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)

Complex diseases require precise phenotyping if their genetic basis is to be properly understood. This process is more complex than the analysis used for monogenic diseases. Collecting family phenotypic data is costly and time consuming, making such studies difficult. We have developed a family-oriented, field working approach that relies on index patients, their primary-care physicians, and a minimum number of field working staff. The index patients recruit family members by distributing packs containing the materials necessary for participation. Computer analysis of the data returned enables construction of the medical family tree. We have extended this genetic field working approach to patients with lipid disorders, arterial hypertension, non-insulin-dependent diabetes mellitus, and the 'Metabolic Syndrome'. Data from these groups can be used to identify susceptibility genes for premature arteriosclerosis. We describe a cost-effective methodology that can be used in the primary-care setting to identify 'at-risk' patients and facilitate effective targeting of limited health-care resources.
 ...
PMID:Phenotyping and genotyping patients with cardiovascular risk factors. 927 15

A critical role is proposed for the quantity and quality of dietary carbohydrate in the pathogenesis of the insulin resistance and hyperinsulinaemia which characterise the Metabolic Syndrome. We propose that an insulin-resistant genotype evolved to provide survival and reproductive advantages for the cold-climate, large game hunters of the last Ice Age who consumed a low carbohydrate, high protein diet with periodic starvation. Insulin resistance would have minimised glucose utilisation by muscles thereby facilitating the preferential utilisation of glucose by the brain, foetus and mammary gland. But beginning about 10,000 years ago following the end of the last Ice Age and the development of agriculture, dietary carbohydrate increased and the selection pressure for insulin resistance decreased in some groups. Agriculture began in the Middle East and spread throughout Europe long before it was developed elsewhere. Hence the prevalence of the insulin-resistant genotype decreased in Europeans and other groups exposed to a high carbohydrate intake for sufficiently long. Some geographically isolated groups such as the Pima Indians and Nauruans experienced conditions which further diminished the gene pool diversity and resulted in particularly insulin resistant populations. Traditional carbohydrate foods have a low glycaemic index and produce only modest increases in plasma insulin. However, the constant supply of highly refined high glycaemic index carbohydrate in modern diets, results in postprandial hyperinsulinaemia. The insulin-resistant genotype is now disadvantageous and predisposes to the development of the Metabolic Syndrome.
Exp Clin Endocrinol Diabetes 1997
PMID:The metabolic syndrome: from inherited survival trait to a health care problem. 928 47

Insulin resistance is associated with a variety of cardiovascular risk factors including hypertension, dyslipidemia, and non-insulin-dependent diabetes. In blacks, the relation between insulin resistance, hypertension, and atherosclerosis has been questioned. Most data collected on the Insulin Resistance Syndrome have been collected in nondiabetic subjects; therefore, no inference can be drawn to exogenous insulin use in diabetic subjects where improved glycemic control is usually associated with improved cardiovascular risk factors (especially dyslipidemia) in the absence of weight gain.
 ...
PMID:Progress in population analyses of the insulin resistance syndrome. 932 38

What is clear from the research thus far is that dietary fat intake does influence insulin action. However, whether the effect is good, bad, or indifferent is strongly related to the fatty acid profile of that dietary fat. The evidence has taken many forms, including in vitro evidence of differences in insulin binding and glucose transport in cells grown with different types of fat in the incubation medium, in vivo results in animals fed different fats, relationships demonstrated between the membrane structural lipid fatty acid profile and insulin resistance in humans, and finally epidemiological evidence linking particularly high saturated fat intake with hyperinsulinemia and increased risk of diabetes. This contrasts with the lack of relationship, or even possible protective effect, of polyunsaturated fats. In particular, habitual increased n-3 polyunsaturated dietary fat intake (as fish fats) would appear to be protective against the development of glucose intolerance. It is reassuring that the patterns of dietary fatty acids that appear beneficial for insulin action and energy balance are also the patterns that would seem appropriate in the fight against thrombosis and cardiovascular disease. Mechanisms, though, still need to be defined. However, there are strong indicators that defining the ways in which changes in the fatty acid profile of membrane structural lipids are achieved, and in turn influence relevant transport events, plus understanding the processes that control accumulation and availability of storage lipid in muscle may be fruitful avenues for future research. One of the problems of moving the knowledge gained from research at the cellular level through to the individual and on to populations is the need for more accommodating research designs. In vitro studies may provide in-depth insights into intricate mechanisms, but they do not give the "big picture" for practical recommendations. On the other hand, correlational studies tend to be fairly blunt instruments, requiring large numbers that are very often not feasible if a greater depth of understanding of the biological processes is to be incorporated. There may be benefit in turning to the clinical case study as a framework for a more comprehensive analysis of the links between dietary fats and insulin action. The real challenge is to keep the depth of analysis rigorous enough to be able to explain and accommodate individual variation (i.e., the diversity of both environmental and genetic backgrounds) while at the same time satisfying the cultural need to provide appropriate overall dietary guidelines. Finally, David Kritchevsky brought to our attention a delightful quote from Mark Twain: "There is something fascinating about science. One gets such a wholesale return of conjecture for such a trifling investment of fact." In the field of dietary fats and the Metabolic Syndrome, this quotation is, unfortunately, apt. Much more research is necessary to define how dietary fats really work to affect insulin action. Well designed, long-term studies in "free range" humans must be undertaken if dietary guidelines for the Metabolic Syndrome are to be based on anything more than a "trifling" amount of "fact."
 ...
PMID:Does dietary fat influence insulin action? 932 62

The statistical associations between stress and cardiovascular and other prevalent diseases have not been explained. Perceived stress, resulting in an uncontrollable defeat reaction, has been shown by James Henry (Henry 1993) to be followed by specific endocrine abnormalities, including sensitization of the hypothalamo-pituitary-adrenal (HPA) axis, and inhibited sex steroid and growth hormone secretions. With an elevated waist/hip circumference ratio (WHR)--a simple, surrogate, measurement of intraabdominal, visceral fat masses--combined with insulin resistance, similar endocrine perturbations are found. Based on considerable evidence, such endocrine abnormalities seem to be followed by accumulation of intraabdominal, visceral fat masses and insulin resistance, both powerful risk factors for cardiovascular disease, diabetes and stroke. A postulated chain of events is therefore that the endocrine perturbations are primary factors, followed by visceral fat accumulation, insulin resistance and other risk factors dependent on the hyperinsulinemia following insulin resistance. This highlights the importance of elucidating the cause(s) to the endocrine abnormalities. These are identical to those described by Henry (1993) to follow a stress reaction of a defeat type. Findings of several psychosocial and socio-economic handicaps might provide a basis for such a reaction, supported by experimental studies in primates. Furthermore, depression, anxiety, alcohol consumption and smoking, all known activators of the HPA axis, are also often found. The low sex steroid and growth hormone secretions might be secondary to the hypersensitive HPA-axis. They could also be caused by other factors, and are, each alone, capable of causing both visceral fat accumulation and insulin resistance. Visceral fat accumulation is only an indirect, surrogate measurement of the underlying endocrine abnormalities, but is useful for screening purposes on a population basis. Developments of novel techniques for sensitive, yet simple measurements of HPA axis activity under undisturbed conditions seem to allow a better definition of pathogenetic factors. Utilizing such methods, subgroups of the syndrome including visceral fat accumulation, insulin resistance and other associated risk factors (Metabolic Syndrome), are beginning to emerge. A more detailed information on noxious factors in society leading to a defeat reaction to perceived stress, endocrine abnormalities and the Metabolic Syndrome, with increased risk for prevalent disease may hopefully be developed by these new methods.
 ...
PMID:Stress and cardiovascular disease. 940 28

Syndromes of risk factor disturbance may contribute to the development of coronary heart disease and non-insulin-dependent diabetes mellitus, but their definition and quantification remain problematic. Using factor analysis, constellations of risk factor variables that could indicate distinct syndromes of metabolic disturbance were explored in the baseline data of the first follow-up cohort of 742 men from the Heart Disease and Diabetes Risk Indicators in a Screened Cohort (HDDRISC) study. The primary analysis considered 16 intercorrelated variables measured in more than 90% of cohort participants. A missing-values estimation routine was used to ensure inclusion of all participants in the analysis. Subanalyses were undertaken, including a repeat of the primary analysis on the 522 individuals who had received measurement of HDL cholesterol, an oblique rather than orthogonal factor rotation procedure performed on primary and HDL subset analyses, a repeat of these two primary and HDL subset analyses using only those participants with complete measurements, and a repeat of these six analyses including only the seven variables conventionally associated with the metabolic syndrome. The principal factor that emerged in all analyses undertaken comprised oral glucose tolerance test insulin and glucose response, serum uric acid, and body mass index. Fasting serum triglyceride concentration was included in this factor in 11 of the 12 analyses undertaken, fasting plasma insulin in 8, fasting plasma glucose in 5, and mean arterial pressure in 3. HDL cholesterol factored in isolation from insulin in all analyses undertaken. These findings provide strong support for a core metabolic cluster, which is unlikely to include blood pressure and does not include HDL. The factor scores relating to this cluster will provide a means of assessing its quantitative importance in prospective analysis of the development of CHD and diabetes in this cohort.
 ...
PMID:Factors of the metabolic syndrome: baseline interrelationships in the first follow-up cohort of the HDDRISC Study (HDDRISC-1). Heart Disease and Diabetes Risk Indicators in a Screened Cohort. 948 85

We report on a 33-year-old male patient with generalized acquired lipodystrophy, insulin resistant diabetes mellitus and acanthosis nigricans (Lawrence Syndrome). First probable symptoms of lipodystrophy (weight loss, shrinkage of subcutaneous fatty tissue, and loss of muscular strength) became evident three years ago, with the onset of diabetes mellitus occurring about six months later. The patient suffered from the following clinical symptoms: IDDM with increasing insulin-requirement, extreme reduction of fatty tissue, fatty liver hepatitis with elevated liver enzymes, glomerulopathy, muscular and neuropathic pains, as well as hypertriglyceridaemia. A basal C-peptide concentration is rather high. Definitely, the endogenous insulin secretion is increased. In other words, insulin resistance is documented. In an effort to identify the pathogenetic mechanisms of lipoatrophic diabetes mellitus in this patient and to develop a therapeutic strategy, antibodies against different tissues and endocrinologic regulation were investigated. It was possible to demonstrate the presence of serum autoantibodies against lipocytes of the subcutis and other tissues, against hepatic stellate cells, together with autoantibodies against different endocrine organs. By studying the basis of diabetic abnormalities relating to the growth hormone (GH), the insulin-like growth factor (IGF) dynamics in this patient, i.e. reductions of GH, IGF-I, IGF-II, IGF-Binding protein (IGF-BP) 2 and IGF-BP 3, were detected. An immunosuppressive treatment strategy was not beneficial.
Exp Clin Endocrinol Diabetes 1998
PMID:Dysregulation of insulin-like growth factors in a case of generalized acquired lipoatrophic diabetes mellitus (Lawrence Syndrome) connected with autoantibodies against adipocyte membranes. 951 65

Insulin resistance is instrumental in the pathogenesis of type 2 diabetes mellitus and the Insulin Resistance Syndrome. While insulin resistance involves decreased glucose transport activity in skeletal muscle, its molecular basis is unknown. Since muscle GLUT4 glucose transporter levels are normal in type 2 diabetes, we have tested the hypothesis that insulin resistance is due to impaired translocation of intracellular GLUT4 to sarcolemma. Both insulin-sensitive and insulin-resistant nondiabetic subgroups were studied, in addition to type 2 diabetic patients. Biopsies were obtained from basal and insulin-stimulated muscle, and membranes were subfractionated on discontinuous sucrose density gradients to equilibrium or under nonequilibrium conditions after a shortened centrifugation time. In equilibrium fractions from basal muscle, GLUT4 was decreased by 25-29% in both 25 and 28% sucrose density fractions and increased twofold in both the 32% sucrose fraction and bottom pellet in diabetics compared with insulin-sensitive controls, without any differences in membrane markers (phospholemman, phosphalamban, dihydropyridine-binding complex alpha-1 subunit). Thus, insulin resistance was associated with redistribution of GLUT4 to denser membrane vesicles. No effects of insulin stimulation on GLUT4 localization were observed. In non-equilibrium fractions, insulin led to small GLUT4 decrements in the 25 and 28% sucrose fractions and increased GLUT4 in the 32% sucrose fraction by 2.8-fold over basal in insulin-sensitive but only by 1.5-fold in both insulin-resistant and diabetic subgroups. The GLUT4 increments in the 32% sucrose fraction were correlated with maximal in vivo glucose disposal rates (r = +0.51, P = 0.026), and, therefore, represented GLUT4 recruitment to sarcolemma or a quantitative marker for this process. Similar to GLUT4, the insulin-regulated aminopeptidase (vp165) was redistributed to a dense membrane compartment and did not translocate in response to insulin in insulin-resistant subgroups. In conclusion, insulin alters the subcellular localization of GLUT4 vesicles in human muscle, and this effect is impaired equally in insulin-resistant subjects with and without diabetes. This translocation defect is associated with abnormal accumulation of GLUT4 in a dense membrane compartment demonstrable in basal muscle. We have previously observed a similar pattern of defects causing insulin resistance in human adipocytes. Based on these data, we propose that human insulin resistance involves a defect in GLUT4 traffic and targeting leading to accumulation in a dense membrane compartment from which insulin is unable to recruit GLUT4 to the cell surface.
 ...
PMID:Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance. 961 9

The Kennedy-Syndrome is a X-linked recessive bulbospinal muscular atrophy, in some cases associated with endocrinological disturbances such as androgen resistance and diabetes mellitus. The age of onset is usually between 20 and 40. Presenting symptoms are proximal flaccid weakness, fasciculations, cramps or tremor. Disease progression is usually slow and live expectancy is normal. It is important to distinguish the Kennedy-Syndrome from amyotrophic lateral sclerosis, spinal muscular atrophy, muscular dystrophies and other types of motor neuron disease. Kennedy disease is caused by an expanded trinucleotide repeat in the androgen receptor gene. Genetic analysis allows a precise-diagnosis on an individual basis and reliable genetic counselling. An effective medical treatment does not yet exist.
 ...
PMID:[X-chromosomal recessive spinobulbar muscular atrophy (Kennedy type). Description of a family, clinical aspects, molecular genetics, differential diagnosis and therapy]. 975 16

One of the key abnormalities of non-insulin-dependent diabetes mellitus (NIDDM) and related diseases of the "Metabolic Syndrome" is impaired insulin action (insulin resistance). Since skeletal muscle plays a major role in insulin-stimulated glucose uptake and whole-body energy expenditure, it is a central player in carbohydrate and lipid metabolism, and hence in the balance between health and disease. This manuscript seeks to describe the evidence both for involvement in insulin resistance of three major muscle variables: membrane lipid composition, storage triacylglycerol and fibre type mixture; and for the interrelationships between these variables. Taken with results provided in other chapters in this volume, the literature described gives insights into the role that certain dietary fats and physical inactivity may play in the development of insulin resistance and hence the disease cluster of the Metabolic Syndrome.
 ...
PMID:Insulin sensitivity, muscle fibre types, and membrane lipids. 978 20


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