Insulin resistance in the Zucker diabetic fatty rat: a metabolic characterisation of obese and lean phenotypes

Leonard, Bridget L.; Richard, Watson; Loomes, Kerry M.; Phillips, Anthony R.J.; Cooper, Garth J. S.

doi:10.1007/s00592-005-0197-8

Cited by 82 publications

(86 citation statements)

References 46 publications

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“…Obesity and hyperphagia accelerate and/or promote the development of pancreatitis and diabetes in this strain. The leptin receptor fatty gene (Lepr fa ) induces insulin resistance and hyperinsulinemia [15]. Hyperinsulinemia in Zucker fatty rats is not affected by dietary restriction [6], but dietary restriction retards the decrease of serum insulin levels in male SDT-fatty rats, which are derived from a strain congenic for the leptin receptor fatty gene [21].…”

Section: Discussionmentioning

confidence: 99%

“…The leptin receptor fatty gene (Lepr fa ) is a recessive mutation that leads to leptin receptor deficiency, and homozygous animals (fa/fa) show obesity, hyperphagia, insulin resistance, hyperinsulinemia, and glucose intolerance [5,15,23,27,28,31]. Zucker diabetic fatty rats are homozygous for the fa allele of the leptin receptor gene and develop type 2 diabetes with obesity.…”

Section: Introductionmentioning

confidence: 99%

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The Influence of Dietary Restriction on the Development of Diabetes and Pancreatitis in Female WBN/Kob-Fatty Rats

et al. 2010

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Abstract:Original WBN/Kob male rats commonly develop chronic pancreatitis by the age of 3 months, while diabetes mellitus occurs at 9 months. In contrast, female rats of this strain do not show pancreatitis or diabetes. The WBN/Kob-fatty rat is a homozygous (fa/fa) congenic strain for the fa allele of the leptin receptor gene (Lepr). In WBN/Kob-fatty rats, both females and males provide a model of non-insulin-dependent diabetes with obesity. The leptin receptor fatty gene (Lepr fa ) induces obesity and hyperphagia. In the present study, we examined the effect of dietary restriction on pancreatitis and diabetes in female WBN/Kob-fatty rats. Five female fatty rats comprised a restricted feeding group with paired-feeding from 3 to 13 weeks of age, and five female lean rats comprised a control group with paired-feeding. At 13 weeks of age, two of the five female fatty rats of the control group developed diabetes mellitus, while no female fatty rats of the restricted feeding group developed diabetes mellitus. At this stage, pathological changes of the pancreas were observed in female fatty rats. All female fatty rats showed severe interlobular, intra-lobular and intra-islet fibrosis. In female fatty rats of the restricted feeding group, pathological changes of the pancreas were milder those of the free-feeding fatty group. Although dietary restriction could not completely prevent pancreatitis in female fatty rats, the development of diabetes was inhibited by its reduction of the severity of pancreatitis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Influence of Dietary Restriction on the Development of Diabetes and Pancreatitis in Female WBN/Kob-Fatty Rats

et al. 2010

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“…This results in the tyrosine phosphorylation of a family of IRS proteins and the activation of a complex network of downstream molecules, including phosphatidylinositol 3-kinase (PI3K) and the serine/threonine kinase AKT. Skeletal muscle is the most important tissue involved in insulin-stimulated glucose disposal, and insulin resistance in skeletal muscle is a major defect in most obese phenotypes (35).…”

Section: Discussionmentioning

confidence: 99%

Astragaloside IV facilitates glucose transport in C2C12 myotubes through the IRS1/AKT pathway and suppresses the palmitate-induced activation of the IKK/IκBα pathway

Zhu

Zheng

Chen

et al. 2016

International Journal of Molecular Medicine

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Abstract. Astragaloside IV is a monomer isolated from Astragalus membranaceus (Fisch.) Bunge, which is one of the most widely used plant-derived drugs in traditional Chinese medicine for diabetes therapy. In the present study, we aimed to examine the effects of astragaloside IV on glucose in C2C12 myotubes and the underlying molecular mechanisms responsible for these effects. Four-day differentiated C2C12 myotubes were exposed to palmitate for 16 h in order to establish a model of insulin resistance and 3 H glucose uptake, using 2-Deoxy-D-[1,2-3 H(N)]-glucose (radiolabeled 2-DG), was detected. Astragaloside IV was added 2 h prior to palmitate exposure. The translocation of glucose transporter 4 (GLUT4) was evaluated by subcellular fractionation, and the expression of insulin signaling molecules such as insulin receptor β (IRβ), insulin receptor substrate (IRS)1/protein kinase B (AKT) and inhibitory κB kinase (IKK)/inhibitor-κBα (IκBα), which are associated with insulin signal transduction, were assessed in the basal or the insulin-stimulated state using western blot analysis or RT-PCR. We also examined the mRNA expression of monocyte chemotactic protein 1 (MCP-1), intermonocyte chemotactic protein 1 (MCP-1), inter-, interleukin 6 (IL-6), tumor necrosis factor α (TNFα) and Toll-like receptor 4 (TLR4). Taken together, these findings demon-. Taken together, these findings demonstrated that astragaloside IV facilitates glucose transport in C2C12 myotubes through a mechanism involving the IRS1/ AKT pathway, and suppresses the palmitate-induced activathe palmitate-induced activation of the IKK/IκBα pathway. IntroductionSkeletal muscle accounts for 40% of body weight in humans, and 75% of infused glucose is cleared by skeletal muscle (1,2); thus, skeletal muscle serves as the major site of insulin-dependent glucose uptake. Due to the key role played by skeletal muscle in glucose homeostasis, deleterious factors which provoke reductions in glucose uptake by skeletal muscle, described as skeletal muscle insulin resistance, may lead to decreases in the disposal rate of serum glucose (3).The etiology of impaired insulin signaling in obese individuals is multifactorial and appears to be associated with at least two major events: a state of chronic, low-grade inflammation and the accumulation of intramyocellular lipids (4). Under physiological conditions, serum free fatty acids (FFAs) are an important fuel source for skeletal muscle, and 98-99% of FFAs bind to bovine serum albumin (5). Therefore, physiological concentrations of FFAs are in the µmol/l range (5). Constantly elevated serum levels of FFAs result in the transportation of FFAs into skeletal muscle cells, and subsequently stored as triglyceride. Whenever the accumulation of triglycerides and/or hydrolysis of triglycerides exceeds the oxidation capacity, incomplete lipid metabolic products, such as acyl-CoA, diacylglycerol and ceramide, are generated. These products inhibit the activation of critical molecules involved in insulin signaling, such as protein kinase B ...

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“…In the present study, only male rats were used, since female ZDF rats are less prone to the development of metabolic syndrome [93,94]. Male ZDF rats develop an age-dependent obese and hyperglycemic phenotype at 10-12 weeks of age accompanied by a metabolic state of obesity, dyslipidemia, hyperinsulinemia and insulin resistance [95,96] which develops to a hyperglycemic insulin-deficient state [95]. The metabolic features manifested in this animal model are in many ways similar to the pathogenesis of metabolic syndrome in humans [95,97].…”

Section: Experimental Setup For Investigation Of Cardiac Gene Expressmentioning

confidence: 99%

“…Male ZDF rats develop an age-dependent obese and hyperglycemic phenotype at 10-12 weeks of age accompanied by a metabolic state of obesity, dyslipidemia, hyperinsulinemia and insulin resistance [95,96] which develops to a hyperglycemic insulin-deficient state [95]. The metabolic features manifested in this animal model are in many ways similar to the pathogenesis of metabolic syndrome in humans [95,97]. Therefore, the ZDF rat is an ideal model for investigation of cardiac gene expression pattern changes related to human metabolic syndrome.…”

Section: Experimental Setup For Investigation Of Cardiac Gene Expressmentioning

confidence: 99%

Cardiovascular risk and stress adaptation in metabolic diseases

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Insulin resistance in the Zucker diabetic fatty rat: a metabolic characterisation of obese and lean phenotypes

Cited by 82 publications

References 46 publications

The Influence of Dietary Restriction on the Development of Diabetes and Pancreatitis in Female WBN/Kob-Fatty Rats

The Influence of Dietary Restriction on the Development of Diabetes and Pancreatitis in Female WBN/Kob-Fatty Rats

Astragaloside IV facilitates glucose transport in C2C12 myotubes through the IRS1/AKT pathway and suppresses the palmitate-induced activation of the IKK/IκBα pathway

Cardiovascular risk and stress adaptation in metabolic diseases

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