Restored Insulin Signaling Research Articles

Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, anti-diabetic drugs in heart failure and cognitive impairment: potential mechanisms of the protective effects.

Heart failure and cognitive impairment emerge as public health problems that need to be addressed due to the aging global population. The conditions that often coexist are strongly related to advancing age and multimorbidity. Epidemiological evidence indicates that cardiovascular disease and neurodegenerative processes shares similar aspects, in term of prevalence, age distribution, and mortality. Type 2 diabetes increasingly represents a risk factor associated not only to cardiometabolic pathologies but also to neurological conditions. The pathophysiological features of type 2 diabetes and its metabolic complications (hyperglycemia, hyperinsulinemia, and insulin resistance) play a crucial role in the development and progression of both heart failure and cognitive dysfunction. This connection has opened to a potential new strategy, in which new classes of anti-diabetic medications, such as glucagon-like peptide-1 receptor (GLP-1R) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, are able to reduce the overall risk of cardiovascular events and neuronal damage, showing additional protective effects beyond glycemic control. The pleiotropic effects of GLP-1R agonists and SGLT2 inhibitors have been extensively investigated. They exert direct and indirect cardioprotective and neuroprotective actions, by reducing inflammation, oxidative stress, ions overload, and restoring insulin signaling. Nonetheless, the specificity of pathways and their contribution has not been fully elucidated, and this underlines the urgency for more comprehensive research.

HM-chromanone reverses the blockade of insulin signaling induced by high glucose levels in human HepG2 cells

This study investigated whether (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone (HM-chromanone) could counteract the high glucose level-induced blockade of insulin signaling in human HepG2 cells. Cells were pre-incubated with glucose (5.5 or 33 mM) and then incubated with a medium containing various concentrations of HM-chromanone. Assays for glucose uptake, glycogen synthesis, and glucose production were performed. Western blotting helped elucidate the underlying molecular mechanisms. High glucose concentration (33 mM) significantly increased p-IRS-1ser307 levels and decreased p-Akt levels. However, HM-chromanone significantly decreased p-IRS-1ser307 levels while increasing p-IRS-1tyr612 and Akt levels, which restored insulin signaling disturbed by high glucose concentration. HM-chromanone significantly increased p-AMPK levels, which were reduced by high glucose in HepG2 cells. Knockdown of AMPK using siRNA increased p-IRS-1ser307 and decreased p-Akt levels, even after treatment with HM-chromanone in high glucose concentration-treated cells. HM-chromanone stimulated glycogen synthesis by increasing p-GSK3βser9 and decreasing p-GSser641 levels in HepG2 cells under high glucose concentration; this effect was blocked by AMPK siRNA. HM-chromanone significantly decreased PEPCK, G6Pase, and hepatic glucose production, which were also blocked by AMPK siRNA. These results suggest that HM-chromanone could reverse insulin signaling blockade (induced by high glucose levels) through the activation of AMPK and stimulation of glucose uptake and glycogen synthesis in HepG2 cells.

Tea polyphenols improve glucose metabolism in ceruloplasmin knockout mice via decreasing hepatic iron deposition

ABSTRACT The present study aimed to investigate the role of tea polyphenols (TP) playing in glucose metabolism in male ceruloplasmin knockout mice (CP −/− ), an iron-overloaded model. Compared to wild-type CP +/+ mice, CP −/− mice exhibited hyperglycemia, insulin resistance and excess iron deposition in liver tissue. Increased hepatic oxidative stress (P＜0.05), apoptosis, and reduced gene expression of insulin receptor substrate 2 (IRS2) and glucose transporter 2 (GLUT2) were found in CP −/− mice (P＜0.05). TP treatment may ameliorate hepatic iron overload, oxidative stress and apoptosis, improve insulin sensitivity by upregulating IRS2 and GLUT2 expressions. TP administration could improve glucose homeostasis in CP −/− mice by alleviating hepatic iron-overload, oxidative stress, hepatocyte apoptosis, and restoring insulin signaling pathway.

Rosiglitazone treatment enhances intracellular actin dynamics and glucose transport in hypertrophic adipocytes

AimsTo accommodate surplus energy, adipose tissue expands by increasing both adipose cell size (hypertrophy) and cell number (hyperplasia). Enlarged, hypertrophic adipocytes are known to have reduced insulin response and impaired glucose transport, which negatively influence whole-body glucose homeostasis. Rosiglitazone is a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, known to stimulate hyperplasia and to efficiently improve insulin sensitivity. Still, a limited amount of research has investigated the effects of rosiglitazone in mature, hypertrophic adipocytes. Therefore, the objective of this study was to examine rosiglitazone's effect on insulin-stimulated glucose uptake in hypertrophic adipocytes. Main methodsC57BL/6J male mice were subjected to 2 weeks of high-fat diet (HFD) followed by 1 week of HFD combined with daily administration of rosiglitazone (10 mg/kg). Adipose cell-size distribution and gene expression were analysed in intact adipose tissue, and glucose uptake, insulin response, and protein expression were examined using primary adipocytes isolated from epididymal and inguinal adipose tissue. Key findingsHFD-feeding induced an accumulation of hypertrophic adipocytes, which was not affected by rosiglitazone-treatment. Still, rosiglitazone efficiently improved insulin-stimulated glucose transport without restoring insulin signaling or GLUT4 expression in similar-sized adipocytes. This improvement occurred concurrently with extracellular matrix remodelling and restored intracellular levels of targets involved in actin turnover. SignificanceThese results demonstrate that rosiglitazone improves glucose transport in hypertrophic adipocytes, and highlights the importance of the cytoskeleton and extracellular matrix as potential therapeutic targets.

Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism

The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes. Progestin and adipoQ receptor 3 (PAQR3), a key regulator of inflammation and metabolism, can negatively regulate the PI3K/AKT signaling pathway. Here, we report that gentiopicroside (GPS), the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa, decreased lipid synthesis and increased glucose utilization in palmitic acid (PA) treated HepG2 cells. Additionally, GPS improved glycolipid metabolism in streptozotocin (STZ) treated high-fat diet (HFD)-induced diabetic mice. Our findings revealed that GPS promoted the activation of the PI3K/AKT axis by facilitating DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Moreover, results of surface plasmon resonance (SPR), microscale thermophoresis (MST) and thermal shift assay (TSA) indicated that GPS directly binds to PAQR3. Results of molecular docking and cellular thermal shift assay (CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40, Asp42, Glu69, Tyr125 and Ser129, and spatially inhibited the interaction between PAQR3 and the PI3K catalytic subunit (P110α) to restore the PI3K/AKT signaling pathway. In summary, our study identified GPS, which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway, as a potential drug candidate for the treatment of diabetes.

Adrenomedullin ameliorates palmitic acid-induced insulin resistance through PI3K/Akt pathway in adipocytes.

White adipose tissue (WAT) dysfunction has been associated with adipose tissue low-grade inflammation and oxidative stress leading to insulin resistance (IR). Adrenomedullin (ADM), an endogenous active peptide considered as an adipokine, is associated with adipocytes function. We evaluated the protective effects of ADM against IR in 3T3-L1 adipocytes treated by palmitic acid (PA) and in visceral white adipose tissue (vWAT) of obese rats fed with high-fat diet. We found that endogenous protein expressions of ADM and its receptor in PA-treated adipocytes were markedly increased. PA significantly induced impaired insulin signaling by affecting phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) axis and glucose transporter-4 (GLUT-4) levels, whereas ADM pretreatment enhanced insulin signaling PI3K/Akt and GLUT-4 membrane protein levels, decreased pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin-1β (IL-1β) and IL-6 levels, and improved oxidative stress accompanied with reduced reactive oxygen species (ROS) levels and increased anti-oxidant enzymes manganese superoxide dismutase 2 (SOD2), glutathione peroxidase (GPx1) and catalase (CAT) protein expressions. Furthermore, ADM treatment not only improved IR in obese rats, but also effectively restored insulin signaling, and reduced inflammation and oxidative stress in vWAT of obese rats. This study demonstrates a prevention potential of ADM against obesity-related metabolic disorders, due to its protective effects against IR, inflammation and oxidative stress in adipocytes.

SiRNA Mediated GSK3β Knockdown Targets Insulin Signaling Pathway and Rescues Alzheimer's Disease Pathology: Evidence from In Vitro and In Vivo Studies.

Sporadic Alzheimer's disease (sAD) is a progressive neurodegenerative disorder with dysfunctional insulin signaling and energy metabolism. Emerging evidence suggests impairments in brain insulin responsiveness, glucose utilization, and energy metabolism may be major causes of amyloid precursor protein mishandling. The support for this notion comes from the studies wherein streptozotocin (STZ) induced brain insulin resistance in rodent model resulted in sAD-like neuropathology with cognitive decline. Our previous study showed a compromised insulin signaling pathway, glucose uptake, glucose metabolism, and energy homeostasis in STZ-induced glial-neuronal coculture and in vivo model of sAD. Various components of insulin signaling pathway were examined to understand the metabolic correlation, and GSK3β was selected for gene knockdown strategy to reverse sAD pathology based on the data. In the present study, we have synthesized carboxylated graphene oxide (GO) nanosheets functionalized with PEG and subsequently with polyethylenimine (PEI) to provide attachment sites for GSK3β siRNA. Our results showed that siRNA mediated knockdown of the GSK3β gene reduced expression of amyloid pathway genes (APP and BACE1), which was further confirmed by reduced amyloid beta (Aβ) levels in the in vitro STZ-induced sAD model. GSK3β knockdown also restored insulin signaling, AMPK and Mapk3 pathway by restoring the expression of corresponding candidate genes in these pathways (IR, Glut1/3, Prkaa1/2, Mapk3, BDNF) that reflected improved cellular energy homeostasis, neuronal proliferation, differentiation, maturation, and repair. Behavioral data from Morris water maze (MWM), open field (OF), novel object recognition (NOR), Y maze, and radial arm maze (RAM) tests showed that 0.5 μg nanoformulation (GOc-PP-siRNAGSK3β) intranasally for 7 days improved spatial memory, rescued anxiety like behavior, improved visual and working memory, and rescued exploratory behavior in STZ-induced sAD rats. GSK3β silencing resulted in decreased BACE1 expression and prevented accumulation of Aβ in the cortex and hippocampus. These molecular findings with improved behavioral performances were further correlated with reduced amyloid beta (Aβ) and neurofibrillary tangle (NFTs) formation in the cortex and hippocampus of GOc-PP-siRNAGSK3β administered sAD rats. Therefore, it is conceivable from the present study that nanoparticle-mediated targeting of GSK3β in the sAD appears to be a promising strategy to reverse sAD pathology.

Insulin receptor cleavage induced by estrogen impairs insulin signaling

IntroductionSoluble insulin receptor (sIR), which is the ectodomain of insulin receptor (IR), is present in human plasma. Plasma sIR levels are positively correlated with blood glucose levels and negatively correlated...

EET Analog Treatment Improves Insulin Signaling in a Genetic Mouse Model of Insulin Resistance.

We previously showed that global deletion of the cytochrome P450 epoxygenase Cyp2c44, a major epoxyeicosatrienoic acid (EET) producing enzyme in mice, leads to impaired hepatic insulin signaling resulting in insulin resistance. This finding led us to investigate whether administration of a water soluble EET analog restores insulin signaling in vivo in Cyp2c44(-/-) mice and investigated the underlying mechanisms by which this effect is exerted. Cyp2c44(-/-) mice treated with the analog EET-A for 4 weeks improved fasting glucose and glucose tolerance compared to Cyp2c44(-/-) mice treated with vehicle alone. This beneficial effect was accompanied by enhanced hepatic insulin signaling, decreased expression of gluconeogenic genes and increased expression of glycogenic genes. Mechanistically, we show that insulin-stimulated phosphorylation of insulin receptor β (IRβ) is impaired in primary Cyp2c44(-/-) hepatocytes and this can be restored by cotreatment with EET-A and insulin. Plasma membrane fractionations of livers indicated that EET-A enhances the retention of IRβ in membrane rich fractions, thus potentiating its activation. Altogether, EET analogs ameliorate insulin signaling in a genetic model of hepatic insulin resistance by stabilizing membrane-associated IRβ and potentiating insulin signaling.

Peganum harmala enhanced GLP-1 and restored insulin signaling to alleviate AlCl3-induced Alzheimer-like pathology model

Peganum harmala (P. harmala) is a folk medicinal herb used in the Sinai Peninsula (Egypt) as a remedy for central disorders. The main constituents, harmine and harmaline, have displayed therapeutic efficacy against Alzheimer’s disease (AD); however, the P. harmala potential on sensitizing central insulin to combat AD remains to be clarified. An AD-like rat model was induced by aluminum chloride (AlCl3; 50 mg/kg/day for six consecutive weeks; i.p), whereas a methanolic standardized P. harmala seed extract (187.5 mg/kg; p.o) was given to AD rats starting 2 weeks post AlCl3 exposure. Two additional groups of rats were administered either the vehicle to serve as the normal control or the vehicle + P. harmala seed extract to serve as the P. harmala control group. P. harmala enhanced cognition appraised by Y-maze and Morris water maze tests and improved histopathological structures altered by AlCl3. Additionally, it heightened the hippocampal contents of glucagon-like peptide (GLP)-1 and insulin, but abated insulin receptor substrate-1 phosphorylation at serine 307 (pS307-IRS-1). Besides, P. harmala increased phosphorylated Akt at serine 473 (pS473-Akt) and glucose transporter type (GLUT)4. The extract also curtailed the hippocampal content of beta amyloid (Aβ)42, glycogen synthase (GSK)-3β and phosphorylated tau. It also enhanced Nrf2, while reduced lipid peroxides and replenished glutathione. In conclusion, combating insulin resistance by P. harmala is a novel machinery in attenuating the insidious progression of AD by enhancing both insulin and GLP-1 trajectories in the hippocampus favoring GLUT4 production.

Imoxin inhibits tunicamycin-induced endoplasmic reticulum stress and restores insulin signaling in C2C12 myotubes.

Prolonged endoplasmic reticulum (ER) stress can mediate inflammatory myopathies and insulin signaling pathways. The double-stranded RNA (dsRNA)-activated protein kinase R (PKR) has been implicated in skeletal muscle dysfunction. However, pathological roles of PKR in ER stress in muscle are not fully understood. The current study aimed to investigate the effect of imoxin (IMX), a selective PKR inhibitor, on tunicamycin (TN)-induced promotion of ER stress and suppression of insulin signaling in C2C12 myotubes. Cells were pretreated with 5 µM IMX for 1 h and exposed to 0.5 µg/mL TN for 23 h. A subset of cells was stimulated with 100 nM insulin for the last 15 min. mRNA expression and protein levels involved in ER stress were measured by RT-PCR and Western blotting, respectively. TN significantly augmented PKR phosphorylation by 231%, which was prevented by IMX. In addition, IMX reduced mRNA and protein levels of ER stress-related markers, including CCAAT-enhancer-binding protein homologous protein (CHOP, mRNA: 95% decrease; protein: 98% decrease), activating transcription factor 4 (ATF4, mRNA: 69% decrease; protein: 99% decrease), cleavage of ATF6, and spliced X-box-binding protein 1 (XBP-1s, mRNA: 88% decrease; protein: 79% decrease), which were induced by TN. Furthermore, IMX ameliorated TN-induced suppression of phospho-insulin receptor β (317% increase) and Akt phosphorylation (by 36% at Ser473 and 30% at Thr308) in myotubes, while augmenting insulin-stimulated AS160 phosphorylation and glucose uptake (by ∼30%). These findings suggest that IMX may protect against TN-induced skeletal muscle ER stress and insulin resistance, which are potentially mediated by PKR.

Bardet-Biedl syndrome proteins regulate intracellular signaling and neuronal function in patient-specific iPSC-derived neurons

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and is characterized by hyperphagic obesity. To investigate the molecular basis of obesity in human BBS, we developed a cellular model of BBS using induced pluripotent stem cell-derived (iPSC-derived) hypothalamic arcuate-like neurons. BBS mutations BBS1M390R and BBS10C91fsX95 did not affect neuronal differentiation efficiency but caused morphological defects, including impaired neurite outgrowth and longer primary cilia. Single-cell RNA sequencing of BBS1M390R hypothalamic neurons identified several downregulated pathways, including insulin and cAMP signaling and axon guidance. Additional studies demonstrated that BBS1M390R and BBS10C91fsX95 mutations impaired insulin signaling in both human fibroblasts and iPSC-derived neurons. Overexpression of intact BBS10 fully restored insulin signaling by restoring insulin receptor tyrosine phosphorylation in BBS10C91fsX95 neurons. Moreover, mutations in BBS1 and BBS10 impaired leptin-mediated p-STAT3 activation in iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling. POMC expression and neuropeptide production were decreased in BBS1M390R and BBS10C91fsX95 iPSC-derived hypothalamic neurons. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBSome in CNS primary cilia mediate effects on energy homeostasis.

Drosophila insulin receptor regulates diabetes-induced mechanical nociceptive hypersensitivity.

Painful diabetic neuropathy (PDN) is one of the predominant complications of diabetes that causes numbness, tingling, and extreme pain sensitivity. Understanding the mechanisms of PDN pathogenesis is important for patient treatments. Here we report Drosophila models of diabetes-induced mechanical nociceptive hypersensitivity. Type 2 diabetes-like conditions and loss of insulin receptor function in multidendritic sensory neurons lead to mechanical nociceptive hypersensitivity. Furthermore, we also found that restoring insulin signaling in multidendritic sensory neurons can block diabetes-induced mechanical nociceptive hypersensitivity. Our work highlights the critical role of insulin signaling in nociceptive sensory neurons in the regulation of diabetes-induced nociceptive hypersensitivities.

NGBR is required to ameliorate type 2 diabetes in mice by enhancing insulin sensitivity

The reduction of insulin resistance or improvement of insulin sensitivity is the most effective treatment for type 2 diabetes (T2D). We previously reported that Nogo-B receptor (NGBR), encoded by the NUS1 gene, is required for attenuating hepatic lipogenesis by blocking nuclear translocation of liver X receptor alpha, suggesting its important role in regulating hepatic lipid metabolism. Herein, we demonstrate that NGBR expression was decreased in the liver of obesity-associated T2D patients and db/db mice. NGBR knockout in mouse hepatocytes resulted in increased blood glucose, insulin resistance, and beta-cell loss. High-fat diet (HFD)/streptozotocin (STZ)-treated mice presented the T2D phenotype by showing increased nonesterified fatty acid (NEFA) and triglyceride (TG) in the liver and plasma and increased insulin resistance and beta-cell loss. AAV-mediated NGBR overexpression in the liver reduced NEFA and TG in the liver and circulation and improved liver functions. Consequently, HFD/STZ-treated mice with hepatic NGBR overexpression had increased insulin sensitivity and reduced beta-cell loss. Mechanistically, NGBR overexpression restored insulin signaling of AMPKα1-dependent phosphorylation of AKT and GSK3β. NGBR overexpression also reduced expression of endoplasmic reticulum stress-associated genes in the liver and skeletal muscle to improve insulin sensitivity. Together, our results reveal that NGBR is required to ameliorate T2D in mice, providing new insight into the role of hepatic NGBR in insulin sensitivity and T2D treatment.

Cyanidin-3-O-glucoside restores insulin signaling and reduces inflammation in hypertrophic adipocytes

Obesity is a metabolic disorder characterized by excess adipose tissue, macrophages infiltration, and inflammation which in turn lead to insulin-resistance. Epidemiological evidences reported that anthocyanins possess not only high antioxidant and antiinflammatory activities, but also improve metabolic complications associated with obesity. The aim of this work was to evaluate the in vitro beneficial effects of cyanidin-3-O-glucoside (C3G) in counteracting inflammation and insulin-resistance in 3T3-L1 hypertrophic adipocytes exposed to palmitic acid (PA). In the present study murine 3T3-L1 adipocytes were pretreated with C3G for 24 h and then exposed to palmitic acid (PA) for 24 h. Real‐time PCR, western blotting analysis and Oil Red O staining were applied for investigating the mechanism involved in adipocytes dysfunction. C3G pretreatment reduced lipid accumulation, PPARγ pathway and NF-κB pathway induced by PA in murine adipocytes. In addition, our data demonstrated that PA reduced insulin signaling via IRS-1 Ser307phosphorylation while C3G dose-dependently improved insulin sensitivity restoring IRS-1/PI3K/Akt pathway. Furthermore, C3G improved adiponectin mRNA levels altered by PA in 3T3-L1 murine and SGBS human adipocytes. Herein reported data demonstrate that C3G ameliorated adipose tissue dysfunction, thus suggesting new potential roles for this compound of nutritional interest in the prevention of pathological conditions linked to obesity.

DPP-4 inhibition resembles exercise in preventing type 2 diabetes development by inhibiting hepatic protein kinase Cε expression in a mouse model of hyperinsulinemia.

ObjectiveInterventions for hyperinsulinemia (HINS), an early indicator of type 2 diabetes mellitus (T2DM), can significantly reduce the T2DM risk. This study aims to determine how dipeptidyl peptidase-4 (DPP-4) inhibition prevents HINS progression to T2DM through ameliorating hepatic steatosis.MethodsKKay mice were used as a HINS model and they underwent exercise or received a DPP-4 inhibitor, MK0626. Hepatic steatosis was examined and liver diacylglycerol levels were determined. Human hepatic cells (LO2) were treated with MK0626 or transfected with DPP-4 siRNA. Protein kinase C ε isoform (PKCε) and DPP-4 expression and insulin receptor substrate 1 (IRS-1) phosphorylation were assessed using immunohistochemistry and western blot.ResultsKKay mice developed HINS spontaneously at 7 weeks of age. Similar to exercise, MK0626 ameliorated hepatic steatosis and reduced the liver triglyceride and diacylglycerol content. Both exercise and MK0626 suppressed diacylglycerol-induced PKCε expression and restored insulin signaling, which was shown by tyrosine phosphorylation of IRS-1, in the livers of KKay mice. Additionally, silencing DPP-4 or MK0626 treatment decreased PKCε expression in LO2 cells.ConclusionsOur data demonstrate that DPP-4 inhibition resembles exercise and effectively delays T2DM onset by suppressing hepatic PKCε expression in the HINS mouse model.

Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice

ObjectiveRecent evidence suggests the substantial pathogenic role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in the development of low-grade chronic inflammatory response, known as “metaflammation,” which contributes to obesity and type 2 diabetes. In this study, we investigated the effects of the JAK1/2 inhibitor baricitinib, recently approved for the treatment of rheumatoid arthritis, in a murine high-fat-high sugar diet model. MethodsMale C57BL/6 mice were fed with a control normal diet (ND) or a high-fat-high sugar diet (HD) for 22 weeks. A sub-group of HD fed mice was treated with baricitinib (10 mg/kg die, p.o.) for the last 16 weeks (HD + Bar). ResultsHD feeding resulted in obesity, insulin-resistance, hypercholesterolemia and alterations in gut microbial composition. The metabolic abnormalities were dramatically reduced by chronic baricitinib administration. Treatment of HD mice with baricitinib did not change the diet-induced alterations in the gut, but restored insulin signaling in the liver and skeletal muscle, resulting in improvements of diet-induced myosteatosis, mesangial expansion and associated proteinuria. The skeletal muscle and renal protection were due to inhibition of the local JAK2-STAT2 pathway by baricitinib. We also demonstrated that restored tissue levels of JAK2-STAT2 activity were associated with a significant reduction in cytokine levels in the blood. ConclusionsIn summary, our data suggest that the JAK2-STAT2 pathway may represent a novel candidate for the treatment of diet-related metabolic derangements, with the potential for EMA- and FDA-approved JAK inhibitors to be repurposed for the treatment of type 2 diabetes and/or its complications.

Loss of CD36 impairs hepatic insulin signaling by enhancing the interaction of PTP1B with IR.

A contradictory role of CD36 in insulin resistance was found to be related to the nutrient state. Here, we examined that the physiological functions of CD36 in insulin signal transduction in mice fed a low-fat diet. CD36 deficiency led to hepatic insulin resistance and decreased insulin-stimulated tyrosine phosphorylation of insulin receptor β (IRβ) in mice fed a low-fat diet. The ability of insulin to bind with IR did not differ between WT and CD36-deficient hepatocytes. CD36 formed a complex with IRβ and dissociation of CD36/Fyn complex or inhibition of Fyn only partially reversed the effects of CD36 on hepatic insulin signaling. Furthermore, we found that CD36 deficiency led to abnormally increased hepatic protein-tyrosine phosphatase 1B (PTP1B) expression and enhanced PTP1B and IR interactions, which contributed to the decreased insulin signaling and disordered glucose metabolism. In addition, increased endoplasmic reticulum (ER) stress was found in the livers of the CD36-deficient mice, while inhibited ER stress normalized the PTP1B expression and restored insulin signaling in the CD36-deficient mice. Our findings suggest that the loss of CD36 impairs hepatic insulin signaling by enhancing the PTP1B/IR interaction that is induced by ER stress, indicating a possible critical step in the progression of hepatic insulin resistance.

Highly bioavailable Berberine formulation improves Glucocorticoid Receptor-mediated Insulin Resistance via reduction in association of the Glucocorticoid Receptor with phosphatidylinositol-3-kinase.

Excess glucocorticoid (GC) production is known to induce obesity and insulin resistance through increased activation of the glucocorticoid receptor (GR). The molecular mechanism for the non-genomic effects of excessive circulating GC on the insulin-signalling pathway in skeletal muscle is unknown. The plant alkaloid berberine has been shown to attenuate insulin resistance and inhibit gluconeogenesis in type 2 diabetic animals. A highly bioavailable berberine formulation termed Huang-Gui solid dispersion (HGSD), is a preparation of berberine coupled to sodium caprate and this markedly improving berberines bioavailability. Here we examined how HGSD treatment attenuated GR-mediated alteration in PI3K signalling and insulin resistance in diabetic rats, dexamethasone-treated mice and in insulin resistant C2C12 skeletal muscle cells. Blood glucose and skeletal muscle GC levels were increased and insulin signalling impaired in skeletal muscle of type 2 diabetic rats compared to controls. Treatment of these animals with HGSD restored blood glucose and skeletal muscle GC levels to that of controls. Insulin resistant C2C12 skeletal muscle cells exhibited impaired insulin signalling compared to controls and treatment of HGSD and RU486, an antagonist of GR, restored insulin signalling to that of control cells. Administration of dexamethasone to mice increased GR/GRα-associated PI3K and reduced IRS1-associated PI3K, phosphorylated-AKT, and membrane GLUT4 translocation resulting in a higher blood glucose concentration compared to controls. HGSD treatment of these mice improved insulin resistance by reducing the association of GR/GRα with PI3K. Excess GC-induced insulin resistance is mediated by increased association of GR with PI3K and treatment with HGSD attenuates these effects. We hypothesize that HGSD may be a promising candidate drug for the treatment of type 2 diabetes by reducing the association of GR with PI3K in skeletal muscle.

Melatonin attenuates streptozotocin-induced Alzheimer-like features in hyperglycemic rats

Diabetes mellitus (DM) is increasingly recognized as a risk for developing of Alzheimer's disease (AD). Accordingly, it has been reported that melatonin level is disturbed in both DM and AD which indicates its involvement in the pathophysiology of these diseases. In this study, the neuroprotective activities and relevant mechanisms of melatonin were evaluated in diabetic rat model. Rats were subcutaneously injected with melatonin (10 mg/kg) for 42 consecutive days. Single dose of streptozotocin (60 mg/kg STZ) was intraperitoneally injected. Morris water maze, Western blot and immunohistochemistry analysis of proteins in the hippocampus were measured. We found that melatonin was effective in protecting against memory impairment and decreased formation of Aβ42 peptide and phosphorylated tau in the hippocampus of STZ-treated rats. Melatonin significantly restored the reduction in phospho-insulin receptor β (p-IRβ) and ameliorated the increase of inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) in STZ-treated rats. Furthermore, it restored the phosphorylation of glycogen synthase kinase 3β (GSK3β), indicating a decreased activity of GSK3β. Melatonin prevented amyloidogenic processing of β-amyloid precursor protein (βAPP) by significantly inhibited β-site APP cleaving enzyme (BACE1), presenilin 1 (PS1), and β-cleaved C-terminal fragment (C99). In conclusion, melatonin ameliorates memory deficits in STZ-induced hyperglycemia rats by restoring insulin signaling pathway which is independent of its effects on blood glucose and insulin levels. Thus, melatonin might be a therapeutic option for helping patients suffering from diabetes and contributed to Alzheimer's disease.