2016 Association between hepatic iron deposition, and serum bilirulin levels, mutations of UGT1A1 and HFE gene in patients with hereditary unconjugated hyperbilirubinemia

So when the process of inflammation is suppressed by bilirubin, hepcidin expression decreases and subsequent upregulation of iron levels occurs. So elevated levels of bilirubin might promote iron loading by decreasing oxidative stress and inhibiting hepcidin expression signaling due to reduced inflammatory activity [20]. These were consistent with the f indings from liver biopsies in our study, that the Ishak score of Inflammation grading of patients with iron deposition was mildly lower than patients without iron deposition.

2004 Insulin activates vascular endothelial growth factor in vascular smooth muscle cells: influence of nitric oxide and of insulin resistance.

We found that in VSMC from humans and from insulin-sensitive Zucker fa/+rats, insulin increases VEGF protein expression and secretion, with mechanisms blunted by wortmannin and LY294002 (PI3-K inhibitors), PD98059 (MAPK inhibitor), L-NMMA (NO inhibitor) and Rp-8pCT-cGMPs (PKG inhibitor). Also the NO donor sodium nitroprusside (SNP) and the cGMP analogue 8-Bromo-cGMP increase VEGF protein expression and secretion, with mechanisms inhibited by wortmannin and PD98059. The insulin effects on VEGF are impaired in VSMC from Zucker fa/fa rats, which also present a reduced insulin ability to increase NO.

Insulin Signaling in Osteoblasts Integrates Bone Remodeling and Energy Metabolism

Insulin dose–response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein E genotype

Insulin - Wikipedia

Insulin - Wikipedia

Osteocalcin acts as a hormone in the body, causing beta cells in the pancreas to release more insulin, and at the same time directing fat cells to release the hormone adiponectin, which increases sensitivity to insulin (R).

Caffeine, Fluid-Electrolyte Balance, Temperature Regulation,... : Exercise and Sport Sciences Reviews

«Dietitians, exercise physiologists, athletic trainers, and other sports medicine personnel commonly recommend that exercising adults and athletes refrain from caffeine use because it is a diuretic, and it may exacerbate dehydration and hyperthermia. This review, contrary to popular beliefs, proposes that caffeine consumption does not result in the following: (a) water-electrolyte imbalances or hyperthermia and (b) reduced exercise-heat tolerance.»

Longevity factor klotho and chronic psychological stress

Original Article

2007 Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17

2011 Aldosterone decreases glucose-stimulated insulin secretion in vivo in mice and in murine islets

«Fasting glucose concentration were reduced in As^−/−mice compared with wild-type. During hyperglycaemic clamps, insulin and C-peptide concentration increased to a greater extent in As^−/− than in wild-type mice. This was not attributable to differences in potassium or angiotensin II, as glucose-stimulated insulin secretion was enhanced in As^−/− mice even during high sodium intake. There was no difference in insulin sensitivity between As^−/− and wild-type mice in euglycaemic-hyperinsulinaemic clamp studies. In islet and MIN6 beta cell studies, aldosterone inhibited glucose and isobutylmethylxanthine-stimulated insulin secretion, an effect that was not blocked by mineralocorticoid receptor antagonism, but was prevented by the superoxide dismutase mimetic tempol.»

2012 Randomized, double-blind, placebo-controlled, linear dose, crossover study to evaluate the efficacy and safety of a green coffee bean extract in overweight subjects

«Significant reductions were observed in body weight (−8.04 ± 2.31 kg), body mass index (−2.92 ± 0.85 kg/m²), and percent body fat (−4.44% ± 2.00%), as well as a small decrease in heart rate (−2.56 ± 2.85 beats per minute), but with no significant changes to diet over the course of the study. Importantly, the decreases occurred when subjects were taking GCA. Body mass index for six subjects shifted from preobesity to the normal weight range (<25.00 kg/m²).»

2014 Regulation of male fertility by the bone-derived hormone osteocalcin

Osteocalcin acts on Leydig cells of the testis to stimulate testosterone biosynthesis and therefore affect male fertility (R).

2014 Chronobiology and Obesity: Interactions between Circadian Rhythms and Energy Regulation

Mice deficient in a circadian gene (Bmal1) had defects in insulin secretion, both at base levels and in response to glucose stimulation. These mice were highly susceptible to diabetes.

2014 AMPK: A cellular metabolic and redox sensor. A minireview

AMPK is a serine/threonine kinase that is found in all eukaryotes and is ubiquitously expressed in all organ systems. Once activated, AMPK stimulates hepatic fatty acid oxidation and ketogenesis, inhibits cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibits adipocyte lipolysis and lipogenesis, stimulates skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulates insulin secretion by the pancreas.

2014 Effects of aldosterone on insulin sensitivity and secretion

«Dr. Conn originally reported an increased risk of diabetes in patients with hyperaldosteronism in the 1950’s, although the mechanism remains unclear. Aldosterone-induced hypokalemia was initially described to impair glucose tolerance by impairing insulin secretion. Correction of hypokalemia by potassium supplementation only partially restored insulin secretion and glucose tolerance, however. Aldosterone also impairs glucose-stimulated insulin secretion in isolated pancreatic islets via reactive oxygen species in a mineralocorticoid receptor-independent manner. Aldosterone-induced mineralocorticoid receptor activation also impairs insulin sensitivity in adipocytes and skeletal muscle. Aldosterone may produce insulin resistance secondarily by altering potassium, increasing inflammatory cytokines, and reducing beneficial adipokines such as adiponectin. Renin-angiotensin system antagonists reduce circulating aldosterone concentration and also the risk of type 2 diabetes in clinical trials. These data suggest that primary and secondary hyperaldosteronism may contribute to worsening glucose tolerance by impairing insulin sensitivity or insulin secretion in humans. Future studies should define the effects of MR antagonists and aldosterone on insulin secretion and sensitivity in humans.»

2015 Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward

«Initial examination of locally evoked [DA]_o monitored with FCV in ex vivo striatal slices from rats with ad libitum (AL) access to food and water revealed the unexpected finding that acute application of insulin across a range of physiologically relevant concentration1,4 increased single-pulse-evoked [DA]_o (Fig. 1a–c), with insulin EC₅₀ values (the concentration at which the effect was half maximal) of 2–12 nM (Fig. 1b). Increased evoked [DA]_o was particularly surprising, given that this was accompanied by a significant increase in the maximal rate (V_max) for DAT-mediated uptake in each subregion (Table 1), which would lead to a competing decrease in evoked [DA]_o, as reported previously22,23. Instead, we found that evoked [DA]_o was maximally amplified 20–55% by 30 nM insulin; the region with the greatest proportional effect was the NAc shell, which is the striatal subregion with highest InsR expression1,14. Slices exposed to 30 nM insulin under identical conditions showed no change in striatal DA content (Supplementary Fig. 1a), implying that insulin alters dynamic release regulation, rather than simply upregulating DA synthesis. Notably, the effect of insulin on evoked [DA]_o was lost at supraphysiological concentration ≥100 nM (Fig. 1b). This was not a result of increased DAT activity overtaking release, as the effect of insulin on V_max was also lost at these concentration (Table 1). Overall, these data show that in the intact striatal microenvironment, the predominant effect of insulin on evoked [DA]_o is to increase release, despite a concurrent increase in DA uptake.»

2017 High Glucose Accelerates Cell Proliferation and Increases the Secretion and mRNA Expression of Osteopontin in Human Pancreatic Duct Epithelial Cells

«Background: The incidence of pancreatic cancer is increasing year-by-year in Japan. Among the diseases that complicate pancreatic cancer, diabetes is the most common. Recently, it has become evident that patients suffering from diabetes and obesity show increased expression of osteopontin (OPN). The purpose of this study was to investigate the effect of high glucose and high insulin culture conditions on a human pancreatic duct epithelial cell line (HPDE-6), focusing particularly on OPN expression. Methods: HPDE-6 were cultured under various conditions, employing several combinations of glucose (normal, 6 mM high, 30 mM, and 60 mM) and insulin (0.1 nM, 1 nM) concentration. Results: HPDE-6 cell proliferation was significantly accelerated under high glucose culture conditions in comparison to samples in 6 mM glucose, and was more prominent under high insulin conditions. At the same time, the expression of OPN mRNA was also increased significantly. In comparison with 6 mM glucose, the expression of 8-OHdG DNA was increased in high glucose culture. Conclusion: HPDE-6 cells show accelerated proliferation and increased OPN expression when cultured under high glucose and high insulin conditions. Furthermore, the cells show increased oxidative stress in the presence of high glucose.»

2002 Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting.

«To review the interaction between melatonin and the dopaminergic system in the hypothalamus and striatum and its potential clinical use in dopamine-related disorders in the central nervous system. Medline-based search on melatonin-dopamine interactions in mammals. Melatonin. the hormone produced by the pineal gland at night. influences circadian and seasonal rhythms, most notably the sleep-wake cycle and seasonal reproduction. The neurochemical basis of these activities is not understood yet. Inhibition of dopamine release by melatonin has been demonstrated in specific areas of the mammalian central nervous system (hypothalamus, hippocampus, medulla-pons, and retina). Antidopaminergic activities of melatonin have been demonstrated in the striatum. Dopaminergic transmission has a pivotal role in circadian entrainment of the fetus, in coordination of body movement and reproduction. Recent findings indicate that melatonin may modulate dopaminergic pathways involved in movement disorders in humans. In Parkinson patients melatonin may, on the one hand, exacerbate symptoms (because of its putative interference with dopamine release) and, on the other, protect against neurodegeneration (by virtue of its antioxidant properties and its effects on mitochondrial activity). Melatonin appears to be effective in the treatment of tardive dyskinesia. a severe movement disorder associated with long-term blockade of the postsynaptic dopamine D2 receptor by antipsychotic drugs in schizophrenic patients. The interaction of melatonin with the dopaminergic system may play a significant role in the nonphotic and photic entrainment of the biological clock as well as in the fine-tuning of motor coordination in the striatum. These interactions and the antioxidant nature of melatonin may be beneficial in the treatment of dopamine-related disorders.»

2004 Establishment of a cell-based assay to screen regulators for Klotho gene promoter.

The expression of luciferase in these cells was under control of Klotho promoter and down-regulated after H2O2 treatment. The down-regulation of luciferase expression was H2O2 concentration-dependent with an IC50 at approximately 0.006 %. This result demonstrated that the Klotho gene promoter was regulated by oxidative stress. Using the cell-based reporter gene assay, we screened natural product extracts for regulation of Klotho gene promoter. Several extracts were identified that could rescue the H2O2 effects and up-regulated Klotho promoter activity.

Keywords: Cells, Cultured;Cloning, Molecular;Drug Evaluation, Preclinical;Drugs, Chinese Herbal;Embryo, Mammalian;Genes, Reporter;Gentiana;Glucuronidase;Humans;Hydrogen Peroxide;Kidney;Luciferases;Membrane Proteins;Promoter Regions, Genetic;Transfection

2006 L-citrulline reduces time to exhaustion and insulin response to a graded exercise test.

It can be concluded that, contrary to the hypothesized improvement in treadmill time following L-citrulline ingestion, there is a reduction in treadmill time following L-citrulline ingestion over the 24 h prior to testing. The normal response of increased plasma insulin following high-intensity exercise is also not present in the L-citrulline condition, indicating that L-citrulline ingestion may reduce nitric oxide-mediated pancreatic insulin secretion or increased insulin clearance.

2007 The role of autophagy in aging: its essential part in the anti-aging mechanism of caloric restriction.

Ann N Y Acad Sci. 2007 Oct;1114:69-78. Epub 2007 Oct 12. Review

2008 Frontiers: skeletal muscle sodium pump regulation: a translocation paradigm.

Am J Physiol Endocrinol Metab. 2008 Sep;295(3):E553-8. doi: 10.1152/ajpendo.90261.2008. Epub 2008 Apr 22. Research Support, Non-U.S. Gov't; Review

2009 Bone mineral densities in individuals with Gilbert's syndrome: a cross-sectional, case-control pilot study.

«RESULTS: A total of 17 GS and 30 control subjects were studied. Overall, there were no significant differences in BMD, PTH, CTX or osteocalcin levels between the two groups. However, when older (older than 40 years of age) and younger (40 years of age and younger) cohorts were considered separately, the older GS cohort had significantly decreased total hip BMD, T scores and Z scores, and femoral neck BMD, T scores and Z scores (P<0.005 for each parameter, respectively) compared with older control subjects. Serum osteocalcin levels were lower in the older versus younger GS cohort (P=0.006). An inverse correlation existed between all subjects' serum unconjugated bilirubin levels and total body BMD determinations (r=-0.42; P=0.04). On univariate analysis, the association between serum unconjugated bilirubin and total body BMD was not significant (P=0.066), nor was serum unconjugated bilirubin identified as a risk factor for low BMD when entered into multivariate analyses.

CONCLUSIONS: The results of the present pilot study warrant further research involving larger numbers of subjects and longitudinal measurements to determine whether GS is associated with decreased BMD, particularly in older GS subjects.»

2010 Energy metabolism in adult neural stem cell fate.

The FoxO family of transcription factors is negatively regulated by the PI3K/Akt branch of the insulin/IGF-1 pathway. There are four FoxO family members in mammals: FoxO1, FoxO3, FoxO4, and FoxO6. Phosphorylation of FoxO1, FoxO3, and FoxO4 by Akt lead to their retention in the cytoplasm, thereby inhibiting their transcriptional activities (Biggs et al., 1999; Brunet et al., 1999; Kops et al., 1999) (Fig. 2). In contrast, FoxO6 phosphorylation by
Akt does not affect its subcellular localization, but still inhibits FoxO6 transcriptional activity (van der Heide et al., 2005). FoxO factors are important in many tissues and cell types for the survival and defense response to cellular stress, such as low energy availability and increased oxidative stress levels (Greer and Brunet,
2005).

2011 Insulin effects in muscle and adipose tissue.

Diabetes Res Clin Pract. 2011 Aug;93 Suppl 1:S52-9. doi: 10.1016/S0168-8227(11)70014-6. Review

2013 Bmal1 and β-cell clock are required for adaptation to circadian disruption, and their loss of function leads to oxidative stress-induced β-cell fai...

Keywords: ARNTL Transcription Factors;Adaptation, Physiological;Animals;Antioxidant;Circadian Rhythm;Diabetes Mellitus, Experimental;Gene Expression Regulation;Glucose;Hyperglycemia;Insulin;Insulin-Secreting Cells;Ion Channels;Male;Mice;Mice, Transgenic;Mitochondrial Proteins;Oxidative Stress;Reactive Oxygen Species;Uncoupling Protein 2

2013 Regulation of male fertility by the bone-derived hormone osteocalcin.

Osteocalcin acts on Leydig cells of the testis to stimulate testosterone biosynthesis and therefore affect male fertility (R).

Keywords: Animals;Bone and Bones;Fertility;Hormone;Humans;Male;Osteocalcin;Reproduction;Testosterone

2014 Glucose induces intestinal human UDP-glucuronosyltransferase (UGT) 1A1 to prevent neonatal hyperbilirubinemia.

«Inadequate calorie intake or starvation has been suggested as a cause of neonatal jaundice, which can further cause permanent brain damage, kernicterus. This study experimentally investigated whether additional glucose treatments induce the bilirubin-metabolizing enzyme--UDP-glucuronosyltransferase (UGT) 1A1--to prevent the onset of neonatal hyperbilirubinemia. Neonatal humanized UGT1 (hUGT1) mice physiologically develop jaundice. In this study, UGT1A1 expression levels were determined in the liver and small intestine of neonatal hUGT1 mice that were orally treated with glucose. In the hUGT1 mice, glucose induced UGT1A1 in the small intestine, while it did not affect the expression of UGT1A1 in the liver. UGT1A1 was also induced in the human intestinal Caco-2 cells when the cells were cultured in the presence of glucose. Luciferase assays demonstrated that not only the proximal region (-1300/-7) of the UGT1A1 promoter, but also distal region (-6500/-4050) were responsible for the induction of UGT1A1 in the intestinal cells. Adequate calorie intake would lead to the sufficient expression of UGT1A1 in the small intestine to reduce serum bilirubin levels. Supplemental treatment of newborns with glucose solution can be a convenient and efficient method to treat neonatal jaundice while allowing continuous breastfeeding.»

2015 L-Citrulline increases hepatic sensitivity to insulin by reducing the phosphorylation of serine 1101 in insulin receptor substrate-1.

L-Cit enhanced the insulin-induced phosphorylation of Akt in H4IIE cells. Moreover, the inhibited expression of Dex/cAMP-induced PEPCK mRNA by insulin was enhanced by the L-Cit treatment. The phosphorylation of tyrosine, which is upstream of Akt, in insulin receptor substrate-1 (IRS-1) was increased by the L-Cit treatment. The L-Cit-induced enhancement in insulin signaling was not related to the binding affinity of insulin to the insulin receptor or to the expression of the insulin receptor, but to a decrease in the phosphorylation of serine 1101 in IRS-1. These results were also confirmed in animal experiments. In the liver of L-Cit-treated rats, PI3K/Akt signaling was improved by decreases in the phosphorylation of serine 1101.

Keywords: Animals;Citrulline;Insulin;Phosphorylation;Rats;Serine

2015 The evaluation of inflammatory and oxidative stress biomarkers on coffee-diabetes association: results from the 10-year follow-up of the ATTICA Stu...

«During follow-up, 191 incident cases of diabetes were documented (incidence 13.4% in men and 12.4% in women). After various adjustments, individuals who consumed ⩾250 ml of coffee (≈1.5cup) had 54% lower odds of developing diabetes (95% confidence interval: 0.24, 0.90), as compared with abstainers. A dose-response linear trend between coffee drinking and diabetes incidence was also observed (P for trend=0.017). When controlling for several oxidative stress and inflammatory biomarkers, the inverse association between habitual coffee drinking and diabetes was found to be mediated by serum amyloid-A levels.»

«This work highlights the significance of long-term habitual coffee drinking against diabetes onset. The anti-inflammatory effect of several coffee components may be responsible for this protection.»

«Caffeine has been also found to stimulate pancreatic
insulin secretion and CGA is believed to act as a potent inhibitor of
glucose-6-phosphatase, which releases glucose to circulation, and, when abnormal, disturbs normoglycaemia. Both caffeine and CGA
decrease glucose gastric absorption, modulating GIP and GLP-1 secretion.»

«CGA has been shown to inhibit the activation of NF-κb in cultured cells.»

2015 Bicarbonate-sensitive calcification and lifespan of klotho-deficient mice.

«Klotho, a protein counteracting aging, is a powerful inhibitor of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] formation and regulator of mineral metabolism. In klotho hypomorphic (kl/kl) mice, excessive 1,25(OH)2D3 formation lead to hypercalcemia, hyperphosphatemia and vascular calcification, severe growth deficits, accelerated aging and early death. Kl/kl mice further suffer from extracellular volume depletion and hypotension, leading to the stimulation of antidiuretic hormone and aldosterone release. A vitamin D-deficient diet, restriction of dietary phosphate, inhibition of mineralocorticoid receptors with spironolactone, and dietary NaCl all extend the lifespan of kl/kl mice. Kl/kl mice suffer from acidosis. The present study explored whether replacement of tap drinking water by 150 mM NaHCO3 affects the growth, tissue calcification, and lifespan of kl/kl mice. As a result, NaHCO3 administration to kl/kl mice did not reverse the growth deficit but substantially decreased tissue calcification and significantly increased the average lifespan from 78 to 127 days. NaHCO3 did not significantly affect plasma concentration of 1,25(OH)2D3 and Ca(2+) but significantly decreased plasma phosphate concentration and plasma aldosterone concentration. The present study reveals a novel effect of bicarbonate, i.e., a favorable influence on vascular calcification and early death of klotho-deficient mice.»

2016 Features of an altered AMPK metabolic pathway in Gilbert's Syndrome, and its role in metabolic health.

«Energy metabolism, involving the ATP-dependent AMPK-PgC-Ppar pathway impacts metabolic health immensely, in that its impairment can lead to obesity, giving rise to disease. Based on observations that individuals with Gilbert's syndrome (GS; UGT1A1(*)28 promoter mutation) are generally lighter, leaner and healthier than controls, specific inter-group differences in the AMPK pathway regulation were explored. Therefore, a case-control study involving 120 fasted, healthy, age- and gender matched subjects with/without GS, was conducted. By utilising intra-cellular flow cytometry (next to assessing AMPKα1 gene expression), levels of functioning proteins (phospho-AMPK α1/α2, PgC 1 α, Ppar α and γ) were measured in PBMCs (peripheral blood mononucleated cells). In GS individuals, rates of phospho-AMPK α1/α2, -Ppar α/γ and of PgC 1α were significantly higher, attesting to a boosted fasting response in this condition. In line with this finding, AMPKα1 gene expression was equal between the groups, possibly stressing the post-translational importance of boosted fasting effects in GS. In reflection of an apparently improved health status, GS individuals had significantly lower BMI, glucose, insulin, C-peptide and triglyceride levels. Herewith, we propose a new theory to explain why individuals having GS are leaner and healthier, and are therefore less likely to contract metabolic diseases or die prematurely thereof.»

1986 Effect of adrenal steroids on insulin release from cultured rat islets of Langerhans.

«The effect of additions to the culture medium of some natural or synthetic corticosteroid hormone was studied in cultured rat islets of Langerhans. The steroids decreased glucose-induced insulin release. The extent of inhibition by dexamethasone was 18-55%, prednisolone 23%, hydrocortisone 21% and aldosterone 18%. None of them affected the basal secretion of insulin or had any effect on diameter or insulin content of the islet. The inhibitory action of dexamethasone on insulin release was observed in the range 63 nmol/l to 6.3 mumol/l. At 6.3 mumol/l during two h, dexamethasone (a) inhibited insulin response to glucose concentration above 5 mmol/l (b) caused a delay in the first phase and markedly reduced the second phase of insulin release of perifused islets, and (c) decreased the incorporation of [H3]-leucine into total islet proteins without affecting [H3]-leucine-incorporation into insulin plus proinsulin. It is suggested that steroids, by directly acting on the islets of Langerhans, may modulate the insulin-release response to secretagogues.»

1999 Stress: metaplastic effects in the hippocampus.

Memory impairments, which occur regularly across species as a result of aging, disease and psychological insults (for example, stress), constitute a useful area for investigation into the neurobiological basis of learning and memory. Memory researchers have identified the hippocampus as a crucial brain structure involved in key aspects of memory formation.

2019 Amygdala NPY Circuits Promote the Development of Accelerated Obesity under Chronic Stress Conditions

«Neuropeptide Y (NPY) exerts a powerful orexigenic effect in the hypothalamus. However, extra-hypothalamic nuclei also produce NPY, but its influence on energy homeostasis is unclear. Here we uncover a previously unknown feeding stimulatory pathway that is activated under conditions of stress in combination with calorie-dense food; NPY neurons in the central amygdala are responsible for an exacerbated response to a combined stress and high-fat-diet intervention. Central amygdala NPY neuron-specific Npy overexpression mimics the obese phenotype seen in a combined stress and high-fat-diet model, which is prevented by the selective ablation of Npy. Using food intake and energy expenditure as readouts, we demonstrate that selective activation of central amygdala NPY neurons results in increased food intake and decreased energy expenditure. Mechanistically, it is the diminished insulin signaling capacity on central amygdala NPY neurons under combined stress and high-fat-diet conditions that lead to the exaggerated development of obesity.»

Insulin - Selfhacked

Read about insulin and how it relates to your health. Insulin has both good and bad properties.

All About Testosterone - Selfhacked

Testosterone is the male sex hormone. It serves a variety of functions in the body in both males and females.

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