Gene/Protein Disease Symptom Drug Enzyme Compound
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The incidence of overweight and obesity is increasing among children with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) or mitochondrial trifunctional (TFP) deficiency. Traditional treatment includes fasting avoidance and consumption of a low-fat, high-carbohydrate diet. A diet higher in protein and lower in carbohydrate may help to lower total energy intake while maintaining good metabolic control. To determine the short-term safety and efficacy of a high protein diet, subjects were admitted to the General Clinical Research Center and fed an ad-libitum high-protein diet and a high-carbohydrate diet for 6 days each using a randomized, crossover design. Nine subjects with LCHAD or TFP deficiency, age 7-14 were enrolled. Body composition was determined by DEXA. Total energy intake was evaluated daily. Resting energy expenditure and substrate utilization were determined by indirect calorimetry. Post-prandial metabolic responses of plasma glucose, insulin, leptin, ghrelin, acylcarnitines, and triglyceride were determined in response to a liquid meal. Subjects had a higher fat mass, lower lean mass and higher plasma leptin levels compared to reference values. While on the high protein diet energy consumption was an average of 50 kcals/day lower (p = 0.02) and resting energy expenditure was an average of 170 kcals/day higher (p = 0.05) compared to the high carbohydrate diet. Short-term higher protein diets were safe, well tolerated, and resulted in lowered energy intake and increased energy expenditure than the standard high-carbohydrate diet. Long-term studies are needed to determine whether higher protein diets will reduce the risk of overweight and obesity in children with LCHAD or TFP deficiency.
Mol Genet Metab 2007 Jan
PMID:Effects of higher dietary protein intake on energy balance and metabolic control in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. 1699 88

Obesity is under the influence of genetic and nutritional factors. The objective was to verify whether variants in the gene encoding the carnitine palmitoyltransferase I (CPT1), a key enzyme in beta-oxidation of fatty acids, are associated with obesity phenotypes, alone or in interaction with fat intake. Sequencing of CPT1 was performed in 40 overweight subjects and 4 controls. Genotypes were determined in 351 French-Canadians. Fat intake was evaluated by a food frequency questionnaire. We identified 14 genetic variations in CPT1A and 26 in CPT1B. Nine variants within CPT1B and one variant within CPT1A were selected for further analyses based on the minor allele frequency (>10%) or on potential functional impact. A significant association between obesity phenotypes (BMI, weight, and waist girth) and CPT1B c.282-18C > T and p.E531K variants was observed (p < 0.05) No other association was found with variants in CPT1A and CPT1B. When subjects were divided into six groups according to p.E531K genotypes and further on the basis of fat using the median value as a cutoff point (34.4% of energy), BMI, weight, and waist girth were higher in E531/K531 on a high-fat diet compared to E531/K531 subjects under a low-fat diet (p = 0.004, p = 0.006, p = 0.003, respectively). There was no difference among E531/E531 and K531/K531. Similar results were obtained with the CPT1A p.A275T variant as BMI and waist girth were higher in A275/A275 on a high fat compared to A275/A275 subjects on a low-fat diet. Among carriers of the T275 allele, obesity indices were not affected by fat intake (p = 0.05 and p = 0.008 for BMI and waist girth, respectively). Among variants within the CPT1B gene, 13 haplotypes were inferred and the two most frequent haplotypes, H7 (38.0%) and H5 (27.7%), were kept for diplotype analysis. These haplotypes were not associated with indices of obesity, but as observed with the CPT1B E531K variant fat intake modulated this association. In conclusion, this finding suggests that indices of obesity might be modulated by an interaction between CPT1 variants and fat intake.
J Mol Med (Berl) 2007 Feb
PMID:Variants within the muscle and liver isoforms of the carnitine palmitoyltransferase I (CPT1) gene interact with fat intake to modulate indices of obesity in French-Canadians. 1708 95

Diet is an important environmental factor interacting with our genes to modulate the likelihood of developing lipid disorders and, consequently, cardiovascular disease risk. Our objective was to study whether dietary intake modulates the association between APOA5 gene variation and body weight in a large population-based study. Specifically, we have examined the interaction between the APOA5-1131T>C and 56C>G (S19W) polymorphisms and the macronutrient intake (total fat, carbohydrate, and protein) in their relation to the body mass index (BMI) and obesity risk in 1,073 men and 1,207 women participating in the Framingham Offspring Study. We found a consistent and statistically significant interaction between the -1131T>C single-nucleotide polymorphism (SNP; but not the 56C>G) and total fat intake for BMI. This interaction was dose-dependent, and no statistically significant heterogeneity by gender was detected. In subjects homozygous for the -1131T major allele, BMI increased as total fat intake increased. Conversely, this increase was not present in carriers of the -1131C minor allele. Accordingly, we found significant interactions in determining obesity and overweight risks. APOA5-1131C minor allele carriers had a lower obesity risk (OR, 0.61, 95%; CI, 0.39-0.98; P = 0.032) and overweight risk (OR, 0.63, 95%; CI, 0.41-0.96; P = 0.031) compared with TT subjects in the high fat intake group (>or=30% of energy ) but not when fat intake was low (OR, 1.16, 95%; CI, 0.77-1.74; P = 0.47 and OR = 1.15, 95%; CI, 0.77-1.71; P = 0.48) for obesity and overweight, respectively). When specific fatty acid groups were analyzed, monounsaturated fatty acids showed the highest statistical significance for these interactions. In conclusion, the APOA5-1131T>C SNP, which is present in approximately 13% of this population, modulates the effect of fat intake on BMI and obesity risk in both men and women.
J Mol Med (Berl) 2007 Feb
PMID:APOA5 gene variation modulates the effects of dietary fat intake on body mass index and obesity risk in the Framingham Heart Study. 1721 8

Food intake and weight gain are influenced by endocannabinoids whose actions are regulated by the fatty acid amide hydrolase (FAAH) enzyme. The homozygous Thr/Thr genotype of the functional Pro129Thr variant (rs324420) in the gene encoding FAAH was recently reported to associate with overweight and obesity in white and black populations. We investigated the Pro129Thr variant in relation to overweight and obesity in a relatively large population-based study sample of Danish whites (n=5,801). In case-control studies of obesity, a borderline association with the major Pro allele was identified; however, after correction for multiple testing, no association was found. Furthermore, a possible association between the major Pro allele and obesity was not supported by studies of obesity-related quantitative traits. In conclusion, in a large study sample, we were unable to find robust evidence of an association of the Pro129Thr FAAH variant with overweight, obesity, and any related quantitative traits among the examined whites.
J Mol Med (Berl) 2007 May
PMID:The functional Pro129Thr variant of the FAAH gene is not associated with various fat accumulation phenotypes in a population-based cohort of 5,801 whites. 1721 8

Obesity is associated with lower levels of serum 25-hydroxyvitamin D (25(OH)D). Obese individuals might need higher doses of vitamin D supplementation than the general population. In this cross-sectional study, associations between 25(OH)D serum levels, body mass index (BMI), and outdoor exercise were assessed in a population of 291 ambulatory patients attending the Osteoporosis Center at the University of Miami, mean age 62+/-13.48 years. Obesity was defined as BMI> or =30 kg/m(2) and hypovitaminosis D as 25(OH)D< or =30 ng/ml. Overall, prevalence of obesity was 14.1% and of hypovitaminosis D was 42.4%. Among Hispanics, there was a significantly higher prevalence of hypovitaminosis D in obese (63.2%) compared to non-obese individuals (35.8%). Outdoor exercise had a significant effect on the prevalence of hypovitaminosis D in Hispanics, with a lower prevalence in those performing outdoor exercise (24.1%) compared to those who did not (47.9%). After adjusting for age, gender, and ethnicity, those reporting outdoor exercise were 47% less likely to have hypovitaminosis D, while those with obesity had more than twice the risk. Since outdoor exercise may protect overweight individuals from hypovitaminosis D, prevention programs involving higher doses of vitamin D and/or outdoor exercise may result in additional metabolic and functional benefits in this population.
J Steroid Biochem Mol Biol 2007 Mar
PMID:Outdoor exercise reduces the risk of hypovitaminosis D in the obese. 1726 9

We have developed a simple and efficient SSCP (single strand conformational polymorphism) method for haplotype determination of beta2AR using four polymorphisms. The six different SSCP patterns were grouped into three major haplotypes named I, II and III. We studied a population of 199 individuals displaying all the haplotypes: 34.9% (group I), 36.1% (group II) and 29.5% (group III). This population was subdivided into three groups: normal weight, overweight and obese individuals. There were no significant differences between the haplotypes of normal and overweight individuals. The haplotype frequencies in the group of normal weight subjects were 39% (I), 33% (II) and 28% (III). The overweight individuals presented frequencies of 38% (I), 33% (II) and 29% (III). The obese group showed marked differences for haplotypes I and II: 27.1% (I), 43.2% (II) and 29.7% (III) when compared to the normal weight group. For haplotype I the p value of normal to obese groups was 0.0403 with an odds ratio of 0.5761. Our two step SSCP method for beta2AR haplotyping is simple, accurate and cost effective for studying large populations and may be a useful tool for easy and accurate identification of haplotype I which appears to have a protective role against developing obesity.
Mol Cell Probes 2007 Jun
PMID:A simple method for the identification of three major haplotypes of the beta2AR. 1730 78

Type I Gaucher disease, a lysosomal storage disorder is associated with metabolic abnormalities such as high resting energy expenditure, low circulating adiponectin and peripheral insulin resistance. Treatment with enzyme replacement therapy (enzyme therapy) leads to a decrease in resting energy expenditure, but its influence on weight and risk of development of type II diabetes is unknown. We studied the BMI, prevalence of overweight, insulin resistance and type II diabetes in untreated and enzyme therapy treated Gaucher patients before and after several years of follow-up and compared this to data on healthy subjects from literature. We established that in untreated Gaucher patients the prevalence of overweight is lower than in the general population. Long-term treatment with enzyme therapy induces a larger than average weight gain leading to a similar prevalence of overweight in enzyme therapy treated patients and the general population. The prevalence of type II diabetes increases significantly during treatment with enzyme therapy, resulting in a comparable prevalence of type II diabetes in enzyme therapy treated patients and the general population.
Blood Cells Mol Dis
PMID:Overweight, insulin resistance and type II diabetes in type I Gaucher disease patients in relation to enzyme replacement therapy. 1795 7

Decreasing the postprandial glucose response is potentially of major importance to public health when low-glycemic index or high-fibre content foods are associated with a decreased risk of diabetes. We investigated in overweight subjects the effect of adding beta-glucan (BG) to a polenta (Pol) meal on postprandial metabolism and glucose bioavailability using stable isotopes. In this single-blind, randomized, crossover trial, 12 subjects ate two meals containing Pol with (Pol + BG) or without (Pol) 5 g BG. Concentrations of glucose, insulin, C-peptide, nonesterified fatty acids, triacylglycerol, total and exogenous glucose kinetics were assessed for 6 h postprandially. The kinetics of total and exogenous glucose importantly differed between the meals, but not the quantity of total and exogenous glucose appearing in plasma. Less total and exogenous glucose appeared during the first 120 min after the Pol + BG meal; the phenomenon was then reversed (both p < 0.0001). After 120 min, glucose and insulin responses declined, but remained higher after the Pol + BG meal (p < 0.05) in parallel to the inhibition of lipolysis. The endogenous glucose production (EGP) was significantly more inhibited after the Pol + BG meal. The addition of BG slowed the appearance of glucose in plasma, resulting in longer-lasting insulin secretion which exerted a prolonged inhibition of EGP and lipolysis.
Mol Nutr Food Res 2009 Mar
PMID:Modulation of the postprandial phase by beta-glucan in overweight subjects: effects on glucose and insulin kinetics. 1883 70

Insulin resistance have been demonstrated in untreated patients with Gaucher type I disease. It was implied in overweight enzyme replacement therapy (ERT) treated patients with Gaucher type I disease. In present study we investigate whether insulin resistance is presented in fourteen ERT treated patients with Gaucher type I disease and without overweight in comparison to normal subjects. This work illustrates the presence of insulin resistance in non-overweight ERT treated patients with Gaucher type I disease.
Mol Genet Metab 2009 Jan
PMID:A cross-sectional, mono-centric pilot study of insulin resistance in enzyme replacement therapy patients with Gaucher type I without overweight. 1900 78

Recent work shows a high prevalence of low testosterone and inappropriately low LH and FSH concentrations in type 2 diabetes. This syndrome of hypogonadotrophic hypogonadism (HH) is associated with obesity, and other features of the metabolic syndrome (obesity and overweight, hypertension and hyperlipidemia) in patients with type 2 diabetes. However, the duration of diabetes or HbA1c were not related to HH. Furthermore, recent data show that HH is also observed frequently in patients with the metabolic syndrome without diabetes but is not associated with type 1 diabetes. Thus, HH appears be related to the two major conditions associated with insulin resistance: type 2 diabetes and the metabolic syndrome. CRP concentrations have been shown to be elevated in patients with HH and are inversely related to plasma testosterone concentrations. This inverse relationship between plasma free testosterone and CRP concentrations in patients with type 2 diabetes suggests that inflammation may play an important role in the pathogenesis of this syndrome. This is of interest since inflammatory mechanisms may have a cardinal role in the pathogenesis of insulin resistance. It is relevant that in the mouse, deletion of the insulin receptor in neurons leads to HH in addition to a state of systemic insulin resistance. It has also been shown that insulin facilitates the secretion of gonadotrophin releasing hormone (GnRH) from neuronal cell cultures. Thus, HH may be the result of insulin resistance at the level of the GnRH secreting neuron. Low testosterone concentrations in type 2 diabetic men have also been related to a significantly lower hematocrit and thus to an increased frequency of mild anemia. Low testosterone concentrations are also related to an increase in total and regional adiposity, and to lower bone density. This review discusses these issues and attempts to make the syndrome relevant as a clinical entity. Clinical trials are required to determine whether testosterone replacement alleviates symptoms related to sexual dysfunction, and features of the metabolic syndrome, insulin resistance and inflammation.
Curr Mol Med 2008 Dec
PMID:Hypogonadotrophic hypogonadism in type 2 diabetes, obesity and the metabolic syndrome. 1907 78


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