Biomedical subjects

A Kissebah

Publications and source records attributed to A Kissebah.

12 recordsLinked to original sources

PubMed2005

The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes.

AIMS/HYPOTHESIS: This study aimed to identify genes that are expressed in skeletal muscle, encode proteins with functional significance in mitochondria, and are associated with type 2 diabetes. METHODS: We screened for differentially expressed genes in skeletal muscle of Psammomys obesus (Israeli sand rats), and prioritised these on the basis of genomic localisation and bioinformatics analysis for proteins with likely mitochondrial functions. RESULTS: We identified a mitochondrial intramembrane protease, known as presenilins-associated rhomboid-like protein (PSARL) that is associated with insulin resistance and type 2 diabetes. Expression of PSARL was reduced in skeletal muscle of diabetic Psammomys obesus, and restored after exercise training to successfully treat the diabetes. PSARL gene expression in human skeletal muscle was correlated with insulin sensitivity as assessed by glucose disposal during a hyperinsulinaemic-euglycaemic clamp. In 1,031 human subjects, an amino acid substitution (Leu262Val) in PSARL was associated with increased plasma insulin concentration, a key risk factor for diabetes. Furthermore, this variant interacted strongly with age to affect insulin levels, accounting for 5% of the variation in plasma insulin in elderly subjects. CONCLUSIONS/INTERPRETATION: Variation in PSARL sequence and/or expression may be an important new risk factor for type 2 diabetes and other components of the metabolic syndrome.

Amino Acid Sequence↗

PubMed2001

The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome.

Here we present the first genetic analysis of adiponectin levels, a newly identified adipocyte-derived protein. Recent work has suggested that adiponectin may play a role in mediating the effects of body weight as a risk factor for coronary artery disease. For this analysis we assayed serum levels of adiponectin in 1100 adults of predominantly northern European ancestry distributed across 170 families. Quantitative genetic analysis of adiponectin levels detected an additive genetic heritability of 46%. The maximum LOD score detected in a genome wide scan for adiponectin levels was 4.06 (P = 7.7 x 10(-6)), 35 cM from pter on chromosome 5. The second largest LOD score (LOD = 3.2; P = 6.2 x 10(-5)) was detected on chromosome 14, 29 cM from pter. The detection of a significant linkage with a quantitative trait locus on chromosome 5 provides strong evidence for a replication of a previously reported quantitative trait locus for obesity-related phenotypes. In addition, several secondary signals offer potential evidence of replications for additional previously reported obesity-related quantitative trait loci on chromosomes 2 and 10. Not only do these results identify quantitative trait loci with significant effects on a newly described, and potentially very important, adipocyte-derived protein, they also reveal the emergence of a consistent pattern of linkage results for obesity-related traits across a number of human populations.

Adiponectin↗

PubMed1999

Identification and functional analysis of novel human melanocortin-4 receptor variants.

Inactivation of the melanocortin-4 receptor (MC4-R) by gene-targeting results in mice that develop maturity-onset obesity, hyperinsulinemia, and hyperglycemia. These phenotypes resemble common forms of human obesity, which are late-onset and frequently accompanied by NIDDM. It is not clear whether sequence variation of the MC4-R gene contributes to obesity in humans. Therefore, we examined the human MC4-R gene polymorphism in 190 individuals ascertained on obesity status. Three allelic variants were identified, including two novel ones, Thr112Met and Ile137Thr. To analyze possible functional alterations, the variants were cloned and expressed in vitro and compared with the wild-type receptor. One of the novel variants, Ile137Thr, identified in an extremely obese proband (BMI 57), was found to be severely impaired in ligand binding and signaling, raising the possibility that it may contribute to development of obesity. Furthermore, our results also suggest that sequence polymorphism in the MC4-R coding region is unlikely to be a common cause of obesity in the population studied, given the low frequency of functionally significant mutations.

Adolescent↗

PubMed1989

Can the hypotriglyceridemic effect of fish oil concentrate be sustained?

STUDY OBJECTIVE: To determine whether high doses of fish oil concentrate followed by low-dose maintenance therapy can sustain the initial plasma triglyceride reductions. DESIGN: Before-and-after trial with 3-month treatment periods. SETTING: Outpatient lipid clinic at a university medical center. PATIENTS: Sixteen patients with hypertriglyceridemia recruited from the General Internal Medicine Clinics. Five had concomitant hypercholesterolemia (type IIb). INTERVENTION: Fish oil supplementation at two doses. After basal measurements, 9.8 g/d omega-3 fatty acids were provided for study months 1 to 3, and 3.9 g/d were provided for study months 4 to 6. MEASUREMENTS AND MAIN RESULTS: Blood was drawn monthly and plasma was analyzed for levels of triglycerides, low-density-lipoprotein (LDL) cholesterol and apolipoprotein B, high-density-lipoprotein (HDL) cholesterol and apolipoprotein A1, and glucose and glycohemoglobin. During therapy with the higher dose, mean plasma triglyceride levels were reduced from 3.65 +/- 0.35 mmol/L at baseline to 1.85 +/- 0.20 mmol/L at 1 month, but increased by 30% to 2.40 +/- 0.30 mmol/L by the third month of therapy (P less than 0.05): this increase could not be explained by changes in body weight or compliance. Plasma triglyceride levels continued to increase with low-dose therapy and remained only 11% below baseline values by the sixth month of therapy (P = not significant). Although fish oil therapy increased HDL cholesterol levels (+18% at high dose; 99% CI, 5% to 31%), favorable changes were not seen in LDL cholesterol, apolipoprotein B, or apolipoprotein A1 levels. CONCLUSIONS: Fish oil concentrate at high doses followed by low-dose maintenance therapy cannot sustain the initial large plasma triglyceride reductions. Moreover, the efficacy of the higher dose becomes less pronounced after the first month of therapy. This reduced efficacy during prolonged therapy, and the lack of beneficial effect on apolipoprotein and LDL cholesterol levels, may limit the practical benefit of fish oil in the treatment of hypertriglyceridemia.

Adult↗

PubMed1988

Polyunsaturated and saturated fat, cholesterol, and fatty acid supplementation.

Almost all of risk factors for arteriosclerosis and coronary heart disease identified in population studies are overrepresented in diabetes. Of these risk factors, plasma lipids and lipoproteins are the target for altered dietary habits, particularly regarding fat. Such an alteration must be qualified with an understanding of the relationship between diabetes mellitus and lipoprotein metabolism and evidence of a favorable outcome of a fat-modified diet on this relationship. In seeking a revision of the current dietary fat recommendations of the American Diabetes Association, we have addressed five major questions. Is the serum lipid or lipoprotein concentration in diabetes different from that of the nondiabetic population? Are the familial or genetic forms of hyperlipidemia coinherited and/or overrepresented in diabetic subjects? What is the mechanism of the lipid/lipoprotein disorder in diabetes, and to what extent could it be related to the diabetic metabolic milieu? What is the effect of antidiabetic treatment on plasma lipids and lipoprotein metabolism? What evidence is there that a modified-fat diet could exert favorable benefits over and above what could be achieved by optimal antidiabetic therapy? This article outlines the revised dietary fat recommendations of the American Diabetes Association Nutrition Task Force and their rationale.

Arteriosclerosis↗

PubMed1987

Endocrine abnormalities in morbid obesity.

Recognizing the hormonal changes that accompany morbid obesity may prevent inappropriate investigations and treatments as well as provide rational approaches to reducing the morbidity and mortality of this disorder. The secondary nature of some of these metabolic changes can be demonstrated by overfeeding nonobese subjects. The crucial role of achieving adequate weight loss is also emphasized by the reversal of most of the hormonal abnormalities following successful weight loss.

Adrenal Cortex Hormones↗

PubMed1974