Female rats do not develop sucrose-induced insulin resistance

Horton, Tracy J.; Gayles, Ellis C.; Prach, P. A.; Koppenhafer, T. A.; Pagliassotti, Michael J.

doi:10.1152/ajpregu.1997.272.5.r1571

Cited by 43 publications

(45 citation statements)

References 19 publications

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“…Considering the decreased soleus PGC-1 and mCPTI mRNA levels found in this study, it may be that the type I fibers of the diabetic vastus lateralis express less ␤-oxidation machinery and thereby oxidize less fatty acid versus nondiabetics, particularly in the adult where the slow fiber phenotype has fully evolved. This is the first study to observe skeletal muscle gender specific differences in a rat model of IUGR and subsequent insulin resistance, though it is consistent with previous reports of more severely effected hepatic gene expression and function of fatty acid metabolizing genes in male IUGR rats (19,46). Moreover, i.v.…”

Section: Discussionsupporting

confidence: 91%

IUGR Alters Postnatal Rat Skeletal Muscle Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 Gene Expression in a Fiber Specific Manner

et al. 2003

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Uteroplacental insufficiency and subsequent intrauterine growth retardation (IUGR) increase the risk of insulin resistance in humans and rats. Aberrant skeletal muscle lipid metabolism contributes to the pathogenesis of insulin resistance. Peroxisome proliferator-activated receptor-␥ co-activator-1 (PGC-1) is a transcriptional co-activator that affects gene expression of key lipid metabolizing enzymes such as carnitine palmitoyltransferase I (mCPTI). Because gene expression of lipid metabolizing enzymes is altered in IUGR postnatal skeletal muscle, and we hypothesized that PGC-1 expression would be similarly affected. To prove this hypothesis, bilateral uterine artery ligation and sham surgery were used to produce IUGR and control rats respectively. Western Blotting demonstrated that PGC-1 hind limb skeletal muscle protein levels were increased in perinatal and postnatal IUGR rats. Conventional RT-PCR demonstrated that PGC-1 mRNA levels were similarly increased in perinatal hind limb skeletal muscle and juvenile extensor digitorum longus (EDL), but were decreased in juvenile soleus. Because a gender specific trend was noted in PGC-1 mRNA levels, real time RT-PCR was used for further differentiation. Real time RT-PCR revealed that changes in postnatal skeletal muscle PGC-1 expression were more marked in male IUGR rats versus female IUGR rats. Down stream targets of PGC-1 followed a similar pattern of expression. We conclude that PGC-1 expression is altered in rat IUGR skeletal muscle and speculate that it contributes to the pathogenesis of insulin resistance in the IUGR rat. Barker's Fetal Origins of Adult Disease Hypothesis proposes that fetal adaptation to a deprived intrauterine milieu leads to permanent changes in cellular biology and systemic physiology (1). Intrauterine growth retardation (IUGR) predisposes affected newborns toward the development of insulin resistance and dyslipidemia (2). Although both insulin deficiency and resistance contribute to the IUGR diabetic phenotype, asymmetrical IUGR individuals are often characterized by insulin resistance. Uteroplacental insufficiency, a morbidity associated with many common complications of pregnancy induces asymmetrical IUGR (3, 4). In the rat, uteroplacental insufficiency results in juvenile IUGR animals whose glucose homeostasis is abnormal only when physiologically challenged on a pharmacological level (5). By adulthood, these IUGR rats develop overt diabetes that is characterized by insulin resistance and hypertriglyceridemia (5,19,20).An important component contributing to the pathogenesis of skeletal muscle insulin resistance is altered fatty acid homeostasis (6, 7

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Section: Discussionsupporting

confidence: 91%

IUGR Alters Postnatal Rat Skeletal Muscle Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 Gene Expression in a Fiber Specific Manner

et al. 2003

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“…A thorough characterisation of the time course of metabolic changes that occur in sucrose-fed male Wistar rats was carried out by Pagliassotti and colleagues [7,21,22] using glucose challenges and hyperinsulinaemic/euglycaemic clamp protocols in unanaesthetised animals. In a separate study, they found that sucrose-fed females were not insulin-resistant after 8 weeks and exhibited neither elevated triglycerides nor hyperinsulinaemia [23]. In the present study, we show that with an additional 1-3 weeks on diet, sucrose-fed females exhibit metabolic changes consistent with sucrosefed males (Table 1) and their ventricular myocytes have impaired relaxation, although not as severe as in males (Table 2 and Figs.…”

Section: Discussionsupporting

confidence: 67%

Cardiomyocyte dysfunction in insulin-resistant rats: a female advantage

et al. 2006

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Aims/hypothesis: The goal of this investigation was to determine whether there are sex-related differences in the development of cardiomyocyte dysfunction in prediabetic, insulin-resistant animals. Materials and methods: Male and female rats were maintained on a high-sucrose diet for 5-11 weeks, and mechanical properties of isolated ventricular myocytes were measured by high-speed video edge detection. Several in vitro interventions were used to manipulate intracellular Ca 2+ in order to determine whether altered Ca 2+ availability contributes to the cardiomyocyte dysfunction. Results: Myocyte shortening and relengthening were significantly slower in sucrose-fed (insulin-resistant) males than in starch-fed (normal) male rats, whereas only relengthening was slower in sucrose-fed females when compared with normal females. Areas under the contraction and relaxation phases for sucrose-fed males were also significantly larger than in diet-matched females, and the slowed cardiomyocyte mechanics appeared earlier in males (7 vs 10 weeks). Prolonged relaxation was ameliorated in myocytes from sucrose-fed female rats by all interventions (i.e. 10 −8 mol/l isoprenaline, elevated extracellular Ca 2+ , and higher rates of stimulation). Twice as much extracellular Ca 2+ (4 mmol/l) was required to restore normal time courses of contraction and relaxation in sucrose-fed males than in females, and mechanical responses to higher frequency stimulation remained impaired (slower) in some myocytes from sucrose-fed male rats. Conclusions/ interpretation: These data suggest that in myocytes from insulin-resistant rats altered Ca 2+ handling occurs, contributing to abnormal excitation-contraction coupling; female rats seem to have some cardioprotection during early stages in the progression towards type 2 diabetes. Females show delayed onset and milder abnormalities in metabolic status and cardiomyocyte function, but with a much tighter temporal coupling of these dysfunctions.

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“…For example, high-sucrose feeding is known to cause insulin resistance in rodents, and Kim et al (29) have reported that the effect of high-sucrose feeding to impair insulin action is comparable in male and female rats. On the other hand, Horton et al (30), conducting similar studies, found that highsucrose feeding effectively produced insulin resistance in male animals, but it had no influence on insulin action in females. High-fat feeding is another dietary means to produce insulin resistance, and, again, sex effects have been shown, at least in some studies (15)(16)(17).…”

Section: Discussionmentioning

confidence: 99%

Female Rats Do Not Exhibit Free Fatty Acid–Induced Insulin Resistance

Hevener

Reichart²,

Janež³

et al. 2002

Diabetes

104

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It is well described that excessive lipid metabolism can cause insulin resistance in both animals and humans, and this has been implicated as a causative factor in the development of insulin resistance and type 2 diabetes in humans. Recently, we have shown that intravenous lipid emulsion (liposyn) infusion during a 120-min euglycemichyperinsulinemic clamp led to significant reductions in insulin action and fatty acid translocase (FAT/CD36) skeletal muscle protein expression. After reviewing the literature, it became evident that essentially all past studies, including our own, were conducted in male animals. Therefore, to determine whether there were sex determinants of fat-induced insulin resistance, we assessed the impact of free fatty acid (FFA) elevation on insulin action in female rats. Here, we report that a fourfold elevation in plasma FFA concentration induced a 40% reduction in the insulin-stimulated glucose disposal rate, a 30% decline in insulin-stimulated skeletal muscle insulin substrate receptor-1 (IRS-1) phosphorylation, a 48% decrease in IRS-1-associated phosphatidylinositol (PI) 3-kinase activity, and a 50% reduction in muscle FAT/CD36 protein expression in male rats. In striking contrast, we found no effect of FFA elevation to cause insulin resistance, changes in IRS-1/PI 3-kinase, or FAT/CD36 protein levels in female animals. Our findings indicate that female animals are protected from lipid-induced reductions in insulin action. Diabetes 51: [1907][1908][1909][1910][1911][1912] 2002 I t is widely held that excessive lipid metabolism, achieved either by high-fat feeding or intravenous infusion of lipid emulsion to raise circulating free fatty acid (FFA) levels, leads to decreased insulinstimulated glucose uptake (1-10). This lipid-induced decrease in insulin-stimulated glucose disposal is associated with a decline in insulin substrate receptor-1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity in skeletal muscle, and these in vivo and in vitro findings have been reported in several articles (1,6,9,10) and are well supported. Interestingly, after reviewing the literature, it became apparent that essentially all studies reporting fat-induced insulin resistance in humans or rodents have been conducted in men or male animals. Because the prevailing concept is that fat-induced impairment of glucose disposal is a major risk factor for the development of insulin resistance and type 2 diabetes, and because type 2 diabetes is equally prevalent in men and women, it is important to determine whether the deleterious effects of increased fat metabolism are the same for males and females.Although women have a lower skeletal muscle mass than men, a review of the literature points to improved glucose tolerance and heightened skeletal muscle insulin sensitivity in normal women compared with men (11-13). Thus, Fernandez-Real et al. (14) have shown that premenopausal women are more insulin sensitive than men when the groups are matched for body fat, and Yki-Jarvinen (13) has shown enhanced insuli...

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Female rats do not develop sucrose-induced insulin resistance

Cited by 43 publications

References 19 publications

IUGR Alters Postnatal Rat Skeletal Muscle Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 Gene Expression in a Fiber Specific Manner

IUGR Alters Postnatal Rat Skeletal Muscle Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 Gene Expression in a Fiber Specific Manner

Cardiomyocyte dysfunction in insulin-resistant rats: a female advantage

Female Rats Do Not Exhibit Free Fatty Acid–Induced Insulin Resistance

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