scholarly journals From population to neuron: exploring common mediators for metabolic problems and mental illnesses

2020 ◽  
Author(s):  
Yoichiro Takayanagi ◽  
Koko Ishizuka ◽  
Thomas M Laursen ◽  
Hiroshi Yukitake ◽  
Kun Yang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Signaling ◽  
Neuronal Cells ◽  
Population Data ◽  
Epidemiological Data ◽  
Population Based ◽  
Mental Illnesses ◽  
Insulin Stimulation ◽  
Physical Conditions ◽  
Metabolic Conditions

Major mental illnesses such as schizophrenia (SZ) and bipolar disorder (BP) frequently accompany metabolic conditions, but their relationship is still unclear, in particular at the mechanistic level. We implemented an approach of "from population to neuron", combining population-based epidemiological analysis with neurobiological experiments using cell and animal models based on a hypothesis built from the epidemiological study. We characterized high-quality population data, olfactory neuronal cells biopsied from patients with SZ or BP, and healthy subjects, as well as mice genetically modified for insulin signaling. We accessed the Danish Registry and observed (1) a higher incidence of diabetes in people with SZ or BP and (2) higher incidence of major mental illnesses in people with diabetes in the same large cohort. These epidemiological data suggest the existence of common pathophysiological mediators in both diabetes and major mental illnesses. We hypothesized that molecules associated with insulin resistance might be such common mediators, and then validated the hypothesis by using two independent sets of olfactory neuronal cells biopsied from patients and healthy controls. In the first set, we confirmed an enrichment of insulin signaling-associated molecules among the genes that were significantly different between SZ patients and controls in unbiased expression profiling data. In the second set, olfactory neuronal cells from SZ and BP patients who were not pre-diabetic or diabetic showed reduced IRS2 tyrosine phosphorylation upon insulin stimulation, indicative of insulin resistance. These cells also displayed an upregulation of IRS1 protein phosphorylation at serine-312 at baseline (without insulin stimulation), further supporting the concept of insulin resistance in olfactory neuronal cells from SZ patients. Finally, Irs2 knockout mice showed an aberrant response to amphetamine, which is also observed in some patients with major mental illnesses. The bi-directional relationships between major mental illnesses and diabetes suggest that there may be common pathophysiological mediators associated with insulin resistance underlying these mental and physical conditions.

scholarly journals Overexpression of Lnk in the Ovaries Is Involved in Insulin Resistance in Women With Polycystic Ovary Syndrome

Endocrinology ◽  
2016 ◽  
Vol 157 (10) ◽  
pp. 3709-3718 ◽  
Author(s):  
Meihua Hao ◽  
Feng Yuan ◽  
Chenchen Jin ◽  
Zehong Zhou ◽  
Qi Cao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Fluorescent Protein ◽  
Polycystic Ovary ◽  
Adaptor Protein ◽  
Sh2 Domain ◽  
Insulin Stimulation ◽  
Ovary Syndrome

Polycystic ovary syndrome (PCOS) progression involves abnormal insulin signaling. SH2 domain-containing adaptor protein (Lnk) may be an important regulator of the insulin signaling pathway. We investigated whether Lnk was involved in insulin resistance (IR). Thirty-seven women due to receive laparoscopic surgery from June 2011 to February 2012 were included from the gynecologic department of the Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University. Samples of polycystic and normal ovary tissues were examined by immunohistochemistry. Ovarian cell lines underwent insulin stimulation and Lnk overexpression. Expressed Lnk underwent coimmunoprecipitation tests with green fluorescent protein-labeled insulin receptor and His-tagged insulin receptor substrate 1 (IRS1), and their colocalization in HEK293T cells was examined. Ovarian tissues from PCOS patients with IR exhibited higher expression of Lnk than ovaries from normal control subjects and PCOS patients without IR; mainly in follicular granulosa cells, the follicular fluid and plasma of oocytes in secondary follicles, and atretic follicles. Lnk was coimmunoprecipitated with insulin receptor and IRS1. Lnk and insulin receptor/IRS1 locations overlapped around the nucleus. IR, protein kinase B (Akt), and ERK1/2 activities were inhibited by Lnk overexpression and inhibited further after insulin stimulation, whereas IRS1 serine activity was increased. Insulin receptor (Tyr1150/1151), Akt (Thr308), and ERK1/2 (Thr202/Tyr204) phosphorylation was decreased, whereas IRS1 (Ser307) phosphorylation was increased with Lnk overexpression. In conclusion, Lnk inhibits the phosphatidylinositol 3 kinase-AKT and MAPK-ERK signaling response to insulin. Higher expression of Lnk in PCOS suggests that Lnk probably plays a role in the development of IR.

Hepatic overexpression of a dominant negative form of raptor enhances Akt phosphorylation and restores insulin sensitivity in K/KAy mice

2008 ◽  
Vol 294 (4) ◽  
pp. E719-E725 ◽  
Author(s):  
Yuko Koketsu ◽  
Hideyuki Sakoda ◽  
Midori Fujishiro ◽  
Akifumi Kushiyama ◽  
Yasushi Fukushima ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Insulin Signaling ◽  
Dominant Negative ◽  
Insulin Stimulation ◽  
Kinase Activation ◽  
Akt Phosphorylation ◽  
Induce Insulin Resistance ◽  
Dominant Negative Form ◽  
Negative Form

Several serine/threonine kinases reportedly phosphorylate serine residues of IRS-1 and thereby induce insulin resistance. In this study, to investigate the effect of mTOR/raptor on insulin signaling and metabolism in K/KAy mice with genetic obesity-associated insulin resistance, a dominant negative raptor, COOH-terminally deleted raptor (raptor-ΔCT), was overexpressed in the liver via injection of its adenovirus into the circulation. Hepatic raptor-ΔCT expression levels were 1.5- to 4-fold that of endogenously expressed raptor. Glucose tolerance in raptor-ΔCT-overexpressing mice improved significantly compared with that of LacZ-overexpressing mice. Insulin-induced activation of p70S6 kinase (p70S6k) was significantly suppressed in the livers of raptor-ΔCT overexpressing mice. In addition, insulin-induced IRS-1, Ser307, and Ser636/639 phosphorylations were significantly suppressed in the raptor-ΔCT-overexpressing liver, whereas tyrosine phosphorylation of IRS-1 was increased. PI 3-kinase activation in response to insulin stimulation was increased approximately twofold, and Akt phosphorylation was clearly enhanced under both basal and insulin-stimulated conditions in the livers of raptor-ΔCT mice. Thus, our data indicate that suppression of the mTOR/p70S6k pathway leads to improved glucose tolerance in K/KAy mice. These observations may contribute to the development of novel antidiabetic agents.

scholarly journals Autotaxin Is Regulated by Glucose and Insulin in Adipocytes

Endocrinology ◽  
2017 ◽  
Vol 158 (4) ◽  
pp. 791-803 ◽  
Author(s):  
Kenneth D’Souza ◽  
Daniel A. Kane ◽  
Mohamed Touaibia ◽  
Erin E. Kershaw ◽  
Thomas Pulinilkunnil ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lysophosphatidic Acid ◽  
Insulin Signaling ◽  
Mitochondrial Respiration ◽  
Hormonal Regulation ◽  
H2o2 Production ◽  
Dependent Manner ◽  
Insulin Stimulation ◽  
Insulin Sensitizer

Abstract Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid. Despite recent studies implicating adipose-derived ATX in metabolic disorders including obesity and insulin resistance, the nutritional and hormonal regulation of ATX in adipocytes remains unclear. The current study examined the regulation of ATX in adipocytes by glucose and insulin and the role of ATX in adipocyte metabolism. Induction of insulin resistance in adipocytes with high glucose and insulin concentrations increased ATX secretion, whereas coincubation with the insulin sensitizer, rosiglitazone, prevented this response. Moreover, glucose independently increased ATX messenger RNA (mRNA), protein, and activity in a time- and concentration-dependent manner. Glucose also acutely upregulated secreted ATX activity in subcutaneous adipose tissue explants. Insulin elicited a biphasic response. Acute insulin stimulation increased ATX activity in a PI3Kinase-dependent and mTORC1-independent manner, whereas chronic insulin stimulation decreased ATX mRNA, protein, and activity. To examine the metabolic role of ATX in 3T3-L1 adipocytes, we incubated cells with the ATX inhibitor, PF-8380, for 24 hours. Whereas ATX inhibition increased the expression of peroxisome proliferator–activated receptor-γ and its downstream targets, insulin signaling and mitochondrial respiration were unaffected. However, ATX inhibition enhanced mitochondrial H2O2 production. Taken together, this study suggests that ATX secretion from adipocytes is differentially regulated by glucose and insulin. This study also suggests that inhibition of autocrine/paracrine ATX–lysophosphatidic acid signaling does not influence insulin signaling or mitochondrial respiration, but increases reactive oxygen species production in adipocytes.

scholarly journals Effects of cellular ATP depletion on glucose transport and insulin signaling in 3T3-L1 adipocytes

2001 ◽  
Vol 280 (3) ◽  
pp. E428-E435 ◽  
Author(s):  
Jione Kang ◽  
Emma Heart ◽  
Chin K. Sung
Keyword(s):  
Insulin Resistance ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Atp Depletion ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Insulin Stimulation ◽  
Glut 1 ◽  
Induce Insulin Resistance ◽  
In Cells

Glucosamine induced insulin resistance in 3T3-L1 adipocytes, which was associated with a 15% decrease in cellular ATP content. To study the role of ATP depletion in insulin resistance, we employed sodium azide (NaN3) and dinitrophenol (DNP), which affect mitochondrial oxidative phosphorylation, to achieve a similar 15% ATP depletion. Unlike glucosamine, NaN3 and DNP markedly increased basal glucose transport, and the increased basal glucose transport was associated with increased GLUT-1 content in the plasma membrane without changes in total GLUT-1 content. These agents, like glucosamine, did not affect the early insulin signaling that is implicated in insulin stimulation of glucose transport. In cells with a severe 40% ATP depletion, basal glucose transport was similarly elevated, and insulin-stimulated glucose transport was similar in cells with 15% ATP depletion. In these cells, however, early insulin signaling was severely diminished. These data suggest that cellular ATP depletion by glucosamine, NaN3, and DNP exerts differential effects on basal and insulin-stimulated glucose transport and that ATP depletion per se does not induce insulin resistance in 3T3-L1 adipocytes.

TNF-α impairs insulin signaling and insulin stimulation of glucose uptake in C2C12muscle cells

1999 ◽  
Vol 276 (5) ◽  
pp. E849-E855 ◽  
Author(s):  
Luis F. del Aguila ◽  
Kevin P. Claffey ◽  
John P. Kirwan
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Insulin Stimulation ◽  
Kinase Activation ◽  
Tnf Α ◽  
Impaired Insulin ◽  
Stimulation Of

Physiological stressors such as sepsis and tissue damage initiate an acute immune response and cause transient systemic insulin resistance. This study was conducted to determine whether tumor necrosis factor-α (TNF-α), a cytokine produced by immune cells during skeletal muscle damage, decreases insulin responsiveness at the cellular level. To examine the molecular mechanisms associated with TNF-α and insulin action, we measured insulin receptor substrate (IRS)-1- and IRS-2-mediated phosphatidylinositol 3-kinase (PI 3-kinase) activation, IRS-1-PI 3-kinase binding, IRS-1 tyrosine phosphorylation, and the phosphorylation of two mitogen-activated protein kinases (MAPK, known as p42MAPK and p44MAPK) in cultured C2C12myotubes. Furthermore, we determined the effects of TNF-α on insulin-stimulated 2-deoxyglucose (2-DG) uptake. We observed that TNF-α impaired insulin stimulation of IRS-1- and IRS-2-mediated PI 3-kinase activation by 54 and 55% ( P< 0.05), respectively. In addition, TNF-α decreased insulin-stimulated IRS-1 tyrosine phosphorylation by 40% ( P < 0.05). Furthermore, TNF-α repressed insulin-induced p42MAPKand p44MAPK tyrosine phosphorylation by 81% ( P < 0.01). TNF-α impairment of insulin signaling activation was accompanied by a decrease ( P < 0.05) in 2-DG uptake in the muscle cells (60 ± 4 vs. 44 ± 6 pmol ⋅ min−1 ⋅ mg−1). These data suggest that increases in TNF-α may cause insulin resistance in skeletal muscle by inhibiting IRS-1- and IRS-2-mediated PI 3-kinase activation as well as p42MAPK and p44MAPK tyrosine phosphorylation, leading to impaired insulin-stimulated glucose uptake.

scholarly journals Impaired insulin signaling in the liver of transgenic rats with low circulating growth hormone levels

2002 ◽  
Vol 172 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Y Furuhata ◽  
T Yonezawa ◽  
M Takahashi ◽  
M Nishihara
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Gh Deficiency ◽  
Pi3 Kinase ◽  
The Body ◽  
Transgenic Rat ◽  
Insulin Stimulation ◽  
Transgenic Rats

GH is known to regulate glucose and lipid metabolism as well as body growth. Controversy exists as to whether GH-deficient adults are indeed insulin sensitive or insulin resistant. In GH-deficient animal models, however, no clear observation indicating insulin resistance has been made, while increased insulin sensitivity has been reported in those animals. We have produced human GH (hGH) transgenic rats characterized by low circulating hGH levels and virtually no endogenous rat GH secretion. Although the body length of the transgenic rat is normal, they develop massive obesity and insulin resistance, indicating that the transgenic rat is a good model for the analysis of insulin resistance under GH deficiency. In this study, we have examined how GH deficiency affects the early steps of insulin signaling in the liver of the transgenic rat. Circulating glucose and insulin concentrations were significantly higher in the transgenic rats than in their littermates. In addition, impaired glucose tolerance was observed in the transgenic rat. The amount of insulin receptor was smaller in the liver of the transgenic rat, resulting in decreased tyrosine phosphorylation in response to insulin stimulation. The amounts of insulin receptor substrate-1 and -2 (IRS-1 and -2) and insulin-stimulated phosphorylation of IRSs were also smaller in the transgenic rat. Despite the decrease in tyrosine phosphorylation levels of IRSs being mild to moderate (45% for IRS-1 and 16% for IRS-2), associated phosphatidylinositol 3-kinase (PI3-kinase) activity was not increased by insulin stimulation at all in the transgenic rat. To elucidate whether this discrepancy resulted from the alteration in binding of the p85 subunit of PI3-kinase to phosphotyrosine residues of the IRSs, we determined the amount of p85 subunit in the immunocomplexes with anti-phosphotyrosine antibody. Insulin did not affect the amount of p85 subunit associated with phosphotyrosine in the transgenic rats, while it significantly increased in the controls, indicating that alteration may have occurred at the sites of phosphorylated tyrosine residues in IRSs. These results suggest that GH deficiency in the transgenic rat leads to impairment in at least the early steps of insulin signaling in the liver with a resultant defect in glucose metabolism.

Folate and vitamin B-12 deficiencies additively impaired memory function and disturbed the gut microbiota in amyloid-β infused rats

2019 ◽  
pp. 1-13 ◽  
Author(s):  
Sunmin Park ◽  
Sunna Kang ◽  
Da Sol Kim
Keyword(s):  
Insulin Resistance ◽  
Gut Microbiota ◽  
Insulin Signaling ◽  
Gut Microbiome ◽  
Metabolic Diseases ◽  
Memory Function ◽  
Amyloid Β ◽  
Impaired Memory ◽  
Ca1 Region ◽  
Folate And Vitamin B12

Abstract. Folate and vitamin B12(V-B12) deficiencies are associated with metabolic diseases that may impair memory function. We hypothesized that folate and V-B12 may differently alter mild cognitive impairment, glucose metabolism, and inflammation by modulating the gut microbiome in rats with Alzheimer’s disease (AD)-like dementia. The hypothesis was examined in hippocampal amyloid-β infused rats, and its mechanism was explored. Rats that received an amyloid-β(25–35) infusion into the CA1 region of the hippocampus were fed either control(2.5 mg folate plus 25 μg V-B12/kg diet; AD-CON, n = 10), no folate(0 folate plus 25 μg V-B12/kg diet; AD-FA, n = 10), no V-B12(2.5 mg folate plus 0 μg V-B12/kg diet; AD-V-B12, n = 10), or no folate plus no V-B12(0 mg folate plus 0 μg V-B12/kg diet; AD-FAB12, n = 10) in high-fat diets for 8 weeks. AD-FA and AD-VB12 exacerbated bone mineral loss in the lumbar spine and femur whereas AD-FA lowered lean body mass in the hip compared to AD-CON(P < 0.05). Only AD-FAB12 exacerbated memory impairment by 1.3 and 1.4 folds, respectively, as measured by passive avoidance and water maze tests, compared to AD-CON(P < 0.01). Hippocampal insulin signaling and neuroinflammation were attenuated in AD-CON compared to Non-AD-CON. AD-FAB12 impaired the signaling (pAkt→pGSK-3β) and serum TNF-α and IL-1β levels the most among all groups. AD-CON decreased glucose tolerance by increasing insulin resistance compared to Non-AD-CON. AD-VB12 and AD-FAB12 increased insulin resistance by 1.2 and 1.3 folds, respectively, compared to the AD-CON. AD-CON and Non-AD-CON had a separate communities of gut microbiota. The relative counts of Bacteroidia were lower and those of Clostridia were higher in AD-CON than Non-AD-CON. AD-FA, but not V-B12, separated the gut microbiome community compared to AD-CON and AD-VB12(P = 0.009). In conclusion, folate and B-12 deficiencies impaired memory function by impairing hippocampal insulin signaling and gut microbiota in AD rats.

scholarly journals Very similar cardiometabolic profile in the moderate and high cardiovascular risk classes: a population-based study

2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
M Chlabicz ◽  
J Jamolkowski ◽  
W Laguna ◽  
P Sowa ◽  
M Paniczko ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Cardiovascular Risk ◽  
High Risk ◽  
Population Based ◽  
Low Risk ◽  
Public Institution ◽  
Population Based Study ◽  
The Metabolic Syndrome ◽  
Cardiometabolic Profile

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Medical University of Bialystok, Poland Background Cardiovascular disease (CVD) is a major, worldwide problem and remain the dominant cause of premature mortality in the word. Simultaneously the metabolic syndrome is a growing problem. The aim of this study was to investigate the cardiometabolic profile among cardiovascular risk classes, and to estimate CV risk using various calculators. Methods The longitudinal, population-based study, was conducted in 2017-2020. A total of 931 individuals aged 20-79 were included. Anthropometric and biochemical profiles were measured according to a standardized protocols. The study population was divided into CV risk classes according to the latest recommendation. Comparisons variables between subgroups were conducted using Dwass-Steele-Critchlow-Fligner test. To estimate CV risk were used: the  Systematic Coronary Risk Estimation system, Framingham Risk Score and LIFEtime-perspective model for individualizing CardioVascular Disease prevention strategies in apparently healthy people (LIFE-CVD). Results The mean age was 49.1± 15.5 years, 43.2% were male. Percentages of low-risk, moderate-risk, high-risk and very-high CV risk were 46.1%, 22.8%, 13.5%, 17.6%, respectively. Most of the analyzed anthropometric, body composition and laboratory parameters did not differ between the moderate and high CV risk participants, whereas the low risk group differed significantly. In the moderate and high-risk groups, abdominal distribution of adipose tissue dominated with significantly elevated parameters of insulin resistance. Interestingly, estimating lifetime risk of myocardial infarction, stroke or CV death using LIFE-CVD calculator yielded similar results in moderate and high CV risk classes. Conclusion The participants belonging to moderate and high CV risk classes have a very similar unfavorable cardiometabolic profile which may result in the similar lifetime CV risk. This may imply the need for more aggressive pharmacological and non-pharmacological management of CV risk factors in the moderate CV risk population. It would be advisable to consider combining the moderate and high risk classes into one high CV risk class, or it may be worth adding one of the parameters of abdominal fat distribution to the CV risk calculators as an expression of increased insulin resistance. Abstract Figure 1.

scholarly journals The Impact of Differentiation on Cytotoxicity and Insulin Sensitivity in Streptozotocin Treated SH-SY5Y Cells

2021 ◽  
Vol 46 (6) ◽  
pp. 1350-1358
Author(s):  
Fruzsina Bagaméry ◽  
Kamilla Varga ◽  
Kitti Kecsmár ◽  
István Vincze ◽  
Éva Szökő ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Glycogen Synthase ◽  
Insulin Metabolism ◽  
Relative Significance ◽  
Differentiated Cells ◽  
Mature Neuron ◽  
The Right ◽  
The Impact

AbstractRecently neuronal insulin resistance was suggested playing a role in Alzheimer’s disease. Streptozotocin (STZ) is commonly used to induce impairment in insulin metabolism. In our previous work on undifferentiated SH-SY5Y cells the compound exerted cytotoxicity without altering insulin sensitivity. Nevertheless, differentiation of the cells to a more mature neuron-like phenotype may considerably affect the significance of insulin signaling and its sensitivity to STZ. We aimed at studying the influence of STZ treatment on insulin signaling in SH-SY5Y cells differentiated by retinoic acid (RA). Cytotoxicity of STZ or low serum (LS) condition and protective effect of insulin were compared in RA differentiated SH-SY5Y cells. The effect of insulin and an incretin analogue, exendin-4 on insulin signaling was also examined by assessing glycogen synthase kinase-3 (GSK-3) phosphorylation. STZ was found less cytotoxic in the differentiated cells compared to our previous results in undifferentiated SH-SY5Y cells. The cytoprotective concentration of insulin was similar in the STZ and LS groups. However, the right-shifted concentration–response curve of insulin induced GSK-3 phosphorylation in STZ-treated differentiated cells is suggestive of the development of insulin resistance that was further confirmed by the insulin potentiating effect of exendin-4. Differentiation reduced the sensitivity of SH-SY5Y cells for the non-specific cytotoxicity of STZ and enhanced the relative significance of development of insulin resistance. The differentiated cells thus serve as a better model for studying the role of insulin signaling in neuronal survival. However, direct cytotoxicity of STZ also contributes to the cell death.

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