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

Adiponectin has been shown to regulate glucose and fatty acid uptake and metabolism in skeletal muscle. Here we investigated the role of the recently cloned adiponectin receptor (AdipoR) isoforms in mediating effects of both globular (gAd) and full-length (fAd) adiponectin, and their regulation by hyperglycemia (25 mM, 20 h) and hyperinsulinemia (100 nM, 20 h). We used L6 rat skeletal muscle cells, which were found to express both AdipoR1 and AdipoR2 mRNA in a ratio of over 6:1 respectively. Hyperglycemia and hyperinsulinemia both decreased AdipoR1 receptor expression by approximately 50%, while the latter induced an increase of approximately threefold in AdipoR2 expression. The ability of gAd to increase GLUT4 myc translocation, glucose uptake, fatty acid uptake and oxidation, as well as AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation, was decreased by both hyperglycemia and hyperinsulinemia. Interestingly, hyperinsulinemia induced the ability of fAd to elicit fatty acid uptake and enhanced fatty acid oxidation in response to fAd. In summary, our results suggest that both hyperglycemia and hyperinsulinemia cause gAd resistance in rat skeletal muscle cells. However, hyperinsulinemia induces a switch toward increased fAd sensitivity in these cells.
J Mol Endocrinol 2005 Dec
PMID:Hyperglycemia- and hyperinsulinemia-induced alteration of adiponectin receptor expression and adiponectin effects in L6 myoblasts. 1632 33

Findings discussed in this review stress the importance of normal estrogen and androgen signaling at appropriate developmental time points in maintaining normal phenotypic expression, reproductive and metabolic function and document how inappropriate steroid signaling, at inopportune times can have undesirable outcomes. For example, inappropriate testosterone exposure during fetal life alters the developmental trajectory of the female culminating in a suite of disorders, which include intrauterine growth-retardation and postnatal catch up growth, phenotypic masculinization, reproductive neuroendocrine and ovarian disruptions leading to progressive loss of cyclicity and metabolic disruptions manifested as hyperinsulinemia.
Mol Cell Endocrinol 2006 Feb 26
PMID:Prenatal testosterone excess programs reproductive and metabolic dysfunction in the female. 1641 12

Obesity is typically associated with resistance to leptin, yet the mechanism by which leptin signaling becomes impaired is poorly understood. Here we sought to determine if the development of obesity and leptin resistance correlates with increased expression of protein tyrosine phosphatase 1B (PTP1B) in peripheral tissues and whether over-expression of this phosphatase, specifically in liver, could alter the leptin-mediated effects on feeding and glucose metabolism. Obesity was induced in mice through a high-fat diet that resulted in hyperglycemia, hyperinsulinemia and hyperleptinemia. Resistance to leptin was confirmed as exogenous leptin administration reduced food intake in animals on low-fat, but not high-fat diets. Diet-induced resistance to leptin and insulin was associated with increased hepatic levels of PTP1B. Intriguingly, hepatic adenoviral over-expression of PTP1B in ob/ob mice attenuated the ability of exogenous leptin to reduce both plasma glucose levels and food intake. These findings suggest that leptin reduces both plasma glucose and food intake in part through actions on the liver, and hepatic leptin resistance resulting from over-expression of PTP1B may contribute to the development of both diabetes and obesity.
J Mol Endocrinol 2006 Feb
PMID:Leptin resistance following over-expression of protein tyrosine phosphatase 1B in liver. 1646 36

: 1. The use of tritiated norepinephrine (NE) to measure the turnover rate of NE in sympathetically innervated organs was pioneered in the laboratory of Julius Axelrod. This technique provides an organ specific assessment of sympathetic activity, integrated over a 24 h period, in free living laboratory animals. As such it has proved useful in estimating changes in sympathetic outflow in different physiologic and patho-physiologic states. 2. Studies employing NE turnover techniques in laboratory rodents have demonstrated conclusively that fasting suppresses and overfeeding stimulates the sympathetic nervous system (SNS). These changes in sympathetic activity also occur in humans. 3. Diet-induced changes in SNS activity are regulated by insulin-mediated glucose uptake and metabolism in central neurons sensitive to insulin and located anatomically in the ventro-medial hypothalamus. The regulation is imposed by descending inhibition of tonically active sympathetic brainstem centers. 4. Diet-induced changes in SNS activity mediate changes in energy production known as dietary thermogenesis. The capacity for dietary thermogenesis serves as a potential buffer against weight gain.5. Insulin stimulated SNS activity contributes to obesity-related hypertension. The insulin resistance of obesity, and consequent hyperinsulinemia, drives sympathetically mediated thermogenesis, restoring energy balance at the expense of SNS over activity. The association of obesity and hypertension, therefore, may be the unintended consequence of mechanisms recruited in the obese to limit further weight gain.
Cell Mol Neurobiol
PMID:Feast or famine: the sympathetic nervous system response to nutrient intake. 1670 81

Medium- and short-chain l-3-hydroxy-acyl-CoA dehydrogenase (M/SCHAD) deficiency is a recessively inherited disorder of fatty acid oxidation. Currently, only four patients from three families have been reported in the literature. All these patients presented with hypoglycemia associated with hyperinsulinism (HI). This association suggests that there is a role for M/SCHAD in regulating the pancreatic secretion of insulin. We present a fifth patient whose presentation was similar to Reye syndrome, a feature in common with most of the previously recognized disorders of fatty acid oxidation but with no clinical evidence of HI. Sequencing of the HAD1 gene on chromosome 4 revealed compound heterozygosity for two novel missense mutations, 170A>G, resulting in D45G, and 676T>C, resulting in Y214H. The mutant enzymes were expressed and subjected to kinetic analysis. Y214H has no detectable activity, whilst D45G, which resides in the cofactor-binding pocket, has an altered K(m) for NADH (96 microM versus 24 microM for the wild-type). This represents the first kinetic M/SCHAD mutant, which explains the high residual activity in skin fibroblasts. The lack of obvious HI in this patient may be related to the high residual activity and indicates that HI associated with M/SCHAD deficiency may only be present with complete deficiency. The spectrum of M/SCHAD phenotype should be broadened to include acute liver disease.
Mol Genet Metab
PMID:Reye-like syndrome resulting from novel missense mutations in mitochondrial medium- and short-chain l-3-hydroxy-acyl-CoA dehydrogenase. 1743 78

Polycystic ovary syndrome (PCOS) is a heterogeneous familial disorder characterized by chronic anovulation and hyperandrogenism. This multi-system, polygenic, multi-factorial disorder is associated with an increased risk for metabolic abnormalities such as type 2 diabetes mellitus. Signs and symptoms of PCOS often emerge during the peri-pubertal years with premature pubarche (PP) being the earliest manifestation for some girls. Insulin resistance and hyperinsulinemia are important pathophysiological features that are common to both PP and PCOS. Future investigations are needed to uncover the relevant genetic and hormonal factors and identify effective interventions.
Mol Cell Endocrinol 2006 Jul 25
PMID:Puberty and polycystic ovary syndrome. 1675 May 96

Recent advances in functional genomics afford the opportunity to interrogate the expression profiles of thousands of genes simultaneously and examine the function of these genes in a high-throughput manner. In this study, we describe a rational and efficient approach to identifying novel regulators of insulin secretion by the pancreatic beta-cell. Computational analysis of expression profiles of several mouse and cellular models of impaired insulin secretion identified 373 candidate genes involved in regulation of insulin secretion. Using RNA interference, we assessed the requirements of 10 of these candidates and identified four genes (40%) as being essential for normal insulin secretion. Among the genes identified was Hadhsc, which encodes short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD), an enzyme of mitochondrial beta-oxidation of fatty acids whose mutation results in congenital hyperinsulinism. RNA interference-mediated gene suppression of Hadhsc in insulinoma cells and primary rodent islets revealed enhanced basal but normal glucose-stimulated insulin secretion. This increase in basal insulin secretion was not attenuated by the opening of the KATP channel with diazoxide, suggesting that SCHAD regulates insulin secretion through a KATP channel-independent mechanism. Our results suggest a molecular explanation for the hyperinsulinemia hypoglycemic seen in patients with SCHAD deficiency.
Mol Endocrinol 2007 Mar
PMID:Functional genomics of the beta-cell: short-chain 3-hydroxyacyl-coenzyme A dehydrogenase regulates insulin secretion independent of K+ currents. 1718 91

ATP-sensitive potassium (KATP) channels play a key role in the regulation of insulin secretion by coupling glucose metabolism to the electrical activity of pancreatic beta-cells. To generate an electric signal of suitable magnitude, the plasma membrane of the beta-cell must contain an appropriate number of channels. An inadequate number of channels can lead to congenital hyperinsulinism, whereas an excess of channels can result in the opposite condition, neonatal diabetes. KATP channels are made up of four subunits each of Kir6.2 and the sulphonylurea receptor (SUR1), encoded by the genes KCNJ11 and ABCC8, respectively. Following synthesis, the subunits must assemble into an octameric complex to be able to exit the endoplasmic reticulum and reach the plasma membrane. While this biosynthetic pathway ensures supply of channels to the cell surface, an opposite pathway, involving clathrin-mediated endocytosis, removes channels back into the cell. The balance between these two processes, perhaps in conjunction with endocytic recycling, would dictate the channel density at the cell membrane. In this review, we discuss the molecular signals that contribute to this balance, and how an imbalance could lead to a disease state such as neonatal diabetes.
Expert Rev Mol Med 2007 Aug 01
PMID:Molecular cell biology of KATP channels: implications for neonatal diabetes. 1766 35

Similar to phosphorylation, O-GlcNAcylation (or simply GlcNAcylation) is an abundant, dynamic, and inducible post-translational modification. In some cases, GlcNAcylation and phosphorylation occur at the same or adjacent sites, modulating each other. GlcNAcylated proteins are crucial in regulating virtually all cellular processes, including signaling, cell cycle, and transcription, among others. GlcNAcylation affects protein-protein interactions, activity, stability, and expression. Several GlcNAcylated proteins are involved in diabetes and Alzheimer's disease. Hyperglycemia increases GlcNAcylation of proteins within the insulin signaling pathway and contributes to insulin resistance. In addition, hyperinsulinemia and hyperlipidemia are also associated with increased GlcNAcylation, which affect and regulate several insulin signaling proteins, as well as proteins involved on the pathology of diabetes. With respect to Alzheimer's disease, several proteins involved in the etiology of the disease, including tau, neurofilaments, beta-amyloid precursor protein, and synaptosomal proteins are GlcNAcylated in normal brain. The impairment of brain glucose uptake/metabolism is a known metabolic defect in Alzheimer's neurons. Data support the hypothesis that hypoglycemia within the brain may reduce the normal GlcNAcylation of tau, exposing kinase acceptor sites, thus leading to hyperphosphorylation, which induces tangle formation and neuronal death. Alzheimer's disease and type II diabetes represent two metabolic disorders where dysfunctional protein GlcNAcylation/phosphorylation may be important for disease pathology.
Mol Biosyst 2007 Nov
PMID:O-GlcNAc modification in diabetes and Alzheimer's disease. 1794 Jun 59

Previously, we found that a loss of plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated filamentous actin (F-actin) structure contributes to insulin-induced insulin resistance. Interestingly, we also demonstrated that chromium picolinate (CrPic), a dietary supplement thought to improve glycemic status in insulin-resistant individuals, augments insulin-regulated glucose transport in insulin-sensitive 3T3-L1 adipocytes by lowering PM cholesterol. Here, to gain mechanistic understanding of these separate observations, we tested the prediction that CrPic would protect against insulin-induced insulin resistance by improving PM features important in cytoskeletal structure and insulin sensitivity. We found that insulin-induced insulin-resistant adipocytes display elevated PM cholesterol with a reciprocal decrease in PM PIP2. This lipid imbalance and insulin resistance was corrected by the cholesterol-lowering action of CrPic. The PM lipid imbalance did not impair insulin signaling, nor did CrPic amplify insulin signal transduction. In contrast, PM analyses corroborated cholesterol and PIP2 interactions influencing cytoskeletal structure. Because extensive in vitro study documents an essential role for cytoskeletal capacity in insulin-regulated glucose transport, we next evaluated intact skeletal muscle from obese, insulin-resistant Zucker (fa/fa) rats. Because insulin resistance in these animals likely involves multiple mechanisms, findings that cholesterol-lowering restored F-actin cytoskeletal structure and insulin sensitivity to that witnessed in lean control muscle were striking. Also, experiments using methyl-beta-cyclodextrin to shuttle cholesterol into or out of membranes respectively recapitulated the insulin-induced insulin-resistance and protective effects of CrPic on membrane/cytoskeletal interactions and insulin sensitivity. These data predict a PM cholesterol basis for hyperinsulinemia-associated insulin resistance and importantly highlight the reversible nature of this abnormality.
Mol Endocrinol 2008 Apr
PMID:Antidiabetogenic effects of chromium mitigate hyperinsulinemia-induced cellular insulin resistance via correction of plasma membrane cholesterol imbalance. 2051 88


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