scholarly journals ENDOCRINE SIDE EFFECTS OF ANTI-CANCER DRUGS: Effects of anti-cancer targeted therapies on lipid and glucose metabolism

2014 ◽  
Vol 170 (2) ◽  
pp. R43-R55 ◽  
Author(s):  
Bruno Vergès ◽  
Thomas Walter ◽  
Bertrand Cariou
Keyword(s):  
Blood Glucose ◽  
Glucose Metabolism ◽  
Glucose Homeostasis ◽  
Targeted Therapies ◽  
Ldl Cholesterol ◽  
Mtor Inhibitors ◽  
Receptor Expression ◽  
Plasma Triglycerides ◽  
Anti Cancer ◽  
Ldl Catabolism

During the past years, targeted therapies for cancer have been developed using drugs that have significant metabolic consequences. Among them, the mammalian target of rapamycin (mTOR) inhibitors and, to a much lesser extent, the tyrosine kinase inhibitors (TKIs) are involved. mTOR plays a key role in the regulation of cell growth as well as lipid and glucose metabolism. Treatment with mTOR inhibitors is associated with a significant increase in plasma triglycerides and LDL cholesterol. mTOR inhibitors seem to increase plasma triglycerides by reducing the activity of the lipoprotein lipase which is in charge of the catabolism of triglyceride-rich lipoproteins. The increase in LDL cholesterol observed with mTOR inhibitors seems to be due to a decrease in LDL catabolism secondary to a reduction of LDL receptor expression. In addition, treatment with mTOR inhibitors is associated with a high incidence of hyperglycemia, ranging from 13 to 50% in the clinical trials. The mechanisms responsible for hyperglycemia with new onset diabetes are not clear, but are likely due to the combination of impaired insulin secretion and insulin resistance. TKIs do not induce hyperlipidemia but alter glucose homeostasis. Treatment with TKIs may be associated either with hyperglycemia or hypoglycemia. The molecular mechanism by which TKIs control glucose homeostasis remains unknown. Owing to the metabolic consequences of these agents used as targeted anti-cancer therapies, a specific and personalized follow-up of blood glucose and lipids is recommended when using mTOR inhibitors and of blood glucose when using TKIs.

scholarly journals Simvastatin Impairs Glucose Homeostasis in Mice Depending on PGC-1α Skeletal Muscle Expression

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 351
Author(s):  
Miljenko Valentin Panajatovic ◽  
François Singh ◽  
Stephan Krähenbühl ◽  
Jamal Bouitbir
Keyword(s):  
Skeletal Muscle ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Glucose Homeostasis ◽  
Simvastatin Treatment ◽  
Skeletal Muscle Glucose Uptake ◽  
Skeletal Muscle Insulin Sensitivity ◽  
Glycogen Stores

Several studies showed an increased risk for diabetes with statin treatment. PGC-1α is an important regulator of muscle energy metabolism and mitochondrial biogenesis. Since statins impair skeletal muscle PGC-1α expression and reduced PGC-1α expression has been observed in diabetic patients, we investigated the possibility that skeletal muscle PGC1α expression influences the effect of simvastatin on muscle glucose metabolism. Mice with muscle PGC-1α knockout (KO) or PGC-1α overexpression (OE), and wild-type (WT) mice were investigated. Mice were treated orally for 3 weeks with simvastatin (5 mg/kg/day) and investigated by intraperitoneal glucose tolerance (iGTT), in vivo skeletal muscle glucose uptake, muscle glycogen content, and Glut4 and hexokinase mRNA and protein expression. Simvastatin impaired glucose metabolism in WT mice, as manifested by increased glucose blood concentrations during the iGTT, decreased skeletal muscle glucose uptake and glycogen stores. KO mice showed impaired glucose homeostasis with increased blood glucose concentrations during the iGTT already without simvastatin treatment and simvastatin induced a decrease in skeletal muscle glucose uptake. In OE mice, simvastatin treatment increased blood glucose and insulin concentrations during the iGTT, and increased skeletal muscle glucose uptake, glycogen stores, and Glut4 and hexokinase protein expression. In conclusion, simvastatin impaired skeletal muscle insulin sensitivity in WT mice, while KO mice exhibited impaired skeletal muscle insulin sensitivity already in the absence of simvastatin. In OE mice, simvastatin augmented muscular glucose uptake but impaired whole-body insulin sensitivity. Thus, simvastatin affected glucose homeostasis depending on PGC-1α expression.

scholarly journals Acyl Ghrelin Acts in the Brain to Control Liver Function and Peripheral Glucose Homeostasis in Male Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 858-868 ◽  
Author(s):  
Romana Stark ◽  
Alex Reichenbach ◽  
Sarah H. Lockie ◽  
Corinna Pracht ◽  
Qunli Wu ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Neural Circuit ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Nonesterified Fatty Acids ◽  
Ad Libitum ◽  
Acyl Ghrelin

Abstract Recent evidence suggests that peripheral ghrelin regulates glucose metabolism. Here, we designed experiments to examine how central acyl ghrelin infusion affects peripheral glucose metabolism under pair-fed or ad libitum feeding conditions. Mice received intracerebroventricular (icv) infusion of artificial cerebrospinal fluid (aCSF), ghrelin, and allowed to eat ad libitum (icv ghrelin ad lib) or ghrelin and pair-fed to the aCSF group (icv ghrelin pf). Minipumps delivered acyl ghrelin at a dose of 0.25 μg/h at 0.5 μL/h for 7 days. There was no difference in daily blood glucose, insulin, glucagon, triglycerides, or nonesterified fatty acids. Body weight gain and food intake was significantly higher in icv ghrelin ad lib mice. However, both icv ghrelin ad lib and icv ghrelin pf groups exhibited heavier white adipose mass. Icv ghrelin pf mice exhibited better glucose tolerance than aCSF or icv ghrelin ad lib mice during a glucose tolerance test, although both icv ghrelin ad lib and icv ghrelin pf increased insulin release during the glucose tolerance test. Central acyl ghrelin infusion and pair feeding also increased breakdown of liver glycogen and triglyceride, and regulated genes involved in hepatic lipid and glucose metabolism. Icv ghrelin pf mice had an increase in plasma blood glucose during a pyruvate tolerance test relative to icv ghrelin ad lib or aCSF mice. Our results suggest that under conditions of negative energy (icv ghrelin pf), central acyl ghrelin engages a neural circuit that influences hepatic glucose function. Metabolic status affects the ability of central acyl ghrelin to regulate peripheral glucose homeostasis.

scholarly journals AMPK Subunits Harbor Largely Nonoverlapping Genetic Determinants for Body Fat Mass, Glucose Metabolism, and Cholesterol Metabolism

2019 ◽  
Vol 105 (1) ◽  
pp. 14-25
Author(s):  
Elko Randrianarisoa ◽  
Angela Lehn-Stefan ◽  
Johannes Krier ◽  
Anja Böhm ◽  
Martin Heni ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Body Fat ◽  
Ldl Cholesterol ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Genetic Determinants ◽  
The Impact

Abstract Context Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a heterotrimeric enzyme and central regulator of cellular energy metabolism. The impact of single nucleotide polymorphisms (SNPs) in all 7 AMPK subunit genes on adiposity, glucose metabolism, and lipid metabolism has not yet been systematically studied. Objective To analyze the associations of common SNPs in all AMPK genes, and of different scores thereof, with adiposity, insulin sensitivity, insulin secretion, blood glucose, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, total cholesterol, and triglycerides. Study Design and Methods A cohort of 2789 nondiabetic participants from the Tübingen Family study of type 2 diabetes, metabolically characterized by oral glucose tolerance test and genotyped by genome-wide SNP array, was analyzed. Results We identified 6 largely nonoverlapping SNP sets across 4 AMPK genes (PRKAA1, PRKAA2, PRKAG2, PRKAG3) associated with adiposity, insulin sensitivity, insulin secretion, blood glucose, total/LDL cholesterol, or HDL cholesterol, respectively. A genetic score of body-fat-increasing alleles revealed per-allele effect sizes on body mass index (BMI) of +0.22 kg/m2 (P = 2.3 × 10–7), insulin sensitivity of −0.12 × 1019 L2/mol2 (P = 9.9 × 10–6) and 2-hour blood glucose of +0.02 mmol/L (P = 0.0048). Similar effects on blood glucose were observed with scores of insulin-sensitivity-reducing, insulin-secretion-reducing and glucose-raising alleles, respectively. A genetic cholesterol score increased total and LDL cholesterol by 1.17 mg/dL per allele (P = 0.0002 and P = 3.2 × 10–5, respectively), and a genetic HDL score decreased HDL cholesterol by 0.32 mg/dL per allele (P = 9.1 × 10–6). Conclusions We describe largely nonoverlapping genetic determinants in AMPK genes for diabetes-/atherosclerosis-related traits, which reflect the metabolic pathways controlled by the enzyme. Formation of trait-specific genetic scores revealed additivity of allele effects, with body-fat-raising alleles reaching a marked effect size. (J Clin Endocrinol Metab 105: 14–25, 2020)

scholarly journals Models for the Study of Whole-Body Glucose Kinetics: A Mathematical Synthesis

2013 ◽  
Vol 2013 ◽  
pp. 1-16 ◽  
Author(s):  
Leslie L. McKnight ◽  
Secundino Lopez ◽  
Anna Kate Shoveller ◽  
James France
Keyword(s):  
Mathematical Modeling ◽  
Blood Glucose ◽  
Glucose Metabolism ◽  
Glucose Homeostasis ◽  
Whole Body ◽  
Glucose Kinetics ◽  
Isotope Tracer ◽  
Glucose System ◽  
Blood Glucose Homeostasis

The maintenance of blood glucose homeostasis is complex and involves several key tissues. Most of these tissues are not easily accessible, making direct measurement of the physiological parameters involved in glucose metabolism difficult. The use of isotope tracer methodology and mathematical modeling allows indirect estimates of in vivo glucose metabolism through relatively noninvasive means. The purpose of this paper was to provide a mathematical synthesis of the models developed for describing glucose kinetics. As many of the models were developed using dogs, example data from the canine literature are presented. However, examples from the human and feline literature are also given in the absence of dog data. The glucose system is considered in both the steady and nonsteady states, and the models are examined by grouping them into schemes consisting of one, two, and three glucose compartments. Noncompartmental schemes are also considered briefly.

scholarly journals Effect of Konjac Mannan Oligosaccharides on Glucose Homeostasis via the Improvement of Insulin and Leptin Resistance In Vitro and In Vivo

Nutrients ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1705 ◽  
Author(s):  
Di Zhu ◽  
Qiaojuan Yan ◽  
Yanxiao Li ◽  
Jun Liu ◽  
Haijie Liu ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Homeostasis ◽  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
Leptin Receptor ◽  
Fasting Blood Glucose ◽  
Receptor Expression ◽  
Leptin Resistance ◽  
Ampk Pathway ◽  
Mannan Oligosaccharides

Functional oligosaccharides, particularly konjac mannan oligosaccharides (KMOS), can regulate glucose metabolism. However, the molecular mechanisms involved in the hypoglycemic effect of KMOS remain largely unknown. Here, the effect of KMOS supplementation on glucose homeostasis was evaluated in both high-fat diet (HFD)-fed C57BL/6J mice and high-glucosamine-induced HepG2 cells. KMOS supplementation remarkably ameliorated the fasting blood glucose, glucose tolerance, and insulin tolerance of HFD-fed mice. Abnormalities of triglyceride and glycogen metabolism in the liver induced by the HFD were reversed by KMOS supplementation. The insulin signaling pathway was activated by KMOS, with stimulation of GLUT2 membrane translocation and glucose uptake in HepG2 cells via the AMPK pathway. Moreover, KMOS suppressed p-mTOR expression and stimulated the GSK-3β/CREB pathway via the AMPK pathway. KMOS significantly upregulated leptin receptor expression and downregulated PTP1B and SOCS3 levels in the liver and brain, with a decreased serum leptin concentration. Phosphorylation of JAK2 and STAT3 in the liver was activated by KMOS supplementation, while the expressions of Sirt1, Tfam, and Pgc1-α in the brain were elevated. Conclusively, KMOS attenuated HFD-induced glucose metabolism dysfunction through the regulation of insulin resistance and leptin resistance. This finding indicates that KMOS have potential value as an anti-hyperglycemic dietary supplement.

Thermoneutral housing does not influence fat mass or glucose homeostasis in C57BL/6 mice

2018 ◽  
Vol 239 (3) ◽  
pp. 313-324 ◽  
Author(s):  
Lewin Small ◽  
Henry Gong ◽  
Christian Yassmin ◽  
Gregory J Cooney ◽  
Amanda E Brandon
Keyword(s):  
Glucose Metabolism ◽  
Ambient Temperature ◽  
Fat Mass ◽  
Glucose Homeostasis ◽  
Dietary Intervention ◽  
Whole Body ◽  
Housing Temperature ◽  
Brown Adipose ◽  
Normal Chow ◽  
Obesogenic Diet

One major factor affecting physiology often overlooked when comparing data from animal models and humans is the effect of ambient temperature. The majority of rodent housing is maintained at ~22°C, the thermoneutral temperature for lightly clothed humans. However, mice have a much higher thermoneutral temperature of ~30°C, consequently data collected at 22°C in mice could be influenced by animals being exposed to a chronic cold stress. The aim of this study was to investigate the effect of housing temperature on glucose homeostasis and energy metabolism of mice fed normal chow or a high-fat, obesogenic diet (HFD). Male C57BL/6J(Arc) mice were housed at standard temperature (22°C) or at thermoneutrality (29°C) and fed either chow or a 60% HFD for 13 weeks. The HFD increased fat mass and produced glucose intolerance as expected but this was not exacerbated in mice housed at thermoneutrality. Changing the ambient temperature, however, did alter energy expenditure, food intake, lipid content and glucose metabolism in skeletal muscle, liver and brown adipose tissue. Collectively, these findings demonstrate that mice regulate energy balance at different housing temperatures to maintain whole-body glucose tolerance and adiposity irrespective of the diet. Despite this, metabolic differences in individual tissues were apparent. In conclusion, dietary intervention in mice has a greater impact on adiposity and glucose metabolism than housing temperature although temperature is still a significant factor in regulating metabolic parameters in individual tissues.

scholarly journals Atorvastatin treatment does not abolish inflammatory mediated cardiovascular risk in subjects with chronic kidney disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Renate M. Hoogeveen ◽  
Simone L. Verweij ◽  
Yannick Kaiser ◽  
Jeffrey Kroon ◽  
Hein J. Verberne ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Chronic Kidney Disease ◽  
Cardiovascular Risk ◽  
Kidney Disease ◽  
Arterial Wall ◽  
Ldl Cholesterol ◽  
Statin Treatment ◽  
Receptor Expression ◽  
Disease Stage ◽  
Cellular Inflammation

AbstractIndividuals with chronic kidney disease are at an increased risk for cardiovascular disease. This risk may partially be explained by a chronic inflammatory state in these patients, reflected by increased arterial wall and cellular inflammation. Statin treatment decreases cardiovascular risk and arterial inflammation in non-CKD subjects. In patients with declining kidney function, cardiovascular benefit resulting from statin therapy is attenuated, possibly due to persisting inflammation. In the current study, we assessed the effect of statin treatment on arterial wall and cellular inflammation. Fourteen patients with chronic kidney disease stage 3 or 4, defined by an estimated Glomerular Filtration Rate between 15 and 60 mL/min/1.73 m2, without cardiovascular disease were included in a single center, open label study to assess the effect of atorvastatin 40 mg once daily for 12 weeks (NTR6896). At baseline and at 12 weeks of treatment, we assessed arterial wall inflammation by 18F-fluoro-deoxyglucose positron-emission tomography computed tomography (18F-FDG PET/CT) and the phenotype of circulating monocytes were assessed. Treatment with atorvastatin resulted in a 46% reduction in LDL-cholesterol, but this was not accompanied by an attenuation in arterial wall inflammation in the aorta or carotid arteries, nor with changes in chemokine receptor expression of circulating monocytes. Statin treatment does not abolish arterial wall or cellular inflammation in subjects with mild to moderate chronic kidney disease. These results imply that CKD-associated inflammatory activity is mediated by factors beyond LDL-cholesterol and specific anti-inflammatory interventions might be necessary to further dampen the inflammatory driven CV risk in these subjects.

scholarly journals Role of small leucine zipper protein in hepatic gluconeogenesis and metabolic disorder

2020 ◽  
Author(s):  
Minsoo Kang ◽  
Sun Kyoung Han ◽  
Suhyun Kim ◽  
Sungyeon Park ◽  
Yerin Jo ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Glucose Metabolism ◽  
Metabolic Disorder ◽  
Leucine Zipper ◽  
Metabolic Diseases ◽  
Adenosine Monophosphate ◽  
The Body ◽  
Hepatic Gluconeogenesis ◽  
Leucine Zipper Protein

Abstract Hepatic gluconeogenesis is the central pathway for glucose generation in the body. The imbalance between glucose synthesis and uptake leads to metabolic diseases such as obesity, diabetes, and cardiovascular diseases. Small leucine zipper protein (sLZIP) is an isoform of LZIP and it mainly functions as a transcription factor. Although sLZIP is known to regulate the transcription of genes involved in various cellular processes, the role of sLZIP in hepatic glucose metabolism is not known. In this study, we investigated the regulatory role of sLZIP in hepatic gluconeogenesis and its involvement in metabolic disorder. We found that sLZIP expression was elevated during glucose starvation, leading to the promotion of phosphoenolpyruvate carboxylase and glucose-6-phosphatase expression in hepatocytes. However, sLZIP knockdown suppressed the expression of the gluconeogenic enzymes under low glucose conditions. sLZIP also enhanced glucose production in the human liver cells and mouse primary hepatic cells. Fasting-induced cyclic adenosine monophosphate impeded sLZIP degradation. Results of glucose and pyruvate tolerance tests showed that sLZIP transgenic mice exhibited abnormal blood glucose metabolism. These findings suggest that sLZIP is a novel regulator of gluconeogenic enzyme expression and plays a role in blood glucose homeostasis during starvation.

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