Aberrant Insulin Signaling Research Articles

Exercise and Glycemic Control: Focus on Redox Homeostasis and Redox-Sensitive Protein Signaling.

Physical inactivity, excess energy consumption, and obesity are associated with elevated systemic oxidative stress and the sustained activation of redox-sensitive stress-activated protein kinase (SAPK) and mitogen-activated protein kinase signaling pathways. Sustained SAPK activation leads to aberrant insulin signaling, impaired glycemic control, and the development and progression of cardiometabolic disease. Paradoxically, acute exercise transiently increases oxidative stress and SAPK signaling, yet postexercise glycemic control and skeletal muscle function are enhanced. Furthermore, regular exercise leads to the upregulation of antioxidant defense, which likely assists in the mitigation of chronic oxidative stress-associated disease. In this review, we explore the complex spatiotemporal interplay between exercise, oxidative stress, and glycemic control, and highlight exercise-induced reactive oxygen species and redox-sensitive protein signaling as important regulators of glucose homeostasis.

Repurposing of Anti-Diabetic Agents for the Treatment of Cognitive Impairment and Mood Disorders.

Impairments in cognitive function represent a consistent, non-specific, and clinically significant feature in metabolic, mood, and dementing disorders. The foregoing observation is instantiated by evidence demonstrating that these disorders share pathophysiological mechanisms including, but not limited to, aberrant insulin signaling, inflammation, and glucocorticoid activity. Moreover, these mechanisms have been consistently reported to increase vulnerability to and/or exacerbate impairments in cognitive function. Notwithstanding evidence suggesting a bidirectional relationship between disturbances in the metabolic milieu, mood, and increased risk for dementia, efficacious treatments that target cognitive impairments in these populations do not presently exist. Taken together, it is proposed that anti-diabetic agents may aid the management of mood disorders and future risk for dementia through disease modification by targeting underlying pathophysiological mechanisms (e.g., aberrant metabolic function) rather than focusing solely on symptom mitigation. The current aim is to provide a brief narrative review of extant studies that report on the potential neurotherapeutic effects of anti-diabetic agents on disturbances in mood and impairments in cognitive function.

Diabetes Mellitus Induces Alzheimer's Disease Pathology: Histopathological Evidence from Animal Models.

Alzheimer’s disease (AD) is the major causative disease of dementia and is characterized pathologically by the accumulation of senile plaques (SPs) and neurofibrillary tangles (NFTs) in the brain. Although genetic studies show that β-amyloid protein (Aβ), the major component of SPs, is the key factor underlying AD pathogenesis, it remains unclear why advanced age often leads to AD. Interestingly, several epidemiological and clinical studies show that type II diabetes mellitus (DM) patients are more likely to exhibit increased susceptibility to AD. Moreover, growing evidence suggests that there are several connections between the neuropathology that underlies AD and DM, and there is evidence that the experimental induction of DM can cause cognitive dysfunction, even in rodent animal models. This mini-review summarizes histopathological evidence that DM induces AD pathology in animal models and discusses the possibility that aberrant insulin signaling is a key factor in the induction of AD pathology.

Asiaticoside attenuates diabetes-induced cognition deficits by regulating PI3K/Akt/NF-κB pathway

Diabetes-associated cognitive dysfunction, referred as “diabetic encephalopathy”, has been confirmed in a great deal of literature. Current evidence support that oxidative stress, inflammation, energy metabolism imbalance, and aberrant insulin signaling are associated with cognition deficits induced by diabetes. The present study explore the effect of asiaticoside on the cognition behaviors, synapses, and oxidative stress in diabetic rats. Asiaticoside could markedly ameliorate the performance in the Morris Water Maze (decreased latency time and path length, and increased time spent in the target quadrant), which was correlated with its capabilities of suppressing oxidative stress, restoring Na+-K+-ATPase activity and protecting hippocampal synapses. In vitro, asiaticoside could up-regulate synaptic proteins expression via modulating Phosphoinositide 3-kinase (PI3K)/Protein Kinase B(AKT)/Nuclear Factor -kappa B (NF-κB)-mediated inflammatory pathway in SH-SY5Y cells incubated with high glucose chronically. In conclusion, asiaticoside had beneficial effects on the prevention and treatment of diabetes-associated cognitive deficits, which was involved in oxidative stress, PI3K/Akt/NF-κB pathway and synaptic function in the development of cognitive decline induced by diabetes.

Aberrant insulin signaling in Alzheimer's disease: current knowledge.

Alzheimer's disease (AD) is the most common form of dementia affecting elderly people. AD is a multifaceted pathology characterized by accumulation of extracellular neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neuronal loss mainly in the cortex and hippocampus. AD etiology appears to be linked to a multitude of mechanisms that have not been yet completely elucidated. For long time, it was considered that insulin signaling has only peripheral actions but now it is widely accepted that insulin has neuromodulatory actions in the brain. Insulin signaling is involved in numerous brain functions including cognition and memory that are impaired in AD. Recent studies suggest that AD may be linked to brain insulin resistance and patients with diabetes have an increased risk of developing AD compared to healthy individuals. Indeed insulin resistance, increased inflammation and impaired metabolism are key pathological features of both AD and diabetes. However, the precise mechanisms involved in the development of AD in patients with diabetes are not yet fully understood. In this review we will discuss the role played by aberrant brain insulin signaling in AD. In detail, we will focus on the role of insulin signaling in the deposition of neuritic plaques and intracellular NFTs. Considering that insulin mitigates beta-amyloid deposition and phosphorylation of tau, pharmacological strategies restoring brain insulin signaling, such as intranasal delivery of insulin, could have significant therapeutic potential in AD treatment.

Aberrant insulin signaling results in mTOR suppression and immune dysfunction during diabetic infections. (INM7P.427)

Abstract Diabetics have defects in several aspects of immunity that result in increased infection rates; however, the underlying mechanisms of immune dysfunction are not well defined. Previous studies in this area concluded that infections in diabetics are hyper-inflamed as indicated by increased cytokine production. Conversely, despite high levels of pro-inflammatory cytokines, our research shows that innate immune cells from diabetics cannot produce inflammatory effectors such as reactive oxygen species (ROS) and nitric oxide (NO). ROS/RNS generation by immune cells is essential for killing bacteria and requires cells to undergo a metabolic shift reminiscent of Warburg metabolism. This shift is required for NADPH production, the sole reductant needed for ROS/RNS generation. Using murine infection models and cell culture, we show that Toll-like receptor signaling induces Warburg metabolism through activation of the mammalian target of rapamycin (mTOR). Moreover, we show that mTOR signaling is suppressed in diabetics and results in decreased ROS/RNS generation and worse infection outcomes. Finally, we demonstrate that mTOR inhibition in diabetes is caused by the activation of AMP-activated protein kinase (AMPK) as a result of deficient insulin signaling. Thus, diabetic infections are not hyper-inflamed. Instead, immune dysfunction in diabetic infections is caused by aberrant insulin signaling resulting in mTOR suppression and diminished antimicrobial effector production.

Muscle Mitohormesis Promotes Longevity via Systemic Repression of Insulin Signaling

Mitochondrial dysfunction is usually associated with aging. To systematically characterize the compensatory stress signaling cascades triggered in response to muscle mitochondrial perturbation, we analyzed a Drosophila model of muscle mitochondrial injury. We find that mild muscle mitochondrial distress preserves mitochondrial function, impedes the age-dependent deterioration of muscle function and architecture, and prolongs lifespan. Strikingly, this effect is mediated by at least two prolongevity compensatory signaling modules: one involving a muscle-restricted redox-dependent induction of genes that regulate the mitochondrial unfolded protein response (UPR(mt)) and another involving the transcriptional induction of the Drosophila ortholog of insulin-like growth factor-binding protein 7, which systemically antagonizes insulin signaling and facilitates mitophagy. Given that several secreted IGF-binding proteins (IGFBPs) exist in mammals, our work raises the possibility that muscle mitochondrial injury in humans may similarly result in the secretion of IGFBPs, with important ramifications for diseases associated with aberrant insulin signaling.

Ski Overexpression in Skeletal Muscle Modulates Genetic Programs That Control Susceptibility to Diet‐Induced Obesity and Insulin Signaling

Transgenic mice overexpressing chicken Ski (c-Ski) have marked decrease in adipose mass with skeletal muscle hypertrophy. Recent evidence indicates a role for c-Ski in lipogenesis and energy expenditure. In the present study, wild type (WT) and c-Ski mice were challenged on a high-fat (HF) diet to determine whether c-Ski mice were resistant to diet-induced obesity. During the HF feeding WT mice gained significantly more weight than chow-fed animals, while c-Ski mice were partially resistant to the effects of the HF diet on weight. Body composition analysis confirmed the decreased adipose mass in c-Ski mice compared to WT mice. c-Ski mice possess a similar metabolic rate and level of food consumption to WT littermates, despite lower activity levels and on chow diet show mild glucose intolerance relative to WT littermates. On HF diet, glucose tolerance surprisingly remained unchanged in c-Ski mice, while it became worse in WT mice. Skeletal muscle of c-Ski mice exhibit impaired insulin-stimulated Akt phosphorylation and glucose uptake. In concordance, gene expression profiling of skeletal muscle of chow and HF-fed mice indicated that Ski suppresses gene expression associated with insulin signaling and glucose uptake and alters gene pathways involved in myogenesis and adipogenesis. In conclusion, c-Ski mice are partially resistant to diet-induced obesity and display aberrant insulin signaling and glucose homeostasis which is associated with alterations in gene expression that inhibit lipogenesis and insulin signaling. These results suggest Ski plays a major role in skeletal muscle metabolism and adipogenesis and hence influences risk of obesity and diabetes.

The Diabetes Drug Liraglutide Ameliorates Aberrant Insulin Receptor Localisation and Signalling in Parallel with Decreasing Both Amyloid-β Plaque and Glial Pathology in a Mouse Model of Alzheimer’s Disease

Alzheimer's disease (AD) has been shown to involve desensitised insulin receptor (IR) signalling. Liraglutide, a novel glucagon-like peptide 1 (GLP-1) analogue that facilitates insulin signalling, is currently approved for use in type 2 diabetes mellitus. In the present study, we show that distinctive alterations in the localisation and distribution of the IR and increased levels of insulin receptor substrate (IRS)-1 phosphorylated at serine 616 (IRS-1 pS(616)), a key marker of insulin resistance, are associated with amyloid-β plaque pathology in the frontal cortex of a mouse model of AD, APPSWE/PS1dE9. Altered IR status in APPSWE/PS1dE9 is most evident in extracellular deposits with the appearance of dystrophic neurites, with significantly increased IRS-1 pS(616) levels detected within neurons and neurites. The IR and IRS-1 pS(616) changes occur in the vicinity of all plaques in the APPSWE/PS1dE9 brain, and a significant upregulation of astrocytes and microglia surround this pathology. We show that liraglutide treatment for 8weeks at 25nmol/kg body weight i.p. once daily in 7-month-old mice significantly decreases IR aberrations in conjunction with a concomitant decrease in amyloid plaque load and levels of IRS-1 pS(616). Liraglutide also induces a highly significant reduction in astrocytosis and microglial number associated with both plaques and IR pathology. The amelioration of IR aberrations and attenuation of IRS-1 pS(616) upregulation, plaque and glial activation in APPSWE/PS1dE9 mice treated with liraglutide support the investigation of the therapeutic potential of liraglutide and long-lasting GLP-1 agonists in patients with AD.

Coupling mitochondrial dysfunction to endoplasmic reticulum stress response: A molecular mechanism leading to hepatic insulin resistance

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are considered critical components in the development of insulin resistance and Type 2 diabetes. However, understanding the molecular mechanisms underlying these individual disorders and how they are linked has been challenging. Here, we provide evidence that elevated levels of cytosolic free Ca 2+ due to mitochondrial dysfunction and concomitant activation of p38 mitogen activated protein kinase (MAPK) induce ER stress response in human liver sk-HepI cells. Blocking Ca 2+ release from mitochondria or ER using ruthenium red or ryanodine ameliorated the increase in expression of gluconeogenic enzymes due to mitochondrial dysfunction. Disturbance in mitochondrial function results in the activation of p38 MAPK and related transcription factors that are directly responsible for increased phosphoenolpyruvate carboxykinase (PEPCK) expression. In addition, abnormal activation of c-Jun N-terminal kinase (JNK) influences the PEPCK expression by affecting insulin signaling and Forkhead box O (Foxo) 1 activity. Alleviation of ER stress response using a chemical chaperone reduces p38 MAPK activation, as well as PEPCK overexpression, indicating that ER stress response strengthens mitochondrial stress-induced abnormalities. Our results demonstrate that mitochondrial dysfunction is directly linked to the ER stress response, and together, cause aberrant insulin signaling and an abnormal increase of hepatic gluconeogenesis.

Postprandial dyslipidemia in insulin resistance: Mechanisms and role of intestinal insulin sensitivity

Insulin resistance is strongly associated with metabolic dyslipidemia, which is largely a postprandial phenomenon. Though previously regarded as a consequence of delayed triglyceride-rich lipoprotein clearance, emerging evidence present intestinal overproduction of apoB-48-containing lipoproteins as a major contributor to postprandial dyslipidemia. The majority of mechanistic information is however derived from animal models, namely the fructose-fed Syrian Golden hamster, and extension to human studies to date has been limited. Work in our laboratory has established that aberrant insulin signalling exists in the enterocyte, and that inflammation appears to induce intestinal insulin resistance. The intestine is a major site of lipid synthesis in the body, and upregulated intestinal de novo lipogenesis and cholesterogenesis have been noted in insulin resistant and diabetic states. There is also enhanced dietary lipid absorption attributable to changes in ABCG5/8, NPC1L1, CD36/FAT, and FATP4. Proteins that are involved in chylomicron assembly and secretion, including MTP, MGAT, DGAT, apoAI-V, and Sar1 GTPase, show evidence of increased expression and activity levels. Increased circulating free fatty acids, typically observed in insulin resistant states, may serve to deliver lipid substrates to the intestine for enhanced chylomicron assembly and secretion. To compound the dysregulation of intestinal lipid metabolism, there are changes in the secretion of gut-derived peptides, which include GLP-1, GLP-2, and GIP. Thus, accumulating evidence presents intestinal lipoprotein secretion as a highly regulated process that is sensitive to perturbations in whole body energy homeostasis, and is severely perturbed in insulin resistant states.

Insulin signaling in Goto‐Kakizaki rat model of type II diabetes

Aberrant insulin signaling is a hallmark of insulin resistance. Decreased phosphorylation of insulin receptor substrate (IRS‐1) proteins and Akt, in particular, results in reduced glucose uptake by the tissues thereby contributing to the insulin resistant state. We have previously shown that insulin‐mediated aortic relaxation is reduced in Goto‐Kakizaki (GK) rat model of Type II diabetes. This study tested the hypothesis that blunted insulin signaling contributes to impaired vascular function and glucose metabolism in this lean model of diabetes. In GK rats, blood glucose was higher (168 ± 5 vs. 108 ± 3 mg/dl, p<0.05) and hyperinsulinemic euglycemic clamp studies showed decreased glucose utilization indicative of insulin resistance. Assessment of total and phosphorylated (p) IRS‐1 and Akt expression in aorta, liver, and skeletal muscle showed that IRS‐1 activation (pIRS‐1/total IRS‐1) was significantly decreased in all tissues as compared to Wistar controls (n= 4–5, p<0.05). Similarly, Akt activation (pAkt/total Akt) was reduced in the aorta and the liver (p<0.05). Akt activation in skeletal muscle, however, was significantly increased in GKs (p<0.05), suggesting a possible compensatory mechanism to promote peripheral glucose utilization.

Mitochondrial dysfunction induces aberrant insulin signalling and glucose utilisation in murine C2C12 myotube cells

Mitochondrial dysfunction is considered a critical component in the development of diabetes. The aim of this study was to elucidate the molecular mechanisms involved in the development of insulin resistance and diabetes through investigation of mitochondrial retrograde signalling. Mitochondrial function of C2C12 myotube cells was impaired by genetic (ethidium bromide) and metabolic (oligomycin) stress, and changes in target molecules related to insulin signalling were analysed. Concomitant with reductions in mitochondrial membrane potential (DeltaPsim) and ATP synthesis, production of IRS1 and solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4, formerly known as GLUT4) were reduced. Moreover, serine phosphorylation of IRS1 increased, resulting in decreased tyrosine phosphorylation. This indicates that mitochondrial dysfunction decreases insulin-stimulated SLC2A4 translocation and glucose uptake. Mitochondrial stress activated c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) signalling in a Ca(2+)-dependent manner, and removal of free Ca(2+) by BAPTA-AM, as well as inhibition of JNK and p38 MAPK, abrogated mitochondrial stress-induced reductions in IRS1 and SLC2A4 production. Mitochondrial dysfunction after oligomycin treatment significantly increased levels of activating transcription factor 3 (ATF3), which represses Irs1 promoter activity. Removal of the 5' flanking region of Irs1 demonstrated that the promoter region within 191 bases from the transcription site may be involved in the transcriptional repression of Irs1 by mitochondrial stress. We show distinct mitochondrial retrograde signalling, where Irs1 is downregulated through ATF3 in a Ca(2+)-, JNK- and p38 MAPK-dependent manner, and IRS1 is inactivated. Therefore, mitochondrial dysfunction causes aberrant insulin signalling and abnormal utilisation of glucose, as observed in many insulin resistance states.

Intestinal Insulin Resistance and Aberrant Production of Apolipoprotein B48 Lipoproteins in an Animal Model of Insulin Resistance and Metabolic Dyslipidemia

Postprandial dyslipidemia is recognized as an important complication of insulin-resistant states, and recent evidence implicates intestinal lipoprotein overproduction as a causative factor. The mechanisms linking intestinal lipoprotein overproduction and aberrant insulin signaling in intestinal enterocytes are currently unknown. Intestinal insulin sensitivity and lipid metabolism were studied in a fructose-fed hamster model of insulin resistance and metabolic dyslipidemia. Intestinal lipoprotein production in chow-fed hamsters was responsive to the inhibitory effects of insulin, and a decrease in circulating levels of triglyceride-rich apolipoprotein (apo)B48-containing lipoproteins occurred 60 min after insulin administration. However, fructose-fed hamster intestine was not responsive to the insulin-induced downregulation of apoB48-lipoprotein production, suggesting insulin insensitivity at the level of the intestine. Enterocytes from the fructose-fed hamster exhibited normal activity of the insulin receptor but reduced levels of insulin receptor substrate-1 phosphorylation and mass and Akt protein mass. Conversely, the protein mass of the p110 subunit of phosphatidylinositol 3-kinase, protein tyrosine phosphatase-1B, and basal levels of phosphorylated extracellular signal-related kinase (ERK) were significantly increased in the fructose-fed hamster intestine. Modulating the ERK pathway through in vivo inhibition of mitogen-activated protein/ERK kinase 1/2, the upstream activator of ERK1/2, we observed a significant decrease in intestinal apoB48 synthesis and secretion. Interestingly, enhanced basal ERK activity in the fructose-fed hamster intestine was accompanied by an increased activation of sterol regulatory element-binding protein. In summary, these data suggest that insulin insensitivity at the level of the intestine and aberrant insulin signaling are important underlying factors in intestinal overproduction of highly atherogenic apoB48-containing lipoproteins in the insulin-resistant state. Basal activation of the ERK pathway may be an important contributor to the aberrant insulin signaling and lipoprotein overproduction in this model.

Insulin Signaling and Glucose Transport in Skeletal Muscle From First-Degree Relatives of Type 2 Diabetic Patients

Aberrant insulin signaling and glucose metabolism in skeletal muscle from type 2 diabetic patients may arise from genetic defects and an altered metabolic milieu. We determined insulin action on signal transduction and glucose transport in isolated vastus lateralis skeletal muscle from normal glucose-tolerant first-degree relatives of type 2 diabetic patients (n = 8, 41 +/- 3 years, BMI 25.1 +/- 0.8 kg/m(2)) and healthy control subjects (n = 9, 40 +/- 2 years, BMI 23.4 +/- 0.7 kg/m(2)) with no family history of diabetes. Basal and submaximal insulin-stimulated (0.6 and 1.2 nmol/l) glucose transport was comparable between groups, whereas the maximal response (120 nmol/l) was 38% lower (P < 0.05) in the relatives. Insulin increased phosphorylation of Akt and Akt substrate of 160 kDa (AS160) in a dose-dependent manner, with comparable responses between groups. AS160 phosphorylation and glucose transport were positively correlated in control subjects (R(2) = 0.97, P = 0.01) but not relatives (R(2) = 0.46, P = 0.32). mRNA of key transcriptional factors and coregulators of mitochondrial biogenesis were also determined. Skeletal muscle mRNA expression of peroxisome proliferator-activated receptor (PPAR) gamma coactivator (PGC)-1alpha, PGC-1beta, PPARdelta, nuclear respiratory factor-1, and uncoupling protein-3 was comparable between first-degree relatives and control subjects. In conclusion, the uncoupling of insulin action on Akt/AS160 signaling and glucose transport implicates defective GLUT4 trafficking as an early event in the pathogenesis of type 2 diabetes.

Upper abdominal obesity, insulin resistance and breast cancer risk.

A majority of prospective studies show breast cancer risk to be higher in obese postmenopausal women with upper abdominal adiposity than in those with overall adiposity. The evidence is more limited and inconsistent in the case of premenopausal women. The review examines evidence that aberrant insulin signalling may be involved in the promotion of mammary carcinogenesis. The aetiology and concomitants of abdominal visceral obesity are examined. Clinical and experimental evidence suggests that the higher breast cancer risk associated with greater abdominal visceral obesity may be related to aberrant insulin signalling through the insulin receptor substrate 1 pathway, leading to insulin resistance, hyperinsulinaemia and increased concentrations of endogenous oestrogen and androgen. The putative role of aberrant insulin signalling in the promotion of mammary carcinogenesis may help to explain clinical relationships between breast cancer risk and age at menarche, pregnancies and onset of obesity. Overall adiposity in women adversely affects breast cancer risk mainly by greater exposure of mammary epithelial tissue to endogenous oestrogen. Upper abdominal adiposity appears to involve an additional effect related to the presence of insulin resistance. Aetiological factors in the development of hyperinsulinaemic insulin resistance are still uncertain but may involve aberrant susceptibility genes in adipocyte insulin receptors or in the insulin receptor substrate 1 pathway. Epigenetic factors are also likely to contribute, including high free fatty acid levels and obesity. Dietary fatty acids, particularly polyunsaturated fatty acids, are known to regulate adipocyte differentiation through the nuclear peroxisome proliferator-activated receptor gamma, and may also have a role in insulin resistance. These aetiological factors are likely to be relevant to the high risk of postmenopausal breast cancer in industrialised Western populations.