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

We have identified a novel cDNA encoding a protein highly homologous to the mammalian brown fat uncoupling protein (UCP). Unlike the known UCP, which is expressed specifically in brown adipose tissue, the UCP homolog (UCPH) mRNA is expressed in a variety of tissues, with predominant expression in human white adipose tissue and skeletal muscle. In the white adipose tissue of ob/ob and db/db mice, the UCPH transcript is induced approximately fivefold relative to lean littermate controls. Expression of murine UCPH in yeast results in growth inhibition under conditions that require aerobic respiration, but does not affect growth under anaerobic conditions. Furthermore, UCPH expression in yeast causes a decrease in the mitochondrial membrane potential, as judged by staining with the potential-sensitive dye DiOC6. These observations suggest that UCPH, like UCP, uncouples oxidative phosphorylation. The possibility that the UCPH protein is an important mediator of human thermogenesis is discussed.
Diabetes 1997 May
PMID:Cloning and characterization of an uncoupling protein homolog: a potential molecular mediator of human thermogenesis. 913 62

The anti-obesity and anti-diabetic effects of a highly specific beta 3-adrenoceptor agonist, CL316,243 (CL; beta 1: beta 2: beta 3 = 0:1:100,000), were investigated in Otsuka Long-Evans Tokushima Fatty (fatty) and Long-Evans Tokushima Otsuka (control) rats. Daily injection of CL (0.1 mg/kg, s.c.) to these rats (10 weeks old) for 14 weeks caused a significant reduction in body weight (fatty, 27%; control, 15%), associated with a marked decrease in fat pad weight (inguinal: fatty, 60%; control, 36%; retroperitoneal: fatty, 75%; control, 77%) without affecting food intake. The levels of uncoupling protein mRNA and protein levels of uncoupling protein (UCP), as well as guanosine 5'-diphosphate-binding (a reliable index of thermogenesis) in brown adipose tissue, were lower in the fatty than in the control rats. However, after CL treatment, these parameters in brown adipose tissue increased significantly 2- to 3-fold in both groups. Furthermore, uncoupling protein was induced in white adipose tissue as well as in brown adipose tissue. The fatty rats showed hyperglycemia and hyperinsulinemia during the glucose tolerance test, but CL ameliorated these parameters. These findings suggest that decreased thermogenesis in brown adipose tissue may be one of the causes of obesity in the fatty rats and that administration of CL prevents obesity by decreasing white fat mass, by activating brown adipose tissue thermogenesis, and by inducing uncoupling protein in white adipose tissue. Furthermore, CL treatment may inhibit diabetes mellitus by ameliorating obesity and by activating glucose transporter 4 in white adipose tissue and brown adipose tissue.
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PMID:Anti-obesity and anti-diabetic effects of CL316,243, a highly specific beta 3-adrenoceptor agonist, in Otsuka Long-Evans Tokushima Fatty rats: induction of uncoupling protein and activation of glucose transporter 4 in white fat. 915 Jun 93

Recent discoveries about the roles of 2 uncoupling proteins are changing the way we view obesity and its treatment. The author is also a coauthor of a recent Nature report that mice deficient in uncoupling protein 1 (UCP1) did not become fat, as anticipated, but lean. She found that the other uncoupling protein (UCP2) was up-regulated in the brown adipose tissue (BAT) of these mice, compensating, at least in part, for the lack of UCP1 and preventing obesity. Researchers have known for 40 years that the function of BAT is heat production. In 1978, researchers discovered UCP1, the protein responsible for this function. Subsequent investigation focused on the role of this protein in staving off obesity in animal models. In the early 1990s, surprising evidence from tissues other than BAT show that 20% to 40% of resting cellular energy expenditure is used to counter a proton leak down the electrochemical gradient across the mitochondrial inner membrane. This leak was found to be related to metabolic rate; the search for the mechanism of the leak led to the discovery of UCP2. Both uncoupling proteins have been found to act as leaks in mitochondrial inner membranes, allowing the dissipation of proton motive force. These findings could lead to new treatments for obesity and non-insulin-dependent diabetes mellitus.
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PMID:Obesity research continues to spring leaks. 925 78

Despite the fact that mutations resulting in the absence of leptin or its receptor have been associated with severe obesity and diabetes, such mutations do not appear to be responsible for most human obesity. Indeed, diet-induced obesity in animals and humans has been characterized by hyperleptinemia. This has been interpreted as evidence for leptin resistance. However, no careful longitudinal studies evaluating the role of leptin in the development of obesity exist. We report a series of studies in A/J and C57BL/6J (B/6) mice that demonstrate a direct relationship between the ability to increase plasma leptin levels in response to a high-fat diet and resistance to the subsequent development of obesity and diabetes. While leptin levels are similar in lean, low-fat-fed A/J and B/6 mice, the effects of a high-fat diet on plasma leptin differ dramatically between the two strains. After 4 weeks of high-fat feeding, leptin levels in A/J mice increased 10-fold, and this elevated level was maintained independent of weight gain throughout a 14-week feeding period. However, in B/6 mice, leptin levels remained at least twofold lower and only rose very gradually along with a significant increase in adiposity, hyperglycemia, and hyperinsulinemia. These differences in the response of leptin to diet are independent of food intake and plasma insulin levels during the 1st month of feeding. Further, we demonstrated that leptin administration did not influence the expression of the novel uncoupling protein UCP2, which also responds to dietary fat. From these results, we suggest that the response of leptin to fat feeding may be an important predictor of the development of subsequent obesity.
Diabetes 1997 Sep
PMID:Low plasma leptin in response to dietary fat in diabetes- and obesity-prone mice. 928 57

Humans and rats tend to gain weight as they age. Leptin is one regulator of food intake and energy expenditure. To determine if the increase in adiposity with age is related to altered leptin gene expression, we assessed adiposity levels, leptin mRNA levels in epididymal and inguinal white adipose tissue (EWAT and IWAT), and uncoupling protein (UCP1) mRNA levels in interscapular brown adipose tissue (IBAT) from F344 x BN rats ages 3, 12, 18, 24, and 30 months (n = 8/age). Levels of adiposity determined by the adiposity index and the Lee index increased between ages 3 and 24 months, with a decrease at age 30 months. There were parallel increases with age in body weight, EWAT, and IWAT depot size up to age 24 months, followed by a nonsignificant decrease at age 30 months. Daily food intake was unchanged with age. In EWAT, leptin mRNA per microgram of RNA was unchanged with age, whereas in IWAT, it increased up to 24 months, then declined at 30 months. Total leptin mRNA levels in both IWAT and EWAT depots increased with age, peaking at age 24 months, and were correlated with adiposity. Serum leptin levels increased with age, also peaking at age 24 months, and were correlated with total leptin mRNA in WAT pads and adiposity. The rate of increase in serum leptin was greater than the increase in adiposity with age, suggesting contributions from both the increase in leptin expression per unit of WAT and the increase in WAT depot size. In addition, UCP1 mRNA levels in IBAT did not change with age. These data suggest that adiposity increases with age and cannot be attributed to increased food intake, impaired leptin gene expression, or decreased UCP1 mRNA level in IBAT. Furthermore, leptin gene expression in IWAT increases with age independent of increasing adiposity.
Diabetes 1997 Dec
PMID:Leptin gene expression increases with age independent of increasing adiposity in rats. 939 92

Continuous (4 days) intracerebroventricular leptin infusion (12 microg/day) was performed in lean rats, and its hormonometabolic effects were determined. Intracerebroventricular leptin administration did not result in leakage of the hormone into the peripheral circulation. Thus, its effects were elicited by its presence within the central nervous system. Intracerebroventricular leptin infusion produced marked decreases in food intake and body weight gain relative to vehicle-infused fed ad libitum rats. Because decreases in food intake alter hormonometabolic homeostasis, additional control rats pair-fed to the amount of food consumed by leptin-infused ones were included in the study. Intracerebroventricular leptin-infused and vehicle-infused pair-fed rats were characterized, relative to vehicle-infused ad libitum-fed animals, by decreases in body weight and insulinemia and by increases in insulin-stimulated overall glucose utilization and muscle and brown adipose tissue glucose utilization index. Brown adipose tissue uncoupling protein (UCP)1, UCP2, and UCP3 mRNA levels were markedly decreased in pair-fed animals relative to those of fed ad libitum control animals, as were liver and white adipose tissue UCP2 and muscle UCP3 mRNA levels. In marked contrast, intracerebroventricular leptin administration was accompanied by the maintenance of high UCP1, UCP2, and UCP3 expression in all these tissues. Thus, despite analogies between leptin's effects and those of pair-feeding with regard to glucose handling, their respective underlying mechanisms differ. While leptin maintains or favors energy-dissipating mechanisms (UCP1, UCP2, and UCP3), the latter are markedly depressed in pair-fed rats. This effect of leptin may prevent subsequent excessive storage processes, thereby maintaining normal body homeostasis.
Diabetes 1998 Jul
PMID:Chronic central leptin infusion enhances insulin-stimulated glucose metabolism and favors the expression of uncoupling proteins. 964 22

We report a study of 10 candidate genes presumably involved in diabetes or insulin resistance or obesity among Pondicherian Tamil Indians, an isolated population with a high prevalence of diabetes. Forty-nine families with at least two affected patients in the sibship (567 individuals) were selected and tested by PCR-RFLP techniques for reported mutations in 10 diabetes or obesity candidate genes: glucagon receptor, insulin receptor substrate 1, insulin receptor, human beta 3 adrenergic receptor, fatty acid binding protein 2, mitochondrial tRNA(Leu(UUR)), sulphonylurea receptor, human uncoupling protein and the glycogen-associated regulatory subunit of protein phosphatase-1. Glucokinase gene was also screened for mutations. No mutations were found in glucokinase, glucagon receptor and mitochondrial genes in any of the 49 probands. Frequencies of polymorphisms at other loci were similar to those reported in Caucasian populations, except for 4 of the loci at which a higher frequency of variants was observed: human beta 3 adrenergic receptor, human uncoupling type 1 protein, fatty acid binding protein 2 and the glycogen-associated regulatory subunit of protein phosphatase-1. However, no evidence of association between any of these gene variants and non-insulin-dependent diabetes mellitus (NIDDM) or quantitative traits related to NIDDM (including body mass index, waist/hip ratio, insulinaemia, glycaemia, triglycerides and total cholesterol) was found in our sample. These results suggest that none of these gene variants commonly found in the Pondicherian Tamil population of South India is a major NIDDM predisposing locus, although it cannot be excluded that they may contribute to the polygenic background of the metabolic syndrome in Pondichery.
Diabetes Metab 1998 Jun
PMID:Genetic studies of polymorphisms in ten non-insulin-dependent diabetes mellitus candidate genes in Tamil Indians from Pondichery. 969 58

Two recently described proteins in the mitochondrial uncoupling protein (UCP) family, UCP-2 and UCP-3, have been linked to phenotypes of obesity and NIDDM. We determined the mRNA levels of UCP-2 and UCP-3 in skeletal muscle of NIDDM patients and of healthy control subjects. No difference in the mRNA levels or in the protein expression of UCP-2 was observed between the two groups. In contrast, mRNA levels of UCP-3 were significantly reduced in skeletal muscle of NIDDM patients compared with control subjects. In the NIDDM patients, a positive correlation between UCP-3 expression and whole-body insulin-mediated glucose utilization rate was also noted. These results suggest that UCP-3 regulation may be altered in states of insulin resistance.
Diabetes 1998 Sep
PMID:Uncoupling protein 3 is reduced in skeletal muscle of NIDDM patients. 972 46

To explore the potential role of the uncoupling protein (UCP) family in human obesity and diabetes, we have used the reverse transcription-polymerase chain reaction to quantify UCP mRNA expression in human skeletal muscle. Levels of mRNA for UCP2, and for both short (UCP3S) and long (UCP3L) forms of UCP3, were highly correlated in individuals, indicating that gene transcription of these UCPs may be coordinately regulated by common mechanisms. In normal glucose-tolerant individuals, muscle UCP2 mRNA levels were positively correlated with percentage of body fat and with BMI (r = 0.6 and P < 0.05 for both). UCP3S mRNA levels were also positively correlated with percentage of body fat (r = 0.52, P < 0.05), and UCP3L mRNA tended to increase as a function of obesity (0.05 < P < 0.1). UCP mRNA levels, however, were not correlated with resting metabolic rate. UCP3S and UCP3L mRNA levels (P < 0.05) and the UCP2 mRNA level (P = 0.09) were increased by 1.8- to 2.7-fold in type 2 diabetes, an effect that could not be explained by obesity. No significant difference was found for UCP2, UCP3S, or UCP3L mRNA levels between insulin-sensitive and insulin-resistant nondiabetic subgroups. We conclude that 1) skeletal muscle mRNA levels encoding UCP2 and UCP3 are correlated among individuals and may be coordinately regulated; 2) UCP3 expression is not regulated by differential effects on UCP3L and UCP3S forms of the mRNA; and 3) UCP mRNA expression tends to increase in muscle as a function of obesity but not of resting metabolic rate or insulin resistance, and is increased in patients with type 2 diabetes.
Diabetes 1998 Dec
PMID:Expression of mRNAs encoding uncoupling proteins in human skeletal muscle: effects of obesity and diabetes. 983 27

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.
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PMID:Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice. 986 Oct 26


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