The Effect of Leptin, Tumor Necrosis Factor-&amp;alpha; (TNF-&amp;alpha;), and Nitric Oxide (NO) Production on Insulin Resistance in Otsuka Long-Evans Fatty Rats

Iwai, Hiroshi; Ohno, Yasuhiro; Aoki, Norihiko

doi:10.1507/endocrj.50.673

Cited by 16 publications

(18 citation statements)

References 54 publications

(73 reference statements)

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“…22 The OLETF rats exhibit leptin resistance, 26 which was confirmed in this study as elevated leptin levels despite hyperphagia and obesity in the untreated OLETF. Leptin level was suppressed at 30 weeks only in the PS-treated OLETF, which showed less food intake and body weight compared with the untreated and AS-treated groups.…”

Section: Mechanisms For the Differential Effects Of Statin Therapy Onsupporting

confidence: 73%

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Differential Impact of Atorvastatin vs Pravastatin on Progressive Insulin Resistance and Left Ventricular Diastolic Dysfunction in a Rat Model of Type II Diabetes

Chen

Ohmori

Mizukawa

et al. 2007

Circ J

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iabetes mellitus (DM) and metabolic syndrome frequently result in congestive heart failure (CHF) with either preserved or unpreserved left ventricular (LV) systolic function, independent of coronary atherosclerosis. 1,2 This is because insulin resistance (IR) and impaired glucose metabolism facilitate not only coronary atherosclerosis leading to coronary events, but also myocardial interstitial fibrosis 3 and coronary microangiopathy, 4,5 at least partly through nitric oxide (NO)/superoxide imbalance. 2,4 In this regard, new-onset DM during medical treatment of hypertensive patients was reported to significantly increase the risk of cardiovascular events, including CHF, during a long-term follow-up period. 6 Therefore, attention should be paid to the influence of cardiovascular agents on glycemic control during prevention of cardiovascular diseases.The hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) have been widely prescribed to reduce cardiovascular events, based on the results of several clinical trials in which lower lipid levels were related to lower coronary event rates. 7-9 Intensive lipid-lowering therapy with atorvastatin (AS) can stop 10 or reverse 11 the further progression of coronary plaques and shows greater prevention of recurrent coronary events after acute coronary syndrome, compared with standard lipid lowering by pravastatin (PS). 9 Thus, the benefit of intensive lipid lowering to prevent coronary events by stabilizing coronary plaques has been established. However, the effects of statin therapy on glycemic control [12][13][14][15][16][17][18][19][20] or on the development of CHF have not been fully investigated and remain controversial. We have recently shown that early and long-term treatment with PS eliciting moderate lipid-lowering effects can retard the development of DM and progression of LV diastolic dysfunction, 15 a manifestation of diabetic cardiomyopathy, in a model of spontaneously developing type II DM, the Otsuka Long-Evans Tokushima Fatty (OLETF) rats. 21 However, whether intensive lipid lowering by other statins can exert greater or similar effects remains unknown. Moreover, although adipocytokines [22][23][24] have been emerging as factors affecting IR and should play an important role in the development of DM, the effects of statin therapy on them also remain to be studied.Therefore, in this study, we compared intensive lipid Background Controversy exists regarding the effects of statin therapy on progressive insulin resistance (IR) and its consequences, in the present study a rat model of spontaneously developing type II diabetes mellitus (DM) was used to examine the impact of atorvastatin (AS) vs pravastatin (PS). Methods and ResultsThe Otsuka Long-Evans Tokushima Fatty rats were either untreated or treated with 100 mg/kg per day of AS or PS from 6 weeks of age for 24 weeks. AS achieved much greater lipid lowering than PS. Serial oral glucose tolerance tests revealed new-onset diabetes was delayed by PS only. The untreated rats exhibited a progressive decrea...

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Section: Mechanisms For the Differential Effects Of Statin Therapy Onsupporting

confidence: 73%

“…IR was evaluated based on the product of fasting glucose and insulin concentrations. 26 Plasma NO levels were measured by the Griess reaction using a TCI-NOX1000W (Tokyo Kasei Kogyo, Japan) as the total of NO end-products, nitrite and nitrate (NOx). 27 …”

Section: Biochemical Analysesmentioning

confidence: 99%

Differential Impact of Atorvastatin vs Pravastatin on Progressive Insulin Resistance and Left Ventricular Diastolic Dysfunction in a Rat Model of Type II Diabetes

Chen

Ohmori

Mizukawa

et al. 2007

Circ J

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“…Also, a statistically significant negative correlation was noted between testis weight and the HOMA index in diabetic rats. The HOMA index is generally used as an indicator of insulin resistance in both human and rodents [15,16,24]. Our studies suggest that hyperglycemia or insulin resistance may primarily induce testis atrophy, subsequently causing a reduction in spermatogenesis, which was more remarkably observed in diabetic rats than in non-diabetic rats.…”

Section: Discussionmentioning

confidence: 60%

“…As an indicator of insulin resistance, the HOMA (Homeostasis Model Assessment) index, which is given by the fasting blood glucose level (mg/dl) × IRI (mU/ml)/405, was used [15,16].…”

Section: Rat Shbg Measurement [11]mentioning

confidence: 99%

Gonadal Hormones and Gonadal Function in Type 2 Diabetes Model OLETF (Otsuka Long Evans Tokushima Fatty) Rats

2005

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Abstract. Gonadal functions, with special reference to blood levels of sex-related markers such as 17b-estradiol (E2), free testosterone (free Te) and lutenizing hormone (LH), were examined in male OLETF (Otsuka Long Evans Tokushima Fatty) diabetic rats, a model of human type 2 diabetes mellitus. Male rats of the OLETF strain and male rats of the LETO strain, which act as a control of OLETF, both supplied by Otsuka Pharmaceutical Co., Ltd. (Tokushima, Japan), were periodically examined for blood levels of E2, free Te and LH at the age of 4, 5, 32, 40 and 64 weeks. The weight of the testis, the number of sperm contained within and histological findings of the testis were comparatively studied in both strains. Glucose and insulin (IRI) at fasting were examined to evaluate the homeostasis model assessment (HOMA) index. In order to investigate any sex hormone imbalance, sex hormone-binding globulin (SHBG) was measured by a dextrancharcoal assay. All of the OLETF rats became diabetic at the age of 32 weeks. There were no significant differences between OLETF and LETO rats regarding free Te, E2, LH or SHBG during the observation period from 4 to 64 weeks. Testis weight was significantly decreased in OLETF rats at 32 and 64 weeks and sperm counts at 64 weeks of age were also significantly decreased. Histologically, there was seminiferous tubule atrophy in the OLETF rats at 64 weeks of age. A significant negative correlation between testis weight and fasting blood glucose, as well as HOMA index, was observed in OLETF rats. In male diabetic OLETF rats, with a variety of hypogonadisms such as atrophy of the testis and low sperm count, the serum levels of E2, free Te, LH and SHBG were normally preserved. [5,6]. From about 20 weeks of age, OLETF rats begin to develop diabetes accompanied by obesity, and almost all of the rats develop diabetes by the age of 30 weeks. This study was intended to make clear, whether sexual dysfunctions, if any, occur in diabetic OLETF rats by examining serum levels of sex-related hormones and sex hormone-binding globulin (SHBG), as well as testis findings. SHBG is a factor affecting sex hormone activities by binding both testosterone and 17b-estradiol (E2), with a higher affinity for the former [7,8]. Materials and Methods AnimalsBoth OLETF rats and their controls, named LETO (Long-Evans Tokushima Otsuka) rats, which are nondiabetic, were supplied by Otsuka Pharmaceutical Co., Ltd. (Tokushima, Japan). OLETF rats comprising 4, 5, 32, 40 and 64 weeks of age and control LETO rats corresponding to each OLETF age were studied. After

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“…Therefore, we diagnosed her as having type 1 diabetes and started her on an intensive insulin therapy for the condition. Late pregnancies have been known to contribute to insulin resistance [20], of which there are various factors causing this, such as free fatty acid (FFA) and tumor necrosis factor-a (TNF-a) [16][17][18][19]. Acromegalic patients during pregnancy are therefore at a greater risk for hyperglycemia [2,3,20].…”

Section: Discussionmentioning

confidence: 99%

Type 1 Diabetes Associated with Asymptomatic Acromegaly Successfully Treated with Surgery after Pregnancy: A Case Report

Iwai

Ito

et al. 2005

Endocr J

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Abstract. We report a rare case of type 1 diabetes in a woman associated with acromegaly who was treated with surgery after pregnancy. An 18-year-old woman came to our hospital in April, 1998, complaining of thirst, polydipsia, polyuria, appetite loss, body weight loss of 8 kg in a month, and amenorrhea beginning 2 months earlier. Based on laboratory data, she was diagnosed as having type 1 diabetes mellitus. Although we suspected her of having acromegaly because of high growth hormone (GH) levels (6.9 or 8.5 ng/ml), blood levels of insulin-like growth factor 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) were within normal range and the circadian rhythm of her blood GH levels was normally maintained. Her blood GH level was elevated to 12.6 ng/ml 15 minutes after a TRH administration. Blood GH levels were suppressed from 49 ng/ml to 1.5 ng/ml 4 hours after an oral administration of 2.5 mg of bromocriptine. A magnetic resonance images (MRIs) showed pituitary swelling, but no nodules were found in the pituitary. Therefore, we diagnosed her as having acromegaly and observed her without surgery, while prescribing diet therapy and intensive insulin therapy for diabetes. We started a treatment of oral administration of 7.5 mg of bromocriptine per day for the acromegaly from April 28, 2000, because her elevated GH was suspected of causing her diabetes to be poorly controlled. During a pregnancy from October, 2000 to September, 2001, diabetic control was improved with increased administration of insulin under a constant dose of bromocriptine. She delivered a normal full-term infant. After the bromocriptine therapy was stopped as she hoped to breastfeed, blood levels of GH and IGF-1 became elevated and her diabetic control deteriorated. As her pituitary tumor observed in pituitary MRIs became larger during the course, a transsphenoidal surgery was performed on March 8, 2002. After the surgery, blood levels of GH and IGF-1 lowered and diabetic control improved again. We concluded as follows: to rule out acromegaly in patients with poorly controlled diabetes, 1) measurements of serum GH and IGF-1 should be performed, and 2) pituitary MRIs should be performed if blood levels of GH or IGF-1 are high.

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The Effect of Leptin, Tumor Necrosis Factor-α (TNF-α), and Nitric Oxide (NO) Production on Insulin Resistance in Otsuka Long-Evans Fatty Rats

Cited by 16 publications

References 54 publications

Differential Impact of Atorvastatin vs Pravastatin on Progressive Insulin Resistance and Left Ventricular Diastolic Dysfunction in a Rat Model of Type II Diabetes

Differential Impact of Atorvastatin vs Pravastatin on Progressive Insulin Resistance and Left Ventricular Diastolic Dysfunction in a Rat Model of Type II Diabetes

Gonadal Hormones and Gonadal Function in Type 2 Diabetes Model OLETF (Otsuka Long Evans Tokushima Fatty) Rats

Type 1 Diabetes Associated with Asymptomatic Acromegaly Successfully Treated with Surgery after Pregnancy: A Case Report

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