Genetic analysis of non-insulin-dependent diabetes mellitus in KK and KK-Ay mice

Suto, Jun‐ichi; Matsuura, Shouhei; Imamura, Kenkichi; Yamanaka, Harumichi; Sekikawa, Kenji

doi:10.1530/eje.0.1390654

Cited by 94 publications

(58 citation statements)

References 24 publications

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“…KK-Ay mice result from a cross between glucose-intolerant black KK female mice and male yellow obese A y mice and are known to serve as an excellent model of type 2 diabetes. 12 Adult male Agtr2ϩ and Agtr2Ϫ mice 13 (age 10 to 12 weeks) were also used. They were given a standard diet (MF; Oriental Yeast Co Ltd) and water ad libitum.…”

Section: Animals and Treatmentmentioning

confidence: 99%

Angiotensin II Type-1 Receptor Blocker Valsartan Enhances Insulin Sensitivity in Skeletal Muscles of Diabetic Mice

et al. 2004

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Abstract-Angiotensin II has been shown to contribute to the pathogenesis of insulin resistance; however, the mechanism is not well understood. The present study was undertaken to investigate the potential effect of an angiotensin II type-1 (AT 1 ) receptor blocker, valsartan, to improve insulin resistance and to explore the signaling basis of cross-talk of the AT 1 receptor-and insulin-mediated signaling in type 2 diabetic KK-Ay mice. 3 H]DG uptake and superoxide production in skeletal muscle of KK-Ay mice. Moreover, we observed that valsartan treatment exaggerated the insulin-induced phosphorylation of IRS-1, the association of IRS-1 with the p85 regulatory subunit of phosphoinositide 3 kinase (PI 3-K), PI 3-K activity, and translocation of GLUT4 to the plasma membrane. It also reduced tumor necrosis factor-␣ (TNF-␣) expression and superoxide production in skeletal muscle of KK-Ay mice. Specific AT 1 receptor blockade increases insulin sensitivity and glucose uptake in skeletal muscle of KK-Ay mice via stimulating the insulin signaling cascade and consequent enhancement of GLUT4 translocation to the plasma membrane. Key Words: angiotensin II Ⅲ insulin Ⅲ glucose Ⅲ diabetes mellitus T he renin-angiotensin system plays an important role in the regulation of cardiovascular and fluid volume homeostasis, and in the control of various hormone secretion, tissue growth and neuronal activity. Angiotensin (Ang) II seems to be involved in the pathogenesis of hypertension and insulin resistance, although few studies have examined the relationship between the two. Insulin resistance occurs in a wide variety of pathological states and is commonly associated with obesity, type 2 diabetes, accelerated atherosclerosis, and hypertension. 1,2 Shimamoto et al demonstrated that the insulin sensitivity of fructose-fed rats is improved by treatment with an Ang II receptor blocker (ARB), olmesartan, caused by changes in muscle fiber composition and a decrease in tumor necrosis factor (TNF)-␣ expression in skeletal muscle. 3,4 Henriksen et al 5 reported that an ARB, irbesartan, either acutely or chronically, improves glucose tolerance in the obese Zucker rat, at least in part through enhancement of skeletal muscle glucose transport, and the effect of chronic Ang II receptor antagonism on skeletal muscle glucose uptake is associated with an increase in GLUT4 protein expression. Recent large clinical trials revealed that angiotensin II receptor blockade by losartan was associated with a lower risk of development of diabetes. 6 However, it remains unclear whether Ang II has a direct effect on the insulin-mediated pathway of glucose metabolism in addition to changes in local blood flow in insulinsensitive organs such as skeletal muscle.Recent studies have suggested that Ang II might negatively modulate insulin-mediated actions by regulating multiple levels of the insulin signaling cascade such as the insulin receptor, insulin receptor substrate (IRS), and phosphatidylinositol 3-kinase (PI 3-K). 7-9 Therefore, we examined the possibility tha...

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Section: Animals and Treatmentmentioning

confidence: 99%

Angiotensin II Type-1 Receptor Blocker Valsartan Enhances Insulin Sensitivity in Skeletal Muscles of Diabetic Mice

et al. 2004

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“…4 In brief, C57BL=6J females were crossed with KK-A y males to produce F 1 -A y mice, which were intercrossed to produce two kinds of F 2 with regard to the agouti locus; that is, F 2 -a=a and F 2 -A y =a. An intraperitoneal glucose tolerance test (IPGTT) was conducted on 91 F 2 females (42 F 2 -a=a and 49 F 2 -A y =a) at the age of 20 weeks (148 AE 5 days in a=a and 135 AE 3 days in A y =a).…”

Section: Methodsmentioning

confidence: 99%

“…3 We previously analyzed NIDDM-related traits in F 2 progeny of a cross between normoglycemic C57BL=6J and KK-A y mice. 4 In consequence, several quantitative trait loci (QTLs) were identified for NIDDM traits; however, only two suggestive QTLs were identified for glucose intolerance on chromosomes 1 and 8. Because the A y allele causes massive obesity, F 2 -a=a mice and F 2 -A y =a mice were analyzed separately on the basis of genotypes at the agouti locus.…”

Section: Introductionmentioning

confidence: 99%

A quantitative trait locus that accounts for glucose intolerance maps to chromosome 8 in hereditary obese KK-Ay mice

Suto

Sekikawa

2002

Int J Obes

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KK and KK-A y mice serve as animal models of non-insulin-dependent diabetes mellitus with moderate obesity. Quantitative trait locus (QTL) analysis was performed to identify gene loci that account for fasting hyperglycemia, glucose intolerance and plasma insulin in 91 F 2 females of a C57BL=6JÂKK-A y intercross. For glucose intolerance, a significant QTL was identified on chromosome 8, with a maximum lod score of 5.6. This locus had strong influence on the late phase of the intraperitoneal glucose tolerance test (IPGTT), suggesting that the locus may have role in glucose clearance rather than in mere hyperglycemia. In addition, three suggestive QTLs were identified on chromosomes 1 (fasting glucose), 3 (fasting insulin) and 4, (blood glucose at 120 min during IPGTT, and glucose intolerance).

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“…KK-A y mice result from a cross between glucose-intolerant black KK female mice and male yellow obese A y mice, and are known to serve as an excellent model of type II diabetes. 11 They were given a standard diet (MF, Oriental Yeast Co. Ltd, Tokyo, Japan) and water ad libitum. KK-A y mice at 8 weeks of age were administered pravastain (CS-514: 1, 5 and 20 mg kg À1 day À1 , donated by Daiich Sankyo Co. Ltd, Tokyo, Japan) orally for 2 weeks and/or olmesartan (RNH-6270; 0.5 mg kg À1 day À1 , donated by Daiich Sankyo Co. Ltd) for 2 weeks using an osmotic mini-pump implanted intraperitoneally.…”

Section: Animals and Treatmentmentioning

confidence: 99%

Improvement of glucose intolerance by combination of pravastatin and olmesartan in type II diabetic KK-Ay mice

et al. 2009

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The effects of the coadministration of pravastatin and an angiotensin type 1 (AT 1 ) receptor blocker, olmesartan, on glucose intolerance were examined using type II diabetic mice. Male KK-A y mice (8 weeks of age) were treated with pravastatin and/or olmesartan for 2 weeks. An oral glucose tolerance test (OGTT) was performed with an administration of 2 g kg -1 glucose. Tissue glucose uptake was determined using 2-[ 3 H]deoxyglucose. The treatment of mice with pravastatin attenuated the increase in the plasma glucose level during OGTT in a dose-dependent manner, without affecting the plasma insulin level. Pravastatin increased glucose uptake in insulin-sensitive tissue such as the skeletal muscle and adipose tissue after treatment at 5-20 mg kg À1 day À1 for 2 weeks, but not at 1 mg kg À1 day À1 . The combination of a noneffective dose of pravastatin (1 mg kg À1 day À1 ) and a noneffective dose of olmesartan (0.5 mg kg À1 day À1 ) synergistically improved OGTT without affecting the plasma insulin level. This combination also increased 2-[ 3 H]deoxyglucose uptake in the skeletal muscle and adipose tissue. The effects of pravastatin or olmesartan on OGTT and tissue 2-[ 3 H]deoxyglucose uptake were significantly enhanced by an antioxidant, tempol, whereas the effects of a pravastatin-olmesartan combination were not further enhanced by tempol. These results indicate that the combination of pravastatin and olmesartan synergistically improves glucose intolerance through an increase in tissue glucose uptake. The effects seem to be mediated by an increase in insulin sensitivity through the inhibition of oxidative stress. Keywords: angiotensin; glucose intolerance; oxidative stress; receptor; statin INTRODUCTIONThe renin-angiotensin system (RAS) has a critical role in cardiovascular function. Angiotensin (Ang) II is a major bioactive substance in RAS. Most actions of Ang II are mediated through angiotensin type 1 (AT 1 ) receptor stimulation. AT 1 receptor blockers (ARB) show beneficial effects on cardiovascular disorders, such as vascular remodeling, inflammation, cardiac remodeling after infarction and atherosclerosis. Previous reports indicate that RAS is also involved in insulin resistance and metabolic disorders. 1-3 In our previous report, an ARB, valsartan, improved glucose intolerance in diabetes model mice by enhancing insulin sensitivity. 4 Moreover, recent studies suggest that a coadministration of ARBs with other antihypertensive drugs shows beneficial effects on cardiovascular diseases. We recently reported that a calcium channel blocker, azelnidipine, synergistically enhanced the inhibitory action of an ARB, olmesartan, on brain ischemia. 5 On the other hand, statins are widely used for patients with hypercholesterolemia and atherosclerosis. The beneficial effects of

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Genetic analysis of non-insulin-dependent diabetes mellitus in KK and KK-Ay mice

Cited by 94 publications

References 24 publications

Angiotensin II Type-1 Receptor Blocker Valsartan Enhances Insulin Sensitivity in Skeletal Muscles of Diabetic Mice

Angiotensin II Type-1 Receptor Blocker Valsartan Enhances Insulin Sensitivity in Skeletal Muscles of Diabetic Mice

A quantitative trait locus that accounts for glucose intolerance maps to chromosome 8 in hereditary obese KK-Ay mice

Improvement of glucose intolerance by combination of pravastatin and olmesartan in type II diabetic KK-Ay mice

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