Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms underlying the increase in energy expenditure during leptin treatment are not clear. We recently showed that a 5-h intravenous or intracerebroventricular infusion of leptin elevated basal glucose uptake in skeletal muscle (SM) and brown adipose tissue and increased whole-body glucose turnover in C57Bl/6J mice (Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ: Acute stimulation of glucose metabolism in mice by leptin treatment. Nature 389:374-377, 1997). We extended the previous study by measuring steady-state levels of uncoupling protein (UCP)-2 mRNA and UCP-3 mRNA in white adipose tissue (WAT) and SM. Leptin by intravenous or intracerebroventricular infusion for 5 h was associated with a decrease in UCP-2 mRNA in WAT (47-52%) and UCP-3 mRNA in SM (33-37%). Because overexpression of UCP-2 or UCP-3 can depolarize the inner mitochondrial membrane, suppression of UCP-2 mRNA and UCP-3 mRNA may in fact lower respiratory demands in WAT and SM. This is consistent with the parallel suppression of cytochrome oxidase subunit IV (COX-IV) mRNA in WAT (35-39%) after leptin infusion. COX-IV mRNA in SM did not respond to acute leptin treatment. Mitochondrial inorganic phosphate carrier (P1C) mRNA was also suppressed in WAT (33-35%) by either method of leptin infusion, but only intravenous infusion of leptin reduced P1C mRNA in SM (40%). Denervation suppressed mRNA levels for UCP-2 (49%), UCP-3 (36%), and COX-IV (59%) and eliminated the acute response to leptin in SM. The comparable response to leptin under intravenous or intracerebroventricular infusion and the loss of responsiveness after denervation strongly suggest that the acute effects of leptin involve central signaling pathways.
Diabetes 1999 Jan
PMID:Downregulation of uncoupling protein 2 mRNA in white adipose tissue and uncoupling protein 3 mRNA in skeletal muscle during the early stages of leptin treatment. 989 33

The recent discovery of uncoupling protein (UCP)-2 and UCP-3, and their high expression in skeletal muscle, has renewed interest in a possible role for these proteins in underlying the variability in energy expenditure and therefore metabolic efficiency. Using reverse transcription-polymerase chain reaction, levels of expression of UCP-2 and long and short forms of UCP-3 were measured in skeletal muscle of 19 nondiabetic, male Pima Indians covering a wide range of body weight. Twenty-four-hour energy expenditure was measured in a respiratory chamber in 16 of these individuals. BMI was negatively correlated with the expression levels of the long (r = -0.53, P = 0.025) and short (r = -0.46, P = 0.047) forms of UCP-3. BMI was not correlated with UCP-2 expression. Metabolic rate during sleep, adjusted for fat-free mass and fat mass, was positively correlated with the long form of UCP-3 (r = 0.69, P = 0.006). These results indicate that UCP-3 may be a determinant of energy expenditure and metabolic efficiency in Pima Indians.
Diabetes 1999 Jan
PMID:Skeletal muscle uncoupling protein 3 expression is a determinant of energy expenditure in Pima Indians. 989 36

The discovery of uncoupling protein (UCP)-2, a ubiquitously expressed protein homologous to UCP-1, has raised the possibility that energy balance of cells might be regulated in tissues other than brown adipocytes. In normal pancreatic islets, UCP-2 is upregulated by leptin and is low in leptin-resistant islets of ZDF rats. To determine whether UCP-2 does, in fact, have uncoupling activity and, if so, whether such activity would favorably influence the abnormalities in leptin-unresponsive UCP-2-underexpressing islets of diabetic ZDF rats, we transferred the UCP-2 gene to the islets of diabetic ZDF rats and lean (+/+) ZDF control rats. Although ATP was reduced by 23% in both groups of islets, the ATP:ADP ratio increased by 42 and 141%, respectively. [3H]palmitate oxidation was increased by 50%, and [3H]glucose oxidation was 42-63% higher. Preproinsulin mRNA was 2.9-fold above control levels, and glucose-stimulated insulin secretion, which was negligible in control ZDF rat islets, was improved in UCP-2-overexpressing islets. The high fat content of the islets was not reduced, however. We conclude that UCP-2 has uncoupling function when overexpressed in leptin-insensitive islets and that its overexpression corrects the underexpression of the insulin gene and ameliorates glucose-stimulated insulin secretion, possibly by increasing the ATP:ADP ratio.
Diabetes 1999 May
PMID:Adenovirus-mediated overexpression of uncoupling protein-2 in pancreatic islets of Zucker diabetic rats increases oxidative activity and improves beta-cell function. 1033 6

It has been claimed that factors favoring the development or maintenance of animal or human obesity may include increases in glucocorticoid production or hyperresponsiveness of the hypothalamic-pituitary-adrenal axis. In normal rats, glucocorticoids have been shown to be necessary for chronic intracerebroventricular infusion of neuropeptide Y to produce obesity and related abnormalities. Conversely, glucocorticoids inhibited the body weight-lowering effect of leptin. Such dual action of glucocorticoids may occur within the central nervous system, since both neuropeptide Y and leptin act within the hypothalamus. The aim of this study was to determine the effects of glucocorticoids (dexamethasone) given intracerebroventricularly to normal rats on body weight homeostasis and hypothalamic levels of neuropeptide Y and corticotropin-releasing hormone. Continuous central glucocorticoid infusion for 3 days resulted in marked sustained increases in food intake and body weight relative to saline-infused controls. The infusion abolished endogenous corticosterone output and produced hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, three salient abnormalities of obesity syndromes. Central glucocorticoid infusion also produced a marked decrease in the expression of uncoupling protein (UCP)-1 and UCP-3 in brown adipose tissue and UCP-3 in muscle. Finally, chronic central glucocorticoid administration increased the hypothalamic levels of neuropeptide Y and decreased those of corticotropin-releasing hormone. When the same dose of glucocorticoids was administered peripherally, it resulted in decreases in food intake and body weight, in keeping with the decrease in hypothalamic neuropeptide Y levels. These results suggest that glucocorticoids induce an obesity syndrome in rodents by acting centrally and not peripherally.
Diabetes 1999 Feb
PMID:Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat. 1033 15

Diabetic rats have a deficiency in their heart ATP concentrations, and although the mechanism remains to be elucidated, this deficiency may involve increased uncoupling of oxidative phosphorylation. To investigate whether heart uncoupling proteins (UCPs) are subject to transcriptional regulation in diabetes, we examined changes in UCP mRNA expression in the heart of streptozotocin-induced diabetic (STZ-DM) rats. Heart UCP3 mRNA expression significantly increased by 9.4-fold in STZ-DM rats, while levels of UCP2 mRNA expression were not significantly altered. Insulin supplementation in STZ-DM rats returned UCP3 mRNA concentrations to control levels. The expression of UCP3 mRNA was similarly elevated in the heart of fasted rats, which also have hypoinsulinemia and hyper-free fatty acidemia but, unlike the STZ-DM rats, are hypoglycemic. Since hyperinsulinemia alone was previously reported to not affect UCP3 gene expression in the muscle, these results indicate that hyper-free fatty acidemia is a potent enhancer of UCP3 gene expression in the diabetic rat heart. Interestingly, we found no changes in UCP3 mRNA levels in Zucker fatty (fa/fa) rats with excessive chronic hyper-free fatty acidemia, which suggests that upregulation of heart UCP3 mRNA may depend on an acute change in free fatty acid concentrations rather than on their sustained elevation. High-energy ATP deficiencies in the diabetic rat heart may primarily result from proton leakage due to the upregulation of UCP3 expression.
Diabetes 1999 Feb
PMID:Streptozotocin treatment upregulates uncoupling protein 3 expression in the rat heart. 1033 27

UCP2 and UCP3 are two recently cloned genes with high sequence homology to the gene for uncoupling protein (UCP)-1, which regulates thermogenesis in brown adipose tissue. In the context of the current debate about whether UCP2 and UCP3 in the skeletal muscle may also function as mediators of thermogenesis or as regulators of lipids as fuel substrate, we have examined their mRNA expressions in rat gastrocnemius muscle in response to dietary manipulations known to differentially affect thermogenesis during the phase of weight recovery after starvation. Compared with ad libitum-fed control rats, the refeeding of isocaloric amounts of a low-fat (high-carbohydrate) diet resulted in lower energy expenditure and lower mRNA levels of muscle UCP2 and UCP3. This downregulation of UCP homologs was abolished by the refeeding of a high-fat diet, even though energy expenditure was significantly lower during refeeding on the high-fat than on the low-fat diet. Furthermore, major alterations in the fatty acid composition of the refeeding diet in favor of n-6 polyunsaturated or medium-chain fatty acids resulted in significant increases in energy expenditure, but with no significant changes in the expression of skeletal muscle UCP homologs. Regression analysis of gastrocnemius UCP mRNA levels against parameters that included body composition, energy expenditure, and plasma levels of free fatty acids (FFAs), insulin, and glucose as well as the increase in plasma glucose after a glucose load, revealed that only the latter (an index of insulin resistance) could explain the variability in muscle UCP2 and UCP3 mRNA expressions (r = 0.41, P < 0.02; r = 0.45, P < 0.01, respectively). Taken together, these data are at variance with a role for skeletal muscle UCP2 and UCP3 in dietary regulation (or modulation) of thermogenesis. However, they are consistent with the notion that these UCP homologs may function as regulators of lipids as fuel substrate and raise the possibility that high-fat induced upregulation of muscle UCP2 and UCP3 may be more closely linked to insulin resistance than to changes in circulating FFAs.
Diabetes 1999 Feb
PMID:Post-starvation gene expression of skeletal muscle uncoupling protein 2 and uncoupling protein 3 in response to dietary fat levels and fatty acid composition: a link with insulin resistance. 1033 28

We studied by PCR-RFLP 6 polymorphisms in these 5 candidate genes: Ala54Thr in the fatty acid binding protein 2 gene (FABP2), A to G substitution in the uncoupling protein type 1 gene (UCP1), Asp905Tyr in the protein phosphatase type 1 gene (PP1G), Trp64Arg in the human beta 3 adrenergic receptor gene (beta 3AR) and 2 RFLP sites of the vitamin D receptor (VDR) gene (VDRTaq1 and VDRApa1). This study was conducted among 89 cases and 100 controls matched according to age, gender and absence of first degree family link (11 triplets with 2 controls for 1 case and 78 pairs with 1 control for 1 case). Cases and controls were taken among a sample of 429 individuals selected for the study of the prevalence of diabetes in this ethnic group from Guadeloupe. By conditional logistic regression analysis, there was a significant relation (p = 0.02) between the Ala54Thr FABP2 polymorphism and Type 2 DM. Multivariate analysis discriminate the FABP2 polymorphism (p = 0.10), a triglyceridemia over 2 g/l (p < 10(-3)) and high blood pressure (p = 10(-2)) as variables associated with Type 2 DM in this population. These findings suggest that FABP2 does not represent a major gene for Type 2 DM in this migrant Indian population living in Guadeloupe, but seems to be related to the metabolic insulin resistance syndrome.
Diabetes Metab 1999 Jun
PMID:Type 2 diabetes mellitus: association study of five candidate genes in an Indian population of Guadeloupe, genetic contribution of FABP2 polymorphism. 1044 26

By virtue of its potential effects on rates of energy expenditure, uncoupling protein 3 (UCP3) is an obesity candidate gene. We identified nine sequence variants in UCP3, including Val9Met, Val102Ile, Arg282Cys, and a splice site mutation in the intron between exons 6 and 7. The splice mutation results in an inability to synthesize mRNA for the long isoform (UCP3L) of UCP3. Linkage (sib pair), association, and transmission disequilibrium testing studies on 942 African-Americans did not suggest a significant effect of UCP3 on body composition in this group. In vastus lateralis skeletal muscle of individuals homozygous for the splice mutation, no UCP3L mRNA was detectable; the short isoform (UCP3S) was present in an increased amount. In this muscle, we detected no alterations of in vitro mitochondrial coupling activity, mitochondrial respiratory enzyme activity, or systemic oxygen consumption or respiratory quotient at rest or during exercise. These genetic and physiologic data suggest the following possibilities: UCP3S has uncoupling capabilities equivalent to UCP3L; other UCPs may compensate for a deficiency of bioactive UCP3L; UCP3L does not function primarily as a mitochondrial uncoupling protein.
Diabetes 1999 Sep
PMID:Genetic and physiologic analysis of the role of uncoupling protein 3 in human energy homeostasis. 1048 Jun 26

Immortalized fetal brown adipocyte cell lines have been generated from homozygous (-/-) and heterozygous (+/-) insulin receptor substrate (IRS)-1-deficient mice, as well as from wild-type mice (+/+). Under growing conditions, these cell lines maintained the expression of the adipogenic marker fatty acid synthase and uncoupling protein-1, a tissue-specific thermogenic marker. The IRS-1 (-/-) brown adipocytes lacked IRS-1 protein expression and had a significant increase in IRS-2 protein expression. Insulin-induced tyrosine phosphorylation of IRS-1 was reduced by 50% in heterozygous IRS-1-deficient cells and was totally absent in homozygous cells, while tyrosine phosphorylation of IRS-2 showed a gradual increase. Insulin receptor alpha-subunit protein content and beta-subunit tyrosine kinase activity remained unchanged upon insulin stimulation, regardless of the lack of IRS-1. Brown adipocytes from homozygous IRS-1-deficient mice showed no IRS-1-associated p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase) or IRS-1-associated PI 3-kinase activity in response to insulin, but exhibited enhanced IRS-2-associated p85alpha subunit and IRS-2-associated PI 3-kinase activity. Overall insulin-induced PI 3-kinase activity associated to antiphosphotyrosine immune complexes was decreased by 30% in the homozygous IRS-1-deficient brown adipocytes. Downstream PI 3-kinase, activated Akt (protein kinase B) was decreased by 92% in an insulin-stimulated homozygous IRS-1-deficient brown adipocyte cell line, whereas the expression of Akt was similar in the three cell lines. However, activated p70 S6 kinase (p70s6k) remained unchanged. Although brown adipocyte cell lines showed similar cytosolic lipid content in the presence of 10% fetal calf serum, cytosolic lipid content was reduced in both serum-deprived heterozygous and homozygous IRS-1-deficient cells. Insulin treatment for 24 h doubled the cytosolic lipid content in wild-type and heterozygous IRS-1-deficient brown adipocyte cell lines but failed to increase the cytosolic lipid content in homozygous IRS-1-deficient cells. Our results strongly suggest that IRS-1/PI 3-kinase/Akt activation is an essential requirement for insulin stimulation of lipid synthesis in brown adipocytes.
Diabetes 1999 Nov
PMID:Insulin signaling in insulin receptor substrate (IRS)-1-deficient brown adipocytes: requirement of IRS-1 for lipid synthesis. 1053 44

The vulnerability of streptozotocin (STZ)-induced diabetic rats to cold stress has been established. One of the elements controlling body temperature is thermogenesis, in which uncoupling protein (UCP) is known to play an important role. We have examined UCP2 and UCP3 expressions in brown adipose tissue (BAT), white adipose tissue (WAT), and skeletal muscle (MSL) during the acute and chronic phases of STZ-induced diabetes in rats. The long-term effect and the effect of insulin treatment thereafter were also unexplored previously and are examined in this study. In the acute phase of diabetes (2.5 days after STZ injection), UCP2 gene expression in BAT, WAT, and MSL, and UCP3 expression in the muscle were significantly increased. In the chronic phase of diabetes (21 days after STZ injection), UCP2 and UCP3 expression in the MSL were restored to the control levels without insulin supplementation. UCP2 in BAT and WAT remained high in the chronic phase, whereas UCP3 expression in BAT and WAT, which did not change in the acute phase, was significantly decreased. Insulin supplementation restored UCP2 expression in BAT and WAT, but over-corrected UCP3 in WAT above the control and did not affect UCP3 expression in BAT. Insulin supplementation depressed UCP3 expression in the MSL below control. These results indicate that the effects of STZ-induced diabetes on UCPs gene expression are tissue-specific as well as dependent on the duration of diabetes.
 ...
PMID:Tissue-specific expression of the uncoupling protein family in streptozotocin-induced diabetic rats. 1086 33


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>