Gender Differences in Metabolic Disorders and Related Diseases in Spontaneously Diabetic Torii-LeprfaRats

Ohta, Takeshi; Katsuda, Yoshiaki; Miyajima, Katsuhiro; Sasase, Tomohiko; Kimura, Shuichi; Tong, Bin; Yamada, Takahisa

doi:10.1155/2014/841957

Cited by 36 publications

(29 citation statements)

References 30 publications

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“…Because the same dosage of STZ induces different levels of hyperglycemia in male and female rodents (May et al ), it has been difficult to directly compare type 1 DKD in experimental animals. Furthermore, female rodents also appear more resistant to type 2 diabetes, because food intake is usually higher in males which is associated with earlier increases in blood glucose and earlier declines in insulin (Chow et al ; Ohta et al ). These sex differences have resulted in a failure to adequately compare the development of DKD in males and females in experimental animal models and to compare the outcomes of therapeutic interventions in both sexes.…”

Section: Introductionmentioning

confidence: 99%

Establishing equivalent diabetes in male and female Nos3‐deficient mice results in a comparable onset of diabetic kidney injury

Tian

Tesch

2019

Physiol Rep

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Clinical studies indicate that sex differences exist in susceptibility for developing diabetic kidney disease (DKD), supporting the need to examine both sexes in animal studies of DKD. Streptozotocin (STZ) is commonly used in male mice to induce diabetes and DKD. However, females are not normally included because their sex hormones partially protect them from STZ‐induced islet injury and consequent diabetes. To address this issue, we identified a strategy to induce comparable diabetes in male and female mice using STZ and determined whether both sexes develop equivalent renal injury. Male and female mice lacking the gene for endothelial nitric oxide synthase (Nos3‐/‐) were made diabetic with five or six low‐dose STZ injections, respectively. Groups of male and female mice with equivalent hyperglycemia at week 3 after STZ were assessed for DKD at week 8. STZ‐treated male and female Nos3‐/‐ mice maintained comparable hyperglycemia between weeks 3 and 8 had an equivalent increase in HbA1c levels and comparable hypertension. Urine albumin/creatinine levels were elevated eightfold in mice of both sexes at week 8, accompanied by an equivalent loss of podocytes. In diabetic males and females, plasma cystatin C levels and glomerular collagen deposition were similarly increased. Kidney mRNA levels of proinflammatory and profibrotic markers and kidney injury molecule‐1 (KIM‐1) were equally elevated in males and females, indicating comparable kidney injury. This study shows that equivalent diabetes induces a comparable onset of DKD in male and female Nos3‐/‐ mice, demonstrating that it is possible to include males and females together in studies of DKD.

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Section: Introductionmentioning

confidence: 99%

Establishing equivalent diabetes in male and female Nos3‐deficient mice results in a comparable onset of diabetic kidney injury

Tian

Tesch

2019

Physiol Rep

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“…The risk of obesity-related comorbidities is well established in men, but less so for age matched pre-menopausal women [6]. There are a number of experimental and clinical studies showing sex differences in the susceptibility to various diseases like IR, T2DM and metabolic syndrome [7][8][9][10][11]. Moreover, CVD develops earlier and are more frequently in men compared with premenopausal women [12].…”

Section: Introductionmentioning

confidence: 99%

Influence of a High-Fat Diet on Cardiac iNOS in Female Rats

Jovanović

Sudar-Milovanović

Obradović

et al. 2017

CVP

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Overexpression of inducible nitric oxide synthase (iNOS) is a key link between high-fat (HF) diet induced obesity and cardiovascular (CV) disease. Several studies have reported that oestradiol has cardioprotective effects that may be mediated through reduction of iNOS activity/expression. In the present study, female Wistar rats were fed a standard diet or a HF diet (balanced diet for laboratory rats enriched with 42% fat) for 10 weeks. Gene and protein expression of iNOS were measured in heart tissue. HF diet-fed rats exhibited a significant increase in cardiac iNOS mRNA by 695% (p<0.05), iNOS protein level by 248% (p<0.01), without changes in nitrate/nitrite levels. Expression of CD36 protein in plasma membranes was increased by 37% (p<0.05), while the concentration of free fatty acids (FFA) was reduced by 25% (p<0.01) in HF diet-fed rats. Expression of the p50 subunit of nuclear factor-κB (NFκB-p50) in heart lysate was increased by 77% (p<0.01) in HF diet-fed rats.Expression and phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinases 1/2 (ERK1/2) in control and HF diet-fed rats were also examined. Expression of Akt and ERK1/2 were unchanged between the groups. There was a significant increase in the ratio of phospho-Akt/total Akt but not for phospho-ERK1/2/total ERK1/2/ in HF-fed rats.Estrogen receptor-α levels (by 50%; p<0.05) and serum oestradiol concentrations (by 35%; p<0.05) were examined and shown to be significantly reduced in HF diet-fed rats. Our results revealed that a HF diet led to increased iNOS expression, most likely via a mechanism involving Akt and NFκB-p50 proteins. Decreased levels of oestradiol and ERα protein in the HF-fed group, in combination with increased iNOS levels are consistent with the hypothesis that oestradiol has a cardioprotective effect through its ability to regulate iNOS expression.Key words: cardioprotection, cardiovascular disease, oestradiol, inducible nitric oxide synthase, obesity Abbreviations: Akt, protein kinase B; CD36, cluster of differentiation 36; CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; DMT2, diabetes mellitus type 2; ERα, oestrogen receptor-α; ERs, oestrogen receptors; ERK1/2, extracellular signalregulated kinases 1/2; FFA, free fatty acids; HF, high fat; HOMA-IR, HOMA-index of insulin resistance; HOMA-β, HOMA-index of β-cell function; IκB, inhibitor of NFκB; iNOS, inducible nitric oxide synthase; IR, insulin resistance; NFκB-p50, the p50 subunit of nuclear factor-κB; TES, N-[Tris(hydroxymethyl)methyl]-2-aminoethanesulfonic acid; TG, triglycerides VSMCs, vascular smooth muscle cells.

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“…However, if premenopausal women are compared with age-matched men, the differences are striking (6,50). In rodents, a sexual dimorphism in T2DM development can also be observed (37,39). The New Zealand obese (NZO) mouse, a model of polygenic obesity and T2DM (25), shows that females are protected from T2DM unless they are fed an extremely high-fat diet (40,52).…”

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confidence: 99%

Diabetes prevalence in NZO females depends on estrogen action on liver fat content

Lubura

Hesse

Kræmer

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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In humans and rodents, risk of metabolic syndrome is sexually dimorphic, with an increased incidence in males. Additionally, the protective role of female gonadal hormones is ostensible, as prevalence of type 2 diabetes mellitus (T2DM) increases after menopause. Here, we investigated the influence of estrogen (E2) on the onset of T2DM in female New Zealand obese (NZO) mice. Diabetes prevalence (defined as blood glucose levels >16.6 mmol/l) of NZO females on high-fat diet (60 kcal% fat) in week 22 was 43%. This was markedly dependent on liver fat content in week 10, as detected by computed tomography. Only mice with a liver fat content >9% in week 10 plus glucose levels >10 mmol/l in week 9 developed hyperglycemia by week 22. In addition, at 11 wk, diacylglycerols were elevated in livers of diabetes-prone mice compared with controls. Hepatic expression profiles obtained from diabetes-prone and -resistant mice at 11 wk revealed increased abundance of two transcripts in diabetes-prone mice: Mogat1, which catalyzes the synthesis of diacylglycerols from monoacylglycerol and fatty acyl-CoA, and the fatty acid transporter Cd36. E2 treatment of diabetes-prone mice for 10 wk prevented any further increase in liver fat content and reduced diacylglycerols and the abundance of Mogat1 and Cd36, leading to a reduction of diabetes prevalence and an improved glucose tolerance compared with untreated mice. Our data indicate that early elevation of hepatic Cd36 and Mogat1 associates with increased production and accumulation of triglycerides and diacylglycerols, presumably resulting in reduced hepatic insulin sensitivity and leading to later onset of T2DM.

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Gender Differences in Metabolic Disorders and Related Diseases in Spontaneously Diabetic Torii-Lepr^faRats

Cited by 36 publications

References 30 publications

Establishing equivalent diabetes in male and female Nos3‐deficient mice results in a comparable onset of diabetic kidney injury

Establishing equivalent diabetes in male and female Nos3‐deficient mice results in a comparable onset of diabetic kidney injury

Influence of a High-Fat Diet on Cardiac iNOS in Female Rats

Diabetes prevalence in NZO females depends on estrogen action on liver fat content

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