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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The JCR:LA-cp rat is one of a number of strains that carry the mutant autosomal recessive cp gene. Animals, of all strains, that are homozygous, for the gene (cp/cp) become obese, insulin resistant, and hypertriglyceridemic. Heterozygotes or homozygous normal rats (+/+) are lean and metabolically normal. The JCR:LA-cp rat is unique in the development of a frank vasculopathy with atherosclerotic lesions and associated ischemic myocardial lesions. The cardiovascular disease is strongly correlated with the hyperinsulinemia, which develops as the animals mature from 4 to 8 weeks of age. The hyperinsulinemia can be decreased by marked food restriction, ethanol consumption, or reduction of the postprandial glucose and insulin responses through the use of alpha-glucosidase inhibitors. Any treatment that reduces plasma insulin levels is associated with a reduction in cardiovascular disease. In contrast, a reduction in plasma triglyceride concentrations, alone, has no effect on end-stage lesions. JCR:LA-cp rats, particularly those that are cp/cp, are, however, sensitive to cholesterol in the diet, unlike other strains that are highly resistant. Further, the rats have abnormal vascular smooth muscle cells that, especially in the cp/cp animals, are hyperplastic and activated and migrate into the intimal space. Our findings suggest that susceptibility to cardiovascular disease requires hypermsulinemic stress coupled with excessive dietary intake and the presence of one or more other necessary, but not sufficient, genetic factors. One of these may be a genetic abnormality of vascular smooth muscle cells. A similar situation may occur in humans.
Mol Cell Biochem 1998 Nov
PMID:Cardiovascular disease in the JCR:LA-cp rat. 982 17

KK obese mice exhibit a multigenic syndrome of moderate obesity, hyperinsulinemia and hyperglycemia. Here we show that the syndrome is accompanied by a marked elevation of leptin protein in adipose tissue, as well as leptin levels in serum, which corresponds with the degree of obesity. The cDNA sequence of leptin is normal in KK mice, whereas three nucleotide polymorphisms were found in the cDNA of the leptin receptor, one of them resulting in exchange of an aspartate residue for asparagine (Asp600Asn) in a highly conserved part of the second extracellular cytokine-receptor homology module. In female (but not male) F2 mice of a C57BL/6JxKK intercross, the weight of gonadal, retroperitoneal and mesenteric adipose tissue was positively correlated with the number of alleles inherited from the KK parental strain at a microsatellite marker (D4Mit175) which maps close (0.7 centimorgan proximal) to the leptin receptor gene. It is suggested that the Asp600Asn leptin receptor variant contributes to the obesity syndrome in KK female mice, but that its contribution is only a part of the multigenic syndrome.
J Mol Endocrinol 1998 Dec
PMID:Hyperleptinemia and leptin receptor variant Asp600Asn in the obese, hyperinsulinemic KK mouse strain. 984 74

Acute immunoneutralization of circulating leptin, with an anti-leptin antibody, significantly reduced rectal temperature at 30 min and 75 min post-injection in overnight fasted and at 30 min in overnight fed mice, while no effects in metabolic and ponderal indicators were observed after antibody administration for 22 days. Furthermore, hyperinsulinemia and hypoglycemia were induced by passive immunization against leptin, being both influenced by the post-prandrial status. These experiments confirm through an indirect approach that leptin is involved in energy, but also in glucose homeostasis.
Int J Mol Med 1998 Dec
PMID:Induction of hypothermia, hypoglycemia and hyperinsulinemia after acute leptin immunoneutralization in overnight fasted mice. 985 Jul 36

The tissue-specific expression of the mitochondrial pyruvate dehydrogenase complex (PDHc) has been studied in an animal model of obesity with hyperinsulinemia, the obese (fa/fa) Zucker rat. Liver and heart were obtained from 4 and 8 week-old obese rats and age-matched lean animals, and in each tissue the following parameters were analyzed: (1) total activity of the mitochondrial PDHc; (2) abundance of the mitochondrial PDHc subunits on Western blots; and (3) abundance of the E1alpha and E1beta subunit mRNAs on Northern blots and semi-quantitative RT-PCR. Regardless of age, obese rats showed an increase in liver total PDHc activity and a coordinate increase in liver E1alpha and E1beta PDHc subunit abundance. At 4 weeks, obese rats also showed an increase in liver PDH E1alpha mRNA level, but regardless of age E1beta mRNA level was unchanged. In contrast, neither total PDHc activity nor the concentration of its protein subunits were increased in heart of obese rats. Thus, obese Zucker rats display a liver-specific early increase in PDHc which results from a selective up-regulation of the E1alpha gene expression.
Mol Cell Endocrinol 1998 Sep 25
PMID:Longitudinal study of tissue- and subunit-specific obesity-induced regulation of the pyruvate dehydrogenase complex. 986 34

The skeletal muscle activity of protein tyrosine phosphates 1B (PTP1B), a modulator of insulin and IGF-1 signaling, is reduced in obese nondiabetic subjects and in subjects with type 2 diabetes in comparison with leaner, nondiabetic controls. PTP1B mRNA, like many other signaling molecules, including the insulin receptor, is alternatively spliced. Since we have shown that the ratio of the insulin receptor splice variants is modulated by insulin in vitro and is related to insulin levels in vivo, we hypothesized that the relative ratios of the alternatively spliced PTP1B mRNA might also vary in humans in proportion to the degree of hyperinsulinemia. This was tested in 21 nondiabetic Pima Indians, a population at increased risk for obesity and type 2 diabetes. The relative ratio of the PTP1B splice variants was quantified using RT-PCR of total RNA extracted from fractionated monocytes. The ratio of the splice variants was positively correlated with fasting plasma insulin concentration (r = 0.757; P = 0.0001), 2-h plasma insulin concentration following an oral glucose tolerance test (r = 0.614; P = 0.01, n = 16), and percentage of body fat (r = 0.746; P = 0.0001). These data indicate that variability in the ratio of the two splice variants is due, in part, to in vivo levels of chronic hyperinsulinemia. This simple, noninvasive assay is therefore a potential biomarker for chronic hyperinsulinemia, similar to the HbAlc assay in use to monitor glucose management in diabetic patients.
Mol Genet Metab 1999 Mar
PMID:Insulin-inducible changes in the relative ratio of PTP1B splice variants. 1006 87

Human obesity, which is very common in Polycystic Ovaries Syndrome and in "X Syndrome", constitutes an insulin-resistance state in which multiple clinical, biochemical and hemodynamic alterations coexist. Insulin resistance in the obese has been recently associated with an endothelial dysfunction. To investigate the possibility that clinical and metabolic derangements related to insulin resistance could induce changes in vascular blood flows, we have studied the levels of mesenteric (MBF), renal (RBF) and femoral (FBF) blood flows in Beagle dogs kept for 2 years on a normal (control group) or high fat diet (obese group). This experimental model exhibits many of the abnormalities with the human syndrome. In addition, we have tested the effects of chronic treatment with captopril (capto group) in monotherapy or in association with pravastatin (prava+capto group) on the hemodynamic changes associated with this diet. After the two year follow-up, Transonic flow probes were placed around the three arteries to measure basal blood flows and their response to a hyperinsulinemic-normoglycemic test in anesthetized animals. During this test the degree of insulin sensitivity was estimated. In association with higher body weight, blood pressure, insulin resistance, and fasting levels of insulin and total cholesterol, the obese group exhibited decreased basal levels of FBF and a greater femoral vasoconstriction during hyperinsulinism (P < 0.05 vs control). Combined therapy with captopril and pravastatin ameliorated the reduction in basal FBF and hyperinsulinism-induced vasoconstriction (P < 0.05), in addition to the beneficial effects on insulin sensitivity, and clinical and metabolic parameters. Synergistic beneficial effects of both drugs on lipid and carbohydrate profiles may account for this positive outcome, by attenuating the atherogenic process associated with this model.
J Steroid Biochem Mol Biol
PMID:Effects of hyperinsulinemia on vascular blood flows in experimental obesity. 1041 2

We investigated the contribution made by hyperinsulinemia and endothelial dysfunction to the hypertension of rats that had received 10% fructose in their drinking water for 12 weeks. As control animals with endothelial dysfunction, we used streptozotocin-induced diabetic rats. Measurements were made at 12 weeks after the start of fructose feeding or a single streptozotocin injection. Systolic blood pressure was greater in fructose-fed rats than in either streptozotocin-diabetic rats or age-matched controls. By comparison with the age-matched controls, the plasma levels of glucose, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol and free fatty acids were all significantly raised in both fructose-fed rats and streptozotocin-diabetic rats. The plasma insulin was significantly raised in fructose-fed rats, whereas it was significantly lowered in streptozotocin-diabetic rats. The vasodilatation induced in the perfused kidney by acetylcholine was weaker in both fructose-fed rats and streptozotocin-diabetic rats than in the age-matched controls and these weakened responses were further attenuated by indomethacin. Acetylcholine increased the nitrite and nitrate (NO2- and NO3-) levels in the renal perfusate in age-matched controls. This effect was much weaker in the two experimental groups. These results suggest that endothelial dysfunction in fructose-fed rats and streptozotocin-diabetic rats may be due to a decreased synthesis of nitric oxide at least in the perfused kidney. It is further suggested that hyperinsulinemia is more important than endothelial dysfunction as a cause of hypertension in fructose-fed rats.
Res Commun Mol Pathol Pharmacol 1999 Feb
PMID:Insulin resistance and impaired endothelium-dependent renal vasodilatation in fructose-fed hypertensive rats. 1046 86

Sulpiride (SUL, 20 mg kg-1 day-1) induces weight gain, hyperphagia, hyperprolactinemia, hypogonadism, and perhaps increased insulin sensitivity in rats. Leptin seems to signal the brain about the size of body fat stores and nutrient metabolism. We evaluated the basal serum leptin levels in rats after acute (1 h) or prolonged SUL or vehicle administration (10, 20 and 30 days). At days 10 and 30 leptin was also assessed during a glucose overload test. As the maximal weight gain during SUL administration is observed at days 10-15 of treatment, leptin was measured in a comparison group of insulin-treated rats (5 IU day-1 for 10 days). SUL-treated rats significantly gained weight. However, leptin levels were not significantly increased at any time-point of treatment. SUL did not affect insulin levels either. By contrast, leptin levels were significantly elevated after insulin administration, along with weight gain and hyperinsulinemia. An opposite correlation was also observed at day 10: leptin and insulin correlated negatively in the SUL group and positively in the insulin group. In addition, leptin and the magnitude of weight gain tended to correlate positively after SUL treatment, but negatively after insulin administration. SUL-treated rats, thus, appear to exhibit an unusual type of weight gain, characterized by normal circulating leptin and insulin levels. Such a particular leptin profile may be related to hyperprolactinemia, hypogonadism or lack of hyperinsulinemia. Molecular Psychiatry (2000) 5, 70-76.
Mol Psychiatry 2000 Jan
PMID:Antipsychotic drug-induced obesity in rats: correlation between leptin, insulin and body weight during sulpiride treatment. 1067 71

Insulin regulates expression and production of leptin in rodents but whether this is also true in humans remains unclear. To test the effects of acute hyperinsulinemia on expression of leptin mRNA in humans, percutaneous needle biopsies of abdominal subcutaneous adipose tissue were performed at baseline and immediately following a 200-min two-step hyperinsulinemic-euglycemic glucose clamp in 16 Pima Indians (8M/8F). Leptin mRNA was quantified by reverse transcription, PCR amplification and expressed relative to actin mRNA. Leptin mRNA levels were higher in women than men (25.6 +/- 1.7 v 16.9 +/- 2.1 relative units, P = 0.003) at baseline. Baseline levels were directly related to percentage body fat (r = 0.54, P = 0. 03) and fasting plasma glucose concentrations (r = 0.57, P = 0.02) and were negatively correlated to glucose disposal at physiologic insulin concentrations (750 +/- 40 pmol/L) during the clamp (r = -0. 51, P = 0.04). Acute hyperinsulinemia (final insulin concentration 11560 +/- 950 pmol/L) increased leptin mRNA levels in 13 of 16 individuals an average of 13% (21.3 +/- 1.7 to 24.2 +/- 1.2 relative units, P = 0.01). Changes in leptin mRNA were directly related to glucose disposal rates during physiologic hyperinsulinemia (r = 0.54, P < 0.04). These results suggest that the expression of leptin mRNA is regulated by insulin in humans, as it is in rodents.
Mol Genet Metab 2000 May
PMID:Insulin increases leptin mRNA expression in abdominal subcutaneous adipose tissue in humans. 1083 28

In mice with too little fat (lipodystrophy) or too much fat (ob/ob), leptin deficiency leads to hyperglycemia, hyperinsulinemia, and insulin resistance. In both disorders, the liver overproduces glucose as a result of resistance to the normal action of insulin in repressing mRNAs for gluconeogenic enzymes. Here we show that chronic hyperinsulinemia downregulates the mRNA for IRS-2, an essential component of the insulin-signaling pathway in liver, thereby producing insulin resistance. Despite IRS-2 deficiency, insulin continues to stimulate production of SREBP-1c, a transcription factor that activates fatty acid synthesis. The combination of insulin resistance (inappropriate gluconeogenesis) and insulin sensitivity (elevated lipogenesis) establishes a vicious cycle that aggravates hyperinsulinemia and insulin resistance in lipodystrophic and ob/ob mice.
Mol Cell 2000 Jul
PMID:Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. 1094 29


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