Muscle Akt Research Articles

Hypoxic Preconditioning Alleviates Reoxygenation Injury via AKT in Respiratory Skeletal Muscle

Hypoxic Preconditioning Alleviates Reoxygenation Injury via AKT in Respiratory Skeletal Muscle

Effects of baicalin on Akt /TBC1D1 phosphorylation in mouse skeletal muscle (1142.13)

Insulin resistance is a common pathophysiological basis of type 2 diabetes. Related studies have confirmed that high lipid environment can decrease insulin sensitivity in liver, fat and skeletal muscle. TBC1D1 was recently discovered as a member of the TBC1 Rab‐GTPase family, which involved in the regulation of glucose transport and highly expressed in skeletal muscle.The phosphorylation of TBC1D1 may play a key role in regulating insulin‐stimulated glucose transport. TBC1D1 Thr590 is match for the Akt recognition motifs. Akt may activate its downstream substrate TBC1D1 Thr590 phosphorylation, and trigger glucose transporter protein GLUT4 translocation to cell surface. Baicalin is a natural compound extracted from scutellaria root, which is a kind of flavonoids. It has been reported that baicalin can show improvement diabetic rats, and also increase the glucose uptake in fat cells. However ,the effect of baicalin on skeletal muscle less reported. The aim of our study was to identify whether the beneficial effects of baicalin are related to regulate the phosphorylation of Akt and TBC1D1 in skeletal muscle. Our study results showed that baicalin can improve blood lipid, reduce the fasting blood glucose and postprandial glucose tolerance, and simultaneously increase Akt and TBC1D1 phosphorylation in skeletal muscle. These data demonstrate for the first time that intervention with baicalin may improve insulin sensitivity in skeletal muscle, which is related in part to regulate Akt /TBC1D1 signaling pathway.

Evaluating the effect of 20‐hydroxyecdysone on leucine signaling in the skeletal muscle and liver of male rats (820.7)

Phytoecdysteroids such as 20HE are ingredients in various nutritional supplements marketed to enhance physical performance and lean body mass. Recent in vitro studies suggest 20HE may activate protein synthesis via a phosphoinositide‐3‐kinase‐Akt signaling mechanism. To confirm these findings in vivo and evaluate downstream activation of mammalian target of rapamycin complex 1 (mTORC1) signaling, overnight fasted 4‐6 week old male rats (n=5‐6 per group) were randomized to one of three study designs: 1) gavaged with 0, 10, 50, 200 mg/kg 20HE and euthanized 30 min post‐gavage; 2) gavaged with 200 mg/kg 20HE or excipient and euthanized at 30 min, 60 min, 120 min, 240 min post‐gavage, and 3) administered excipient or 200 mg/kg 20HE alone or in combination with 1.35 g/kg L‐leucine and euthanized 30 min post‐gavage. Independent evaluation of 20HE confirmed purity as reported by Sigma before solubilization in 3% DMSO or 70% Labrasol® as excipient. Phosphorylation of Akt at Thr308 and Ser473, mTOR at Ser2448, ribosomal S6 kinase (S6K1) at Thr389, and eukaryotic initiation factor 4E binding protein 1 (4E‐BP1) at Thr 37/46 were evaluated by immunoblot. Leucine administered in 3% DMSO or Labrasol robustly increased phosphorylation of mTOR, S6K1 and 4E‐BP1 but not Akt in muscle and liver. In contrast, at all doses and times, 20HE did not significantly increase phosphorylation of Akt, mTOR, S6K1 or 4E‐BP1 as compared to excipient controls. Furthermore, 20HE dampened mTORC1 signaling by leucine in both muscle and liver. These data do not support the idea that anabolic effects of 20HE are acutely mediated by mTORC1.Grant Funding Source: Supported by NJAES and USDA Multistate NC1184

Grape skin extract protects against programmed changes in the adult rat offspring caused by maternal high-fat diet during lactation

Maternal overnutrition during suckling period is associated with increased risk of metabolic disorders in the offspring. We aimed to assess the effect of Vitis vinifera L. grape skin extract (ACH09) on cardiovascular and metabolic disorders in adult male offspring of rats fed a high-fat (HF) diet during lactation. Four groups of female rats were fed: control diet (7% fat), ACH09 (7% fat plus 200 mg kg−1 d−1 ACH09 orally), HF (24% fat), and HF+ACH09 (24% fat plus 200 mg kg−1 d−1 ACH09 orally) during lactation. After weaning, all male offspring were fed a control diet and sacrificed at 90 or 180 days old. Systolic blood pressure was increased in adult offspring of HF-fed dams and ACH09 prevented the hypertension. Increased adiposity, plasma triglyceride, glucose levels and insulin resistance were observed in offspring from both ages, and those changes were reversed by ACH09. Expression of insulin cascade proteins IRS-1, AKT and GLUT4 in the soleus muscle was reduced in the HF group of both ages and increased by ACH09. The plasma oxidative damage assessed by malondialdehyde levels was increased, and nitrite levels decreased in the HF group of both ages, which were reversed by ACH09. In addition, ACH09 restored the decreased plasma and mesenteric arteries antioxidant activities of superoxide dismutase, catalase and glutathione peroxidase in the HF group. In conclusion, the treatment of HF-fed dams during lactation with ACH09 provides protection from later-life hypertension, body weight gain, insulin resistance and oxidative stress. The protective effect ACH09 may involve NO synthesis, antioxidant action and activation of insulin-signaling pathways.

High-Density Lipoprotein

For >30 years it has been known that elevated high-density lipoprotein (HDL) cholesterol is preventative against the development of atherosclerosis.1 Besides its role in cholesterol removal, HDL is also an antioxidant,2,3 it inhibits inflammation4 and thrombosis,5 and also stimulates endothelial nitric oxide6 and prostacyclin7 release. In addition to these cardiovascular protective actions, recent research findings have elucidated the important role of HDL and its constitutive apoprotein components for glucose metabolism. HDL can lower blood glucose levels by mechanisms that include stimulation of insulin secretion from pancreatic β-cells8,9 and activation of the AMPK signaling pathway in skeletal muscle.8,10 These findings have opened up for an important area of investigation, especially given the increasing prevalence of metabolic disorders such as type 2 diabetes mellitus. Article see p 2364 The recent work by Lehti and colleagues11 appearing in this issue of Circulation uses a mouse model of apolipoprotein A-I (ApoA-I; the major protein component of HDL) knockout and overexpression (ApoA-I tg) to examine loss and gain of function effects on fasting plasma cholesterol, lipoprotein profile, glucose homeostasis, body composition, and exercise performance in vivo. From tissue extracts they examine liver and muscle glycogen, muscle AKT phosphorylation, mitochondrial function, and protein expression of mitochondrial ATP …

Physical inactivity affects skeletal muscle insulin signaling in a birth weight-dependent manner

AimsWe investigated whether physical inactivity could unmask defects in insulin and AMPK signaling in low birth weight (LBW) subjects. MethodsTwenty LBW and 20 normal birth weight (NBW) subjects were investigated using the euglycemic–hyperinsulinemic clamp with excision of skeletal muscle biopsies pre and post 9days of bed rest. Employing Western blotting, we investigated skeletal muscle Akt, AS160, GLUT4, and AMPK signaling. ResultsPeripheral insulin action was similar in the two groups and was decreased to the same extent post bed rest. Insulin and AMPK signaling was unaffected by bed rest in NBW individuals. LBW subjects showed decreased insulin-stimulated Akt phosphorylation and increased AMPK α1 and γ3 protein expression post bed rest. Insulin response of AS160 phosphorylation was lower in LBW subjects both pre and post bed rest. ConclusionsBed rest-induced insulin resistance is not explained by impaired muscle insulin or AMPK signaling in subjects with or without LBW. Lower muscle insulin signaling in LBW subjects post bed rest despite similar degree of insulin resistance as seen in controls may to some extent support the idea that LBW subjects are at higher risk of developing type 2 diabetes when being physically inactive.

Peripheral Effects of Nesfatin-1 on Glucose Homeostasis

Aims/hypothesisThe actions of peripherally administered nesfatin-1 on glucose homeostasis remain controversial. The aim of this study was to characterize the mechanisms by which peripheral nesfatin-1 regulates glucose metabolism.MethodsThe effects of nesfatin-1 on glucose metabolism were examined in mice by continuous infusion of the peptide via osmotic pumps. Changes in AKT phosphorylation and Glut4 were investigated by Western blotting and immnuofluorescent staining. Primary myocytes, adipocytes and hepatocytes were isolated from male mice.ResultsContinuous peripheral infusion of nesfatin-1 altered glucose tolerance and insulin sensitivity in mice fed either normal or high fat diet, while central administration of nesfatin-1 demonstrated no effect. Nesfatin-1 increases insulin secretion in vivo, and in vitro in cultured min6 cells. In addition, nesfatin-1 up-regulates the phosphorylation of AKT in pancreas and min6 islet cells. In mice fed normal diet, peripheral nesfatin-1 significantly increased insulin-stimulated phosphorylation of AKT in skeletal muscle, adipose tissue and liver; similar effects were observed in skeletal muscle and adipose tissue in mice fed high fat diet. At basal conditions and after insulin stimulation, peripheral nesfatin-1 markedly increased GLUT4 membrane translocation in skeletal muscle and adipose tissue in mice fed either diet. In vitro studies showed that nesfatin-1 increased both basal and insulin-stimulated levels of AKT phosphorylation in cells derived from skeletal muscle, adipose tissue and liver.ConclusionsOur studies demonstrate that nesfatin-1 alters glucose metabolism by mechanisms which increase insulin secretion and insulin sensitivity via altering AKT phosphorylation and GLUT 4 membrane translocation in the skeletal muscle, adipose tissue and liver.

Fish Oil Increases Muscle Protein Mass and Modulates Akt/FOXO, TLR4, and NOD Signaling in Weanling Piglets After Lipopolysaccharide Challenge1–3

Proinflammatory cytokines play a key role in the pathophysiology of muscle atrophy. In addition, n3 polyunsaturated fatty acids (PUFAs) exert an inhibitory effect on proinflammatory cytokines affecting many inflammatory diseases. We hypothesized that dietary supplementation of fish oil could attenuate lipopolysaccharide (LPS)-induced muscle atrophy. Weanling pigs were used in a 2 × 2 factorial design and the main factors included diet (5% corn oil or 5% fish oil) and immunological challenge (LPS or saline). After 21 d of treatment with either fish oil or corn oil, pigs received an i.p. injection of either saline or LPS. At 4 h postinjection, blood and muscle samples were obtained. Fish oil led to enrichment of eicosapentaenoic acid, docosahexaenoic acid, and total n3 PUFAs in muscles. Fish oil increased muscle protein mass, indicated by a higher protein:DNA ratio in gastrocnemius and longissimus dorsi (LD) muscles. In addition, fish oil increased Akt1 mRNA abundance and decreased Forkhead Box O (FOXO) 1 and FOXO4 mRNA abundance. Fish oil also increased phosphorylation of Akt and FOXO1 in gastrocnemius and LD muscles. Fish oil decreased the mRNA abundance of muscle atrophy F-box (MAFbx) and muscle RING finger 1 in gastrocnemius and LD muscles. Moreover, fish oil reduced the plasma tumor necrosis factor (TNF) α, muscle TNFα, and prostaglandin E2 concentrations, and muscle TNFα and cyclooxygenase 2 (COX2) mRNA abundance. Finally, fish oil downregulated the mRNA abundance of muscle toll-like receptor (TLR4) and its downstream signaling molecules [myeloid differentiation factor 88 (MyD88), TNFα receptor-associated factor 6 (TRAF6), and NF-κB p65], and nucleotide-binding oligomerization domain protein (NOD1), NOD2, and their adaptor molecule [receptor-interacting serine/threonine-protein kinase 2 (RIPK2)]. These results indicate fish oil may suppress muscle proinflammatory cytokine production via regulation of TLR and NOD signaling pathways and therefore improve muscle protein mass, possibly through maintenance of Akt/FOXO signaling.

Insulin and GLP-1 infusions demonstrate the onset of adipose-specific insulin resistance in a large fasting mammal: potential glucogenic role for GLP-1

Prolonged food deprivation increases lipid oxidation and utilization, which may contribute to the onset of the insulin resistance associated with fasting. Because insulin resistance promotes the preservation of glucose and oxidation of fat, it has been suggested to be an adaptive response to food deprivation. However, fasting mammals exhibit hypoinsulinemia, suggesting that the insulin resistance-like conditions they experience may actually result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin. To determine whether fasting results in insulin resistance or in pancreatic dysfunction, we infused early- and late-fasted seals (naturally adapted to prolonged fasting) with insulin (0.065 U/kg), and a separate group of late-fasted seals with low (10 pmol/L per kg) or high (100 pmol/L per kg) dosages of glucagon-like peptide-1 (GLP-1) immediately following a glucose bolus (0.5 g/kg), and measured the systemic and cellular responses. Because GLP-1 facilitates glucose-stimulated insulin secretion, these infusions provide a method to assess pancreatic insulin-secreting capacity. Insulin infusions increased the phosphorylation of insulin receptor and Akt in adipose and muscle of early- and late-fasted seals; however, the timing of the signaling response was blunted in adipose of late-fasted seals. Despite the dose-dependent increases in insulin and increased glucose clearance (high dose), both GLP-1 dosages produced increases in plasma cortisol and glucagon, which may have contributed to the glucogenic role of GLP-1. Results suggest that fasting induces adipose-specific insulin resistance in elephant seal pups, while maintaining skeletal muscle insulin sensitivity, and therefore suggests that the onset of insulin resistance in fasting mammals is an evolved response to cope with prolonged food deprivation.

Fructooligosaccharide augments benefits of quercetin-3-O-β-glucoside on insulin sensitivity and plasma total cholesterol with promotion of flavonoid absorption in sucrose-fed rats

The aim was to investigate both individual and synergistic effects of quercetin-3-O-β-glucoside (Q3G) and fructooligosaccharide (FOS) on indices of metabolic syndrome and plasma total cholesterol level with potential mechanisms of action. Five groups of rats were fed a dextrin-based diet as the normal reference group, or sucrose-based (S) diets with 0.3% Q3G, 5% FOS, or 0.3% Q3G + 5% FOS (Q3G + FOS) for 48 days. Oral glucose tolerance tests (OGTTs) were conducted on days 0, 14, 28, and 45, and adipose tissue and aortic blood were collected on day 48. Effects of Q3G and FOS on portal GLP-1 secretion were separately examined using rats after ileal administration. Abdominal fat weight reduced in FOS-fed groups. Blood glucose levels of the Q3G + FOS group at 60 min in OGTT and HOMA-IR (0.25 ± 0.03 vs 0.83 ± 0.12 on day 45) were clearly lower in the Q3G + FOS group than in S group throughout the experimental period. Muscle Akt phosphorylation was enhanced only in the Q3G group. The plasma quercetin was largely increased by FOS feeding on day 48 (18.37 ± 1.20 with FOS, 2.02 ± 0.30 without FOS). Plasma total cholesterol levels in the Q3G + FOS group (3.10 ± 0.12, P < 0.05 on day 45) were clearly suppressed compared to the S group (4.03 ± 0.18). GLP-1 secretion was enhanced in Q3G + FOS group than in Q3G or FOS group. Q3G + FOS diet improved glucose tolerance, insulin sensitivity, and total cholesterol level with increasing GLP-1 secretion and a higher level of blood quercetin. Q3G + FOS may reduce the risk of T2DM.

Impact of fasting on the rhythmic expression of myogenic and metabolic factors in skeletal muscle of adult mice

Circadian rhythms and metabolism are tightly integrated, and rhythmic expression of metabolic factors is common in homeostatic processes. We measured the temporal changes in the expression of myogenic regulatory factors and expression and activity level of molecules involved in protein metabolism in skeletal muscles and livers in mice and examined the impact of fasting. Tissues were collected over 24 h (at zeitgeber times ZT1, ZT5, ZT9, ZT13, ZT17, ZT21, and ZT1 the following day) from adult male C57Bl/6J mice that had been either freely fed or fasted for 24 h. In skeletal muscle, there was a robust rise in the mRNA expression of the myogenic regulatory factors MyoD and myogenin during dark hours which was strongly suppressed by fasting. Circadian pattern was observed for mRNA of MuRF1, Akt1, and ribosomal protein S6 in muscles in fed and fasted mice and for Fbxo32 in fed mice. Activity (phosphorylation) levels of Akt(Ser473) displayed temporal regulation in fasted (but not fed) mice and were high at ZT9. Fasting caused significant reductions in phosphorylation for both Akt and S6 in muscles, indicative of inactivation. Hepatic phosphorylated Akt(Ser473) and S6(Ser235/236) proteins did not exhibit daily rhythms. Fasting significantly reduced hepatic Akt(473) phosphorylation compared with fed levels, although (unlike in muscle) it did not affect S6(Ser235/236) phosphorylation. This in vivo circadian study addresses for the first time the signaling activities of key molecules related to protein turnover and their possible cross-regulation of expression of genes related to protein degradation.

Stereological analysis of Akt in muscles of young and old rats following a single bout of stretch‐shortening contractions

Careful design of resistance training programs is critical for offsetting age‐related sarcopenia. To address this, we implemented a non‐injurious stretch‐shortening contraction (SSC) protocol to muscles of rats. Following 4.5 weeks of resistance‐type training, muscles of young rats increased force by ~30% and mass by ~16%, while old rats sustained force deficits of ~30% with no change in muscle mass; no overt signs of histopathology were noted. Age‐related maladaptation to training may be due to aberrant Akt signaling – signaling influential in cellular survival/growth.PurposeTo characterize volume density of Akt positive muscle fibers following an acute bout of non‐injurious SSCs with aging.MethodsDorsiflexor muscles of 12wk. and 30mo. old Fischer 344xBN Hybrid rats were exposed to SSCs in vivo. At 6h, 3d, and 5d, tibialis anterior muscles were removed for stereological analysis of transverse sections labeled for pan‐Akt (N =3 per group).ResultsFor control muscles and muscles at 6h, pan‐Akt volume density represented ~40% of total tissue volume and was independent of age. At 3d and 5d post SSC, pan‐Akt levels were unaltered for old rats while values for young rats were decreased relative to values for old (p&lt;0.05).ConclusionWhile the training‐induced decrease in Akt at young age needs further study, the lack of change in Akt levels at old age is consistent with an overall blunted response to training.

Regulation of glucose metabolism by nesfatin‐1

Nesfatin‐1 is an 82‐amino acid anorexigenic peptide which also contributes to the regulation of glucose homeostasis. Mechanisms by which nesfatin‐1 modulates glucose metabolism remain largely unknown. Our studies showed that chronic infusion of nesfatin‐1 by a subcutaneous micro‐pump for two weeks significantly improves the glucose tolerance in both lean and high fat diet induced obese mice, while central administration of nesfatin‐1 demonstrated no effect. Plasma insulin increased significantly after nesfatin‐1 infusion in normal chow diet mice, while no further increment was observed in obese mice. Analysis of insulin signaling revealed that both levels of basal and insulin‐stimulated AKT phosphorylation in the skeletal muscle were markedly increased by nesfatin‐1 relative to the control treatment. Consistent with the alteration of pAKT, the expression and membrane translocation of glucose transporter 4 in the skeletal muscle were significantly increased by nesfatin‐1. In conclusion, nesfatin‐1 may improve glucose metabolism by regulating phosphorylation of AKT in skeletal muscle.

Metabolic flexibility and carnitine flux: The role of carnitine acyltransferase in glucose homeostasis

Metabolic flexibility and carnitine flux: The role of carnitine acyltransferase in glucose homeostasis

AdR1-TG/TALLYHO mice have improved lipid accumulation and insulin sensitivity

BackgroundOverexpression of adiponectin receptor 1 in macrophages can physiologically modulate metabolic activities in vivo by enhancing adiponectin actions in distal metabolically active tissues. To investigate the effects of enhanced adiponectin actions in TALLYHO (TH) diabetic mouse model, we crossed the adiponectin receptor 1 macrophage-specific transgenic mice (AdR1-TG) with the TALLYHO diabetic mice (TH) to examine the changes of lipid accumulation and insulin sensitivity in these mice. MethodsAdR1-TG/TH and the control WT/TH mice were fed either normal diet or high fat diet for 28weeks. Whole body weights of these mice were measured and mouse sera were analyzed for the levels of cholesterol, triglyceride, and free fatty acids. Glucose tolerance testing (GTT) and insulin tolerance testing (ITT) in these mice were performed to investigate systemic insulin sensitivity in vivo. Molecular markers for insulin signaling pathway in mouse skeletal muscle tissues, IRS-1 and AKT, were examined. Mouse serum insulin levels were measured and Sirt1 gene expression in mouse pancreatic tissues was also quantified related to the insulin secretion. The Caspase 3 protein levels were analyzed by Western blot methods. ResultsCompared to the control WT/TH mice, AdR1-TG/TH mice showed significantly lower body weights under either normal diet or high fat diet and the mouse serum levels of cholesterol, triglyceride and free fatty acids were significantly decreased in the transgenic crossed mice when compared to those from the control mice. Improved GTT and ITT tests indicating increased systemic insulin sensitivity in the transgenic crossed mice demonstrated the enhanced adiponectin actions on the systemic metabolism in vivo. The increases of insulin secretion and its related gene expression were also detected in the transgenic crossed mice. In contrast, the control mice showed hypertrophy pancreases companying with high apoptosis gene expression. These results suggest that enhanced adiponectin actions by overexpressing adiponectin receptor 1 in macrophages can provide unique interactions with the metabolic tissues/cells, improving lipid accumulation and insulin sensitivity in TALLYHO diabetic mice.

Intracellular β2-adrenergic receptor signaling specificity in mouse skeletal muscle in response to single-dose β2-agonist clenbuterol treatment and acute exercise

The aim of this study was to clarify the intracellular β2-adrenergic receptor signaling specificity in mouse slow-twitch soleus and fast-twitch tibialis anterior (TA) muscles, resulting from single-dose β2-agonist clenbuterol treatment and acute exercise. At 1, 4, and 24 h after single-dose treatment with clenbuterol or after acute running exercise, the soleus and TA muscles were isolated and subjected to analysis. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) increased after single-dose clenbuterol treatment and acute exercise in the soleus muscle but not in the TA muscle. Although there was no change in the phosphorylation of Akt after acute exercise in either muscle, phosphorylation of Akt in the soleus muscle increased after single-dose clenbuterol treatment, whereas that in the TA muscle remained unchanged. These results suggest that p38 MAPK and Akt pathways play a functional role in the adaptation to clenbuterol treatment and exercise, particularly in slow-twitch muscles.

Prenatal androgen excess programs metabolic derangements in pubertal female rats

Owing to the heterogeneity in the clinical symptoms of polycystic ovary syndrome (PCOS), the early pathophysiological mechanisms of PCOS remain unclear. Clinical, experimental, and genetic evidence supports an interaction between genetic susceptibility and the influence of maternal environment in the pathogenesis of PCOS. To determine whether prenatal androgen exposure induced PCOS-related metabolic derangements during pubertal development, we administrated 5α-dihydrotestosterone (DHT) in pregnant rats and observed their female offspring from postnatal 4 to 8 weeks. The prenatally androgenized (PNA) rats exhibited more numerous total follicles, cystic follicles, and atretic follicles than the controls. Fasting glucose, insulin, leptin levels, and homeostatic model assessment for insulin resistance were elevated in the PNA rats at the age of 5-8 weeks. Following intraperitoneal glucose tolerance tests, glucose and insulin levels did not differ between two groups; however, the PNA rats showed significantly higher 30- and 60-min glucose levels than the controls after insulin stimulation during 5-8 weeks. In addition, prenatal DHT treatment significantly decreased insulin-stimulated phosphorylation of AKT in the skeletal muscles of 6-week-old PNA rats. The abundance of IR substrate 1 (IRS1) and IRS2 was decreased in the skeletal muscles and liver after stimulation with insulin in the PNA group, whereas phosphorylation of insulin-signaling proteins was unaltered in the adipose tissue. These findings validate the contribution of prenatal androgen excess to metabolic derangements in pubertal female rats, and the impaired insulin signaling through IRS and AKT may result in the peripheral insulin resistance during pubertal development.

Hydrogen Sulfide Treatment Promotes Glucose Uptake by Increasing Insulin Receptor Sensitivity and Ameliorates Kidney Lesions in Type 2 Diabetes

To examine if hydrogen sulfide (H2S) can promote glucose uptake and provide amelioration in type 2 diabetes. Treatment with sodium hydrosulfide (NaHS, an H2S donor) increased glucose uptake in both myotubes and adipocytes. The H2S gas solution showed similar effects. The NaHS effects were blocked by an siRNA-mediated knockdown of the insulin receptor (IR). NaHS also increased phosphorylation of the IR, PI3K, and Akt. In Goto-Kakizaki (GK) diabetic rats, chronic NaHS treatment (30 μmol·kg(-1)·day(-1)) decreased fasting blood glucose, increased insulin sensitivity, and increased glucose tolerance with increased phosphorylation of PI3K and Akt in muscles. Similar insulin-sensitizing effects of NaHS treatment were also observed in Wistar rats. Moreover, glucose uptake was reduced in the cells with siRNA-mediated knockdown of the H2S-generating enzyme cystathionine γ-lyase in the presence or absence of exogenous H2S. Moreover, chronic NaHS treatment reduced oxygen species and the number of crescentic glomeruli in the kidney of GK rats. This study provides the first piece of evidence for the insulin-sensitizing effect of NaHS/H2S in the both in vitro and in vivo models of insulin resistance. REBOUND TRACK: This work was rejected during a standard peer review and rescued by the Rebound Peer Review (Antoxid Redox Signal 16: 293-296, 2012) with the following serving as open reviewers: Jin-Song Bian, Samuel Dudley, Hideo Kimura, and Xian Wang.

Impaired PI3 K Akt expression in liver and skeletal muscle of ovariectomized rats

It is well established that estrogen deficiency is strongly linked to the development of insulin resistance (IR), but the mechanism is still unclear. Since IR is characterized by a marked reduction in insulin-stimulated PI3 K-mediated activation of Akt in liver and skeletal muscle, we hypothesized that ovariectomized rats (OVX) would exhibit reductions in the expression of proteins in PI3 K signaling pathway, including PI3 K and Akt. As hypothesized, after observing for 12 weeks, compared with the SHAM rats, ovariectomy led to decreased plasma estrogen level and increased HOMA-IR index; in addition, ovariectomy also caused decreased PI3 K and Akt expression levels in the liver and skeletal muscle. Interestingly, the expression patterns differed in tissue-dependent fashion: Akt1 was only found reduction in liver, whereas Akt2 decreased in muscle; these changes can be reversed by estrogen supplement (OVXE). In conclusion, data demonstrate that estrogen withdrawals may cause IR at least in part by impaired PI3 K/Akt signaling proteins in liver and skeletal muscle, and Akt1 and Akt2 might be tissue-specific expressions.

Antidiabetic Effects of Pterosin A, a Small-Molecular-Weight Natural Product, on Diabetic Mouse Models

The therapeutic effect of pterosin A, a small-molecular-weight natural product, on diabetes was investigated. Pterosin A, administered orally for 4 weeks, effectively improved hyperglycemia and glucose intolerance in streptozotocin, high-fat diet–fed, and db/db diabetic mice. There were no adverse effects in normal or diabetic mice treated with pterosin A for 4 weeks. Pterosin A significantly reversed the increased serum insulin and insulin resistance (IR) in dexamethasone-IR mice and in db/db mice. Pterosin A significantly reversed the reduced muscle GLUT-4 translocation and the increased liver phosphoenolpyruvate carboxyl kinase (PEPCK) expression in diabetic mice. Pterosin A also significantly reversed the decreased phosphorylations of AMP-activated protein kinase (AMPK) and Akt in muscles of diabetic mice. The decreased AMPK phosphorylation and increased p38 phosphorylation in livers of db/db mice were effectively reversed by pterosin A. Pterosin A enhanced glucose uptake and AMPK phosphorylation in cultured human muscle cells. In cultured liver cells, pterosin A inhibited inducer-enhanced PEPCK expression, triggered the phosphorylations of AMPK, acetyl CoA carboxylase, and glycogen synthase kinase-3, decreased glycogen synthase phosphorylation, and increased the intracellular glycogen level. These findings indicate that pterosin A may be a potential therapeutic option for diabetes.