scholarly journals β-cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome

2013 ◽  
Vol 219 (3) ◽  
pp. 231-241 ◽  
Author(s):  
Liselotte Fransson ◽  
Stephanie Franzén ◽  
Victoria Rosengren ◽  
Petra Wolbert ◽  
Åke Sjöholm ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Drinking Water ◽  
Mouse Model ◽  
Glucose Intolerance ◽  
Body Weight Gain ◽  
Β Cell ◽  
Cell Adaptation ◽  
The Metabolic Syndrome ◽  
Islet Volume

Glucocorticoids (GCs) are stress hormones primarily responsible for mobilizing glucose to the circulation. Due to this effect, insulin resistance and glucose intolerance are concerns in patients with endogenous overproduction of GCs and in patients prescribed GC-based therapy. In addition, hypercortisolemic conditions share many characteristics with the metabolic syndrome. This study reports on a thorough characterization, in terms of glucose control and lipid handling, of a mouse model where corticosterone is given via the drinking water. C57BL/6J mice were treated with corticosterone (100 or 25 μg/ml) or vehicle in their drinking water for 5 weeks after which they were subjected to insulin or glucose tolerance tests. GC-treated mice displayed increased food intake, body weight gain, and central fat deposit accumulations. In addition, the GC treatment led to dyslipidemia as well as accumulation of ectopic fat in the liver and skeletal muscle, having a substantial negative effect on insulin sensitivity. Also glucose intolerance and hypertension, both part of the metabolic syndrome, were evident in the GC-treated mice. However, the observed effects of corticosterone were reversed after drug removal. Furthermore, this study reveals insights into β-cell adaptation to the GC-induced insulin resistance. Increased pancreatic islet volume due to cell proliferation, increased insulin secretion capacity, and increased islet chaperone expression were found in GC-treated animals. This model mimics the human metabolic syndrome. It could be a valuable model for studying the complex mechanisms behind the development of the metabolic syndrome and type 2 diabetes, as well as the multifaceted relations between GC excess and disease.

scholarly journals Transgenerational Inheritance of Glucose Intolerance in a Mouse Model of Neonatal Overnutrition

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5617-5623 ◽  
Author(s):  
Thais Pentinat ◽  
Marta Ramon-Krauel ◽  
Judith Cebria ◽  
Ruben Diaz ◽  
Josep C. Jimenez-Chillaron
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Mouse Model ◽  
Glucose Intolerance ◽  
Cell Function ◽  
Male Mice ◽  
Rapid Weight Gain ◽  
Abnormal Growth ◽  
Peripheral Insulin Resistance ◽  
The Metabolic Syndrome

Epidemiological and clinical data show that rapid weight gain early in life is strongly associated with several components of the metabolic syndrome. Strikingly, abnormal growth rates in early life can additionally influence diabetes risk in subsequent generations. Here we aim to study whether neonatal overgrowth induces diabetes in offspring and grand-offspring of affected individuals using a mouse model of neonatal overfeeding. We induced neonatal overgrowth (ON-F0) by culling offspring to four pups per dam during lactation. By age 4 months, ON-F0 mice developed many features of the metabolic syndrome, including obesity, insulin resistance, and glucose intolerance. We then studied whether male offspring (ON-F1) and grand-offspring (ON-F2) of ON-F0 male mice, which were not overfed during lactation, developed features of the metabolic syndrome with aging. ON-F1 mice developed fed and fasting hyperinsulimemia, hypertryglyceridemia, insulin resistance, and glucose intolerance, but not obesity, by age 4 months. In contrast, ON-F2 male mice showed a more moderate phenotype and only developed fasting hyperglycemia and glucose intolerance by age 4 months. Impaired glucose tolerance in ON-F1 and ON-F2 mice appeared to be accounted for primarily by peripheral insulin resistance, because beta-cell function remained normal or even increased in these cohorts. Nutritional challenges occurring during sensitive periods of development may have adverse metabolic consequences well beyond the lifespan of affected individuals and manifest in subsequent generations. Transgenerational progression of metabolic phenotypes through the male lineage supports a potential role for epigenetic mechanisms in mediating these effects.

scholarly journals ADAM19: A Novel Target for Metabolic Syndrome in Humans and Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Lakshini Weerasekera ◽  
Caroline Rudnicka ◽  
Qing-Xiang Sang ◽  
Joanne E. Curran ◽  
Matthew P. Johnson ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Mouse Model ◽  
White Adipose Tissue ◽  
Mononuclear Cells ◽  
Western World ◽  
Diet Induced Obesity ◽  
The Metabolic Syndrome

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF-α levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF-α levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D.

Increased Aβ production prompts the onset of glucose intolerance and insulin resistance

2012 ◽  
Vol 302 (11) ◽  
pp. E1373-E1380 ◽  
Author(s):  
Margarita Jiménez-Palomares ◽  
Juan José Ramos-Rodríguez ◽  
José Francisco López-Acosta ◽  
Mar Pacheco-Herrero ◽  
Alfonso M. Lechuga-Sancho ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Glucose Metabolism ◽  
Glucose Intolerance ◽  
Cell Mass ◽  
Phenotypic Characterization ◽  
Β Cell ◽  
Altered Glucose ◽  
Islet Volume ◽  
Aβ Production

Type 2 diabetes (T2D) mellitus and Alzheimer's disease (AD) are two prevalent diseases with comparable pathophysiological features and genetic predisposition. Patients with AD are more susceptible to develop T2D. However, the molecular mechanism linking AD and T2D remains elusive. In this study, we have generated a new mouse model to test the hypothesis that AD would prompt the onset of T2D in mice. To test our hypothesis, we crossed Alzheimer APPswe/PS1dE9 (APP/PS1) transgenic mice with mice partially deficient in leptin signaling ( db/+). Body weight, plasma glucose, and insulin levels were monitored. Phenotypic characterization of glucose metabolism was performed using glucose and insulin tolerance tests. β-Cell mass, islet volume, and islet number were analyzed by histomorphometry. APP/PS1 coexpression in mice with intact leptin receptor signaling did not show any metabolic perturbations in glucose metabolism or insulin sensitivity. In contrast, APP/PS1 coexpression in db/+ mice resulted in nonfasting hyperglycemia, hyperinsulinemia, and hypercholesterolemia without changes in body weight. Conversely, fasting blood glucose and cholesterol levels remained unchanged. Coinciding with altered glucose metabolism, APP/PS1 coexpression in db/+ mice resulted in glucose intolerance, insulin resistance, and impaired insulin signaling. In addition, histomorphometric analysis of pancreata revealed augmented β-cell mass. Taken together, these findings provide experimental evidence to support the notion that aberrant Aβ production might be a mechanistic link underlying the pathology of insulin resistance and T2D in AD.

scholarly journals Metabolic Syndrome: From Molecular Mechanisms to Novel Therapies

2021 ◽  
Vol 22 (18) ◽  
pp. 10038
Author(s):  
Ali Abbas Rizvi ◽  
Anca Pantea Stoian ◽  
Manfredi Rizzo
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Glucose Intolerance ◽  
Central Obesity ◽  
Molecular Mechanisms ◽  
Atherogenic Dyslipidemia ◽  
Metabolic Abnormalities ◽  
Novel Therapies ◽  
The Metabolic Syndrome

The metabolic syndrome (MetS) consists of a cluster of metabolic abnormalities including central obesity, insulin resistance, glucose intolerance, hypertension, and atherogenic dyslipidemia [...]

Phenotypic and genetic analyses of subcongenic BB.SHR rat lines shorten the region on chromosome 4 bearing gene(s) for underlying facets of metabolic syndrome

2004 ◽  
Vol 18 (3) ◽  
pp. 325-330 ◽  
Author(s):  
Nora Klöting ◽  
Barbara Wilke ◽  
Ingrid Klöting
Keyword(s):  
Metabolic Syndrome ◽  
Glucose Intolerance ◽  
Body Weight Gain ◽  
Serum Insulin ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Chromosome 4 ◽  
Serum Triglycerides ◽  
Cholesterol Ratio ◽  
The Metabolic Syndrome

Congenic BB.SHR ( D4Got41-Npy-Tacr1; BB.4S) rats develop an incomplete metabolic syndrome with obesity, hyperleptinemia, and dyslipidemia compared with their progenitor strain, the diabetes-prone BB/OK rat. To narrow down the underlying gene(s), two subcongenic BB.SHR rat lines, briefly termed BB.4Sa and BB.4Sb, were generated. Male BB.4S ( n = 20), BB.4Sa ( n = 24), and BB.4Sb ( n = 26) were longitudinally characterized for facets of the metabolic syndrome and analyzed for expression of genes located in the region of interest in liver and blood. Body weight gain was comparable, serum triglycerides and leptin were significantly increased, and total cholesterol and HDL-cholesterol ratio were decreased in BB.4S compared with both subcongenics. Serum insulin was significantly higher in BB.4S and BB.4Sa than in BB.4Sb. The adiposity index showed a graduated decrease from BB.6S to BB.4Sb. Obvious differences in relative expression were found in 6 of 10 genes in liver and in 2 of 9 genes in blood. Only one gene, the eukaryotic translation initiation factor 2α kinase 3 ( Eif2ak3 also called Perk or Pek), was significantly less expressed in liver and in blood of both subcongenic BB.4Sa and BB.4Sb compared with their “parental” BB.4S rats. Based on the phenotype and genotype in BB.4S and its subcongenic derivatives, the most important region on chromosome 4 can be said to lie between D4Got72 and Tacr1. Eif2ak3 is mapped in this region. Considering the function of Eif2ak3, it may be a candidate gene for the development of glucose intolerance found in both subcongenics but not in BB.4S. Allelic variants between BB/OK and SHR could influence Eif2ak3 function, possibly leading not only to glucose intolerance but also to the disturbances in hepatic and renal function found in human Wolcott-Rallison syndrome.

scholarly journals Chronic Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Activity Decreases Hypertension, Insulin Resistance, and Hypertriglyceridemia in Metabolic Syndrome

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Christine G. Schnackenberg ◽  
Melissa H. Costell ◽  
Daniel J. Krosky ◽  
Jianqi Cui ◽  
Charlene W. Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Glucose Intolerance ◽  
Body Weight Gain ◽  
Plasma Renin ◽  
Hydroxysteroid Dehydrogenase ◽  
Common Mechanism ◽  
Metabolic Activities

Metabolic syndrome is a constellation of risk factors including hypertension, dyslipidemia, insulin resistance, and obesity that promote the development of cardiovascular disease. Metabolic syndrome has been associated with changes in the secretion or metabolism of glucocorticoids, which have important functions in adipose, liver, kidney, and vasculature. Tissue concentrations of the active glucocorticoid cortisol are controlled by the conversion of cortisone to cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Because of the various cardiovascular and metabolic activities of glucocorticoids, we tested the hypothesis that 11β-HSD1 is a common mechanism in the hypertension, dyslipidemia, and insulin resistance in metabolic syndrome. In obese and lean SHR/NDmcr-cp (SHR-cp), cardiovascular, metabolic, and renal functions were measured before and during four weeks of administration of vehicle or compound 11 (10 mg/kg/d), a selective inhibitor of 11β-HSD1. Compound 11 significantly decreased 11β-HSD1 activity in adipose tissue and liver of SHR-cp. In obese SHR-cp, compound 11 significantly decreased mean arterial pressure, glucose intolerance, insulin resistance, hypertriglyceridemia, and plasma renin activity with no effect on heart rate, body weight gain, or microalbuminuria. These results suggest that 11β-HSD1 activity in liver and adipose tissue is a common mediator of hypertension, hypertriglyceridemia, glucose intolerance, and insulin resistance in metabolic syndrome.

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