scholarly journals Elevated GH/IGF-I, Due to Somatotrope-Specific Loss of Both IGF-I and Insulin Receptors, Alters Glucose Homeostasis and Insulin Sensitivity in a Diet-Dependent Manner

Endocrinology ◽  
2011 ◽  
Vol 152 (12) ◽  
pp. 4825-4837 ◽  
Author(s):  
Manuel D. Gahete ◽  
José Córdoba-Chacón ◽  
Chike V. Anadumaka ◽  
Qing Lin ◽  
Jens C. Brüning ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Mouse Model ◽  
Caloric Intake ◽  
Insulin Receptors ◽  
Tumor Formation ◽  
Metabolic Phenotype ◽  
Whole Body ◽  
Dependent Manner ◽  
Hepatic Lipid Accumulation ◽  
Igf I

A unique mouse model was developed with elevated endogenous GH (2- to 3-fold) and IGF-I (1.2- to 1.4-fold), due to somatotrope-specific Cre-mediated inactivation of IGF-I receptor (IgfIr) and insulin receptor (Insr) genes (IgfIr,InsrrGHpCre, referred to as HiGH mice). We demonstrate that the metabolic phenotype of HiGH mice is diet dependent and differs from that observed in other mouse models of GH excess due to ectopic heterologous transgene expression or pituitary tumor formation. Elevated endogenous GH promotes lean mass and whole-body lipid oxidation but has minimal effects on adiposity, even in response to diet-induced obesity. When caloric intake is moderated, elevated GH improves glucose clearance, despite low/normal insulin sensitivity, which may be explained in part by enhanced IGF-I and insulin output. However, when caloric intake is in excess, elevated GH promotes hepatic lipid accumulation, insulin resistance, hyperglycemia, and ketosis. The HiGH mouse model represents a useful tool to study the role endogenous circulating GH levels play in regulating health and disease.

459-P: Liver-Targeted Mitochondrial Uncoupling by CRMP Improves Whole-Body Insulin Sensitivity and Attenuates Atherosclerosis in A LDLR-/- Mouse Model of Metabolic Syndrome

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 459-P
Author(s):  
LEIGH GOEDEKE ◽  
NOEMI ROTLLAN ◽  
KESHIA TOUSSAINT ◽  
ALI NASIRI ◽  
XINBO ZHANG ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Mouse Model ◽  
Whole Body ◽  
Mitochondrial Uncoupling

scholarly journals Effects of birth weight, sex and neonatal glucocorticoid overexposure on glucose–insulin dynamics in young adult horses

2016 ◽  
Vol 8 (2) ◽  
pp. 206-215 ◽  
Author(s):  
O. A. Valenzuela ◽  
J. K. Jellyman ◽  
V. L. Allen ◽  
N. B. Holdstock ◽  
A. J. Forhead ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Birth Weight ◽  
Insulin Sensitivity ◽  
Young Adult ◽  
Glucose Tolerance ◽  
Metabolic Phenotype ◽  
Whole Body ◽  
Sexually Dimorphic ◽  
Genetic And Environmental Factors ◽  
Glucose Stimulated Insulin Secretion

In several species, adult metabolic phenotype is influenced by the intrauterine environment, often in a sex-linked manner. In horses, there is also a window of susceptibility to programming immediately after birth but whether adult glucose–insulin dynamics are altered by neonatal conditions remains unknown. Thus, this study investigated the effects of birth weight, sex and neonatal glucocorticoid overexposure on glucose–insulin dynamics of young adult horses. For the first 5 days after birth, term foals were treated with saline as a control or ACTH to raise cortisol levels to those of stressed neonates. At 1 and 2 years of age, insulin secretion and sensitivity were measured by exogenous glucose administration and hyperinsulinaemic–euglycaemic clamp, respectively. Glucose-stimulated insulin secretion was less in males than females at both ages, although there were no sex-linked differences in glucose tolerance. Insulin sensitivity was greater in females than males at 1 year but not 2 years of age. Birth weight was inversely related to the area under the glucose curve and positively correlated to insulin sensitivity at 2 years but not 1 year of age. In contrast, neonatal glucocorticoid overexposure induced by adrenocorticotropic hormone (ACTH) treatment had no effect on whole body glucose tolerance, insulin secretion or insulin sensitivity at either age, although this treatment altered insulin receptor abundance in specific skeletal muscles of the 2-year-old horses. These findings show that glucose–insulin dynamics in young adult horses are sexually dimorphic and determined by a combination of genetic and environmental factors acting during early life.

Effect of exercise training on whole-body insulin sensitivity and responsiveness

1984 ◽  
Vol 56 (5) ◽  
pp. 1217-1222 ◽  
Author(s):  
D. E. James ◽  
E. W. Kraegen ◽  
D. J. Chisholm
Keyword(s):  
Insulin Sensitivity ◽  
Exercise Training ◽  
Glucose Utilization ◽  
Insulin Receptors ◽  
Whole Body ◽  
Glucose Disposal ◽  
Significant Shift ◽  
Insulin Levels ◽  
Plasma Insulin Levels

Exercise training causes a decline in basal and glucose-stimulated plasma insulin levels and improves glucose tolerance. Furthermore evidence has been presented for effects on both insulin receptors and postreceptor events. However, it is unclear how these changes affect the in vivo dose-response relationship between insulin levels and whole-body glucose utilization. The aim was to examine the effect of exercise training on this relationship and distinguish between changes in insulin sensitivity and responsiveness. Euglycemic clamps were performed in trained (ET, running 1 h/day for 7 wk), sedentary (CON), and sedentary food-restricted ( SFR ) rats. ET rats showed no increase in maximal net glucose utilization in response to insulin (ET 29.5 +/- 0.6 vs. CON 28.2 +/- 1.5 mg X kg-1 X min-1, NS), whereas insulin sensitivity was increased as indicated by the insulin concentration causing half-maximal stimulation (ED50) (49 +/- 20 for ET and 133 +/- 30 mU/l for CON). Thus 7 wk of moderate exercise training resulted in a significant shift of whole-body insulin sensitivity to place ED50 well within the physiological range of insulin concentrations. This would undoubtedly result in improved glucose disposal in the postprandial state and emphasizes the potential benefit of exercise in obesity and type II diabetes.

scholarly journals Lectin-induced alterations of the interaction of insulin and insulin-like growth factor 1 receptors with their ligands

2008 ◽  
Vol 73 (8-9) ◽  
pp. 793-804 ◽  
Author(s):  
Romana Masnikosa ◽  
Anna Nikolic ◽  
Olgica Nedic
Keyword(s):  
Growth Factor ◽  
Cell Membrane ◽  
Wheat Germ ◽  
Insulin Receptors ◽  
Insulin Binding ◽  
Dependent Manner ◽  
Con A ◽  
High Affinity ◽  
Igf I ◽  
Dose Dependent

In order to study whether the carbohydrate moieties of the human placental IGF-I receptor (IGF1R), IGF-II receptor (IGF2R) and insulin receptors (IRs) play a role in ligand binding, solubilised cell membrane preparations were incubated with 125I-labelled IGF-I, IGF-II and insulin in the presence of lectins with different sugar specificities. Three incubation procedures were tested: ligand-first, co-incubation and lectin-first incubation. Wheat germ agglutinin (WGA), concanavalin A (Con A) and phytohaemagglutinin (PHA) altered the binding of IGF-I and insulin to their high-affinity receptors in a lectin specific and dose-dependent manner, whereas these lectins did not affect the interaction of IGF-II with its receptor(s). Moreover, the same lectins either inhibited or enhanced IGF-I and insulin binding, depending on the incubation scheme. These results also suggest that IR-A and IR-B from human placenta might be differently glycosylated.

scholarly journals Paternal High-Protein Diet Programs Offspring Insulin Sensitivity in a Sex-Specific Manner

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 751
Author(s):  
Pengfei Gong ◽  
Danielle Bailbé ◽  
Lola Bianchi ◽  
Gaëlle Pommier ◽  
Junjun Liu ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Cell Mass ◽  
High Protein Diet ◽  
High Protein ◽  
Protein Diet ◽  
Metabolic Phenotype ◽  
Whole Body ◽  
Standard Diet ◽  
Β Cell ◽  
The Impact

The impact of maternal nutrition on offspring is well documented. However, the implication of pre-conceptional paternal nutrition on the metabolic health of the progeny remains underexplored. Here, we investigated the impact of paternal high-protein diet (HPD, 43.2% protein) consumption on the endocrine pancreas and the metabolic phenotype of offspring. Male Wistar rats were given HPD or standard diet (SD, 18.9% protein) for two months. The progenies (F1) were studied at fetal stage and in adulthood. Body weight, glycemia, glucose tolerance (GT), glucose-induced insulin secretion in vivo (GIIS) and whole-body insulin sensitivity were assessed in male and female F1 offspring. Insulin sensitivity, GT and GIIS were similar between F1 females from HPD (HPD/F1) and SD fathers (SD/F1). Conversely, male HPD/F1 exhibited increased insulin sensitivity (p < 0.05) and decreased GIIS (p < 0.05) compared to male SD/F1. The improvement of insulin sensitivity in HPD/F1 was sustained even after 2 months of high-fat feeding. In male HPD/F1, the β cell mass was preserved and the β cell plasticity, following metabolic challenge, was enhanced compared to SD/F1. In conclusion, we provide the first evidence of a sex-specific impact of paternal HPD on the insulin sensitivity and GIIS of their descendants, demonstrating that changes in paternal nutrition alter the metabolic status of their progeny in adulthood.

scholarly journals A Low ω-6 to ω-3 PUFA Ratio (n–6:n–3 PUFA) Diet to Treat Fatty Liver Disease in Obese Youth

2020 ◽  
Vol 150 (9) ◽  
pp. 2314-2321 ◽  
Author(s):  
Michelle A Van Name ◽  
Mary Savoye ◽  
Jennifer M Chick ◽  
Brittany T Galuppo ◽  
Ariel E Feldstein ◽  
...  
Keyword(s):  
At Risk ◽  
Liver Disease ◽  
Insulin Sensitivity ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Metabolic Phenotype ◽  
Whole Body ◽  
Pufa Ratio ◽  
Obese Youth ◽  
Pufa Diet

ABSTRACT Background Recent literature suggests that the Western diet's imbalance between high ω-6 (n–6) and low ω-3 (n–3) PUFA intake contributes to fatty liver disease in obese youth. Objectives We tested whether 12 wk of a low n–6:n–3 PUFA ratio (4:1) normocaloric diet mitigates fatty liver and whether the patatin-like containing domain phospholipase 3 (PNPLA3) rs738409 variant affects the response. Methods In a single-arm unblinded study, obese youth 9–19 y of age with nonalcoholic fatty liver disease were treated with a normocaloric low n–6:n–3 PUFA ratio diet for 12 wk. The primary outcome was change in hepatic fat fraction (HFF%), measured by abdominal MRI. Metabolic parameters included alanine aminotransferase (ALT), lipids, measures of insulin sensitivity, and plasma oxidized linoleic acid metabolites (OXLAMs). Outcomes were also analyzed by PNPLA3 rs738409 genotype. Wilcoxon's signed rank test, the Mann–Whitney U test, and covariance pattern modeling were used. Results Twenty obese adolescents (median age: 13.3 y; IQR: 10.5–16.4 y) were enrolled and 17 completed the study. After 12 wk of dietary intervention, HFF% decreased by 25.8% (P = 0.009) despite stable weight. We observed a 34.4% reduction in ALT (P = 0.001), 21.9% reduction in triglycerides (P = 0.046), 3.28% reduction in LDL cholesterol (P = 0.071), and a 26.3% improvement in whole body insulin sensitivity (P = 0.032). The OXLAMs 9-hydroxy-octadecandienoic acid (9-HODE) (P = 0.011), 13-HODE (P = 0.007), and 9-oxo-octadecadienoic acid (9-oxoODE) (P = 0.024) decreased after 12 wk. HFF% declined in both the not-at-risk (CC/CG) and at-risk (GG) PNPLA3 rs738409 genotype groups, with significant (P = 0.016) HFF% reduction in the GG group. Changes in 9-HODE (P = 0.023), 9-oxoODE (P = 0.009), and 13-oxoODE (P = 0.003) differed between the 2 genotype groups over time. Conclusions These data suggest that, independently of weight loss, a low n–6:n–3 PUFA diet ameliorates the metabolic phenotype of adolescents with fatty liver disease and that response to this diet is modulated by the PNPLA3 rs738409 genotype. This trial was registered at clinicaltrials.gov as NCT01556113.

scholarly journals Akr1d1-/- mice have a sexually dimorphic metabolic phenotype with reduced fat mass, increased insulin sensitivity and hypertriglyceridemia in males

2021 ◽  
Author(s):  
Laura L Gathercole ◽  
Nikolaos Nikolaou ◽  
Anastasia Arvaniti ◽  
Shelley E Harris ◽  
Toryn M Poolman ◽  
...  
Keyword(s):  
Bile Acid ◽  
Insulin Sensitivity ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Metabolic Phenotype ◽  
Lipid Homeostasis ◽  
Bile Acid Metabolism ◽  
Sexually Dimorphic ◽  
Dependent Manner

AbstractBackgroundSteroid 5β-reductase (AKR1D1) plays important roles in hepatic glucocorticoid clearance and bile acid synthesis. Glucocorticoids and bile acids are potent metabolic regulators, but whether AKR1D1 controls metabolic phenotype in vivo is unknown.MethodsAkr1d1-/-mice were generated on a C57BL/6 background. Liquid chromatography / mass spectrometry, metabolomic and transcriptomic approaches were used to determine effects on glucocorticoid and bile acid homeostasis. Metabolic phenotypes including body weight and composition, lipid homeostasis, glucose tolerance and insulin sensitivity were evaluated. Molecular changes were assessed by RNASeq and western blotting. Male Akr1d1-/-mice were challenged with a 60% high fat diet.ResultsAkr1d1-/-mice had a sex specific metabolic phenotype. At 30-weeks of age male, but not female, Akr1d1-/-mice were more insulin sensitive and had reduced lipid accumulation in the liver and adipose tissue, concomitant with hypertriglyceridemia and increased intramuscular triacylglycerol. This phenotype was underpinned by sexually dimorphic changes in bile acid metabolism and composition, but without overt effects on glucocorticoid action. Male Akr1d1-/-mice were not protected against diet induced obesity and insulin resistance.ConclusionThis study shows that AKR1D1 controls bile acid homeostasis in vivo and that altering its activity can affect insulin sensitivity and lipid homeostasis in a sex dependent manner.

scholarly journals IL-6 Trans-Signaling in the Brain Influences the Metabolic Phenotype of the 3xTg-AD Mouse Model of Alzheimer’s Disease

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1605
Author(s):  
Anna Escrig ◽  
Amalia Molinero ◽  
Brenda Méndez ◽  
Mercedes Giralt ◽  
Gemma Comes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Neurodegenerative Disorder ◽  
Metabolic Phenotype ◽  
Soluble Form ◽  
Dependent Manner ◽  
Model Of Alzheimer’S Disease ◽  
The Brain ◽  
Ad Mouse Model

Alzheimer’s disease (AD) is a neurodegenerative disorder that causes the most prevalent dementia in the elderly people. Obesity and insulin resistance, which may cause major health problems per se, are risk factors for AD, and cytokines such as interleukin-6 (IL-6) have a role in these conditions. IL-6 can signal either through a membrane receptor or by trans-signaling, which can be inhibited by the soluble form of the co-receptor gp130 (sgp130). We have addressed the possibility that blocking IL-6 trans-signaling in the brain could have an effect in the triple transgenic 3xTg-AD mouse model of AD and/or in obesity progression, by crossing 3xTg-AD mice with GFAP-sgp130Fc mice. To serve as control groups, GFAP-sgp130Fc mice were also crossed with C57BL/6JOlaHsd mice. Seventeen-month-old mice were fed a control diet (18% kcal from fat) and a high-fat diet (HFD; 58.4% kcal from fat). In our experimental conditions, the 3xTg-AD model showed a mild amyloid phenotype, which nevertheless altered the control of body weight and related endocrine and metabolic factors, suggestive of a hypermetabolic state. The inhibition of IL-6 trans-signaling modulated some of these traits in both 3xTg-AD and control mice, particularly during HFD, and in a sex-dependent manner. These experiments provide evidence of IL-6 trans-signaling playing a role in the CNS of a mouse model of AD.

Abstract 13133: Silencing of Angiopoietin-like Protein 3 ( ANGPTL3 ) in IHH- Hepatocytes Results in Increased Insulin Sensitivity and Reduced Triglyceride-rich VLDL Secretion

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Anna M Tikka ◽  
Pirkka-Pekka Laurila ◽  
Jarkko Soronen ◽  
Jari Metso ◽  
Christian Ehnholm ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Secretory Protein ◽  
Whole Body ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Insulin Stimulation ◽  
Vldl Secretion ◽  
Immortalized Hepatocytes ◽  
Pkb Phosphorylation

AIMS: Homozygosity of loss-of-function mutations in ANGPTL3 -gene results in familial combined hypolipidemia (FHBL2,OMIM #605019) characterized by reduction of all major plasma lipoprotein classes VLDL, LDL, HDL and low circulating free fatty acids, glucose and insulin levels. Thus complete lack of ANGPTL3 in humans not only affects lipid metabolism but also whole-body insulin and glucose balance. Our aim was to investigate the function of ANGPTL3, a hepatic secretory protein, in promoting hypolipidemia and hepatic insulin sensitivity. METHODS: We used wild type and ANGPTL3-silenced human immortalized hepatocytes (IHH) to investigate the effect of ANGPTL3-silencing on hepatic VLDL secretion and glucose uptake. RESULTS: We demonstrate that insulin downregulates hepatic secretion of ANGPTL3 and triglyceride-enriched VLDL1-type particles in a dose dependent manner. Similar effect on VLDL secretion was demonstrated with a treatment of PPAR[[Unable to Display Character: &#436;]] agonist rosiglitazone. We further show that ANGPTL3-silenced cells display a more pronounced shift from the secretion of TG-enriched VLDL1-type particles to a secretion of lipid poor VLDL2-type particles during insulin stimulation. Silencing of ANGPTL3 improved hepatic glucose uptake by 20-50 % depending on the glucose and insulin concentration, resulted in a trend towards increased AKT/PKB phosphorylation upon insulin stimulation and downregulated fasting induced transcription factor PGC1α and its downstream targets. CONCLUSION: Our results indicate a similar function of both insulin and rosiglitazone regarding regulation of ANGPTL3 and VLDL secretion in hepatocytes, and suggest that insulin and PPAR[[Unable to Display Character: &#436;]] might mediate some of their functions via ANGPTL3. Our results give more insight into the liver specific role of ANGPTL3 and links silencing of ANGPTL3 with Insulin sensitivity. Since humans with elevated levels of ANGPTL3 display hyperlipidemia and insulin resistance it might be beneficial to target ANGPTL3 silencing in the liver, the major site of ANGPTL3 expression, to balance lipid and glucose homeostasis and lower risk for cardiovascular diseases.

Selective activation of PPARγ in skeletal muscle induces endogenous production of adiponectin and protects mice from diet-induced insulin resistance

2010 ◽  
Vol 298 (1) ◽  
pp. E28-E37 ◽  
Author(s):  
Rajesh H. Amin ◽  
Suresh T. Mathews ◽  
Heidi S. Camp ◽  
Liyun Ding ◽  
Todd Leff
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Transgenic Mice ◽  
Muscle Tissue ◽  
Glucose Homeostasis ◽  
Muscle Cells ◽  
Whole Body ◽  
Fiber Types ◽  
Dependent Manner

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ plays a key role in regulating whole body glucose homeostasis and insulin sensitivity. Although it is expressed most highly in adipose, it is also present at lower levels in many tissues, including skeletal muscle. The role muscle PPARγ plays in metabolic regulation and in mediating the antidiabetic effects of the thiazolidinediones is not understood. The goal of this work was to examine the molecular and physiological effects of PPARγ activation in muscle cells. We found that pharmacological activation of PPARγ in primary cultured myocytes, and genetic activation of muscle PPARγ in muscle tissue of transgenic mice, induced the production of adiponectin directly from muscle cells. This muscle-produced adiponectin was functional and capable of stimulating adiponectin signaling in myocytes. In addition, elevated skeletal muscle PPARγ activity in transgenic mice provided a significant protection from high-fat diet-induced insulin resistance and associated changes in muscle phenotype, including reduced myocyte lipid content and an increase in the proportion of oxidative muscle fiber types. Our findings demonstrate that PPARγ activation in skeletal muscle can have a significant protective effect on whole body glucose homeostasis and insulin resistance and that myocytes can produce and secrete functional adiponectin in a PPARγ-dependent manner. We propose that activation of PPARγ in myocytes induces a local production of adiponectin that acts on muscle tissue to improve insulin sensitivity.

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