß cells and is largely regulated by glucose, which is the main physiological stimulator of insulin secretion. Results of in vitro studies clearly show that glucose-induced insulin release is associated with a concomitant inhibition of AMPK in ß cells. However, pharmacological activation of AMPK significantly potentiates the insulin-secretory response of ß cells to glucose and to some other stimuli. This effect is primarily due to increased intracellular calcium concentrations. AMPK is also involved in the regulation of gene expression and may protect ß cells against glucolipotoxic conditions. It was shown that in pancreatic islets of humans with type 2 diabetes, AMPK is downregulated. Moreover, studies with animal models demonstrated impaired link between glucose and AMPK activity in pancreatic islet cells. These data suggest that AMPK may be a target for compounds improving the functionality of ß cells. However, more studies are required to better elucidate the relevance of AMPK in the (patho)physiology of the insulin-secreting cells.

Effects of Resveratrol in Goto-Kakizaki Rat, a Model of Type 2 Diabetes.

Resveratrol exhibits a pleiotropic, favorable action under various pathological conditions, including type 2 diabetes. However, its anti-diabetic effects in animal models and human trials have not been fully elucidated. The aim of the present study was to determine whether resveratrol is capable of inducing beneficial changes in the Goto-Kakizaki rat, a spontaneous model of diabetes, which in several aspects is similar to type 2 diabetes in humans. Goto-Kakizaki (GK) rats and control Sprague-Dawley (SD) rats were treated intragastrically with resveratrol (20 mg/kg b.w./day) for 10 weeks. Then, a glucose tolerance test was performed and levels of some adipokines in blood were measured. Moreover, lipid contents in skeletal muscle and liver tissues, along with the expression and phosphorylation of pivotal enzymes (AMP-activated protein kinase-AMPK, acetyl-CoA carboxylase-ACC, protein kinase B-Akt) in these tissues were determined. Histology of pancreatic islets was also compared. GK rats non-treated with resveratrol displayed a marked glucose intolerance and had increased lipid accumulation in the skeletal muscle. Moreover, upregulation of the expression and phosphorylation of AMPK, ACC and Akt was shown in the muscle tissue of GK rats. Those rats also had an abnormal structure of pancreatic islets compared with control animals. However, treatment with resveratrol improved glucose tolerance and prevented lipid accumulation in the skeletal muscle of GK rats. This effect was associated with a substantial normalization of expression and phosphorylation of ACC and Akt. In GK rats subjected to resveratrol therapy, the structure of pancreatic islets was also clearly improved. Moreover, blood adiponectin and leptin levels were partially normalized by resveratrol in GK rats. It was revealed that resveratrol ameliorates key symptoms of diabetes in GK rats. This compound improved glucose tolerance, which was largely linked to beneficial changes in skeletal muscle. Resveratrol also positively affected pancreatic islets. Our new findings show that resveratrol has therapeutic potential in GK rats.

Genistein, a plant-derived isoflavone, counteracts the antilipolytic action of insulin in isolated rat adipocytes.

Genistein is a phytoestrogen exerting numerous biological effects. Its direct influence on adipocyte metabolism and leptin secretion was previously demonstrated. This study aimed to determine whether genistein antagonizes the antilipolytic action of insulin in rat adipocytes. Freshly isolated adipose cells were incubated for 90 min with epinephrine, epinephrine with insulin and epinephrine with a specific inhibitor of protein kinase A (H-89) at different concentrations of genistein (0, 6.25, 12.5, 25, 50 and 100 microM). Genistein failed to affect epinephrine-induced glycerol release, however, the inhibitory action of insulin on epinephrine-induced lipolysis was significantly abrogated in cells exposed to the phytoestrogen (12.5-100 microM). The increase in insulin concentration did not suppress the genistein effect. Its inhibitory influence on the antilipolytic action of insulin was accompanied by a substantial rise in cAMP in adipocytes. This rise appeared despite the presence of 10nM insulin in the incubation medium. Further experiments, in which insulin was replaced by H-89, revealed that the antilipolytic action of protein kinase A inhibitor on epinephrine-induced lipolysis was not affected by genistein. This means that genistein counteracted the antilipolytic action of insulin due to the increase in cAMP levels and activation of protein kinase A in adipocytes. The observed attenuation of the inhibitory effect of insulin on triglyceride breakdown evoked by genistein was not related to its estrogenic activities, as evidenced in experiments employing the intracellular estrogen receptor blocker, ICI 182,780. Moreover, it was found that genistein-induced impairment of the antilipolytic action of insulin was not accompanied by changes in the proportion between fatty acids and glycerol released from adipocytes. The ability of genistein to counteract the antilipolytic action of insulin may contribute to the decreased triglyceride accumulation in adipose tissue.

Potential of resveratrol in mitigating metabolic disturbances induced by ethanol.

Alcohol abuse is associated with numerous health problems, including metabolic disturbances and liver damage. Therefore, different compounds are continuously being tested to evaluate their potential effectiveness in reducing these harmful changes. Animal studies clearly show that resveratrol is capable of ameliorating some consequences of ethanol ingestion. Resveratrol is a naturally occurring diphenolic compound having pleiotropic, health-promoting properties. Its beneficial action have been also demonstrated in animal models with ethanol-induced metabolic disturbances and liver injury. In ethanol treated animals, resveratrol effectively reduced liver lipid accumulation. Moreover, this compound diminished necrosis of hepatocytes, and also reduced liver fibrosis. The hepatoprotective action of resveratrol is largely associated with its ant-oxidant and anti-inflammatory properties, and also covers changes in activities of some enzymes. It is known that this compound upregulates the adiponectin-SIRT1-AMPK signaling pathway in the liver. Resveratrol was also found to positively affect blood lipids in animals exposed to ethanol. Moreover, administration of resveratrol to animals with ethanol-induced hypoinsulinemia and insulin resistance was shown to alleviate these disturbances. These outcomes clearly indicate that resveratrol holds great potential to reduce some consequences of ethanol ingestion. However, human studies are required to fully assess its therapeutic value.

Lack of effects of myo-inositol on metabolism of primary rat adipocytes.

Myo-inositol is a ubiquitous cyclitol, has an important regulatory role, and its intracellular depletion is associated with pathological changes. Effects of myo-inositol on adipose tissue are poorly elucidated. In this report, short-term influence of 20, 100, and 500 µM myo-inositol on metabolism of the isolated rat adipocytes was studied. Cells were incubated for 90 min with glucose and insulin with or without myo-inositol and glucose conversion to lipids and lactate release were measured. Moreover, effects of myo-inositol on lipolysis and on the antilipolytic action of insulin were also studied. It was demonstrated that lipogenesis and lactate release were unchanged by myo-inositol. Moreover, lipolytic response to epinephrine and dibutyryl-cAMP was also unchanged. Myo-inositol was also found to be without influence on the antilipolytic action of insulin. Results of this study show that metabolism of the isolated rat adipocytes is not affected by short-term exposure of these cells to myo-inositol.

Genistein--a dietary compound inducing hormonal and metabolic changes.

Genistein is a plant-derived compound possessing well-known preventive activity in breast and prostate cancer, cardiovascular diseases and post-menopausal problems. Lately, the interests in genistein have widened. The studies concerning effects of genistein performed on animals and humans revealed other aspects of its action -- the metabolic alterations at the cellular level and in the whole organism. It was shown that genistein decreased body and fat tissue weight gains accompanied by reduced food intake. After ingestion of dietary genistein, the alterations in concentrations of hormones such as: insulin, leptin, thyroid hormones, adrenocorticotropic hormone, cortisol and corticosterone were observed. The changes in lipid parameters -- triglycerides and cholesterol were also noticed as a consequence of genistein administration. Moreover, the altered expression of genes engaged in lipid metabolism, disturbed glucose transport into cells, affected lipolysis and lipogenesis and changed ATP synthesis were found as a result of genistein action.

Effects of AMPK activation on lipolysis in primary rat adipocytes: studies at different glucose concentrations.

Adipose tissue plays a key role in energy homeostasis. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an important intracellular energy sensor. Effects of activation of AMPK by aminomidazole-4-carboxamide ribonucleotide (AICAR) on lipolysis in the rat adipocytes were determined in the presence of 3 or 12 mM glucose. Response to epinephrine or dibutyryl-cAMP was higher in the presence of 12 mM glucose. AICAR decreased lipolysis, also when glucose was replaced by alanine or succinate and without decrease in cAMP levels. AICAR attenuated epinephrine-induced decrease in adenosine triphosphate (ATP) levels, reduced glucose uptake and lactate release. These results indicate that short-term activation of AMPK by AICAR in the rat adipocytes inhibits lipolysis, due to changes in the final, followed by protein kinase A (PKA), steps of the lipolytic cascade and improves intracellular energy status. Similar effects of AICAR were observed in the presence of 3 and 12 mM glucose, which indicates that the AMPK system is operative at high glucose concentrations.

Effects of the activation of heme oxygenase-1 on hormonal and metabolic changes in rats fed a high-fat diet.

Heme oxygenase-1 (HO-1) is the inducible isoform of the heme oxygenase system, which catalyzes heme degradation. Up-regulation of this enzyme under pathological conditions is associated with beneficial effects in the whole organism. However, the potential of HO-1 in the alleviation of disturbances induced by a high-fat diet (HFD) is poorly elucidated. The present study was undertaken to determine the effects of pharmacological activation of HO-1 by hemin on some hormones and metabolic parameters in rats fed an HFD for 8 weeks. It was demonstrated that, in rats fed an HFD, blood glucose levels were increased compared with control animals. However, this hyperglycemic effect was alleviated by induction of HO-1. The observed decrease in glycemia was not associated with an increase in blood insulin concentrations, but was accompanied by improved glucose tolerance, which points to the potentiation of insulin action. Concentrations of free fatty acids were elevated in response to HFD; however, this effect appeared to be mitigated by hemin. Rats fed an HFD displayed clear-cut hyperleptinemia, which is a hallmark of leptin resistance. This derangement was effectively prevented by hemin therapy. Feeding with an HFD also increased blood ghrelin levels, whereas hemin slightly reduced blood ghrelin concentration. Carbohydrate and lipid metabolism in the liver of rats on an HFD was found to be disturbed, leading to increased lipid accumulation and reduced glycogen stores. However, negative changes in liver metabolism were partially attenuated as a result of induction of HO-1. Our results show that activation of HO-1 by hemin ameliorates some changes induced by HFD feeding. Normalization of blood leptin levels in these animals seems to be the most relevant finding, since hyperleptinemia is associated with dysregulation of energy homeostasis and with numerous other disorders. These results indicate that the HO system holds great potential to alleviate alterations induced by HFD.