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)

To elucidate the role of neuropeptide Y (NPY)-Y1 receptor (Y1-R) in food intake, energy expenditure, and other possible functions, we have generated Y1-R-deficient mice (Y1-R-/-) by gene targeting. Contrary to our hypothesis that the lack of NPY signaling via Y1-R would result in impaired feeding and weight loss, Y1-R-/- mice showed a moderate obesity and mild hyperinsulinemia without hyperphagia. Although there was some variation between males and females, typical characteristics of Y1-R-/- mice include: greater body weight (females more than males), an increase in the weight of white adipose tissue (WAT) (approximately 4-fold in females), an elevated basal level of plasma insulin (approximately 2-fold), impaired insulin secretion in response to glucose administration, and a significant changes in mitochondrial uncoupling protein (UCP) gene expression (up-regulation of UCP1 in brown adipose tissue and down-regulation of UCP2 in WAT). These results suggest either that the Y1-R in the hypothalamus is not a key molecule in the leptin/NPY pathway, which controls feeding behavior, or that its deficiency is compensated by other receptors, such as NPY-Y5 receptor. We believe that the mild obesity found in Y1-R-/- mice (especially females) was caused by the impaired control of insulin secretion and/or low energy expenditure, including the lowered expression of UCP2 in WAT. This model will be useful for studying the mechanism of mild obesity and abnormal insulin metabolism in noninsulin-dependent diabetes mellitus.
 ...
PMID:Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice. 986 Oct 26

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

The effects of n-3 polyunsaturated fatty acids (n-3PUFA) on obesity and diabetes were examined using KK-Ay mice fed with perilla oil (P), soybean oil (S), or lard (L), and those containing 30% fish oil (PF, SF, or LF), containing eicosapentaenoic acid (EPA = 9.9%) and docosahexaenoic acid (DHA = 18.0%). Perilla oil contained the largest proportion of linolenic acid (LNA = 61.9%). Computerized tomography (CT) scans showed narrower areas of visceral fat in the abdominal cross sections of groups given fish oil (PF, SF, and LF) and lower leptin levels (p < 0.05-p < 0.001) compared with controls (P, S, and L), without significant changes in energy intake and body weight. The highest plasma n-3PUFA content (21.31 +/- 0.35%) was attained with PF. This group contained 2.6-fold more plasma DHA (p < 0.001), and expressed 2.7-fold more UCP2 mRNA in white adipose tissue (p < 0.01) than in the P group. The epididymal fat pad (p < 0.05) weighed less, and levels of blood glucose (p < 0.05) and total cholesterol (p < 0.01) were reduced in PF compared with P.
 ...
PMID:Increased uncoupling protein2 mRNA in white adipose tissue, and decrease in leptin, visceral fat, blood glucose, and cholesterol in KK-Ay mice fed with eicosapentaenoic and docosahexaenoic acids in addition to linolenic acid. 1033 20

Beta 3-adrenoceptor (beta 3-AR) agonists were found to have remarkable anti-obesity and anti-diabetic effects in rodents shortly after their discovery in the early 1980s. Despite these promising qualities, several pharmaceutical problems and theoretical concerns have slowed the development of these products as therapeutic agents in humans during the last 15 years. To date, the pharmaceutical industry has not been successful in developing a beta 3-AR agonist for use in the treatment of human obesity and type 2 diabetes. Pharmaceutical problems in this area concern important differences between rodent and human beta 3-AR and the difficulty in finding a compound with sufficient bioavailability that is a highly selective and full agonist at the human receptor. Some of these problems seem to have been solved with the cloning of the human beta 3-AR, which has made it possible to develop novel compounds directly and specifically against the human receptor. However, several theoretical concerns still remain. These include the major question as to whether the number of biologically active beta 3-ARs in adult humans is sufficient to produce relevant metabolic effects and, if so, whether their long-term stimulation is safe and free of unwarranted side effects. In addition, the mechanisms of action of beta 3-AR agonists remain poorly understood. Recent studies using CL 316,243, a highly selective beta 3-adrenergic compound, have provided new insights into the potential mechanisms of action of these drugs in rodents as well as the first evidence that treatment with a highly selective beta 3-AR agonist exerts relevant metabolic effects in humans. It appears that chronic beta 3-adrenergic stimulation in white adipose tissue increases the expression of newly discovered mitochondrial uncoupling proteins (UCP 2 and 3) and a "reawakening" of dormant brown adipocytes. In addition, beta 3-ARs may be present in skeletal muscle where ectopic expression of UCP-1 has been reported. If these findings are confirmed, tissues other than brown fat may play an important role in mediating beta 3-adrenergic effects on thermogenesis and substrate oxidation. In humans, treatment with CL 316,243 for 8 weeks, in spite of limited bioavailability, induced marked plasma concentration-dependent increases in insulin sensitivity, lipolysis, and fat oxidation in lean volunteers, without causing beta 1-, or beta 2-mediated side effects. These results clearly indicate that favourable metabolic effects can be achieved by selective beta 3-AR stimulation in humans. The compounds of the next generation currently emerging from preclinical development are full agonists at the human beta 3-AR. These agents have demonstrated promising results in non-human primates. It will be interesting to see whether their efficacy in clinical trials is superior to that achieved with previous (rodent) beta 3-AR agonists and, if so, whether their effects will eventually translate into weight loss and improved metabolic control that could facilitate their use as effective drugs for the treatment of obesity and Type 2 diabetes in humans.
Diabetes Metab 1999 Mar
PMID:Development of beta 3-adrenoceptor agonists for the treatment of obesity and diabetes--an update. 1033 19

We examined genetic mutations in the coding regions of the uncoupling protein 2 (UCP2) gene in 100 patients with non-insulin-dependent diabetes mellitus (NIDDM). The sequences of each exon-intron boundary were detected by polymerase chain reaction (PCR) using specific primer pairs designed in the cDNA sequence of UCP2 and a cycle-sequence method. Using the specific primer pairs in the intron 5'- or 3'-untranslated region, each exon with its exon-intron boundaries was amplified with the PCR method, and the PCR products were analyzed using a single-strand conformation polymorphism (SSCP) method. One nucleotide substitution in exon 4 was found, which exchanged Ala (gcc) at position 55 of the amino acid sequence for Val (gtc), previously reported in Denmark by Urhammer et al in 1997. The polymorphism was reanalyzed in all patients and 120 normal subjects using a PCR-restriction fragment length polymorphism method. There was no difference in the genotype distribution between patients and normal subjects, and our genotype distribution was similar to the Danish study. Furthermore, there were no clinical differences between genotype groups among the patients. No other mutation including the exon-intron boundary was found in these patients. Genetic mutations of UCP2 may not be commonly associated with obesity or diabetes in Japanese subjects.
 ...
PMID:Screening for variants of the uncoupling protein 2 gene in Japanese patients with non-insulin-dependent diabetes mellitus. 1033 57

Genetic studies in humans provide a method to test hypotheses about the biological roles of specific genes. So far, ten published papers have chosen to examine the hypothesis that uncoupling protein-2 (UCP2) and/or UCP3 influence energy expenditure and/or body fat accumulation. These genes were chosen because they are candidate energy expenditure genes, based on their homology to UCP1. Studies of UCP2 and UCP3 are intrinsically intertwined because the two genes are separated by only 6000 base pairs on human chromosome 11. Linkage studies in families have suggested that UCP2 and/or UCP3, or a closely linked gene, may influence resting metabolic rate (RMR) Some association studies using a 3' untranslated region insertion/deletion variant of UCP2 have produced statistically positive evidence for association with body mass index (BMI) and RMR. In contrast, association studies of UCP2 using an Ala to Val variant at amino acid 55 have produced negative results. Positive results have also been reported for association of a UCP3 splice variant with respiratory quotient in African Americans. In addition, no studies have reported linkage or association of UCP2 or UCP3 with diabetes. Overall, the results suggest that some variants of UCP2 and UCP3 may be associated with obesity traits in some populations. The UCPs, to date, show positive results in associations with obesity traits but not with diabetes traits. Further work will be needed to settle the role of UCP2 and UCP3 alleles in human body weight regulation.
 ...
PMID:Genetics of uncoupling proteins in humans. 1045 22

To study the effect of nonesterified fatty acids (NEFAs) on uncoupling protein-2 (UCP-2) and uncoupling protein-3 (UCP-3) gene expression, a triglyceride emulsion was infused for 5 h in 14 healthy volunteers. A euglycemic-hyperinsulinemic clamp was administered concomitantly in 7 of the 14 subjects. The mRNA levels of UCP-2 and of the short (UCP-3S) and long (UCP-3L) isoforms of UCP-3 were quantified by reverse transcription-competitive polymerase chain reaction in tissue biopsies taken before and at the end of the infusion periods. Plasma NEFA concentrations increased from 362+/-52 to 989+/-157 micromol/l (P = 0.018) during triglyceride infusion. UCP-3L (8+/-1 vs. 19+/-2 amol/microg total RNA, P = 0.018) and UCP-3S (11+/-2 vs. 17+/-3 amol/microg total RNA, P = 0.027) mRNA levels increased in skeletal muscle during triglyceride infusion. UCP-3L mRNA levels were positively correlated with plasma NEFA concentrations (r = 0.53, P = 0.005) and with lipid oxidation rates (r = 0.56, P = 0.004) determined by indirect calorimetry. In contrast, the expression of UCP-2 was not affected by lipid infusion in skeletal muscle or in subcutaneous adipose tissue. During the hyperinsulinemic clamp (plasma insulin concentrations 202+/-12 pmol/l), NEFA levels (405+/-49 vs. 648+/-77 micromol/l, P = 0.063) and lipid oxidation rates (0.67+/-0.09 vs. 0.84+/-0.10 mg x kg(-1) x min(-1), P = 0.091) were not significantly increased during triglyceride infusion. Under such conditions, the induction of UCP-3L and UCP-3S mRNA expression was totally prevented (8+/-2 vs. 8+/-1 and 8 +/-2 vs. 9+/-2 amol/microg total RNA, respectively). We conclude that increased plasma NEFA levels by lipid infusion for 5 h induces the expression of UCP-3 but not UCP-2 in humans. During triglyceride infusion, physiological hyperinsulinemia appears to prevent the induction of UCP-3 mRNA levels.
Diabetes 2000 Jan
PMID:Regulation of uncoupling protein-2 and uncoupling protein-3 mRNA expression during lipid infusion in human skeletal muscle and subcutaneous adipose tissue. 1061 46

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

Mitochondria use energy derived from fuel combustion to create a proton electrochemical gradient across the mitochondrial inner membrane. This intermediate form of energy is then used by ATP synthase to synthesize ATP. Uncoupling protein-1 (UCP1) is a brown fat-specific mitochondrial inner membrane protein with proton transport activity. UCP1 catalyzes a highly regulated proton leak, converting energy stored within the mitochondrial proton electrochemical potential gradient to heat. This uncouples fuel oxidation from conversion of ADP to ATP. In rodents, UCP1 activity and brown fat contribute importantly to whole-body energy expenditure. Recently, two additional mitochondrial carriers with high similarity to UCP1 were molecularly cloned. In contrast to UCP1, UCP2 is expressed widely, and UCP3 is expressed preferentially in skeletal muscle. Biochemical studies indicate that UCP2 and UCP3, like UCP1, have uncoupling activity. While UCP1 is known to play an important role in regulating heat production during cold exposure, the biological functions of UCP2 and UCP3 are unknown. Possible functions include 1) control of adaptive thermogenesis in response to cold exposure and diet, 2) control of reactive oxygen species production by mitochondria, 3) regulation of ATP synthesis, and 4) regulation of fatty acid oxidation. This article will survey present knowledge regarding UCP1, UCP2, and UCP3, and review proposed functions for the two new uncoupling proteins.
Diabetes 2000 Feb
PMID:Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. 1086 29


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