A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents

2007 ◽  
Vol 292 (5) ◽  
pp. E1358-E1363 ◽  
Author(s):  
Arvinder K. Dhalla ◽  
Mei Yee Wong ◽  
Peter J. Voshol ◽  
Luiz Belardinelli ◽  
Gerald M. Reaven
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Adenosine Receptor ◽  
Infusion Rate ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Oral Glucose ◽  
Acute Administration ◽  
High Fat ◽  
Adenosine Receptor Agonist

There is substantial evidence in the literature that elevated plasma free fatty acids (FFA) play a role in the pathogenesis of type 2 diabetes. CVT-3619 is a selective partial A1 adenosine receptor agonist that inhibits lipolysis and lowers circulating FFA. The present study was undertaken to determine the effect of CVT-3619 on insulin resistance induced by high-fat (HF) diet in rodents. HF diet feeding to rats for 2 wk caused a significant increase in insulin, FFA, and triglyceride (TG) concentrations compared with rats fed chow. CVT-3619 (1 mg/kg) caused a time-dependent decrease in fasting insulin, FFA, and TG concentrations. Acute administration of CVT-3619 significantly lowered the insulin response, whereas glucose response was not different with an oral glucose tolerance test. Treatment with CVT-3619 for 2 wk resulted in significant lowering of FFA, TG, and insulin concentrations in rats on HF diet. To determine the effect of CVT-3619 on insulin sensitivity, hyperinsulinemic euglycemic clamp studies were performed in C57BL/J6 mice fed HF diet for 12 wk. Glucose infusion rate was decreased significantly in HF mice compared with chow-fed mice. CVT-3619 treatment 15 min prior to the clamp study significantly ( P < 0.01) increased glucose infusion rate to values similar to that for chow-fed mice. In conclusion, CVT-3619 treatment lowers FFA and TG concentrations and improves insulin sensitivity in rodent models of insulin resistance.

scholarly journals Glucose mediates insulin sensitivity via a hepatoportal mechanism in high-fat-fed rats

2019 ◽  
Vol 241 (3) ◽  
pp. 189-199 ◽  
Author(s):  
Holly M Johnson ◽  
Erin Stanfield ◽  
Grace J Campbell ◽  
Erica E Eberl ◽  
Gregory J Cooney ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
High Fat Diet ◽  
Glucose Infusion ◽  
Whole Body ◽  
Glucose Turnover ◽  
Oral Glucose ◽  
Glucose Load ◽  
High Fat ◽  
Whole Body Metabolism

Poor nutrition plays a fundamental role in the development of insulin resistance, an underlying characteristic of type 2 diabetes. We have previously shown that high-fat diet-induced insulin resistance in rats can be ameliorated by a single glucose meal, but the mechanisms for this observation remain unresolved. To determine if this phenomenon is mediated by gut or hepatoportal factors, male Wistar rats were fed a high-fat diet for 3 weeks before receiving one of five interventions: high-fat meal, glucose gavage, high-glucose meal, systemic glucose infusion or portal glucose infusion. Insulin sensitivity was assessed the following day in conscious animals by a hyperinsulinaemic-euglycaemic clamp. An oral glucose load consistently improved insulin sensitivity in high-fat-fed rats, establishing the reproducibility of this model. A systemic infusion of a glucose load did not affect insulin sensitivity, indicating that the physiological response to oral glucose was not due solely to increased glucose turnover or withdrawal of dietary lipid. A portal infusion of glucose produced the largest improvement in insulin sensitivity, implicating a role for the hepatoportal region rather than the gastrointestinal tract in mediating the effect of glucose to improve lipid-induced insulin resistance. These results further deepen our understanding of the mechanism of glucose-mediated regulation of insulin sensitivity and provide new insight into the role of nutrition in whole body metabolism.

scholarly journals Ginsenoside Re Reduces Insulin Resistance through Inhibition of c-Jun NH2-Terminal Kinase and Nuclear Factor-κB

2008 ◽  
Vol 22 (1) ◽  
pp. 186-195 ◽  
Author(s):  
Zhiguo Zhang ◽  
Xiaoying Li ◽  
Wenshan Lv ◽  
Yisheng Yang ◽  
Hong Gao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Infusion Rate ◽  
Glucose Infusion ◽  
Signaling Cascades ◽  
Glucose Infusion Rate ◽  
Nuclear Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Ginsenoside Re

Abstract Ginsenoside Re (Re), a compound derived from Panax ginseng, shows an antidiabetic effect. However, the molecular basis of its action remains unknown. We investigated insulin signaling and the antiinflammatory effect by Re in 3T3-L1 adipocytes and in high-fat diet (HFD) rats to dissect its anti-hyperglycemic mechanism. Glucose uptake was measured in 3T3-L1 cells and glucose infusion rate determined by clamp in HFD rats. The insulin signaling cascade, including insulin receptor (IR) β-subunit, IR substrate-1, phosphatidylinositol 3-kinase, Akt and Akt substrate of 160 kDa, and glucose transporter-4 translocation are examined. Furthermore, c-Jun NH2-terminal kinase (JNK), MAPK, and nuclear factor (NF)-κB signaling cascades were also assessed. The results show Re increases glucose uptake in 3T3-L1 cells and glucose infusion rate in HFD rats. The activation of insulin signaling by Re is initiated at IR substrate-1 and further passes on through phosphatidylinositol 3-kinase and downstream signaling cascades. Moreover, Re demonstrates an impressive suppression of JNK and NF-κB activation and inhibitor of NF-κBα degradation. In conclusion, Re reduces insulin resistance in 3T3-L1 adipocytes and HFD rats through inhibition of JNK and NF-κB activation.

scholarly journals The Insulin-Sensitizing Effect of Rosiglitazone in Type 2 Diabetes Mellitus Patients Does Not Require Improved in Vivo Muscle Mitochondrial Function

2008 ◽  
Vol 93 (7) ◽  
pp. 2917-2921 ◽  
Author(s):  
Vera B. Schrauwen-Hinderling ◽  
Marco Mensink ◽  
Matthijs K. C. Hesselink ◽  
Jean-Pierre Sels ◽  
M. Eline Kooi ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Mitochondrial Function ◽  
Infusion Rate ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Diabetic Patients ◽  
Half Time ◽  
Sensitizing Effect

Abstract Aims: Our objective was to investigate whether improved in vivo mitochondrial function in skeletal muscle and intramyocellular lipids (IMCLs) contribute to the insulin-sensitizing effect of rosiglitazone. Methods: Eight overweight type 2 diabetic patients (body mass index = 29.3 ± 1.1 kg/m2) were treated with rosiglitazone for 8 wk. Before and after treatment, insulin sensitivity was determined by a hyperinsulinemic euglycemic clamp. Muscular mitochondrial function (half-time of phosphocreatine recovery after exercise) and IMCL content were measured by magnetic resonance spectroscopy. Results: Insulin sensitivity improved after rosiglitazone (glucose infusion rate: 19.9 ± 2.8 to 24.8 ± 2.1 μmol/kg·min; P &lt; 0.05). In vivo mitochondrial function (phosphocreatine recovery half-time: 23.8 ± 3.5 to 20.0 ± 1.7 sec; P = 0.23) and IMCL content (0.93 ± 0.18% to 1.37 ± 0.40%; P = 0.34) did not change. Interestingly, the changes in PCr half-time correlated/tended to correlate with changes in fasting insulin (R2 = 0.50; P = 0.05) and glucose (R2 = 0.43; P = 0.08) levels. Changes in PCr half-time did not correlate with changes in glucose infusion rate (R2 = 0.08; P = 0.49). Conclusion: The rosiglitazone-enhanced insulin sensitivity does not require improved muscular mitochondrial function.

scholarly journals Oxidative Stress Is Associated with Adiposity and Insulin Resistance in Men

2003 ◽  
Vol 88 (10) ◽  
pp. 4673-4676 ◽  
Author(s):  
Hideki Urakawa ◽  
Akira Katsuki ◽  
Yasuhiro Sumida ◽  
Esteban C. Gabazza ◽  
Shuichi Murashima ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Body Mass Index ◽  
Body Mass ◽  
Body Fat ◽  
Plasma Levels ◽  
Infusion Rate ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Total Fat

Abstract To investigate the direct relationship of oxidative stress with obesity and insulin resistance in men, we measured the plasma levels of 8-epi-prostaglandin F2α (PGF2α) in 14 obese and 17 nonobese men and evaluated their relationship with body mass index; body fat weight; visceral, sc, and total fat areas, measured by computed tomography; and glucose infusion rate during a euglycemic hyperinsulinemic clamp study. Obese men had significantly higher plasma concentrations of 8-epi-PGF2α than nonobese men (P &lt; 0.05). The plasma levels of 8-epi-PGF2α were significantly correlated with body mass index (r = 0.408; P &lt; 0.05), body fat weight (r = 0.467; P &lt; 0.05), visceral (r = 0.387; P &lt; 0.05) and total fat area (r = 0.359; P &lt; 0.05) in all (obese and nonobese) men. There was also a significant correlation between the plasma levels of 8-epi-PGF2α and glucose infusion rate in obese men (r = −0.552; P &lt; 0.05) and all men (r = −0.668; P &lt; 0.01). In all subjects, the plasma levels of 8-epi-PGF2α were significantly correlated with fasting serum levels of insulin (r = 0.487; P &lt; 0.01). In brief, these findings showed that the circulating levels of 8-epi-PGF2α are related to adiposity and insulin resistance in men. Although correlation does not prove causation, the results of this study suggest that obesity is an important factor for enhanced oxidative stress and that this oxidative stress triggers the development of insulin resistance in men.

Effect of heterozygous PPARγ deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding

2003 ◽  
Vol 284 (3) ◽  
pp. E618-E626 ◽  
Author(s):  
Philip D. G. Miles ◽  
Yaacov Barak ◽  
Ronald M. Evans ◽  
Jerrold M. Olefsky
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Tolerance Test ◽  
Hepatic Insulin Resistance ◽  
Oral Glucose ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Age Related ◽  
Adipocyte Hypertrophy

Peroxisome proliferator-activated receptor-γ (PPARγ) is the target receptor for thiazolidinedione (TZD) compounds, which are a class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. Paradoxically, however, mice deficient in PPARγ ( PPARγ+/− ) are more insulin sensitive than their wild-type (WT) littermates, not less, as would be predicted. To determine whether PPARγ deficiency could prevent the development of the insulin resistance associated with increasing age or high-fat (HF) feeding, insulin sensitivity was assessed in PPARγ+/− and WT mice at 2, 4, and 8 mo of age and in animals fed an HF diet. Because TZDs elicit their effect through PPARγ receptor, we also examined the effect of troglitazone (a TZD) in these mice. Glucose metabolism was assessed by hyperinsulinemic euglycemic clamp and oral glucose tolerance test. Insulin sensitivity declined with age for both groups. However, the decline in the PPARγ+/− animals was substantially less than that of the WT animals, such that, by 8 mo of age, the PPARγ+/− mice were markedly more insulin sensitive than the WT mice. This greater sensitivity in PPARγ+/− mice was lost with TZD treatment. HF feeding led to marked adipocyte hypertrophy and peripheral tissue and hepatic insulin resistance in WT mice but also in PPARγ+/− mice. Treatment of these mice with troglitazone completely prevented the adipocyte hypertrophy and normalized insulin action. In conclusion, PPARγ deficiency partially protects against age-related insulin resistance but does not protect against HF diet-induced insulin resistance.

scholarly journals O9.2. ANTIPSYCHOTIC DRUGS IMPAIR BRAIN GLUCOSE SENSING RESULTING IN WHOLE BODY INSULIN RESISTANCE

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S21-S21
Author(s):  
Laura Castellani ◽  
Chantel Kowalchuk ◽  
Roshanak Asgariroozbehani ◽  
Veronica Tran ◽  
William Brett McIntyre ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Infusion Rate ◽  
Second Generation ◽  
Glucose Sensing ◽  
Glucose Infusion ◽  
Whole Body ◽  
Glucose Kinetics ◽  
Brain Glucose

Abstract Background Antipsychotics (APs) remain the cornerstone treatment for schizophrenia, and are widely used on- and off-label for other psychiatric disorders. However, their use presents a significant risk for serious adverse glycemic effects. Independent of changes in adiposity, APs directly dysregulate whole body glucose metabolism, and this may occur through the central nervous system (CNS). To this end, we have recently demonstrated that the second-generation AP, olanzapine, impairs hypothalamic insulin-action, resulting in dysregulation of whole-body insulin sensitivity. In addition to a critical role of hormones such as insulin in the CNS, glucose-sensing at the hypothalamus is also pivotal for the regulation of whole-body insulin sensitivity. Glucose also represents the primary fuel for brain function, and the hypothalamus represents the key brain center (through glucose sensing neurons) to partition resources to ensure maintenance of key homeostatic systems. In the current study, we set out to examine the effects of a first generation AP (e.g. haloperidol) and second-generation AP(e.g. olanzapine) on hypothalamic-glucose sensing, and subsequent regulation of peripheral glucose metabolism. Methods Gold-standard, pancreatic-euglycemic clamps were used to assess changes in glucose kinetics in response to a primed, continuous intracerebroventricular (ICV) infusion of glucose or vehicle solution (2mM, 5μL/hour, into the 3rd ventricle). Male rats were co-treated with an acute injection of olanzapine (3mg/kg, S.C.), haloperidol (10mg/kg, S.C.) or a weight adjusted vehicle solution. Dosing of APs was based on clinical D2 occupancies. Groups included (ICV–peripheral) vehicle–vehicle (n = 6), glucose–vehicle (n = 8), glucose–olanzapine (n = 6), vehicle–olanzapine (n = 6), glucose-haloperidol (n = 6) and vehicle-haloperidol (n = 7). The peripheral glucose infusion rate needed to maintain euglycemia during the clamp was used as a measure of whole-body insulin sensitivity. Results As expected and previously demonstrated, ICV (central) glucose infusion caused a significant increase in the peripheral glucose infusion rate of glucose (mg/kg.min) compared to vehicle treated rats (Veh-Veh 3.11±0.73 vs Glu-Veh 8.39±1.61), p&lt;0.05). This effect was mitigated by treatment with both olanzapine (Glu-Veh 8.39±1.61, Glu-Ola 0.63±0.37, p&lt;0.05) and haloperidol (Glu-Veh 8.39±1.61, Glu-Hal 3.01±0.46, p&lt;0.05). In summary, olanzapine and haloperidol both impaired central glucose sensing resulting in whole body insulin resistance. Discussion Hypothalamic glucose-sensing is critical for the regulation of peripheral glucose homeostasis. This data, for the first time, demonstrates evidence that both first- and second-generation APs disrupt hypothalamic glucose-mediated regulation of glucose kinetics. Perturbed glucose-sensing in the CNS is expected to have deleterious consequences for metabolic homeostasis, and possibly other brain glucose-dependent functions such as cognition. The study unveils a novel effect of AP treatment to disrupt brain nutrient-sensing, suggesting this may be a mechanism by which these drugs increase risk of type 2 diabetes.

Acute exercise increases insulin sensitivity in adult sheep: a new preclinical model

2015 ◽  
Vol 308 (6) ◽  
pp. R500-R506 ◽  
Author(s):  
Glenn K. McConell ◽  
Gunveen Kaur ◽  
Filippe Falcão-Tebas ◽  
Yet H. Hong ◽  
Kathryn L. Gatford
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Insulin Signaling ◽  
Infusion Rate ◽  
Acute Exercise ◽  
Citrate Synthase ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Large Animal ◽  
Adult Sheep

In healthy humans and rodents, chronic and acute exercise improves subsequent insulin sensitivity of skeletal muscle. A large animal species with similar metabolic responses to exercise would permit longitudinal studies, including repeated biopsies of muscle and other tissues not possible in rodents, and enable study of interactions with insulin-resistant physiological states not feasible in humans. Therefore, we examined whether acute exercise increases insulin sensitivity in adult sheep. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp (HEC) in mature female sheep ( n = 7). Sheep were familiarized to treadmill walking and then performed an acute exercise bout (30 min, 8% slope, up to 4.4 km/h). A second HEC was conducted ∼18 h after the acute exercise. Musculus semimembranosus biopsies were obtained before and after each HEC. Glucose infusion rate during the HEC increased 40% ( P = 0.003) and insulin sensitivity (glucose infusion rate/plasma insulin concentration) increased 32% ( P = 0.028) after acute exercise. Activation of proximal insulin signaling in skeletal muscle after the HEC, measured as Ser473 phosphorylation of Akt, increased approximately five-fold in response to insulin ( P < 0.001) and was unaltered by acute exercise performed 18 h earlier. PGC1α and GLUT4 protein, glycogen content and citrate synthase activity in skeletal muscle did not change in response to insulin or exercise. In conclusion, improved insulin sensitivity and unchanged proximal insulin signaling on the day after acute exercise in sheep are consistent with responses in humans and rodents, suggesting that the sheep is an appropriate large-animal model in which to study responses to exercise.

Quantity of sucrose alters the tissue pattern and time course of insulin resistance in young rats

1995 ◽  
Vol 269 (3) ◽  
pp. R641-R646 ◽  
Author(s):  
M. J. Pagliassotti ◽  
P. A. Prach
Keyword(s):  
Insulin Resistance ◽  
Total Energy ◽  
Infusion Rate ◽  
Time Course ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Young Rats ◽  
Sucrose Diet

To determine the effects of the amount of sucrose in the diet on insulin-stimulated glucose metabolism, euglycemic hyperinsulinemic clamps were performed on male Wistar rats after one of the following dietary treatments (n = 6-8/treatment): 1) high-starch diet (68% of total energy) for 8 wk (ST8), 16 wk (ST16), or 30 wk (ST30); 2) high-sucrose diet (68% of total energy) for 8 wk (SU8), 16 wk (SU16), or 30 wk (SU30); or 3) low-sucrose diet (18% of total energy) for 8 wk (SUL8), 16 wk (SUL16), or 30 wk (SUL30). Body weights were similar in starch- and sucrose-fed rats at 8 wk (502 +/- 9 g), 16 wk (563 +/- 10 g), and 30 wk (607 +/- 26 g). The glucose infusion rate (mumol.g-1.min-1) required to maintain similar glycemia during clamps was 73.1 +/- 8.8 in ST8, 29.7 +/- 4.9 in SU8 (P < 0.05 vs. ST8 and SUL8), and 76.4 +/- 8.2 in SUL8; 69.9 +/- 8.1 in ST16, 35.1 +/- 5.1 in SU16 (P < 0.05 vs. ST16 and SUL16), and 63.2 +/- 6.5 in SUL16; and 65.4 +/- 7.7 in ST30, 26.0 +/- 5.3 (P < 0.05 vs. ST30), and 36.3 +/- 6.0 in SUL30 (P < 0.05 vs. ST30). Impaired suppression of hepatic glucose production accounted for 43, 39, and 34% of the decrease in the glucose infusion rate in SU8 compared with ST8, SU16 compared with ST16, and SU30 compared with ST30, respectively, but 78% in SUL30 compared with ST30. These results suggest that both high- and low-sucrose diets can produce insulin resistance in young rats.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals The Relationship between Insulin Resistance and the Cardiovascular Biomarker Growth Differentiation Factor-15 in Obese Patients

2011 ◽  
Vol 57 (2) ◽  
pp. 309-316 ◽  
Author(s):  
Greisa Vila ◽  
Michaela Riedl ◽  
Christian Anderwald ◽  
Michael Resl ◽  
Ammon Handisurya ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Gastric Bypass ◽  
Insulin Sensitivity ◽  
Oral Glucose ◽  
Model Assessment ◽  
Obese Patients ◽  
Growth Differentiation Factor 15 ◽  
Homeostatic Model Assessment ◽  
Homeostatic Model ◽  
The Relationship

BACKGROUND Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine linked to obesity comorbidities such as cardiovascular disease, inflammation, and cancer. GDF-15 also has adipokine properties and recently emerged as a prognostic biomarker for cardiovascular events. METHODS We evaluated the relationship of plasma GDF-15 concentrations with parameters of obesity, inflammation, and glucose and lipid metabolism in a cohort of 118 morbidly obese patients [mean (SD) age 37.2 (12) years, 89 females, 29 males] and 30 age- and sex-matched healthy lean individuals. All study participants underwent a 75-g oral glucose tolerance test; 28 patients were studied before and 1 year after Roux-en-Y gastric bypass surgery. RESULTS Obese individuals displayed increased plasma GDF-15 concentrations (P &lt; 0.001), with highest concentrations observed in patients with type 2 diabetes. GDF-15 was positively correlated with age, waist-to-height ratio, mean arterial blood pressure, triglycerides, creatinine, glucose, insulin, C-peptide, hemoglobin A1c, and homeostatic model assessment insulin resistance index and negatively correlated with oral glucose insulin sensitivity. Age, homeostatic model assessment index, oral glucose insulin sensitivity, and creatinine were independent predictors of GDF-15 concentrations. Roux-en-Y gastric bypass led to a significant reduction in weight, leptin, insulin, and insulin resistance, but further increased GDF-15 concentrations (P &lt; 0.001). CONCLUSIONS The associations between circulating GDF-15 concentrations and age, insulin resistance, and creatinine might account for the additional cardiovascular predictive information of GDF-15 compared to traditional risk factors. Nevertheless, GDF-15 changes following bariatric surgery suggest an indirect relationship between GDF-15 and insulin resistance. The clinical utility of GDF-15 as a biomarker might be limited until the pathways directly controlling GDF-15 concentrations are better understood.

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