Insulin resistance in the obese hyperglycemic () mouse. Failure of hyperinsulinemia to activate hepatic pyruvate kinase (PK)

Belfiore, Francesco; Rabuazzo, Agata Maria; Iannello, Silvia; Vasta, D.; Campione, Rosa

doi:10.1016/0026-0495(84)90119-7

Cited by 5 publications

(6 citation statements)

References 13 publications

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“…The increasing evidence indicates that ob/ob mice are a reasonable experimental model of obesity-induced insulin resistance [ 26 , 27 ]. In this study, we first observed the effects of trilobatin on body weight, food, and water drinking, data showed that treatment with 10 mg/kg trilobatin (i. g.) for 4 weeks had no significant impact on the body weight (Fig.…”

Section: Resultsmentioning

confidence: 99%

Trilobatin ameliorates insulin resistance through IRS-AKT-GLUT4 signaling pathway in C2C12 myotubes and ob/ob mice

Liu

Wang

et al. 2020

Chin Med

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Background Trilobatin, a natural compound, has been found to exhibit anti-diabetic properties in high-fat diet (HFD) and streptozotocin (STZ) induced type 2 diabetic mice. But up to now no research has been reported on the effect of trilobatin on insulin resistance in peripheral tissues. Herein, we determined the effects of trilobatin on insulin resistance in palmitate-treated C2C12 myotubes and ob/ob mice. Methods Male ob/ob mice (8-10 weeks) and same background C57BL/6 mice were used to evaluate the role of trilobatin on insulin resistance; protein expression and phosphorylation were measured by western blot; glucose uptake was determined a fluorescent test. Results Treatment with trilobatin prevented palmitate-induced insulin resistance by enhancing glucose uptake and the phosphorylation of insulin resistance substrate 1 (IRS1) and protein Kinase B, (PKB/AKT), recovered the translocation of GLUT4 from cytoplasm to membrane, but preincubation with LY294002, an inhibitor of PI3K, blocked the effects of trilobatin on glucose uptake and the distribution of GLUT4 in C2C12 myotubes. Furthermore, administration with trilobatin for 4 weeks significantly improved insulin resistance by decreasing fasting blood glucose and insulin in serum, enhancing the phosphorylation of IRS1 and AKT, and recovering the expression and translocation of GLUT4 in ob/ob mice. Conclusions IRS-AKT-GLUT4 signaling pathway might be involved in trilobatin ameliorating insulin resistance in skeletal muscle of obese animal models.

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Section: Resultsmentioning

confidence: 99%

Trilobatin ameliorates insulin resistance through IRS-AKT-GLUT4 signaling pathway in C2C12 myotubes and ob/ob mice

Liu

Wang

et al. 2020

Chin Med

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“…In leptin deficient mice, reduced insulin sensitivity is observed [28], [29], and hyperinsulinemia precedes the onset of hyperglycemia [2], [30], [31]. We therefore examined the effects of reducing insulin alleles on fasting glucose, glucose tolerance, and insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

Suppressing hyperinsulinemia prevents obesity but causes rapid onset of diabetes in leptin-deficient Lepob/ob mice

D'souza¹,

Johnson²,

Clee³

et al. 2016

Molecular Metabolism

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ObjectiveHyperinsulinemia is commonly associated with obesity. Mice deficient in the adipose-derived hormone leptin (Lepob/ob) develop hyperinsulinemia prior to onset of obesity and glucose intolerance. Whether the excess of circulating insulin is a major contributor to obesity and impaired glucose homeostasis in Lepob/ob mice is unclear. It has been reported previously that diet-induced obesity in mice can be prevented by reducing insulin gene dosage. In the present study, we examined the effects of genetic insulin reduction in Lepob/ob mice on circulating insulin, body composition, and glucose homeostasis.MethodsLeptin expressing (Lepwt/wt) mice lacking 3 insulin alleles were crossed with Lepob/ob mice to generate Lepob/ob and Lepwt/wt littermates lacking 1 (Ins1+/+;Ins2+/−), 2 (Ins1+/+;Ins2−/−) or 3 (Ins1+/−;Ins2−/−) insulin alleles. Animals were assessed for body weight gain, body composition, glucose homeostasis, and islet morphology.ResultsWe found that in young Lepob/ob mice, loss of 2 or 3 insulin alleles reduced plasma insulin levels by 75–95% and attenuated body weight gain by 50–90% compared to Ins1+/+;Ins2+/−;Lepob/ob mice. This corresponded with ∼30% and ∼50% reduced total body fat in Ins1+/+;Ins2−/−;Lepob/ob and Ins1+/−;Ins2−/−;Lepob/ob mice, respectively. Loss of 2 or 3 insulin alleles in young Lepob/ob mice resulted in onset of fasting hyperglycemia by 4 weeks of age, exacerbated glucose intolerance, and abnormal islet morphology. In contrast, loss of 1,2 or 3 insulin alleles in Lepwt/wt mice did not significantly alter plasma insulin levels, body weight, fat mass, fasting glycemia, or glucose tolerance.ConclusionTaken together, our findings indicate that hyperinsulinemia is required for excess adiposity in Lepob/ob mice and sufficient insulin production is necessary to maintain euglycemia in the absence of leptin.

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“…As ob/ob mice were reported to show a strong liver and muscle insulin resistance [38], we analyzed the role of the Wnt/β-catenin pathway on insulin sensitivity of myotubes isolated from ob/+ and ob/ob mice. Myotubes were treated with 100 μM BIO for 24h in the presence or absence of 10 nM insulin for the last 12h.…”

Section: Resultsmentioning

confidence: 99%

Wnt/β-catenin signaling improves oxidative metabolism in skeletal muscle of obese ob/ob mice

Christodoulou-Vafeiadou,

Lepeigneux,

Naviere

et al. 2024

Preprint

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Background: Canonical Wnt signaling is involved in many physiological and pathological states. As it regulates lipid metabolism and glucose homeostasis, its misregulation may lead to the development of diabetes and obesity. We have already reported that activation of the Wnt/b-catenin canonical signaling pathway increased insulin sensitivity and prevented lipid deposits in rat skeletal muscle through a reciprocal regulation of Wnt10b and the lipogenic factor SREBP-1c. Results: Here we have studied the role of Wnt/b-catenin canonical signaling in skeletal muscle of genetically obese and diabetic (ob/ob) mice and their control ob/+ mice. We showed that Wnt10b and SREBP-1c expressions were conversely regulated in cultured mouse myoblasts isolated from lean ob/+ or obese ob/ob mice. Activation of the Wnt/b-catenin pathway using Wnt10b overexpression or the selective GSK3 inhibitor 6-Bromo-indirubin-3'oxime (BIO) was sufficient to decrease lipogenic genes expression in cultured myoblasts isolated from control and obese mice. In vivo, we performed direct electrotransfection of Wnt10b cDNA or BIO injections in Tibialis Anterior (TA) muscles of ob/ob and ob/+ mice. Both up-regulated Wnt10b gene expression and down-regulated SREBP-1c expression. Canonical Wnt signaling increased slow Myosin Heavy Chain-I (MHC-I) oxidative fiber number as well as fast Myosin Heavy Chain-IIA (MHC-IIA) oxidative fiber number, while decreasing fast glycolytic fiber number in TA muscle. In addition, Wnt signaling increased mitochondrial oxidative metabolism and respiratory reserve capacity by 2- and 3-fold in myotubes cultured from ob/ob and ob/+ mice muscles respectively. Surprisingly, the activation of the Wnt pathway was sufficient to reduce hyperglycemia by 30% within 3 weeks in ob/ob mice. Conclusions: Our results show that activation of Wnt/b-catenin signaling in skeletal muscle induced a shift towards a more oxidative metabolism in myofibers, thus mimicking the effects of exercise training. Wnt10b could be a valuable candidate to develop therapeutic drugs for the treatment of obesity and/or type 2 diabetes.

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Insulin resistance in the obese hyperglycemic () mouse. Failure of hyperinsulinemia to activate hepatic pyruvate kinase (PK)

Cited by 5 publications

References 13 publications

Trilobatin ameliorates insulin resistance through IRS-AKT-GLUT4 signaling pathway in C2C12 myotubes and ob/ob mice

Trilobatin ameliorates insulin resistance through IRS-AKT-GLUT4 signaling pathway in C2C12 myotubes and ob/ob mice

Suppressing hyperinsulinemia prevents obesity but causes rapid onset of diabetes in leptin-deficient Lepob/ob mice

Wnt/β-catenin signaling improves oxidative metabolism in skeletal muscle of obese ob/ob mice

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