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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that the glucose intolerance and the hyperglycemic state in the GK rat, a new spontaneous model of non-insulin-dependent (type II) diabetes without obesity, are partly accounted for by an alteration of the pancreatic B cell response. On the other hand, the hyperglycemic-hyperinsulinemic pattern in these rats suggests a decrease of response to insulin in the basal state. In the present study, in vivo insulin action was assessed in 8-wk-old GK females at basal and submaximal (euglycemic clamp) insulin levels. Overall glucose utilization (OGU), individual tissue glucose utilization (ITGU, in vivo uptake of the glucose analogue 2-deoxy-D-glucose as the relative index of glucose metabolism), as well as hepatic glucose production (GP) and liver insulin receptor properties were determined under these two conditions. The basal OGU was significantly higher in the GK females, compared with that in control Wistar females. The hyperinsulinemic-euglycemic clamp experiments indicated that peripheral insulin resistance was installed at 8 wk of age in the GK females because 1) OGU was significantly lower and 2) in some peripheral tissues (epitrochlearis muscle, periovarian, and inguinal white adipose tissues), but not all, ITGU was significantly lower compared with corresponding ITGU in control rats. In the basal state GP was significantly higher in the GK rats. At submaximal hyperinsulinemia (and euglycemia), it was less effectively suppressed than in the controls, thus demonstrating liver insulin resistance. Under both basal state and clamp condition, binding of 125I-A14-insulin to liver membranes of GK rats was significantly decreased by 20-30%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin resistance in the GK rat: decreased receptor number but normal kinase activity in liver. 823 7

A metabolic hypothesis is presented for insulin resistance in obesity, in the presence or absence of Type 2 (non-insulin-dependent) diabetes mellitus. It is based on physiological mechanisms including a series of negative feed-back mechanisms, with the inhibition of the function of the glycogen cycle in skeletal muscle as a consequence of decreased glucose utilization resulting from increased lipid oxidation in the obese. It considers the inhibition of glycogen synthase activity together with inhibition of glucose storage and impaired glucose tolerance. The prolonged duration of increased lipid oxidation, considered as the initial cause, may lead to Type 2 diabetes. This hypothesis is compatible with others based on the inhibition of insulin receptor kinase and of glucose transporter activities.
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PMID:Metabolic origin of insulin resistance in obesity with and without type 2 (non-insulin-dependent) diabetes mellitus. 830 48

Using the molecular scanning technique of single-stranded conformational polymorphism (SSCP), we have examined the exons encoding the insulin receptor gene in 26 patients with syndromes of insulin resistance. We found 27 variant sequences, 4 of which were mutations that altered an amino acid. One patient with the Rabson-Mendenhall syndrome was homozygous for a mutation in the extracellular alpha-subunit (Ser to Leu323), one type A insulin-resistant patient was heterozygous for Pro to Leu1178, and another type A insulin-resistant patient was heterozygous for a mutation in the COOH-terminus of the receptor (Arg to Gln1351). The previously reported, and probably functionally insignificant, variant Val to Met985 was detected in one patient. No missense or nonsense insulin receptor mutations were found in any patients whose insulin resistance was associated with gross obesity, lipoatrophy, or acromegaloid features. No missense or nonsense mutations were found in subjects with polycystic ovary syndrome or Syndrome X. Putting these findings in the context of other work in this field, we conclude that subjects with leprechaunism or Rabson-Mendenhall syndrome have a high probability of having a missense or nonsense insulin receptor mutation. Nonobese, nondysmorphic, severely insulin-resistant females with hirsutism, acanthosis nigricans, and menstrual disturbance (type A phenotype) have an intermediate probability of having this type of insulin receptor mutation. Although insulin receptor mutations have been occasionally described in other phenotypes of insulin resistance, the frequency of point mutations in the exons of the insulin receptor gene in patients with those phenotypes appears to be low.
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PMID:Molecular scanning of the insulin receptor gene in syndromes of insulin resistance. 831 8

Hyperinsulinism, insulin resistance, and decreased number of insulin receptors are characteristic of obesity in both humans and experimental animals. To assess the role of insulin in developing obesity, diazoxide (DZ), an inhibitor of glucose-stimulated insulin secretion, was administered for 8 weeks to 7-week-old female Zucker rats in two concentrations, 50 mg/kg.day (LD-DZ), and 100 mg/kg.day (HD-DZ). The obese and lean rats were divided into three subgroups: diazoxide (DZ), pair-fed (PF), and control (C) groups (n = 6 rats/subgroup-genotype). Diazoxide-treated obese and lean animals showed significantly lower postabsorptive plasma insulin concentrations (P < 0.005) than their respective obese and lean PF and C subgroups. HD-DZ obese rats consumed more calories (P < 0.001), yet gained less weight (P < 0.05) than PF and C rats. The plasma glucose concentrations in the postabsorptive state and during glucose tolerance tests in HD-DZ obese rats were significantly lower than those in PF and C rats (P < 0.01) despite a decrease in their plasma insulin concentrations (P < 0.01), whereas HD-DZ lean rats displayed a diabetic response (P < 0.01). The adipocyte-specific insulin receptor binding was dose-dependently increased in both lean and obese DZ animals (P < 0.01). DZ had a dual effect on insulin metabolism; it decreased insulin secretion and increased insulin receptor binding. This dual effect was associated with improved glucose tolerance and a decrease in weight gain in obese rats.
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PMID:Modification of insulin resistance by diazoxide in obese Zucker rats. 834 9

The metabolic syndrome (syndrome X) is characterized by elevated insulin levels, obesity of the android type, disturbed lipid metabolism with increased triglycerides (VLDL elevated, HDL decreased) and an association with hypertension. The cause of this syndrome appears to be an insulin resistance of the skeletal muscle. The molecular mechanism leading to skeletal muscle insulin resistance is not understood, however an abnormality of signal transduction from the insulin receptor to glycogen synthase is suggested. It is believed that this syndrome represents a potentially prediabetic situation. Furthermore it is believed that this syndrome gives rise to cardiovascular complications in certain predisposed populations.
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PMID:[Metabolic syndrome--bridge to type II diabetes]. 847 32

Insulin resistance is an essential feature of a great variety of clinical disorders, like diabetes mellitus, obesity, essential hypertension, and is primarily due to a defect in hormone action at the cellular level. In the past decade application of novel research techniques including recombinant DNA technology have paved the way to understand the mechanisms of insulin action and its alterations at the molecular level. The first step in insulin action is the activation of the insulin receptor. The insulin receptor is a tetrameric protein consisting of two extracellular alpha- and two transmembrane beta-subunits. Binding of insulin to the alpha-subunit causes autophosphorylation of the intracellular beta-subunit region on tyrosine residues thereby activating the receptor. How the hormonal signal is subsequently transduced within the cell is still quiet unclear. The activated insulin receptor appears to couple to cytosolic receptor substrates which can affect different signaling cascades eliciting the pleiotropic hormone response on cell metabolism and growth. Most proteins involved in the signal transduction pathway of insulin are not known yet, but each of them might play a role in the various forms of insulin resistance. Taking the insulin receptor as an exemplary protein involved in insulin action we review molecular mechanisms regulating insulin receptor activity, gene expression, and the role of natural occurring insulin receptor gene mutations in patients with insulin resistant diabetes mellitus. It is outlined how the combination of both clinical medicine and molecular biology not only helps to understand insulin action and the pathogenesis of insulin resistance, but also leads to new avenues in the differential diagnosis, therapy, and possibly prevention of this heterogenous but most frequent metabolic and endocrine disorder.
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PMID:Molecular biology of insulin resistance. 847 20

The insulin resistance of skeletal muscle plays an important role in the pathogenesis of the metabolic endocrine syndrome and diabetes mellitus Type II. Impairment of the signal transmission from the insulin receptor to glycogen synthase and the glucose transport system was shown in insulin resistant subjects. A reduced receptor activation contributes also to insulin resistance. We investigated the mechanisms of modulation of receptor function in isolated cell systems which are transfected with human insulin receptor. Action of TNF alpha and acute hyperglycaemic effects were studied in particular. Acute hyperglycaemia gives rise, in the isolated cell system, to inhibition of the tyrosine kinase activity of the insulin receptor within a few minutes. This inhibitory effect seems to be mediated by translocation and activation of various isoforms of protein kinase C. Activation of protein kinase C probably leads to phosphorylation of the beta-subunit of the insulin receptor at serine residues. The domains of the insulin receptor, which are responsible for the inhibitory effect of hyperglycaemia do not seem to be localized either in the C terminus or in the juxtamembranary region of the insulin receptor. The hyperglycaemic effect can be antagonized in the isolated cell system both by protein kinase C inhibitors and so-called insulin sensitizers such as thiazolidindiones. Similar inhibitory effects, as induced by hyperglycaemia, can also be mediated by administration of the cytokine TNF alpha. As TNF alpha is probably increasingly expressed in obesity, the modulation of receptor kinase activity by TNF alpha could be an important factor for insulin resistance in obesity.
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PMID:Pathogenesis of insulin resistance: modulation of the insulin signal at receptor level. 852 11

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor (IR). Treatment of cultured murine adipocytes with TNF-alpha was shown to induce serine phosphorylation of insulin receptor substrate 1 (IRS-1) and convert IRS-1 into an inhibitor of the IR tyrosine kinase activity in vitro. Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF-alpha-mediated inhibition of IR signaling, whereas transfected 32D cells that express IRS-1 were very sensitive to this effect of TNF-alpha. An inhibitory form of IRS-1 was observed in muscle and fat tissues from obese rats. These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling.
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PMID:IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. 857 Nov 33

Hyperinsulinism and insulin resistance are characteristic findings in obese subjects. Obesity in both humans and experimental animals is associated with a reduced number of insulin receptors and a decreased insulin-mediated glucose disposal, whereas sensitivity to insulin's antilipolytic action is unaltered. To evaluate the antiobesity effect of diazoxide (DZ), an inhibitor of glucose-stimulated insulin release, 7-week-old Zucker obese and lean rats were studied. Obese and lean rats were grouped into DZ-treated (150 mg/kg/d) and control (C) groups. DZ-treated obese rats consumed similar amounts of calories per kilogram body weight (BW) compared with C obese animals, but gained less weight (P<.01). Postabsorptive plasma free fatty acids (FFA), cholesterol, and triglycerides were significantly higher in obese versus lean animals (P<.01). DZ treatment reduced plasma triglyceride levels in obese animals (P<.001), but had no significant effect on FFA or cholesterol concentrations. Plasma glucose concentrations in the postabsorptive state and during glucose tolerance tests (GTTs) were significantly lower in DZ obese versus C obese rats (P<.01) despite a decrease in plasma insulin concentrations in DZ-treated animals (P<.01). In contrast, DZ lean rats developed glucose intolerance (P<.05). Sensitivity and responsiveness to the antilipolytic effect of insulin in isolated adipocytes were significantly decreased in DZ obese as compared with C obese rats (P<.01). Moreover, adipocyte specific insulin receptor binding was increased in both DZ lean and DZ obese animals (P<.01). This was accompanied by increased basal and insulin-stimulated glucose transport in both genotypes (P<.01). In conclusion, DZ increased insulin receptor binding and glucose transport while decreasing hyperinsulinemia and insulin sensitivity to the antilipolytic action of insulin. This combined effect resulted in improved glucose tolerance and a decrease in weight gain in obese rats, implying that pharmacologic modification of the disturbed insulin metabolism of obesity may be therapeutically beneficial.
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PMID:Antiobesity effect of diazoxide in obese Zucker rats. 860 40

Impaired skeletal muscle insulin receptor function is a feature of common forms of insulin resistance, including obesity and noninsulin-dependent diabetes mellitus. However, the extent to which this defect accounts for impaired muscle glucose disposal or altered in vivo glucose homeostasis remains to be established. We recently showed that transgenic mice that overexpress dominant-negative insulin receptors specifically in striated muscle have a severe defect in muscle insulin receptor-mediated signaling and modest hyperinsulinemia. Here we performed hindlimb perfusion studies to determine the impact of this defect on muscle glucose uptake and metabolism. Maximal rates of insulin-stimulated muscle 3-O-methylglucose transport were reduced by 32-40% in transgenic mice with proportional defects involving total hindlimb [14C]glucose uptake, lactate production, and muscle glycogen synthesis. To address the hypothesis that muscle insulin resistance could promote an increase in the accretion of body fat, carcass analysis was performed using two independent lines of transgenic mice. Although body weights were normal, transgenic mice had a 22-38% increase in body fat, with a reciprocal decrease (10-15%) in body protein. Mean gonadal fat pad weight was also increased in transgenic mice. Skeletal muscle histology and fiber type distribution were not affected. To determine whether muscle-specific insulin resistance was sufficient to cause impaired glucose tolerance, oral glucose tolerance tests were performed with 6-month-old transgenic and control mice. Fasting glucose levels were increased by 25%, and peak values were 22-40% higher in transgenic mice. Transgenic mice also had a 37% decrease in plasma lactate levels and modest increases in levels of plasma triglycerides and FFA (29% and 15%, respectively). We conclude that 1) severe defects in muscle insulin receptor function result in impaired insulin-stimulated glucose uptake and metabolism in this tissue; 2) muscle-specific insulin resistance can contribute to the development of obesity; and 3) a "pure" defect in insulin-mediated muscle glucose disposal is sufficient to result in impaired glucose tolerance and other features of the insulin resistance syndrome, including hyperinsulinemia and dyslipidemia.
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PMID:Transgenic mice with muscle-specific insulin resistance develop increased adiposity, impaired glucose tolerance, and dyslipidemia. 864 Nov 92


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