scholarly journals Thyroid Hormone Regulation and Insulin Resistance: Insights From Animals Naturally Adapted to Fasting

Physiology ◽  
2017 ◽  
Vol 32 (2) ◽  
pp. 141-151 ◽  
Author(s):  
Bridget Martinez ◽  
Rudy M. Ortiz
Keyword(s):  
Insulin Resistance ◽  
Thyroid Hormone ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Hormone Secretion ◽  
Hormone Regulation ◽  
Insulin Dysregulation ◽  
Physiological Adaptations ◽  
Thyroidal Status ◽  
Insight Into

The contribution of thyroidal status in insulin signaling and glucose homeostasis has been implicated as a potential pathophysiological factor in humans, but the specific mechanisms remain largely elusive. Fasting induces changes in both thyroid hormone secretion and insulin signaling. Here, we explore how mammals that undergo natural, prolonged bouts of fasting provide unique insight into evolved physiological adaptations that allow them to tolerate such conditions despite intermittent states of reversible insulin resistance. Such insights from nature may provide clues to better understand the basis of thyroidal involvement in insulin dysregulation in humans.

Thyroid Hormone Regulation of Glucose Homeostasis in the Miniature Pig*

Endocrinology ◽  
1983 ◽  
Vol 112 (6) ◽  
pp. 2025-2031 ◽  
Author(s):  
MANFRED J. MÜLLER ◽  
ULRICH PASCHEN ◽  
HANS J. SEITZ ◽  
A.TECHNICAL ASSISTANCE HARNEIT ◽  
D. LUDA
Keyword(s):  
Thyroid Hormone ◽  
Glucose Homeostasis ◽  
Hormone Regulation ◽  
Miniature Pig

scholarly journals Deregulation of PP2A-Akt Interaction Contributes to Sucrose Non-Fermenting Related Kinase (SNRK) Deficiency Induced Insulin Resistance in Adipose Tissue (P21-071-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jie Li ◽  
Ran An ◽  
Simin Liu ◽  
Haiyan Xu
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Knockout Model ◽  
Potential Substrate

Abstract Objectives Sucrose Non-Fermenting Related Kinase (SNRK), a serine/threonine kinase, is a novel member of the AMPK/SNF1 family. We previously reported that adipose specific SNRK deficiency induced systemic inflammation and insulin resistance. In this study, we aimed to dissect the role of SNRK in white versus brown adipose tissue in insulin signaling and glucose homeostasis. Methods The SNRKloxp/loxp mice were mated with adiponectin-Cre (A-Cre) transgenic mice to generate the adipose tissue specific knockout model (SNRK−/−, A-Cre), and with UCP1-Cre (U-Cre) mice to generate the brown adipose tissue (BAT) specific knockout model (SNRK−/−, U-Cre). RNA sequencing and phosphoproteomics analysis were applied to identify the signaling pathways affected by SNRK deficiency and the potential substrate of SNRK. Results SNRK deletion exclusively in BAT is sufficient to impair insulin signaling and glucose uptake without inducing local and systemic inflammation. Phosphoproteomic study identified PPP2R5D as the potential substrate of SNRK that regulates insulin signaling through controlling PP2A activity. Dephosphorylated PPP2R5D promotes constitutive assembly of PP2A-Akt complex in SNRK deficient primary brown adipocytes and BAT, therefore reduces insulin stimulated Akt phosphorylation and subsequent glucose uptake. RNA sequencing data provided further evidence to show that the PI3K/AKT signaling pathway is suppressed by SNRK deletion in primary brown adipocytes. Conclusions Insulin resistance in BAT alone is not sufficient to impact whole body glucose homeostasis, indicating that the role of SNRK in WAT and inflammation might be critical for observed systemic insulin resistance in SNRK−/−, A-Cre mice. Funding Sources National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK103699).

Long-term melatonin administration improves glucose homeostasis and insulin resistance state in high-fat-diet fed rats

2013 ◽  
Vol 8 (10) ◽  
pp. 958-967
Author(s):  
Xue-Dong Wan ◽  
San-Qiang Li ◽  
Shou-Min Xi ◽  
Jian-Fei Wang ◽  
Yan-Chun Guo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Reactive Oxygen Species ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Metabolic Profiles ◽  
Oxygen Species ◽  
High Fat

AbstractEmerging evidence support an important role of reactive oxygen species in various forms of insulin resistance. It is identified that melatonin has antioxidant properties and prevents toxic effects of reactive oxygen species. In this study, we sought to assess the involvement of melatonin in the progression of insulin resistance in response to a high-fat diet (HFD) and to investigate the underlying mechanisms. Male rats were fed with a control diet, a high-fat diet, or a high-fat diet supplemented with melatonin (5 mg kg−1, i.p.) for 10 weeks. Glucose homeostasis, insulin sensitivity, antioxidative potency, and metabolic profiles in the rats were evaluated. Our results showed that a HFD led to increasing body mass, adipose tissue weight, plasma insulin, total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), and decreased HDL-cholesterol (HDL-C) in rats. There was also a significant increase in the level of malondialdehyde (MDA) and decrease in superoxide dismutase (SOD) activity, oxidative stress markers both in the plasma and liver. An enhanced hepatic phosphoenolpyruvate carboxy-kinase (PEPCK) activity and RNA expression were observed. Impaired insulin signaling was evidenced by reducing insulin receptor substrate 2 (IRS2) tyrosine phosphorylation and protein kinase B (PKB) serine phosphorylation in response to insulin. Overactivation of stress-activated protein kinases JNK was also observed in the liver of HFD rats. However, simultaneous administration of melatonin to HFD rats significantly reduced oxidative stress in the system and liver, markedly improved impaired glucose homeostasis, insulin sensitivity, antioxidative potency, metabolic profiles and all the aforesaid adverse changes in HFD rats. Our results demonstrated that anti-oxidative property of melatonin is sufficient to ameliorate the insulin resistance condition, leading to the improvement of glucose homeostasis and the restoration of hepatic insulin signaling in a rat model of HFD-induced insulin resistance.

scholarly journals Obesity: The role of desynchronosis and genetic factors in mechanisms of its development

2017 ◽  
Vol 8 (1) ◽  
pp. 23-29
Author(s):  
M. O. Ryznychuk ◽  
V. P. Pishak
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Signaling ◽  
Genetic Factors ◽  
Hormone Secretion ◽  
Insulin Receptors ◽  
Secretory Activity ◽  
Membrane Receptors ◽  
Brown Adipose

The article highlights the role of desynchronosis and certain genetic factors in the development of obesity. Some pathogenetic links of obesity and the influence of melatonin on them are analyzed.Desynchronosis is one of the causes of obesity as a result of dysregulatory changes in the chronoperiodic system – between suprachiasmatic nuclei of the hypothalamus and secretory activity of the pineal gland.In obesity there are some changes in circadian patterns of important physiological parameters. These include acrophases of blood pressure; rhythm of hormone secretion, including insulin; electrolytes; sleep-wake cycle displaced for a period of a day, which is a deviation from the normal course. Phase discrepancies of established circadian oscillations of physiological processes arise. Preconditions of fat metabolism imbalance, particularly visfatin, apelin and vaspin – components of atherosclerotic lesions, gradually emerge.There is abundant evidence for close relationships between metabolism and circadian mechanisms. It is proved, that there is a strong direct impact of endogenous circadian rhythms on the metabolic pathways that do not depend on food intake or sleep. A potential low molecular weight of biomarkers of human circadian phases has been identified. A number of key metabolic enzymes in tissues such as the liver, adipose tissue or the pancreas are chronodependent. Desynchronosis phenomena caused by genetic or environmental factors can lead to serious metabolic disorders, including obesity, insulin resistance and metabolic syndrome.Genesis of pineal removal-induced insulin resistance and reduced glucose tolerance in cells is related to the consequences of melatonin absence, which leads to abnormalities in insulin signaling pathways and reduced GLUT4 gene expression and protein content.Insulin-sensitive tissues (white and brown adipose tissue, skeletal and heart muscles) after pineal removal are characterized by a significant reduction of GLUT4 mRNA and the content of microsomal and membrane proteins, which are compensated during treatment by melatonin. Functional synergy exists between melatonin and insulin. Melatonin is able through the membrane receptors MT1 to cause rapid tyrosine phosphorylation, activate tyrosine kinase of beta subunits of insulin receptors and mobilize several intracellular stages of insulin-signaling pathway transduction.Thus, the protective effect of melatonin in cases of disturbance to the carbohydrate metabolism is manifested in the formation of circadian periodicity by modulating the expression of time genes.

scholarly journals Expression and thyroid hormone regulation of annexins in the anterior pituitary

2007 ◽  
Vol 195 (3) ◽  
pp. 385-392 ◽  
Author(s):  
Jens Mittag ◽  
Wiebke Oehr ◽  
Heike Heuer ◽  
Tuula Hämäläinen ◽  
Bent Brachvogel ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Mrna Expression ◽  
Hormone Secretion ◽  
Pituitary Hormones ◽  
Pituitary Hormone ◽  
Dependent Manner ◽  
Hormone Regulation ◽  
Wild Type ◽  
Transcript Levels ◽  
Redundant Functions

Due to their property to bind to phospholipids in a Ca2+-dependent manner, proteins of the annexin superfamily are involved in many membrane-related events and thus in various forms of physiological and pathological processes. We were therefore interested in analyzing the mRNA expression of the annexins in the severely disorganized pituitaries of the athyroid Pax8−/− mice in comparison with that of control animals. In neither condition was mRNA expression of the annexins A3, A7, A8, A9, A11, and A13 detectable. The annexins A2, A4, and A6 were equally expressed in wild-type and Pax8−/− mice. Transcript levels of A1 and A10 were highly increased and those of A5 were significantly decreased in the athyroid mutants compared with controls. Treatment of Pax8−/− mice with physiological doses of thyroxine for 3 days normalized the mRNA expression of A1, A5, and A10 indicating that the expression of these annexins is directly regulated by thyroid hormone (TH). Since A5 exhibits by far the highest transcript levels of all annexins in the pituitary and its regulation by TH could be also confirmed at the protein level, we analyzed the mRNA expression of pituitary hormones in A5−/− mice. In these mutants, only the β-FSH mRNA expression was found to be significantly reduced, while the mRNA expression levels of the other pituitary hormones were not altered. These results support the concept that annexins might serve important albeit redundant functions as modulators of pituitary hormone secretion.

scholarly journals Isoorientin Reverts TNF-α-Induced Insulin Resistance in Adipocytes Activating the Insulin Signaling Pathway

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5222-5230 ◽  
Author(s):  
Angel Josabad Alonso-Castro ◽  
Rocio Zapata-Bustos ◽  
Guadalupe Gómez-Espinoza ◽  
Luis A. Salazar-Olivo
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Insulin Signaling Pathway ◽  
Insulin Resistant ◽  
Expression Of Genes ◽  
Tnf Α ◽  
Genes Encoding ◽  
Insight Into ◽  
Antidiabetic Effects

Abstract Isoorientin (ISO) is a plant C-glycosylflavonoid with purported antidiabetic effects but unexplored mechanisms of action. To gain insight into its antidiabetic mechanisms, we assayed nontoxic ISO concentrations on the 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2-deoxy-d-glucose (2-NBDG) uptake by murine 3T3-F442A and human sc adipocytes. In insulin-sensitive adipocytes, ISO stimulated the 2-NBDG uptake by 210% (murine) and 67% (human), compared with insulin treatment. Notably, ISO also induced 2-NBDG uptake in murine (139%) and human (60%) adipocytes made resistant to insulin by treatment with TNF-α, compared with the incorporation induced in these cells by rosiglitazone. ISO induction of glucose uptake in adipocytes was abolished by inhibitors of the insulin signaling pathway. These inhibitors also blocked the proper phosphorylation of insulin signaling pathway components induced by ISO in both insulin-sensitive and insulin-resistant adipocytes. Additionally, ISO stimulated the transcription of genes encoding components of insulin signaling pathway in murine insulin-sensitive and insulin-resistant adipocytes. In summary, we show here that ISO exerts its antidiabetic effects by activating the insulin signaling pathway in adipocytes, reverts the insulin resistance caused in these cells by TNF-α by stimulating the proper phosphorylation of proteins in this signaling pathway, and induces the expression of genes encoding these proteins.

scholarly journals Non-classical effects of vitamin D

2018 ◽  
Vol 15 (1) ◽  
pp. 12-18
Author(s):  
Lilit V. Egshatyan
Keyword(s):  
Metabolic Disease ◽  
Insulin Resistance ◽  
Vitamin D ◽  
Inflammatory Response ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Renin Angiotensin System ◽  
Inflammatory Biomarkers ◽  
Angiotensin System ◽  
Normal Metabolism

Some studies support the involvement of vitamin D in modulating the inflammatory response and developing diabetes. Since the activation of inflammatory biomarkers, cytokines and pathways interferes with normal metabolism and disrupts proper insulin signaling and insulin resistance, it is hypothesized that vitamin D could influence lipid and glucose homeostasis by modulating inflammatory response and renin-angiotensin system. In this review discussed the mechanisms of the influence of vitamin D on metabolic disease.

scholarly journals Obesity-induced Insulin Resistance and Hyperglycemia

2008 ◽  
Vol 109 (1) ◽  
pp. 137-148 ◽  
Author(s):  
J A. Jeevendra Martyn ◽  
Masao Kaneki ◽  
Shingo Yasuhara ◽  
David S. Warner ◽  
Mark A. Warner
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Central Nervous System ◽  
Nervous System ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Signaling Proteins ◽  
Peripheral Tissues ◽  
Altered Glucose ◽  
Glucose Output

Obesity is a major cause of type 2 diabetes, clinically evidenced as hyperglycemia. The altered glucose homeostasis is caused by faulty signal transduction via the insulin signaling proteins, which results in decreased glucose uptake by the muscle, altered lipogenesis, and increased glucose output by the liver. The etiology of this derangement in insulin signaling is related to a chronic inflammatory state, leading to the induction of inducible nitric oxide synthase and release of high levels of nitric oxide and reactive nitrogen species, which together cause posttranslational modifications in the signaling proteins. There are substantial differences in the molecular mechanisms of insulin resistance in muscle versus liver. Hormones and cytokines from adipocytes can enhance or inhibit both glycemic sensing and insulin signaling. The role of the central nervous system in glucose homeostasis also has been established. Multipronged therapies aimed at rectifying obesity-induced anomalies in both central nervous system and peripheral tissues may prove to be beneficial.

scholarly journals Requirement of the ATM/p53 Tumor Suppressor Pathway for Glucose Homeostasis

2010 ◽  
Vol 30 (24) ◽  
pp. 5787-5794 ◽  
Author(s):  
Heather L. Armata ◽  
Diane Golebiowski ◽  
Dae Young Jung ◽  
Hwi Jin Ko ◽  
Jason K. Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Tumor Suppressor ◽  
Glucose Homeostasis ◽  
Insulin Signaling ◽  
Germ Line ◽  
Neuronal Degeneration ◽  
Phosphorylation Site ◽  
P53 Tumor Suppressor ◽  
Increased Risk ◽  
Risk Of Cancer

ABSTRACT Ataxia telangiectasia (A-T) patients can develop multiple clinical pathologies, including neuronal degeneration, an elevated risk of cancer, telangiectasias, and growth retardation. Patients with A-T can also exhibit an increased risk of insulin resistance and type 2 diabetes. The ATM protein kinase, the product of the gene mutated in A-T patients (Atm), has been implicated in metabolic disease, which is characterized by insulin resistance and increased cholesterol and lipid levels, blood pressure, and atherosclerosis. ATM phosphorylates the p53 tumor suppressor on a site (Ser15) that regulates transcription activity. To test whether the ATM pathway that regulates insulin resistance is mediated by p53 phosphorylation, we examined insulin sensitivity in mice with a germ line mutation that replaces the p53 phosphorylation site with alanine. The loss of p53 Ser18 (murine Ser15) led to increased metabolic stress, including severe defects in glucose homeostasis. The mice developed glucose intolerance and insulin resistance. The insulin resistance correlated with the loss of antioxidant gene expression and decreased insulin signaling. N-Acetyl cysteine (NAC) treatment restored insulin signaling in late-passage primary fibroblasts. The addition of an antioxidant in the diet rendered the p53 Ser18-deficient mice glucose tolerant. This analysis demonstrates that p53 phosphorylation on an ATM site is an important mechanism in the physiological regulation of glucose homeostasis.

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