scholarly journals Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

Diabetologia ◽  
2008 ◽  
Vol 51 (4) ◽  
pp. 657-667 ◽  
Author(s):  
H. Tsuneki ◽  
S. Murata ◽  
Y. Anzawa ◽  
Y. Soeda ◽  
E. Tokai ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Knockout Mice ◽  
Peripheral Tissues ◽  
Age Related

Tauroursodeoxycholic Acid Attenuates Diet-Induced and Age-Related Peripheral Endoplasmic Reticulum Stress and Cerebral Amyloid Pathology in a Mouse Model of Alzheimer’s Disease

2021 ◽  
pp. 1-12
Author(s):  
T. Ochiai ◽  
T. Nagayama ◽  
K. Matsui ◽  
K. Amano ◽  
T. Sano ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Metabolic Abnormalities ◽  
Intracerebroventricular Administration ◽  
Metabolic State ◽  
Peripheral Tissues ◽  
Age Related ◽  
Obesity And Diabetes ◽  
The Brain

BACKGROUND: Obesity and diabetes are well-established risk factors of Alzheimer’s disease (AD). In the brains of patients with AD and model mice, diabetes-related factors have been implicated in the pathological changes of AD. However, the molecular mechanistic link between the peripheral metabolic state and AD pathophysiology have remained elusive. Endoplasmic reticulum (ER) stress is known as one of the major contributors to the metabolic abnormalities in obesity and diabetes. Interventions aimed at reducing ER stress have been shown to improve the systemic metabolic abnormalities, although their effects on the AD pathology have not been extensively studied. OBJECTIVES: We examined whether interventions targeting ER stress attenuate the obesity/diabetes-induced Aβ accumulation in brains. We also aimed to determine whether ER stress that took place in the peripheral tissues or central nervous system was more important in the Aβ neuropathology. Furthermore, we explored if age-related metabolic abnormalities and Aβ accumulation could be suppressed by reducing ER stress. METHODS: APP transgenic mice (A7-Tg), which exhibit Aβ accumulation in the brain, were used as a model of AD to analyze parameters of peripheral metabolic state, ER stress, and Aβ pathology in the brain. Intraperitoneal or intracerebroventricular administration of taurodeoxycholic acid (TUDCA), a chemical chaperone, was performed in high-fat diet (HFD)-fed A7-Tg mice for ~1 month, followed by analyses at 9 months of age. Mice fed a normal diet were treated with TUDCA by drinking water for 4 months and intraperitoneally for 1 month in parallel, and analyzed at 15 months of age. RESULTS: Intraperitoneal administration of TUDCA suppressed ER stress in the peripheral tissues and ameliorated the HFD-induced obesity and insulin resistance. Concomitantly, Aβ levels in the brain were significantly reduced. In contrast, intracerebroventricular administration of TUDCA had no effect on the Aβ levels. Peripheral administration of TUDCA was also effective against the age-related obesity and insulin resistance, and markedly reduced amyloid accumulation. CONCLUSIONS: Interventions that target peripheral ER stress might be beneficial therapeutic and prevention strategies against brain Aβ pathology associated with metabolic overload and aging.

Female 5[beta]-reductase knockout mice are protected from diet induced obesity, insulin resistance and glucose intolerance

2016 ◽  
Author(s):  
Laura Gathercole ◽  
Matthew Chapman ◽  
Dean Larner ◽  
Petra Klusonova ◽  
Trevor Penning ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Intolerance ◽  
Knockout Mice ◽  
Diet Induced Obesity

Berberine in the treatment of diabetes mellitus: a review

2020 ◽  
Vol 20 ◽  
Author(s):  
Aleksandra Baska ◽  
Kamil Leis ◽  
Przemysław Gałązka
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Intestinal Flora ◽  
Glucose Absorption ◽  
Hepatocyte Nuclear Factor ◽  
Peripheral Tissues ◽  
Macrophages Polarization ◽  
Treatment Of Diabetes ◽  
Hepatocyte Nuclear Factor 4

: Berberine is an alkaloid found in plants. It has e.g. neuroprotective, anti-inflammatory and hypolipidemic activity. The research proves that it also strongly impacts the carbohydrate metabolism. The compound also protects pancreatic βcells and increases sensitivity to insulin in peripheral tissues via the induction of GLUT-1, GLUT-4 and insulin type 1 (Ins1) receptors activity. It also stimulates glycolysis and leads to a decrease in insulin resistance by macrophages polarization, lipolytic processes induction and energy expenditure enhancement (by reducing body mass and limiting insulin resistance caused by obesity). In liver berberine inhibits FOX01, SREBP1 and ChREBP pathways, and HNF-4α (hepatocyte nuclear factor 4 alpha) mRNA that hinder gluconeogenesis processes. In intestines it blocks α-glucosidase contributing to glucose absorption decrease. Its interference in intestinal flora reduces levels of monosaccharides and suppresses diabetes mellitus complications development.

423 INSULIN RESISTANCE ACCELERATES AGE RELATED LOSS OF VASCULAR CREB CONTENT.

2004 ◽  
Vol 52 (Suppl 1) ◽  
pp. S153.3-S153
Author(s):  
J. Grippa ◽  
P. A. Watson ◽  
J. E.B. Reusch
Keyword(s):  
Insulin Resistance ◽  
Age Related

scholarly journals Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer

2021 ◽  
Vol 22 (15) ◽  
pp. 7797
Author(s):  
Joseph A. M. J. L. Janssen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Insulin Secretion ◽  
Early Stage ◽  
Insulin Clearance ◽  
Future Research ◽  
Age Related ◽  
Hepatic Insulin Clearance

For many years, the dogma has been that insulin resistance precedes the development of hyperinsulinemia. However, recent data suggest a reverse order and place hyperinsulinemia mechanistically upstream of insulin resistance. Genetic background, consumption of the “modern” Western diet and over-nutrition may increase insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing hyperinsulinemia. Hyperinsulinemia disturbs the balance of the insulin–GH–IGF axis and shifts the insulin : GH ratio towards insulin and away from GH. This insulin–GH shift promotes energy storage and lipid synthesis and hinders lipid breakdown, resulting in obesity due to higher fat accumulation and lower energy expenditure. Hyperinsulinemia is an important etiological factor in the development of metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer and premature mortality. It has been further hypothesized that nutritionally driven insulin exposure controls the rate of mammalian aging. Interventions that normalize/reduce plasma insulin concentrations might play a key role in the prevention and treatment of age-related decline, obesity, type 2 diabetes, cardiovascular disease and cancer. Caloric restriction, increasing hepatic insulin clearance and maximizing insulin sensitivity are at present the three main strategies available for managing hyperinsulinemia. This may slow down age-related physiological decline and prevent age-related diseases. Drugs that reduce insulin (hyper) secretion, normalize pulsatile insulin secretion and/or increase hepatic insulin clearance may also have the potential to prevent or delay the progression of hyperinsulinemia-mediated diseases. Future research should focus on new strategies to minimize hyperinsulinemia at an early stage, aiming at successfully preventing and treating hyperinsulinemia-mediated diseases.

scholarly journals Palmitic acid promotes resistin-induced insulin resistance and inflammation in SH-SY5Y human neuroblastoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hamza Amine ◽  
Yacir Benomar ◽  
Mohammed Taouis
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Palmitic Acid ◽  
Lipid Rafts ◽  
Acid Treatment ◽  
Protective Action ◽  
Saturated Fatty Acids ◽  
Membrane Lipid ◽  
Human Neuroblastoma ◽  
Peripheral Tissues

AbstractSaturated fatty acids such as palmitic acid promote inflammation and insulin resistance in peripheral tissues, contrasting with the protective action of polyunsaturated fatty acids such docosahexaenoic acid. Palmitic acid effects have been in part attributed to its potential action through Toll-like receptor 4. Beside, resistin, an adipokine, also promotes inflammation and insulin resistance via TLR4. In the brain, palmitic acid and resistin trigger neuroinflammation and insulin resistance, but their link at the neuronal level is unknown. Using human SH-SY5Yneuroblastoma cell line we show that palmitic acid treatment impaired insulin-dependent Akt and Erk phosphorylation whereas DHA preserved insulin action. Palmitic acid up-regulated TLR4 as well as pro-inflammatory cytokines IL6 and TNFα contrasting with DHA effect. Similarly to palmitic acid, resistin treatment induced the up-regulation of IL6 and TNFα as well as NFκB activation. Importantly, palmitic acid potentiated the resistin-dependent NFkB activation whereas DHA abolished it. The recruitment of TLR4 to membrane lipid rafts was increased by palmitic acid treatment; this is concomitant with the augmentation of resistin-induced TLR4/MYD88/TIRAP complex formation mandatory for TLR4 signaling. In conclusion, palmitic acid increased TLR4 expression promoting resistin signaling through TLR4 up-regulation and its recruitment to membrane lipid rafts.

scholarly journals Adipocyte, Immune Cells, and miRNA Crosstalk: A Novel Regulator of Metabolic Dysfunction and Obesity

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1004
Author(s):  
Sonia Kiran ◽  
Vijay Kumar ◽  
Santosh Kumar ◽  
Robert L Price ◽  
Udai P. Singh
Keyword(s):  
Insulin Resistance ◽  
Immune Response ◽  
T Cells ◽  
Immune Cells ◽  
Metabolic Diseases ◽  
Liver Disorder ◽  
Low Grade ◽  
Peripheral Tissues ◽  
Nonalcoholic Fatty Liver ◽  
Cytokines And Chemokines

Obesity is characterized as a complex and multifactorial excess accretion of adipose tissue (AT) accompanied with alterations in the immune response that affects virtually all age and socioeconomic groups around the globe. The abnormal accumulation of AT leads to several metabolic diseases, including nonalcoholic fatty liver disorder (NAFLD), low-grade inflammation, type 2 diabetes mellitus (T2DM), cardiovascular disorders (CVDs), and cancer. AT is an endocrine organ composed of adipocytes and immune cells, including B-Cells, T-cells and macrophages. These immune cells secrete various cytokines and chemokines and crosstalk with adipokines to maintain metabolic homeostasis and low-grade chronic inflammation. A novel form of adipokines, microRNA (miRs), is expressed in many developing peripheral tissues, including ATs, T-cells, and macrophages, and modulates the immune response. miRs are essential for insulin resistance, maintaining the tumor microenvironment, and obesity-associated inflammation (OAI). The abnormal regulation of AT, T-cells, and macrophage miRs may change the function of different organs including the pancreas, heart, liver, and skeletal muscle. Since obesity and inflammation are closely associated, the dysregulated expression of miRs in inflammatory adipocytes, T-cells, and macrophages suggest the importance of miRs in OAI. Therefore, in this review article, we have elaborated the role of miRs as epigenetic regulators affecting adipocyte differentiation, immune response, AT browning, adipogenesis, lipid metabolism, insulin resistance (IR), glucose homeostasis, obesity, and metabolic disorders. Further, we will discuss a set of altered miRs as novel biomarkers for metabolic disease progression and therapeutic targets for obesity.

P1279INSULIN RESISTANCE IN HEMODIALYSIS PATIENS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Pavel Filinyuk ◽  
Aleksander Rumyantsev
Keyword(s):  
Insulin Resistance ◽  
Systemic Inflammation ◽  
Clinical Manifestations ◽  
Biological Response ◽  
Fold Increase ◽  
Atherogenic Dyslipidemia ◽  
Model Assessment ◽  
Peripheral Tissues ◽  
Reactive Protein ◽  
Homeostatic Model Assessment

Abstract Background and Aims insulin resistance (IR) is a decrease in the biological response of sensitive tissues to insulin. IR is known as an adverse risk factor in cardiovascular disease, which largely determines the prognosis of patients receiving hemodialysis (HD). But this issue is not well understood. For the screening of IR, special indices have been developed that characterize the sensitivity of tissues to insulin. The aim of the study was to compare the methods of screening for IR in patients receiving HD in relation to the markers of systemic inflammation and atherogenic dyslipidemia (AtD). Method 124 patients receiving HD for 75.4 ± 44.5 months were examined including 66 men and 58 women aged 57.6 ± 13.6 years. For IR screening, the Homeostatic Model Assessment-1 and 2 indices (HOMA-1 and HOMA-2), the Quantitative Insulin Sensitivity Check Index (QUICKI) and triglycerides / glucose (Tri/G) were used. Patients were examined in accordance with the recommendations of KDIGO. Data analysis was carried out using “STATISTICA 10.0”. Results fasting insulin levels were elevated in 19% of patients. But, the calculated indices were consistent with the idea that IR is much more common. So, the IR index in the HOMA -1 model was increased in 47%, in the HOMA -2 model - in 33%, in the QUICKI model - in 36%, the TriH indicator - in 91%. The sensitivity of peripheral tissues in the HOMA-1 and HOMA-2 models was equally reduced by 35-40%. The results of the correlation analysis between indicators of IR and plasma concentration of C-reactive protein and lipid profile are presented in table 1. Informativeness of IR indicators depending on the presence of obesity is presented in table 2 We were also interested in whether insulin resistance affects the development of clinical manifestations of atherosclerosis, cardiac arrhythmias, and heart failure. An analysis of this relationship did not reveal. Only the IR index in the HOMA-1 model with a value of more than 2.7 units was associated with a 4.5-fold increase in the risk of developing clinical manifestations of atherosclerotic lesions (χ2 = 4.582 p = 0.032). Statistically significant it was only in men. Given our data, perhaps IR is one of the reasons for the higher morbidity and mortality of men at HD. Conclusion a comparison of IR models allows us to distinguish HOMA-2 as the most accurate index. The highest correlation with systemic inflammation and AtD was in the HOMA-1 and HOMA-2 indices.

scholarly journals Endothelial insulin receptors differentially control insulin signaling kinetics in peripheral tissues and brain of mice

2017 ◽  
Vol 114 (40) ◽  
pp. E8478-E8487 ◽  
Author(s):  
Masahiro Konishi ◽  
Masaji Sakaguchi ◽  
Samuel M. Lockhart ◽  
Weikang Cai ◽  
Mengyao Ella Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Cells ◽  
Food Intake ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Insulin Receptors ◽  
Brain Regions ◽  
Peripheral Tissues ◽  
Systemic Insulin Resistance

Insulin receptors (IRs) on endothelial cells may have a role in the regulation of transport of circulating insulin to its target tissues; however, how this impacts on insulin action in vivo is unclear. Using mice with endothelial-specific inactivation of the IR gene (EndoIRKO), we find that in response to systemic insulin stimulation, loss of endothelial IRs caused delayed onset of insulin signaling in skeletal muscle, brown fat, hypothalamus, hippocampus, and prefrontal cortex but not in liver or olfactory bulb. At the level of the brain, the delay of insulin signaling was associated with decreased levels of hypothalamic proopiomelanocortin, leading to increased food intake and obesity accompanied with hyperinsulinemia and hyperleptinemia. The loss of endothelial IRs also resulted in a delay in the acute hypoglycemic effect of systemic insulin administration and impaired glucose tolerance. In high-fat diet-treated mice, knockout of the endothelial IRs accelerated development of systemic insulin resistance but not food intake and obesity. Thus, IRs on endothelial cells have an important role in transendothelial insulin delivery in vivo which differentially regulates the kinetics of insulin signaling and insulin action in peripheral target tissues and different brain regions. Loss of this function predisposes animals to systemic insulin resistance, overeating, and obesity.

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