Obesity, diabetes and insulin resistance. Alterations of insulin signalling

Obesity is often associated with diabetes and insulin resistance. This review summarizes evidence obtained in our lab on the role of the serine phosphorylation of the insulin receptor substrate 1 in the down regulation of insulin signalling. The role of the ERK1 isoform in the development of adipose tissue and insulin sensitivity is also presented.     

Obesity, insulin resistance, and skeletal muscle nitric oxide synthase

The molecular mechanisms responsible for impaired insulin action have yet to be fully identified. Rodent models demonstrate a strong relationship between insulin resistance and an elevation in skeletal muscle inducible nitric oxide synthase (iNOS) expression; the purpose of this investigation was to explore this potential relationship in humans. Sedentary men and women were recruited to participate (means ± SE: nonobese, body mass index = 25.5 ± 0.3 kg/m(2), n = 13; obese, body mass index = 36.6 ± 0.4 kg/m(2), n = 14). Insulin sensitivity was measured using an intravenous glucose tolerance test with the subsequent modeling of an insulin sensitivity index (S(I)). Skeletal muscle was obtained from the vastus lateralis, and iNOS, endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) content were determined by Western blot. S(I) was significantly lower in the obese compared with the nonobese group (～43%; P < 0.05), yet skeletal muscle iNOS protein expression was not different between nonobese and obese groups. Skeletal muscle eNOS protein was significantly higher in the nonobese than the obese group, and skeletal muscle nNOS protein tended to be higher (P = 0.054) in the obese compared with the nonobese group. Alternative analysis based on S(I) (high and low tertile) indicated that the most insulin-resistant group did not have significantly more skeletal muscle iNOS protein than the most insulin-sensitive group. In conclusion, human insulin resistance does not appear to be associated with an elevation in skeletal muscle iNOS protein in middle-aged individuals under fasting conditions.     

Possible implications of insulin resistance and glucose metabolism in Alzheimer's disease pathogenesis

Type 2 diabetes mellitus (DM) appears to be a significant risk factor for Alzheimer disease (AD). Insulin and insulin-like growth factor-1 (IGF-1) also have intense effects in the central nervous system (CNS), regulating key processes such as neuronal survival and longevity, as well as learning and memory. Hyperglycaemia induces increased peripheral utilization of insulin, resulting in reduced insulin transport into the brain. Whereas the density of brain insulin receptor decreases during age, IGF-1 receptor increases, suggesting that specific insulin-mediated signals is involved in aging and possibly in cognitive decline. Molecular mechanisms that protect CNS neurons against β-amyloid-derived-diffusible ligands (ADDL), responsible for synaptic deterioration underlying AD memory failure, have been identified. The protection mechanism does not involve simple competition between ADDLs and insulin, but rather it is signalling dependent down-regulation of ADDL-binding sites. Defective insulin signalling make neurons energy deficient and vulnerable to oxidizing or other metabolic insults and impairs synaptic plasticity. In fact, destruction of mitochondria, by oxidation of a dynamic-like transporter protein, may cause synapse loss in AD. Moreover, interaction between Aβ and τ proteins could be cause of neuronal loss. Hyperinsulinaemia as well as complete lack of insulin result in increased τ phosphorylation, leading to an imbalance of insulin-regulated τ kinases and phosphatates. However, amyloid peptides accumulation is currently seen as a key step in the pathogenesis of AD. Inflammation interacts with processing and deposit of β-amyloid. Chronic hyperinsulinemia may exacerbate inflammatory responses and increase markers of oxidative stress. In addition, insulin appears to act as 'neuromodulator', influencing release and reuptake of neurotransmitters, and improving learning and memory. Thus, experimental and clinical evidence show that insulin action influences cerebral functions. In this paper, we reviewed several mechanisms by which insulin may affect pathophysiology in AD.     

Causal associations of sarcopenia-related traits with cardiometabolic disease and Alzheimer's disease and the mediating role of insulin resistance: A Mendelian randomization study

The causal influence of sarcopenia on cardiometabolic disease and Alzheimer's disease and whether and to what extent insulin resistance plays a mediating role therein were unclear. We performed two-step, two-sample Mendelian randomization applying genetic instruments of sarcopenia-related traits based on GWASs from the UK Biobank (up to 461,026 European participants) to examine their causal associations with six cardiometabolic diseases and Alzheimer's disease extracted from large-scale European descent GWASs with adjustment for body fat percentage and physical activity, and to assess proportions of the causal effects mediated by insulin resistance. Genetic instruments of insulin resistance were derived from the GWASs by Meta-Analyses of Glucose and Insulin-related traits Consortium and Global Lipids Genetics Consortium. Each 1-SD lower grip strength, appendicular lean mass (ALM) and whole-body lean mass (WBLM), as well as lower walking pace, were causally associated with higher risks of diabetes (odds ratio [OR] range: 1.20 [95% confidence interval: 1.10–1.32] for ALM to 2.30 [1.14–4.68] for walking pace), nonalcoholic fatty liver disease ([NAFLD], 1.33 [1.08–1.64] for ALM to 2.30 [1.02–5.18] for grip strength), hypertension (1.12 [1.05–1.20] for ALM to 4.43 [2.68–7.33] for walking pace), coronary heart disease ([CHD], 1.20 [1.13–1.27] for ALM to 2.73 [1.84–4.05] for walking pace), myocardial infarction ([MI], 1.18 [1.11–1.25] for ALM to 2.47 [1.63–3.73] for walking pace), small vessel stroke (1.25 [1.15–1.37] for ALM to 1.29 [1.10–1.52] for WBLM), and Alzheimer's disease (1.10 [1.05–1.15] for ALM to 1.28 [1.19–1.38] for WBLM). These causal associations were largely independent of body fat percentage and physical activity. Insulin resistance mediated 16%–34% of the effect of grip strength and 7%–28% of the effect of ALM on diabetes, NAFLD, hypertension, CHD, and MI. The direct effect of WBLM on diabetes diminished toward null with adjustment for insulin resistance. We found no evidence that insulin resistance was on the causal pathways from walking pace to the studied disease outcomes. Causal findings from the inverse-variance weighted method were validated by sensitivity analyses. These findings support improving sarcopenia-related traits as precautions against major cardiometabolic diseases and Alzheimer's disease, with particular emphasis on insulin resistance as a target in the intervention of sarcopenia-related cardiometabolic risk.     

Obesity accelerates cognitive decline by aggravating mitochondrial dysfunction,insulin resistance and synaptic dysfunction under estrogen-deprived conditions

Chronic consumption of a high-fat diet (HF) causes peripheral insulin resistance, brain insulin resistance, brain mitochondrial dysfunction and cognitive impairment. Estrogen deprivation has also been found to impair cognition. However, the combined effect of both conditions on the brain is unclear. We hypothesized that estrogen deprivation causes brain insulin resistance, brain mitochondrial dysfunction, hippocampal synaptic dysfunction and cognitive impairment, and that consumption of a HF accelerates these impairments in an estrogen-deprived condition. Seventy-two female rats were divided into sham (S) and ovariectomized (O) groups. Rats in each group were further divided into two subgroups to be fed with either a normal diet (ND) or HF for 4, 8 and 12 weeks. At the end of each period, the Morris water maze test was carried out, after which the blood and brain were collected for metabolic and brain function analysis. Obesity, peripheral insulin resistance, increased brain oxidative stress and hippocampal synaptic dysfunction were observed at the eighth week in the NDO, HFS and HFO rats. However, these impairments were worse in the HFO rats. Interestingly, brain insulin resistance, brain mitochondrial dysfunction and cognitive impairment developed earlier (week eight) in the HFO rats, whereas these conditions were observed later at week 12 in the NDO and HFS rats. Either estrogen deprivation or HF appears to cause peripheral insulin resistance, increased brain oxidative stress, hippocampal synaptic dysfunction, brain mitochondrial dysfunction and brain insulin resistance, which together can lead to cognitive impairment. A HF accelerates and aggravates these deleterious effects under estrogen-deprived conditions.     

Obesity and cancer,a case for insulin signaling

Obesity is a worldwide epidemic, with the number of overweight and obese individuals climbing from just over 500 million in 2008 to 1.9 billion in 2014. Type 2 diabetes (T2D), cardiovascular disease and non-alcoholic fatty liver disease have long been associated with the obese state, whereas cancer is quickly emerging as another pathological consequence of this disease. Globally, at least 2.8 million people die each year from being overweight or obese. It is estimated that by 2020 being overweight or obese will surpass the health burden of tobacco consumption. Increase in the body mass index (BMI) in overweight (BMI>25 kg/m²) and obese (BMI>30 kg/m²) individuals is a result of adipose tissue (AT) expansion, which can lead to fat comprising >50% of the body weight in the morbidly obese. Extensive research over the last several years has painted a very complex picture of AT biology. One clear link between AT expansion and etiology of diseases like T2D and cancer is the development of insulin resistance (IR) and hyperinsulinemia. This review focuses on defining the link between obesity, IR and cancer.     

Obesity potentiates development of fatty liver and insulin resistance, but not atherosclerosis, in high-fat diet-fed agouti LDLR-deficient mice

Obesity is increasing at an alarming rate, and its related disorders are placing a considerable strain on our healthcare system. Although they are not always coincident, obesity is often accompanied by hyperlipidemia. Both obesity and hyperlipidemia are independently associated with atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and insulin resistance (IR). Thus, we sought to determine the relative contributions of obesity and hyperlipidemia to these associated pathologies. Obese agouti (A(y)/a) mice and their littermate controls (a/a) were placed on an LDL receptor (LDLR)(-/-) background. At 4 mo of age, mice were either maintained on chow diet (CD) or placed on Western diet (WD) for 12 wk. These genetic and dietary manipulations yielded four experimental groups: 1) lean, a/a;LDLR(-/-)CD; 2) genetic-induced obesity (GIO), A(y)/a;LDLR(-/-)CD; 3) diet-induced obesity (DIO), a/a;LDLR(-/-)WD; and 4) genetic- plus diet-induced obesity (GIO/DIO), A(y)/a;LDLR(-/-)WD. Lipoprotein profiles revealed increased VLDL and LDL particles in WD-fed mice compared with CD-fed controls. The hyperlipidemia present in this mouse model was the result of both increased hepatic triglyceride production and delayed lipoprotein clearance from the plasma. Both WD-fed groups exhibited similar levels of atherosclerotic lesion area, with increased obesity in the GIO/DIO group having no impact on atherogenesis. However, the severe obesity in the GIO/DIO group did aggravate NAFLD and IR. These findings suggest that, although obesity and hyperlipidemia exert individual pathological effects, the combination of the two has the potential to exert an additive effect on NAFLD and IR but not atherosclerosis in this mouse model.     

Phosphorylation of IRS proteins, insulin action, and insulin resistance

Insulin signaling at target tissues is essential for growth and development and for normal homeostasis of glucose, fat, and protein metabolism. Control over this process is therefore tightly regulated. It can be achieved by a negative feedback control mechanism whereby downstream components inhibit upstream elements along the insulin-signaling pathway (autoregulation) or by signals from apparently unrelated pathways that inhibit insulin signaling thus leading to insulin resistance. Phosphorylation of insulin receptor substrate (IRS) proteins on serine residues has emerged as a key step in these control processes under both physiological and pathological conditions. The list of IRS kinases implicated in the development of insulin resistance is growing rapidly, concomitant with the list of potential Ser/Thr phosphorylation sites in IRS proteins. Here, we review a range of conditions that activate IRS kinases to phosphorylate IRS proteins on "hot spot" domains. The flexibility vs. specificity features of this reaction is discussed and its characteristic as an "array" phosphorylation is suggested. Finally, its implications on insulin signaling, insulin resistance and type 2 diabetes, an emerging epidemic of the 21st century are outlined.     

Tau, tangles, and Alzheimer's disease

Neurofibrillary tangles (NFT) are comprised of the microtubule-associated protein tau, in the form of filamentous aggregates. In addition to the well-known changes in phosphorylation state, tau undergoes multiple truncations and shifts in conformation as it transforms from an unfolded monomer to the structured polymer characteristic of NFT. Truncations at both the amino- and carboxy-termini directly influence the conformation into which the molecule folds, and hence the ability of tau to polymerize into fibrils. Certain of these truncations may be due to cleavage by caspases as part of the apoptotic cascade. In this review, we discuss evidence that strongly suggests that these truncations occur in an orderly pattern and directly influence the ability of tau to polymerize into filaments.     

Obesity, lipoproteins, and heart disease.

Studies of lipoproteins in this homogenous study population indicate clear and consistent associations between obesity and abnormalities in lipoproteins. These include both increases in VLDL and lower HDL, which were observed in both men and women. A high production of total body cholesterol in obese subjects, probably associated with increased flux of glucose and free fatty acids, leads to a greater production of VLDL. This, in turn, creates a greater flux of metabolic products of VLDL either back to the liver or through LDL. Obesity induces an increase in hepatic lipase, perhaps in women because of lower estrogen levels, which is associated with lower HDL concentrations, and altered HDL composition. Several of these observed changes, such as the greater proportion of VLDL remnants, the greater flux of particles through the LDL compartment, and the altered HDL composition, may be associated with increased atherosclerosis. However, preliminary data do not show a relationship between obesity and death from coronary heart disease in this population. More studies are needed to resolve this apparent conflict.     

Genes, models and Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder that is claiming an increasing number of victims as the world population ages. The identification of gene mutations and polymorphisms that either cause AD or significantly increase the risk for developing it enabled the creation of a whole generation of realistic rodent models of the disease. Animals expressing mutated human amyloid precursor protein and presenilin 1 show dramatic parallels to AD, although none of the models appear to capture the full range of pathologies that characterize the human disease. Increased refinement of these models will enhance the already tantalizing possibility of treatment.     

Obesity, adiponectin and vascular inflammatory disease

PURPOSE OF REVIEW: Obesity is the most common risk factor for cardiovascular diseases in industrial countries. It is now clear that adipose tissue secretes various bioactive substances, conceptualized as adipocytokines, and that dysregulation of adipocytokines directly contributes to obesity-related diseases. Chronic inflammatory processes contribute to the development of atherosclerosis. In this review, the authors focus on the relationship between adiponectin, a recently discovered anti-atherogenic adipocytokine, and vascular inflammation. RECENT FINDINGS: Plasma concentrations of adiponectin, an adipocyte-specific protein, are reduced in obese subjects and in patients with type 2 diabetes and coronary artery disease. Adiponectin inhibits the expression of tumor necrosis factor-alpha-induced endothelial adhesion molecules, macrophage-to-foam cell transformation, tumor necrosis factor-alpha expression in macrophages and adipose tissues, and smooth muscle cell proliferation. In addition, adenovirus-expressed adiponectin reduces atherosclerotic lesions in a mouse model of atherosclerosis, and adiponectin-deficient mice exhibit an excessive vascular remodeling response to injury. Clinically, hypoadiponectinemia is closely associated with increased levels of inflammatory markers such as C-reactive protein and interleukin-6. SUMMARY: Adiponectin acts as an anti-inflammatory and anti-atherogenic plasma protein. Adiponectin is an endogenous biologically relevant modulator of vascular remodeling linking obesity and vascular disease.     

Gene variants, insulin resistance, and dyslipidaemia

PURPOSE OF REVIEW: Both insulin resistance and dyslipidaemia are determined by genetic and environmental factors. Depending on their expression and their function, gene variants (mutations, polymorphisms) can primarily regulate either insulin action or dyslipidaemia. The purpose of this review is to give some examples from recent studies on gene variants regulating primarily insulin signalling or lipoprotein metabolism. RECENT FINDINGS: Common polymorphisms in the PC-1, insulin receptor substrate 1 and 2, and PPAR-gamma 2 genes have been linked to insulin resistance and dyslipidaemia, although the results have not been consistent. However, the Pro12Pro genotype of the PPAR-gamma 2 gene has been consistently associated with insulin resistance and the risk of type 2 diabetes. Promoter polymorphisms in the hepatic lipase gene, the 54Thr allele of the fatty acid binding protein 2 gene, and genes regulating LDL particle size have been associated with lipid metabolism, but on the other hand their association with insulin resistance is not consistent. SUMMARY: Although results have not always been consistent, gene variants affecting primary insulin action or dyslipidaemia, and particularly their interaction with the environment, are important modulators of glucose and lipoprotein metabolism.     

Brain aging, Alzheimer's disease, and mitochondria

The relationship between brain aging and Alzheimer's disease (AD) is contentious. One view holds AD results when brain aging surpasses a threshold. The other view postulates AD is not a consequence of brain aging. This review discusses this conundrum from the perspective of different investigative lines that have tried to address it, as well as from the perspective of the mitochondrion, an organelle that appears to play a role in both AD and brain aging. Specific issues addressed include the question of whether AD and brain aging should be conceptually lumped or split, the extent to which AD and brain aging potentially share common molecular mechanisms, whether beta amyloid should be primarily considered a marker of AD or simply brain aging, and the definition of AD itself.     

Thiazolidinediones, dyslipidaemia and insulin resistance syndrome

Insulin resistance is known to unite several metabolic abnormalities. The associated dyslipidaemia appears to play a central role in this atherogenic syndrome. Thiazolidinediones, which are recently introduced insulin sensitizing agents, have been shown to be effective not only in reducing elevated glucose levels, but also in improving the other metabolic abnormalities that are associated with insulin resistance. The present review focuses on these potential effects of thiazolidinediones.     

Infection,systemic inflammation,and Alzheimer's disease

Alzheimer's disease (AD) is a leading cause of dementia among elderly. Yet, its etiology remains largely unclear. In this review, we summarize studies that associate systemic infection and neuroinflammation with AD, while highlighting that early-life or life-long exposure to infectious agents predisposes one to develop AD at a later age.     

Isoprenoids,small GTPases and Alzheimer's disease

The mevalonate pathway is a crucial metabolic pathway for most eukaryotic cells. Cholesterol is a highly recognized product of this pathway but growing interest is being given to the synthesis and functions of isoprenoids. Isoprenoids are a complex class of biologically active lipids including for example, dolichol, ubiquinone, farnesylpyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Early work had shown that the long-chain isoprenoid dolichol is decreased but that dolichyl phosphate and ubiquinone are elevated in brains of Alzheimer′s disease (AD) patients. Until recently, levels of their biological active precursors FPP and GGPP were unknown. These short-chain isoprenoids are critical in the post-translational modification of certain proteins which function as molecular switches in numerous signaling pathways. The major protein families belong to the superfamily of small GTPases, consisting of roughly 150 members. Recent experimental evidence indicated that members of the small GTPases are involved in AD pathogenesis and stimulated interest in the role of FPP and GGPP in protein prenylation and cell function. A straightforward prediction derived from those studies was that FPP and GGPP levels would be elevated in AD brains as compared with normal neurological controls. For the first time, recent evidence shows significantly elevated levels of FPP and GGPP in human AD brain tissue. Cholesterol levels did not differ between AD and control samples. One obvious conclusion is that homeostasis of FPP and GGPP but not of cholesterol is specifically targeted in AD. Since prenylation of small GTPases by FPP or GGPP is indispensable for their proper function we are proposing that these two isoprenoids are up-regulated in AD resulting in an over abundance of certain prenylated proteins which contributes to neuronal dysfunction.