Central 5-HTR2C in the Control of Metabolic Homeostasis.

The 5-hydroxytryptamine 2C receptor (5-HTR2C) is a class G protein-coupled receptor (GPCR) enriched in the hypothalamus and the brain stem, where it has been shown to regulate energy homeostasis, including feeding and glucose metabolism. Accordingly, 5-HTR2C has been the target of several anti-obesity drugs, though the associated side effects greatly curbed their clinical applications. Dissecting the specific neural circuits of 5-HTR2C-expressing neurons and the detailed molecular pathways of 5-HTR2C signaling in metabolic regulation will help to develop better therapeutic strategies towards metabolic disorders. In this review, we introduced the regulatory role of 5-HTR2C in feeding behavior and glucose metabolism, with particular focus on the molecular pathways, neural network, and its interaction with other metabolic hormones, such as leptin, ghrelin, insulin, and estrogens. Moreover, the latest progress in the clinical research on 5-HTR2C agonists was also discussed.

Exercise and Urtica dioica extract ameliorate hippocampal insulin signaling, oxidative stress, neuroinflammation, and cognitive function in STZ-induced diabetic rats.

INTRODUCTION: Diabetes mellitus is related to cognitive impairments and molecular abnormalities of the hippocampus. A growing body of evidence suggests that Urtica dioica (Ud) and exercise training (ET) have potential therapeutic effects on diabetes and its related complications. Therefore, we hypothesized that the combined effect of exercise training (ET) and Ud might play an important role in insulin signaling pathway, oxidative stress, neuroinflammation, and cognitive impairment in diabetic rats. METHODS: Forty animals were divided into five groups (N = 8): healthy-sedentary (H-sed), diabetes-sedentary (D-sed), diabetes-exercise training (D-ET), diabetes-Urtica dioica (D-Ud), diabetes-exercise training-Urtica dioica (D-ET-Ud). Streptozotocin (STZ) (Single dosage; 45 mg/kg, i.p.) was used to induce diabetes. Then, ET (moderate intensity/5day/week) and Ud extract (50 mg/kg, oral/daily) were administered for six weeks. We also investigated the effects of ET and Ud on cognitive performance (assessed through Morris Water Maze tests), antioxidant capacity, and lipid peroxidation markers in hippocampus. Furthermore, we measured levels of insulin sensitivity and signaling factors (insulin-Ins, insulin receptor-IR and insulin-like growth factor-1 receptor-IGF-1R), and neuroinflammatory markers (IL-1 ß, TNF-α). This was followed by TUNEL assessment of the apoptosis rate in all regions of the hippocampus. RESULTS: D-sed rats compared to H-sed animals showed significant impairments (P < 0.001) in hippocampal insulin sensitivity and signaling, oxidative stress, neuroinflammation, and apoptosis, which resulted in cognitive dysfunction. Ud extract and ET treatment effectively improved these impairments in D-ET (P < 0.001), D-Ud (P < 0.05), and D-ET-Ud (P < 0.001) groups compared to D-sed rats. Moreover, diabetes mediated hippocampal oxidative stress, neuroinflammation, insulin signaling deficits, apoptosis, and cognitive dysfunction was further reversed by chronic Ud+ET administration in D-ET-Ud rats (P < 0.001) compared to D-sed animals. CONCLUSIONS: Ud extract and ET ameliorate cognitive dysfunction via improvement in hippocampal oxidative stress, neuroinflammation, insulin signaling pathway, and apoptosis in STZ-induced diabetic rats. The results of this study provide new experimental evidence for using Ud+ET in the treatment of hippocampal complications and cognitive dysfunction caused by diabetes.

[Effect of electroacupuncture on the expression of insulin signal pathway related proteins in hippocampus in mice with Alzheimer's disease].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on the expression of insulin phosphatidylinositol-3 kinase/glycogen synthetase kinase-3α (PI3K/GSK3α) signal pathway related proteins in the hippocampus in mice with Alzheimer's disease (AD), and to explore the regulatory mechanism of EA on improving the pathological characteristics of AD. METHODS: Twelve male APP/PS1 double transgenic mice were randomly divided a model group and a treatment group, 6 mice in each group; another 6 wild-type male mice were taken as the control group. The mice in the treatment group were treated with EA (continuous wave, 2 Hz of frequency) at "Baihui" (GV 20) and bilateral "Shenshu" (BL 23), once a day; 7-day treatment was taken as a course of treatment, and 2 courses of treatment were given. The immunohistochemistry method and Western blot method were used to detect the distribution and expression level of hippocampal PI3K/GSK3α signal pathway related proteins P85α, P110α, GSK3α and pS21GSK3α, and the number of hippocampal senile plaques (SP) was observed. RESULTS: The proteins of P85α, P110α, GSK3α and pS21GSK3α were mainly distributed in the cytoplasm of hippocampal neurons, and the GSK3α was also distributed in the axons of neurons in the model group and the treatment group. The immunohistochemistry results showed that the distribution level of GSK3α in the hippocampus in the model group was significantly higher than that in the control group (P<0.001), and the distribution level of pS21GSK3α, P85α and P110α was significantly decreased (P<0.01, P<0.001); compared with the model group, the distribution level of GSK3α in the hippocampus in the treatment group was significantly decreased (P<0.001), and the distribution level of pS21GSK3α, P85α and P110α in hippocampus was significantly increased (P<0.05, P<0.001). The Western blot results showed compared with the control group, the expression of pS21GSK3α, P85α and P110α as well as the ratio of pS21GSK3α/GSK3α in the hippocampus in the model group were significantly decreased (P<0.001), and the expression of GSK3α was increased (P<0.05); compared with the model group, the expression of pS21GSK3α, P85α, P110α and the ratio of pS21GSK3α/GSK3α in the hippocampus in the treatment group were significantly increased (P<0.01, P<0.001), and the expression of GSK3α was decreased (P<0.05). Compared with the control group, the number of hippocampal SP in the model group was significantly increased (P<0.001); compared with the model group, the number of hippocampal SP in the treatment group was significantly decreased (P<0.01). CONCLUSION: EA could effectively regulate the expression of PI3K/GSK3α signal pathway related proteins in the hippocampus in mice with AD, so as to reduce the formation and deposition of SP.

Intra-Pancreatic Insulin Nourishes Cancer Cells: Do Insulin-Receptor Antagonists such as PGG and EGCG Play a Role?

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-[Formula: see text]-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.

Obesity: sex and sympathetics.

Obesity increases sympathetic nerve activity (SNA) in men, but not women. Here, we review current evidence suggesting that sexually dimorphic sympathoexcitatory responses to leptin and insulin may contribute. More specifically, while insulin increases SNA similarly in lean males and females, this response is markedly amplified in obese males, but is abolished in obese females. In lean female rats, leptin increases a subset of sympathetic nerves only during the high estrogen proestrus reproductive phase; thus, in obese females, because reproductive cycling can become impaired, the sporadic nature of leptin-induced sympathoexcitaton could minimize its action, despite elevated leptin levels. In contrast, in males, obesity preserves or enhances the central sympathoexcitatory response to leptin, and current evidence favors leptin's contribution to the well-established increases in SNA induced by obesity in men. Leptin and insulin increase SNA via receptor binding in the hypothalamic arcuate nucleus and a neuropathway that includes arcuate neuropeptide Y (NPY) and proopiomelanocortin (POMC) projections to the paraventricular nucleus. These metabolic hormones normally suppress sympathoinhibitory NPY neurons and activate sympathoexcitatory POMC neurons. However, obesity appears to alter the ongoing activity and responsiveness of arcuate NPY and POMC neurons in a sexually dimorphic way, such that SNA increases in males but not females. We propose hypotheses to explain these sex differences and suggest areas of future research.

Protein Tyrosine Phosphatase (PTP1B): A promising Drug Target Against Life-threatening Ailments.

BACKGROUND: Protein tyrosine phosphatases are enzymes which help in the signal transduction in diabetes, obesity, cancer, liver diseases and neurodegenerative diseases. PTP1B is the main member of this enzyme from the protein extract of human placenta. In phosphate inhibitors development, significant progress has been made over the last 10 years. In early-stage clinical trials, few compounds have reached whereas in the later stage trials or registration, yet none have progressed. Many researchers investigate different ways to improve the pharmacological properties of PTP1B inhibitors. OBJECTIVE: In the present review, authors have summarized various aspects related to the involvement of PTP1B in various types of signal transduction mechanisms and its prominent role in various diseases like cancer, liver diseases and diabetes mellitus. CONCLUSION: There are still certain challenges for the selection of PTP1B as a drug target. Therefore, continuous future efforts are required to explore this target for the development of PTP inhibitors to treat the prevailing diseases associated with it.

Recombinant buckwheat trypsin inhibitor decreases fat accumulation via the IIS pathway in Caenorhabditis elegans.

Buckwheat trypsin inhibitor (BTI) is a low molecular weight polypeptide that can help to prevent metabolic diseases such as obesity, hyperglycemia and hyperlipidemia. Herein, the effects of recombinant BTI (rBTI) on fat accumulation in Caenorhabditis elegans were studied. rBTI prevented fat accumulation under normal and high glucose conditions, and led to significantly shorter body widths without affecting C. elegans feeding behavior. Results also indicate that rBTI altered fat breakdown, synthesis, and accumulation by altering the transcription, expression and activity of key enzymes in lipolysis and fat synthesis. In daf-2 and daf-16 mutants, rBTI did not prevent fat accumulation, indicating that rBTI activity relies on the insulin/insulin-like growth factor (IIS) pathway. Overall rBTI may regulate changes in lipolysis and fat synthesis by down-regulating the IIS pathway, which can affect fat accumulation. These findings support the application of rBTI in preventing obesity, hyperglycemia and hyperlipemia.

Leptin and insulin do not exert redundant control of metabolic or emotive function via dopamine neurons.

Leptin and insulin's hunger-suppressing and activity-promoting actions on hypothalamic neurons are well characterized, yet the mechanisms by which they modulate the midbrain dopamine system to influence energy balance remain less clear. A subset of midbrain dopamine neurons express receptors for leptin (Lepr) and insulin (Insr). Leptin-dopamine signaling reduces running reward and homecage activity. However, dopamine-specific deletion of Lepr does not affect body weight or food intake in mice. We hypothesized insulin-dopamine signaling might compensate for disrupted leptin-dopamine signaling. To investigate the degree to which insulin and leptin exert overlapping (i.e. redundant) versus discrete control over dopamine neurons, we generated transgenic male and female mice exhibiting dopamine-specific deletion of either Lepr (Lepr KO), Insr (Insr KO) or both Lepr and Insr (Dbl KO) and assessed their feeding behavior, voluntary activity, and energy expenditure compared to control mice. No differences in body weight, daily food intake, energy expenditure or hyperphagic feeding of palatable chow were observed between Lepr, Insr or Dbl KO mice and control mice. However, consistent with previous findings, Lepr KO (but not Insr or Dbl KO) male mice exhibited significantly increased running wheel activity compared to controls. These data demonstrate that insulin and leptin do not exert redundant control of dopamine neuron-mediated modulation of energy balance. Furthermore, our results indicate neither leptin nor insulin plays a critical role in the modulation of dopamine neurons regarding hedonic feeding behavior or anxiety-related behavior.

Anti-diabetic effect and mechanism of Kursi Wufarikun Ziyabit in L6 rat skeletal muscle cells.

Kursi Wufarikun Ziyabit (KWZ) is a traditional prescription that used in folk tea drinking for its health care effect in treatment of type 2 diabetes mellitus (T2DM) in central Asia. However, the underlying mechanism of KWZ in T2DM has not been investigated extensively. This study designed to observe the effect of KWZ on glucose consumption and assess the molecular mechanism on associated proteins in insulin signaling and ER stress pathway in L6 rat skeletal muscle cells. The results showed that, KWZ exhibited proteins of PTP-1B and α-glycosidase inhibitory activity in vitro. No cytotoxicity of KWZ was found on L6 cell line. The best effect of glucose consumption of cells was shown at 6.25 µg/mL after KWZ treatment for 12 h. Expression of PTP-1B protein was inhibited by KWZ in L6 moytubes. PI3K-dependent Akt phosphorylation was found to be activated by KWZ. Moreover, the insulin-mediated induction of IRS-1 and GSK-3 were also activated by KWZ. Western blot results indicated that KWZ significantly improved the levels of ER stress proteins, which reduced the expression of GRP78, enhanced the expression of the PERK, eIF2α and XBP1s. The activation of PERK/eIF2α was likely consequence of GRP78 inhibition, and this might be beneficial for improving the stability of ER and alleviating insulin resistance. These results suggest that KWZ might be serving as the potential drug for the prevention and treatment of T2DM.

Stress exposure alters brain mRNA expression of the genes involved in insulin signalling, an effect modified by a high fat/high fructose diet and cinnamon supplement.

In occidental societies, high fat and high sugar diets often coincide with episodes of stress. The association is likely to modify brain energy control. Brain insulin signalling is rarely studied in stressed individuals consuming high fat diets. Furthermore the effects of cinnamon supplement are not known in these conditions. Therefore, we exposed rats, over a 12-week period, to a control (C) or a high fat/high fructose (HF/HFr) diet that induces peripheral insulin resistance. A cinnamon supplement (C+CN and HF/HFr +CN) was added or not. After diet exposure, one group of rats was exposed to a 30-min restraint followed by a 10-min open-field test, their combination featuring a moderate stressor, the other rats staying unstressed in their home cages. The insulin signalling in hippocampus and frontal cortex was studied through the mRNA expression of the following genes: insulin receptor (Ir), insulin receptor substrate (Irs1), glucose transporters (Glut1 and Glut3), glycogen synthase (Gys1) and their modulators, Akt1 and Pten. In C rats, stress enhanced the expression of Ir, Irs1, Glut1, Gys1 and Akt1 mRNA. In C+CN rats, stress induced an increase in Pten but a decrease in Gys1 mRNA expression. In HF/HFr rats, stress was associated with an increase in Pten mRNA expression. In HF/HFr+CN rats, stress increased Pten mRNA expression but also decreased Gys1 mRNA expression. This suggests that a single moderate stress favours energy refilling mechanisms, an effect blunted by a previous HF/HFr diet and cinnamon supplement.

Leptin Replacement Reestablishes Brain Insulin Action in the Hypothalamus in Congenital Leptin Deficiency.

OBJECTIVE: Human obesity is associated with impaired central insulin signaling, and in very rare cases, severe obesity can be caused by congenital leptin deficiency. In such patients, leptin replacement results in substantial weight loss and improvement in peripheral metabolism. RESEARCH DESIGN AND METHODS: In a leptin-deficient patient, we investigated the impact of leptin substitution on central insulin action, as quantified by changes in neuronal activity after intranasal insulin application. This was assessed before and during the first year of metreleptin substitution. RESULTS: After only 1 year, treatment with metreleptin reestablishes brain insulin sensitivity, particularly in the hypothalamus and, to a lesser degree, in the prefrontal cortex. Results are depicted in comparison with a control group. In our patient, brain activation changes were accompanied by substantial weight loss, reduced visceral adipose tissue, reduced intrahepatic lipid content, and improved whole-body insulin sensitivity. CONCLUSIONS: Leptin replacement and weight loss improved homeostatic insulin action in the patient in question.

High-monosaccharide intake inhibits anorexigenic hypothalamic insulin response in male rats.

OBJECTIVE: The aim of this research is to evaluate if intake of 20% fructose solution is able to change the anorexigenic hypothalamic insulin action. METHODS: Thirty day-old male Wistar rats were randomly assigned to one of the following groups: standard chow and water for the rats (Control group, C) and standard chow and 20% fructose solution for the rats (Fructose group, F).These treatments lasted 8 weeks. Three-month-old rats from group C and F received insulin or saline intracerebroventricular injections for evaluation of 24 h food intake, phosphorylated forms of the IR (p-IR) and Akt (p-Akt) proteins and quantified hypothalamic insulin receptor (IR) and insulin receptor substrate 1 (IRS-1) proteins. RESULTS: Insulin injection was able to decrease food intake in group C compared to 0.9% saline. However, insulin infusion failed to inhibit 24 h food intake in group F compared to 0.9% saline. The hypothalamic content of the IRS-1 was 37% higher in group F as well as p-Akt protein was significant higher vs. group C. CONCLUSION: We concluded that the 20% fructose solution compromised insulin signaling considering that it inhibited the anorexigenic hypothalamic response to acute injection of this hormone and increase of IRS-1 and p-Akt content.

Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.

Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-ß, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.

High-sucrose diet induces diabetic-like phenotypes and oxidative stress in Drosophila melanogaster: Protective role of Syzygium cumini and Bauhinia forficata.

Diet is a key component for development and longevity of organisms. Here, the fruit fly was used to evaluate the detrimental effects caused by consumption of high-sucrose diets (HSD), namely phenotypic responses linked to insulin signaling and oxidative stress. The protective effects of extracts from medicinal plants Syzygium cumini and Bauhinia forficata were investigated. HSD intake (15% and 30%) delayed the time to pupation and reduced the number of white pupae. In adult flies, the intake of diets was associated with mortality and increased levels of glucose+trehalose, triacylglycerols and hydrogen peroxide. Indeed, 30% HSD induced body-weight loss, mitochondrial dysfunction and changes in acetylcholinesterase, δ-aminolevulinate dehydratase and antioxidant enzymes activity. Catalase, superoxide dismutase, keap1, HSP70, dILP-5 and Insulin receptor mRNA levels were over-expressed in flies emerged from 30% HSD. The extract treatments blunted the developmental alterations elicited by diets. Syzygium cumini extract was more efficient than B. forficata in reducing hyperglycaemia, redox disturbances and the changes in mRNA expression of insulin receptor.

Dietary saturated fat and monounsaturated fat have reversible effects on brain function and the secretion of pro-inflammatory cytokines in young women.

BACKGROUND: Previous literature suggests that a higher ratio of palmitic acid (PA)/oleic acid (OA) in the diet induces inflammation, which may result in deficient brain insulin signaling, and, secondarily, impaired physical activity, sleep efficiency, and cognitive functioning. OBJECTIVE: We hypothesized that lowering the typical dietary PA/OA would affect the activation of relevant brain networks during a working memory task and would also lower secretion of pro-inflammatory cytokines. DESIGN: In 12 female subjects participating in a randomized, cross-over trial comparing 3-week high PA diet (HPA) and low PA and a high OA diet (HOA), we evaluated functional magnetic resonance imaging (fMRI) using an N-back test of working memory, cytokine secretion by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC), and plasma cytokine concentrations. RESULTS: Brain activation during the HPA diet compared to the HOA diet was increased in regions of the basal ganglia including the caudate and putamen (p<0.005). In addition, compared to the HOA diet, during the HPA diet, the plasma concentrations of IL-6 (p=0.04) and IL-1ß (p=0.05) were higher, and there was a higher secretion of IL-18 (p=0.015) and a trend for higher IL-1ß secretion (p=0.066) from LPS-stimulated PBMCs. CONCLUSIONS: The HPA diet resulted in increased brain activation in the basal ganglia compared to the HOA diet as well as increased secretion of pro-inflammatory cytokines. These data provide evidence that short-term (2week) diet interventions impact brain network activation during a working memory task and that these effects are reversible since the order of the study diets was randomized. These data are consistent with the hypothesis that lowering the dietary PA content via substitution with OA also could affect cognition.

Possible Involvement of Insulin Resistance in the Progression of Cancer Cachexia in Mice.

Malnutrition is a common problem among cancer patients, affecting up to 85% of patients with certain cancers. In severe cases, malnutrition can progress to cachexia, a specific form of malnutrition characterized by loss of lean body mass and muscle wasting. Although this muscle wasting might be a product of enhanced protein degradation, the precise mechanisms of cancer cachexia are not fully elucidated. Based on basic and clinical research, glucose intolerance and insulin resistance have been postulated to be associated with cancer cachexia. Since insulin in the skeletal muscle inhibits protein degradation and promotes protein synthesis, insulin resistance could be a possible cause of cancer cachexia. Therefore, we investigated the involvement of insulin resistance in the development of cancer cachexia in tumor-bearing mice. The signaling protein in the insulin cascade was attenuated in the skeletal muscle and hypothalamus from tumor-bearing mice. We identified Chrysanthemum morifolium RAMAT., known as Kikuka, as a peroxisome proliferator-activated receptor γ (PPARγ) ligand. Treatment with Kikuka attenuates the skeletal muscle changes in tumor-bearing mice. These results suggest that this natural PPARγ activator might be an attractive candidate for the treatment of cancer cachexia. In the symposium, we presented the PPARγ activator-induced improvement of cancer cachexia.

Curcuma longa polyphenols improve insulin-mediated lipid accumulation and attenuate proinflammatory response of 3T3-L1 adipose cells during oxidative stress through regulation of key adipokines and antioxidant enzymes.

Plant polyphenols may exert beneficial action against obesity-related oxidative stress and inflammation which promote insulin resistance. This study evaluated the effect of polyphenols extracted from French Curcuma longa on 3T3-L1 adipose cells exposed to H2 O2 -mediated oxidative stress. We found that Curcuma longa extract exhibited high amounts of curcuminoids identified as curcumin, demethoxycurcumin, and bisdemethoxycurcumin, which exerted free radical-scavenging activities. Curcuma longa polyphenols improved insulin-mediated lipid accumulation and upregulated peroxisome proliferator-activated receptor-gamma gene expression and adiponectin secretion which decreased in H2 O2 -treated cells. Curcuminoids attenuated H2 O2 -enhanced production of pro-inflammatory molecules such as interleukin-6, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and nuclear factor κappa B. Moreover, they reduced intracellular levels of reactive oxygen species elevated by H2 O2 and modulated the expression of genes encoding superoxide dismutase and catalase antioxidant enzymes. Collectively, these findings highlight that Curcuma longa polyphenols protect adipose cells against oxidative stress and may improve obesity-related metabolic disorders. © 2016 BioFactors, 42(4):418-430, 2016.

Reactive oxygen species mediate insulin signal transduction in mouse hypothalamus.

In the hypothalamus, several reports have implied that ROS mediate physiological effects of insulin. In this study, we investigated the mechanisms of insulin-induced ROS production and the effect of ROS on insulin signal transduction in mouse hypothalamic organotypic cultures. Insulin increased intracellular ROS, which were suppressed by NADPH oxidase inhibitor. H2O2 increased phospho-insulin receptor ß (p-IRß) and phospho-Akt (p-Akt) levels. Insulin-induced increases in p-IRß and p-Akt levels were attenuated by ROS scavenger or NADPH oxidase inhibitor. Our data suggest that insulin-induced phosphorylation of IRß and Akt is mediated via ROS which are predominantly produced by NADPH oxidase in mouse hypothalamus.

A glucose-centric perspective of hyperglycemia.

Digestion of food in the intestines converts the compacted storage carbohydrates, starch and glycogen, to glucose. After each meal, a flux of glucose (> 200 g) passes through the blood pool (4-6 g) in a short period of 2 h, keeping its concentration ideally in the range of 80-120 mg/100 mL. Tissue-specific glucose transporters (GLUTs) aid in the distribution of glucose to all tissues. The balance glucose after meeting the immediate energy needs is converted into glycogen and stored in liver (up to 100 g) and skeletal muscle (up to 300 g) for later use. High blood glucose gives the signal for increased release of insulin from pancreas. Insulin binds to insulin receptor on the plasma membrane and activates its autophosphorylation. This initiates the post-insulin-receptor signal cascade that accelerates synthesis of glycogen and triglyceride. Parallel control by phos-dephos and redox regulation of proteins exists for some of these steps. A major action of insulin is to inhibit gluconeogensis in the liver decreasing glucose output into blood. Cases with failed control of blood glucose have alarmingly increased since 1960 coinciding with changed life-styles and large scale food processing. Many of these turned out to be resistant to insulin, usually accompanied by dysfunctional glycogen storage. Glucose has an extended stay in blood at 8 mM and above and then indiscriminately adds on to surface protein-amino groups. Fructose in common sugar is 10-fold more active. This random glycation process interferes with the functions of many proteins (e.g., hemoglobin, eye lens proteins) and causes progressive damage to heart, kidneys, eyes and nerves. Some compounds are known to act as insulin mimics. Vanadium-peroxide complexes act at post-receptor level but are toxic. The fungus-derived 2,5-dihydroxybenzoquinone derivative is the first one known to act on the insulin receptor. The safe herbal products in use for centuries for glucose control have multiple active principles and targets. Some are effective in slowing formation of glucose in intestines by inhibiting α-glucosidases (e.g., salacia/saptarangi). Knowledge gained from French lilac on active guanidine group helped developing Metformin (1,1-dimethylbiguanide) one of the popular drugs in use. One strategy of keeping sugar content in diets in check is to use artificial sweeteners with no calories, no glucose or fructose and no effect on blood glucose (e.g., steviol, erythrytol). However, the three commonly used non-caloric artificial sweeteners, saccharin, sucralose and aspartame later developed glucose intolerance, the very condition they are expected to evade. Ideal way of keeping blood glucose under 6 mM and HbA1c, the glycation marker of hemoglobin, under 7% in blood is to correct the defects in signals that allow glucose flow into glycogen, still a difficult task with drugs and diets.

1-Deoxynojirimycin Alleviates Insulin Resistance via Activation of Insulin Signaling PI3K/AKT Pathway in Skeletal Muscle of db/db Mice.

1-Deoxynojirimycin (DNJ) is widely used for the treatment of diabetes mellitus as an inhibitor of intestinal α-glucosidase. However, there are few reports about its effect on insulin sensitivity improvement. The aim of the present study was to investigate whether DNJ decreased hyperglycemia by improving insulin sensitivity. An economical method was established to prepare large amounts of DNJ. Then, db/db mice were treated with DNJ intravenously (20, 40 and 80 mg·kg(-1)·day(-1)) for four weeks. Blood glucose and biochemical analyses were conducted to evaluate the therapeutic effects on hyperglycemia and the related molecular mechanisms in skeletal muscle were explored. DNJ significantly reduced body weight, blood glucose and serum insulin levels. DNJ treatment also improved glucose tolerance and insulin tolerance. Moreover, although expressions of total protein kinase B (AKT), phosphatidylinositol 3 kinase (PI3K), insulin receptor beta (IR-ß), insulin receptor substrate-1 (IRS1) and glucose transporter 4 (GLUT4) in skeletal muscle were not affected, GLUT4 translocation and phosphorylation of Ser473-AKT, p85-PI3K, Tyr1361-IR-ß and Tyr612-IRS1 were significantly increased by DNJ treatment. These results indicate that DNJ significantly improved insulin sensitivity via activating insulin signaling PI3K/AKT pathway in skeletal muscle of db/db mice.