Abstract 509: Myocardial Fatty Acid Oxidation Rates Remain Elevated in ob/ob Mice Despite Reversal of Obesity and Diabetes by Caloric Restriction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Crystal Sloan ◽  
Joseph Tuinei ◽  
E. Dale Abel
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Cardiac Hypertrophy ◽  
Caloric Restriction ◽  
Serum Triglyceride ◽  
Palmitate Oxidation ◽  
Oxidation Rates ◽  
Leptin Deficiency ◽  
Obesity And Diabetes ◽  
Myocardial Substrate

Leptin deficient ob/ob mice are commonly used to study the effects of obesity and insulin resistance on myocardial substrate metabolism. However, it is difficult to discern the specific contribution of obesity, insulin resistance and diabetes versus leptin deficiency to the observed phenotypes. We therefore adopted a strategy using caloric restriction to normalize body weight and reverse insulin resistance to study the effect of leptin deficiency on myocardial metabolism in lean ob/ob mice. Male 4-week old ob/ob mice were “pair fed” to a leptin-treated group (3mg/kg/day by i.p. injection) for three weeks. Glucose tolerance, serum insulin, serum triglycerides and FA oxidation rates in hearts perfused with 0.4mM palmitate ± 1 nM insulin were determined. Leptin-treated ob/ob mice ate significantly less than non-treated ob/ob mice, and their weight returned to wild type levels. Hyperglycemia, hyperinsulinemia, hypertriglyceridemia and cardiac hypertrophy were also completely reversed in leptin-treated ob/ob mice. In contrast, cardiac hypertrophy persisted in pair fed ob/ob mice and despite normalization of glucose tolerance and insulin levels, serum triglyceride concentrations increased by 2 and 6 -fold in pair fed ob/ob mice relative to untreated ob/ob and wildtype mice respectively (p<0.05). As previously reported, palmitate oxidation rates were 2.1-fold increased in ob/ob hearts relative to controls (p<0.005) and were normalized with leptin treatment. In contrast, palmitate oxidation rates remained elevated in pair fed ob/ob mice relative to wildtype controls (1.9-fold, p<0.01). Insulin has a positive inotropic effect in perfused wildtype hearts, and this effect was absent in ob/ob hearts. The insulin-induced inotropic response was restored by leptin treatment in ob/ob mice but was not restored in pair fed ob/ob mice. These data support a direct antihypertrophic effect of leptin in the heart and suggest that leptin deficiency may directly contribute to myocardial insulin resistance and abnormal FA metabolism. Potential mechanisms include increased hepatic triglyceride production in leptin deficiency or direct effects of leptin signaling in the hypothalamus and/or the periphery on myocardial substrate utilization.

Palmitate oxidation rate and action on glycogen synthase in myoblasts from insulin-resistant subjects

2000 ◽  
Vol 279 (3) ◽  
pp. E561-E569 ◽  
Author(s):  
David M. Mott ◽  
Cristen Hoyt ◽  
Rael Caspari ◽  
Karen Stone ◽  
Richard Pratley ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glycogen Synthase ◽  
Glucose Disposal ◽  
Nonesterified Fatty Acid ◽  
Palmitate Oxidation ◽  
Oxidation Rates ◽  
Glycogen Synthase Activity

Elevated plasma lipid and nonesterified fatty acid concentrations reduce insulin-mediated glucose disposal in skeletal muscle. Cultured myoblasts from 21 subjects were studied for rates of palmitate oxidation and the effect of palmitate on glycogen synthase activity at the end of an 18-h incubation in serum- and glucose-free media. Oxidation rates of 40 μM palmitate in cultured myoblasts correlated with the fasting glucose ( r = 0.71, P = 0.001), log fasting insulin ( r = 0.52, P = 0.03), and insulin-mediated glucose storage rate ( r = −0.50, P = 0.04) of the muscle donors. Myoblast glycogen synthase activity can be regulated by 240 μM palmitate, but the changes are associated with the basal respiratory quotient and not with the insulin resistance of the muscle donor. These results indicate that myoblasts producing elevated palmitate oxidation rates in vitro can be used to identify skeletal muscle abnormalities which are primary contributors to insulin resistance in vivo. Effects of 240 μM palmitate on myoblast glycogen synthase activity appear to be mechanistically different from the relationship between myoblast palmitate oxidation rates and insulin resistance of the muscle donor.

Abstract 689: Cystathionine-Beta-Synthase Deficiency Induces Cardiac Hypertrophy and Contributes to Diminished Fatty Acid Oxidation in Mice with Diet-Induced Obesity

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Melissa B Glier ◽  
Rich B Wambolt ◽  
Rika E Aleliuna ◽  
Sarah L Gerrard ◽  
Robin P da Silva ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cardiac Hypertrophy ◽  
Collagen Type ◽  
Control Diet ◽  
Acid Oxidation ◽  
Palmitate Oxidation ◽  
Oxidation Rates ◽  
Cystathionine Beta Synthase ◽  
Diet Induced Obesity ◽  
Cardiac Lipotoxicity

Obesity-related cardiac lipid accumulation is associated with lipotoxicity and dysfunction. Cysteine is required for the synthesis of the antioxidant glutathione, which can be supplied by the transsulfuration of homocysteine by cystathionine-beta-synthase (Cbs). Cbs+/- mice with diet-induced obesity had greater glucose intolerance and lipotoxicity in the heart. Our objective was to determine the functional effects and mechanisms of cardiac lipotoxicity in Cbs+/- mice with diet-induced obesity. Cbs+/- and Cbs+/+ mice were fed a control diet or a high-fat diet (HFD) from weaning for 20 weeks. As expected, Cbs+/+ and Cbs+/- mice fed the HFD had greater final body weights, visceral (retroperitoneal and epididymal) and subcutaneous (inguinal) adiposity compared to mice fed the control diet. Cbs+/- mice had greater heart weights accompanied by higher concentrations of long chain polyunsaturated fatty acids arachidonic acid, 20:4n6 (AA) and docosahexaenoic acid, 22:6n3 (DHA) in the heart compared to Cbs+/+ mice. Mice fed the HFD had higher AA, but lower DHA concentrations in the heart compared to mice fed the control diet, with the greatest effect in Cbs+/- mice. Isolated working hearts revealed a reduced heart rate and cardiac output in Cbs+/- mice fed the control diet compared to Cbs+/+ mice. Independent of diet, Cbs+/- mice also had reduced aortic flow compared to Cbs+/+ mice, with a higher coronary flow only in Cbs+/- mice fed the HFD. Working hearts also revealed that Cbs+/- mice had lower palmitate oxidation rates compared to Cbs+/+ mice, with higher palmitate oxidation and glycolysis rates in mice fed the HFD compared to mice fed the control diet. Cbs+/- mice had a lower ratio of phosphorylated-AMP activated protein kinase alpha (AMPKα)/AMPKα expression (regulator of cellular energy) in heart compared to Cbs+/+ mice, and this occurred to a greater extent in those fed the HFD. Furthermore, we observed a higher ratio of collagen type 1(COL1α1)/ collagen type 3 (COL3α1) expression (implicated in myocardial stiffness) in heart, only in Cbs+/- mice fed the HFD. Collectively, these findings suggest that cardiac lipotoxicity in Cbs+/- mice with obesity is associated with cardiac hypertrophy, impaired cardiac fatty acid metabolism, and cardiac dysfunction.

Identification of genes contributing to the obese yellowAvyphenotype: caloric restriction, genotype, diet × genotype interactions

2004 ◽  
Vol 18 (3) ◽  
pp. 316-324 ◽  
Author(s):  
Jim Kaput ◽  
Karin G. Klein ◽  
Eric J. Reyes ◽  
Warren A. Kibbe ◽  
Craig A. Cooney ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Quantitative Trait Loci ◽  
Caloric Restriction ◽  
Quantitative Trait ◽  
Obesity And Diabetes ◽  
Ion Imbalance ◽  
Ad Libitum

The incidence and severity of obesity and type 2 diabetes are increasing in Western societies. The progression of obesity to type 2 diabetes is gradual with overlapping symptoms of insulin resistance, hyperinsulinemia, hyperglycemia, dyslipidemias, ion imbalance, and inflammation; this complex syndrome has been called diabesity. We describe here comparisons of gene expression in livers of A/ a (agouti) vs. Avy/ A (obese yellow) segregants (i.e., littermates) from BALB/cStCrlfC3H/Nctr × VYWffC3Hf/Nctr- Avy/ a matings in response to 70% and 100% of ad libitum caloric intakes of a reproducible diet. Twenty-eight ( 28 ) genes regulated by diet, genotype, or diet × genotype interactions mapped to diabesity quantitative trait loci. A subset of the identified genes is linked to abnormal physiological signs observed in obesity and diabetes.

scholarly journals Reduced Cardiac Efficiency and Altered Substrate Metabolism Precedes the Onset of Hyperglycemia and Contractile Dysfunction in Two Mouse Models of Insulin Resistance and Obesity

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5341-5349 ◽  
Author(s):  
Jonathan Buchanan ◽  
Pradip K. Mazumder ◽  
Ping Hu ◽  
Gopa Chakrabarti ◽  
Matthew W. Roberts ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Mouse Models ◽  
Acid Oxidation ◽  
Contractile Dysfunction ◽  
Oxidation Rates ◽  
Myocardial Substrate ◽  
Old Mice

Hyperglycemia is associated with altered myocardial substrate use, a condition that has been hypothesized to contribute to impaired cardiac performance. The goals of this study were to determine whether changes in cardiac metabolism, gene expression, and function precede or follow the onset of hyperglycemia in two mouse models of obesity, insulin resistance, and diabetes (ob/ob and db/db mice). Ob/ob and db/db mice were studied at 4, 8, and 15 wk of age. Four-week-old mice of both strains were normoglycemic but hyperinsulinemic. Hyperglycemia develops in db/db mice between 4 and 8 wk of age and in ob/ob mice between 8 and 15 wk. In isolated working hearts, rates of glucose oxidation were reduced by 28–37% at 4 wk and declined no further at 15 wk in both strains. Fatty acid oxidation rates and myocardial oxygen consumption were increased in 4-wk-old mice of both strains. Fatty acid oxidation rates progressively increased in db/db mice in parallel with the earlier onset and greater duration of hyperglycemia. In vivo, cardiac catheterization revealed significantly increased left ventricular contractility and relaxation (positive and negative dP/dt) in both strains at 4 wk of age. dP/dt declined over time in db/db mice but remained elevated in ob/ob mice at 15 wk of age. Increased β-myosin heavy chain isoform expression was present in 4-wk-old mice and persisted in 15-wk-old mice. Increased expression of peroxisomal proliferator-activated receptor-α regulated genes was observed only at 15 wk in both strains. These data indicate that altered myocardial substrate use and reduced myocardial efficiency are early abnormalities in the hearts of obese mice and precede the onset of hyperglycemia. Obesity per se does not cause contractile dysfunction in vivo, but loss of the hypercontractile phenotype of obesity and up-regulation of peroxisomal proliferator-activated receptor-α regulated genes occur later and are most pronounced in the presence of longstanding hyperglycemia.

scholarly journals Blunted lipolysis and fatty acid oxidation during moderate exercise in HIV-infected subjects taking HAART

2007 ◽  
Vol 292 (3) ◽  
pp. E812-E819 ◽  
Author(s):  
W. Todd Cade ◽  
Dominic N. Reeds ◽  
Bettina Mittendorfer ◽  
Bruce W. Patterson ◽  
William G. Powderly ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Glucose Tolerance ◽  
Fat Free Mass ◽  
Hiv Positive ◽  
Acid Oxidation ◽  
Oral Glucose ◽  
Moderate Exercise ◽  
Oxidation Rates ◽  
A Minor

The protease inhibitor (PI) ritonavir (RTV) has been associated with elevated resting lipolytic rate, hyperlipidemia, and insulin resistance/glucose intolerance. The purpose of this study was to examine relationships between lipolysis and fatty acid (FA) oxidation during rest, moderate exercise and recovery, and measures of insulin sensitivity/glucose tolerance and fat redistribution in HIV-positive subjects taking RTV ( n = 12), HAART but no PI ( n = 10), and HIV-seronegative controls ( n = 10). Stable isotope tracers [1-13C]palmitate and [1,1,2,3,3-2H5]glycerol were continuously infused with blood and breath collection during 1-h rest, 70-min submaximal exercise (50% V̇o2 peak), and 1-h recovery. Body composition was evaluated using DEXA, MRI, and MRS, and 2-h oral glucose tolerance tests with insulin monitoring were used to evaluate glucose tolerance and insulin resistance. Lipolytic and FA oxidation rates were similar during rest and recovery in all groups; however, they were lower during moderate exercise in both HIV-infected groups [glycerol Ra: HIV + RTV 5.1 ± 1.2 vs. HIV + no PI 5.9 ± 2.8 vs. Control 7.4 ± 2.2 μmol·kg fat-free mass (FFM)−1·min−1; palmitate oxidation: HIV + RTV 1.6 ± 0.8 vs. HIV + no PI 1.6 ± 0.8 vs. Control 2.5 ± 1.7 μmol·kg FFM·min, P < 0.01]. Fasting and orally-challenged glucose and insulin values were similar among groups. Lipolytic and FA oxidation rates were blunted during moderate exercise in HIV-positive subjects taking HAART. Lower FA oxidation during exercise was primarily due to impaired plasma FA oxidation, with a minor contribution from lower nonplasma FA oxidation. Regional differences in adipose tissue lipolysis during rest and moderate exercise may be important in HIV and warrant further study.

STUDIES IN CONGENITAL GENERALIZED LIPODYSTROPHY (SEIP-BERARDINELLI SYNDROME)

1973 ◽  
Vol 72 (3) ◽  
pp. 475-494 ◽  
Author(s):  
Svein Oseid
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Normal Glucose Tolerance ◽  
Juvenile Form ◽  
Congenital Generalized Lipodystrophy ◽  
Glucose Levels ◽  
Normal Glucose ◽  
Glucose Tolerance Tests ◽  
The One ◽  
Adipose Organ

ABSTRACT Six cases of congenital generalized lipodystrophy have been studied at different ages from infancy to adolescence with regard to glucose tolerance, insulin secretion, and insulin sensitivity. During the first few years of life there is normal glucose tolerance. The fasting immuno-reactive insulin (IRI) levels are either slightly elevated or normal. The IRI response to glucose is exaggerated and prolonged, at least from the third year of life. Some degree of insulin resistance is already present in infancy. From the age of 8–10 years glucose tolerance decreases rapidly. The fasting IRI levels are usually grossly elevated, while fasting plasma glucose levels are only moderately elevated or normal. The IRI responses to oral and iv administered glucose, and to tolbutamide are exaggerated; the insulinogenic indices are high. Cortisone primed glucose tolerance tests become abnormal. Insulin resistance is marked, and increases with age. After cessation of growth at approximately 12 years of age, frank diabetes with fasting hyperglycaemia and diabetic glucose tolerance curves developed in the one patient followed beyond this age. Her fasting IRI was increased, but there was a poor IRI response to glucose stimulation, suggesting a partial exhaustion of the β-cells. Her initial IRI response to tolbutamide was still good, but not as brisk as in the younger patients. This type of diabetes is quite different from the juvenile form, and also from the diabetes of older age. It may be causally related to the lack of an adequate adipose organ necessary for the disposal of excesses of glucose, or possibly related to another anti-insulin mechanism.

scholarly journals Metabolomics analysis reveals altered metabolites in lean compared with obese adolescents and additional metabolic shifts associated with hyperinsulinaemia and insulin resistance in obese adolescents: a cross-sectional study

Metabolomics ◽  
2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Elisabeth Müllner ◽  
Hanna E. Röhnisch ◽  
Claudia von Brömssen ◽  
Ali A. Moazzami
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Glucose Tolerance ◽  
Insulin Response ◽  
Oral Glucose ◽  
Response Level ◽  
Metabolic Alterations ◽  
Obese Adolescents ◽  
Branched Chain ◽  
Metabolomics Analysis

Abstract Introduction Hyperinsulinaemia and insulin resistance (IR) are strongly associated with obesity and are forerunners of type 2 diabetes. Little is known about metabolic alterations separately associated with obesity, hyperinsulinaemia/IR and impaired glucose tolerance (IGT) in adolescents. Objectives To identify metabolic alterations associated with obesity, hyperinsulinaemia/IR and hyperinsulinaemia/IR combined with IGT in obese adolescents. Methods 81 adolescents were stratified into four groups based on body mass index (lean vs. obese), insulin responses (normal insulin (NI) vs. high insulin (HI)) and glucose responses (normal glucose tolerance (NGT) vs. IGT) after an oral glucose tolerance test (OGTT). The groups comprised: (1) healthy lean with NI and NGT, (2) obese with NI and NGT, (3) obese with HI and NGT, and (4) obese with HI and IGT. Targeted nuclear magnetic resonance-based metabolomics analysis was performed on fasting and seven post-OGTT plasma samples, followed by univariate and multivariate statistical analyses. Results Two groups of metabolites were identified: (1) Metabolites associated with insulin response level: adolescents with HI (groups 3–4) had higher concentrations of branched-chain amino acids and tyrosine, and lower concentrations of serine, glycine, myo-inositol and dimethylsulfone, than adolescents with NI (groups 1–2). (2) Metabolites associated with obesity status: obese adolescents (groups 2–4) had higher concentrations of acetylcarnitine, alanine, pyruvate and glutamate, and lower concentrations of acetate, than lean adolescents (group 1). Conclusions Obesity is associated with shifts in fat and energy metabolism. Hyperinsulinaemia/IR in obese adolescents is also associated with increased branched-chain and aromatic amino acids.

Impact of Glucose Metabolism Disorders on IGF-1 Levels in Patients with Acromegaly

2018 ◽  
Vol 50 (05) ◽  
pp. 408-413 ◽  
Author(s):  
Sema Dogansen ◽  
Gulsah Yalin ◽  
Seher Tanrikulu ◽  
Sema Yarman
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Glucose Tolerance ◽  
Normal Glucose Tolerance ◽  
Glucose Metabolism Disorders ◽  
Insulin Resistant ◽  
Normal Glucose ◽  
Resistant Group ◽  
The Impact

AbstractIn this study, we aimed to evaluate the presence of glucose metabolism abnormalities and their impact on IGF-1 levels in patients with acromegaly. Ninety-three patients with acromegaly (n=93; 52 males/41 females) were included in this study. Patients were separated into three groups such as; normal glucose tolerance (n=23, 25%), prediabetes (n=38, 41%), and diabetes mellitus (n=32, 34%). Insulin resistance was calculated with homeostasis model assessment (HOMA). HOMA-IR > 2.5 or ≤2.5 were defined as insulin resistant or noninsulin resistant groups, respectively. Groups were compared in terms of factors that may be associated with glucose metabolism abnormalities. IGF-1% ULN (upper limit of normal)/GH ratios were used to evaluate the impact of glucose metabolism abnormalities on IGF-1 levels. Patients with diabetes mellitus were significantly older with an increased frequency of hypertension (p<0.001, p=0.01, respectively). IGF-1% ULN/GH ratio was significantly lower in prediabetes group than in normal glucose tolerance group (p=0.04). Similarly IGF-1% ULN/GH ratio was significantly lower in insulin resistant group than in noninsulin resistant group (p=0.04). Baseline and suppressed GH levels were significantly higher in insulin resistant group than in noninsulin resistant group (p=0.024, p<0.001, respectively). IGF-1% ULN/GH ratio is a useful marker indicating glucose metabolism disorders and IGF-1 levels might be inappropriately lower in acromegalic patients with insulin resistance or prediabetes. We suggest that IGF-1 levels should be re-evaluated after the improvement of insulin resistance or glycemic regulation for the successful management of patients with acromegaly.

Sign in / Sign up

Export Citation Format

Share Document