Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The author summarizes mechanisms by which insulin resistance and compensatory hyperinsulinism are manifested in the clinical picture. He divides the mechanisms into prereceptor, receptor and postreceptor mechanisms. The latter dominate in the population quantitatively and thus also by their impact because they create the so-called 5H syndrome (association of hyperinsulinism with hyperglycaemia (NIDDM), hyperlipoproteinaemia, hypertension, hirsutism and the polycystic ovary syndrome) or the so-called hormonal metabolic syndrome X, lethal tetrad, metabolic syndrome, syndrome of insulin resistance). The term syndrome X does not appear suitable as it is frequently mistaken for coronary X syndrome which probably is also conditioned by hyperinsulinism, for the hormonal metabolic X syndrome and probably also fot the "fragile X syndrome" in genetics. The 5H syndrome is caused by a postreceptor disorder of insulin efficiency for which so far the molecular basis and dominating organ site have not yet been defined adequately. Hyperinsulinism is conceived as an insulin resistance compensating phenomenon. In its development participates, however, in addition to compensatory hypersecretion also impaired insulin utilization (liver, muscles) and an impaired primary secretory response caused probably by a disorder of blood sugar control (glucokinase, GLUT 2). This is suggested by the frequently inadequate response of the blood sugar level, IRI and C-peptide during the oral glucose tolerance test (OGGT). A hyperinsulinaemic response may be encountered when the blood sugar curve is normal, flat, in impaired glucose tolerance and in diabetes. Thus OGGT alone is not suited for the early detection of the 5H syndrome unless concurrently the IRI and C-peptide response is recorded.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Clinical manifestations of the insulin resistance syndrome. The hormonal-metabolic syndrome X, the 5H syndrome and their etiopathogenesis]. 772 46

Combined molecular and epidemiological studies are advancing our understanding of the genetic basis of multifactorial diseases. Several of the results obtained during the past year highlight methodological issues associated with these approaches. For example, the affected sib-pair method has been applied successfully to detect linkage between the angiotensinogen gene and susceptibility to hypertension, and a large multi-centre epidemiological study has demonstrated association of a polymorphism of the angiotensin-converting enzyme gene with increased risk of myocardial infarction. The study of Mendelian forms of multifactorial diseases has also led to many new results. These include the characterization of mutations in the glucokinase gene in maturity onset diabetes of the young, localization to chromosome 2 of a gene involved in familial colon cancer, and localization to chromosome 19 of a gene responsible for hemiplegic migraine. New insights have been provided into the genetics of multifactorial disorders such as diabetes and hypertension through the study of animal models. Localization of susceptibility loci in such models has recently led to the identification of new candidate genes that may be implicated in disease.
 ...
PMID:Genetic approaches to common diseases. 776 64

Type 2 diabetes is likely to be a polygenic disease, with a combination of major and minor genes affecting obesity, insulin secretion, and insulin action. Amongst these inputs, the 'thrifty genotype' hypothesis is most likely to apply to the predisposition to develop obesity, since the ability to store scarce fuels in periods of starvation could lead to obesity given a western lifestyle. Other genetic variations that were neutral with respect to food deprivation could be harmful with food excess. These could include 'defects' in islet cell function: examples could be mutations in the glucokinase gene and the genetic factors leading to amyloid deposition. The occurrence of associated lipid abnormalities or hypertension is probably due to additional specific genetic determinants that also become exaggerated by a modern lifestyle. The interactions between different genetic and environmental inputs are complex, and will probably be elucidated piecemeal as different genetic determinants are identified.
 ...
PMID:Complex genetics of type 2 diabetes: thrifty genes and previously neutral polymorphisms. 821 Feb 95

Mutations in glucokinase are associated with defects in insulin secretion and hepatic glycogen synthesis resulting in mild chronic hyperglycaemia, impaired glucose tolerance or diabetes mellitus. We screened members of 35 families with features of maturity-onset diabetes of the young for mutations in the glucokinase gene and found 16 different mutations. They included 14 new mutations in the glucokinase gene: 9 missense mutations (A53S, G80A, H137R, T168P, M210T, C213R, V226M, S336L and V367M); 2 nonsense mutations (E248X and S360X); a deletion of one nucleotide resulting in a frameshift (V401del1); a substitution of a conserved nucleotide at a splice acceptor site (L122-1G-->T); and a 10 base pair deletion that removed the GT of the splice donor site and the following eight nucleotides (K161 + 2del10). In addition, we found two previously identified mutations: R186X and G261R. Study of 260 subjects with glucokinase-deficient hyperglycaemia from 42 families with 36 different GCK mutations made it possible to define the clinical profile of this subtype of non-insulin-dependent diabetes mellitus (NIDDM). Hyperglycaemia due to glucokinase deficiency is often mild (fewer than 50% of subjects have overt diabetes) and is evident during the early years of life. Despite the long duration of hyperglycaemia, glucokinase-deficient subjects have a low prevalence of micro- and macro-vascular complications of diabetes. Obesity, arterial hypertension and dyslipidaemia are also uncommon in this form of NIDDM.
 ...
PMID:Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. 904 84

Diabetes, known since antiquity, has been defined by glycosuria. In 1886, when Minkowski demonstrated that pancreatectomized dogs developed diabetes, the islets of Langerhans became a focus of the search for an active principle culminating in the discovery and the isolation of insulin in 1921 by Banting, Best and Collip. In 1959, the radioimmunoassay of Yalow and Berson solidified the concept of insulin resistance in non-insulin dependent diabetes (NIDDM). In 1971, the insulin receptor was defined as a cell surface protein that initiated the insulin signal transduction cascade. Today, we know that NIDDM accounts for at least 90% of all diabetes worldwide and involves approximately 100 million people. The microvascular complications of NIDDM are the same as for insulin dependent diabetes (IDDM) and are related to the intensity and duration of hyperglycaemia. Further, it is clear from the Diabetes Control and Complications Trial (DCCT) that all microvascular complications can be reduced with intensive control of the blood glucose. Macrovascular disease is also accelerated in NIDDM, including both hypertension and dyslipidemia. The major risk factor for NIDDM are age, obesity, physical inactivity, and genetic background. The earliest features seen in individuals destined to develop NIDDM is insulin resistance, but for hyperglycaemia to ensure there must be a defect in insulin secretion. Thus, insulin resistance defines the prehyperglycaemic phase of NIDDM, but varying degrees of insulin secretory deficiency define the hyperglycaemic phase. Macrovascular risk occurs throughout the lifetime of the individual, whereas microvascular risk ensues with the inception of hyperglycaemia. Tomorrow, we will understand more clearly whether lifestyle changes, such as diet and exercise, or new classes of drugs, can delay or prevent NIDDM. Clinical trials are now beginning to test whether impaired glucose tolerance (IGT) can be delayed or prevented from moving to overt NIDDM. The genetics of NIDDM are under intense study. Mutations in the insulin receptor lead to NIDDM in a small number of patients, and mutations in the glucokinase gene lead to maturity onset diabetes of the young (MODY). Work is now underway to study other candidate genes as well as work on positional cloning techniques to identify diabetes genetic loci. The hormone Leptin has just been discovered and is a major regulator of body weight. In summary, the most important new emphasis on the treatment of NIDDM is the recognition of the importance of hyperglycaemia and our ability to both treat and possibly prevent this metabolic perturbation. This joins the longer-term emphasis on cardiovascular risk reduction from both treatment and prevention of hypertension and dyslipidemia.
 ...
PMID:Non-insulin dependent diabetes--the past, present and future. 928 27

Hypertension is a complex disease with strong genetic influences. Essential hypertension has been shown to be associated with insulin resistance. A molecular variant with G-to-A transition at the nucleotide -258 of the liver glucokinase (GCK) promoter was found in diabetic patients. The variant A allele is associated with insulin resistance. We examine the role of this genetic variant in the pathogenesis of hypertension using a population association study. We recruited 205 Taiwanese subjects and they were divided into two groups based on either presence (65 subjects) or absence (140 subjects) of essential hypertension. Genomic DNA was extracted from peripheral leukocytes. Genotypes at this locus were determined by using a polymerase chain reaction restriction fragment length polymorphism. The distribution of genotypic frequency was different between the hypertensive and control groups (P = .009). The frequency of variant A allele was greater in hypertensive subjects than in control (23% v 10%, P = .001). Subjects with at least an A allele had a risk for hypertension by 2.52 times (95% confidence interval 1.29 to 4.91) as compared with those without an A allele. Thus, we first demonstrate the association between the G-to-A variants at the nucleotide -258 of the liver GCK gene and essential hypertension. This may explain the insulin resistance in essential hypertension and the variant A allele as a risk factor for essential hypertension in the Taiwanese population.
 ...
PMID:Nucleotide(-258) G-to-A transition variant of the liver glucokinase gene is associated with essential hypertension. 932 12

Fetal malnutrition is associated with development of impaired glucose tolerance, diabetes and hypertension in later life in humans and several mammalian species. The mechanisms that underlie this phenomenon of fetal programming are unknown. We hypothesize that adverse effects in utero and early life may influence the basal expression levels of certain genes such that they are re-set with long-term consequences for the organism. An excellent candidate mechanism for this re-setting process is DNA methylation, since post-natal methylation patterns are largely established in utero. We have sought to test this hypothesis by investigating the glucokinase gene (Gck) in rat offspring programmed using a maternal low protein diet model (MLP). Northern blot reveals that fasting levels of Gck expression are reduced after programming, although this distinction disappears after feeding. Bisulphite sequencing of the hepatic Gck promoter indicates a complete absence of methylation at the 12 CpG sites studied in controls and MLP animals. Non-expressing cardiac tissue also showed no DNA methylation in this region, whereas brain and all fetal tissues were fully methylated. These findings are not consistent with the hypothesis that programming results from differential methylation of Gck. However, it remains possible that programming may influence methylation patterns in Gck at a distance from the promoter, or in genes encoding factors that regulate basal Gck expression.
 ...
PMID:Investigation of the role of epigenetic modification of the rat glucokinase gene in fetal programming. 1470 71

In Caucasians, maturity-onset diabetes of the young (MODY) is mostly caused by mutations in the hepatocyte nuclear factor (HNF)-1alpha (MODY3) and glucokinase (MODY2) genes. Most Japanese MODY patients, however, are not linked to known MODY genes. In this study, we examined the genetic and clinical characteristics of Chinese subjects with MODY. The study included 146 unrelated families fulfilling the minimum criteria for MODY: two consecutive generations of type II diabetes with at least one member diagnosed under the age of 25. We screened for mutations in the HNF-4alpha (MODY1), MODY2 and MODY3 genes by direct sequencing. Antibody to glutamic acid decarboxylase (GAD-Ab) was measured in subjects with MODY of unknown cause (MODYX). Insulin resistance index and other clinical data were compared in sex-, age- and duration-matched MODY3 and MODYX patients. In all, 13 families had MODY3 mutations and two had MODY2 mutations. No MODY1 mutation was found. Four of the 12 different MODY3 mutations were newly identified novel mutations (Q243E, A311D, P379R and P488fsdelC). In subjects with MODYX, 3% were GAD-Ab positive and 60% were overweight. Compared to MODY3 patients, MODYX patients had higher body mass index (P<0.02), higher insulin resistance index (P=0.001) and triglyceride level (P<0.02), lower HDL level (P=0.001) and more hypertension (P<0.05), but no significant difference in the prevalence of diabetic complications. In conclusion, MODY3 and MODY2 account for only 9 and 1%, respectively, of Chinese MODY. A majority of Chinese MODY patients are due to defects in unknown genes and appear to be characterized by insulin resistance.
 ...
PMID:Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients. 1565 5

Peroxisome Proliferator-Activate Receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. The three PPARs (alpha, beta/delta, and gamma) are distributed differently in the different organs. PPARalpha is most common in the liver, but also found in kidney, gut, skeletal muscle and adipose tissue, while PPARbeta/delta, is fairly ubiquitous; it may be found in body tissues and brain (for myelination process and lipid metabolism in the brain). PPARgamma has 3 isoforms, such as PPARgamma 1, PPARgamma 2, and PPARgamma 3. The syndrome-X was firstly coined by Reaven in 1988 and then to be provided in 1999 by the name : the metabolic syndrome-X. This metabolic syndrome represents a "Cluster" of metabolic disorders and cardiovascular risk factors which has been collected and summarized by the author and such a cluster includes: insulin resistance/hyperinsulinemia, central obesity, glucose intolerance/DM, atherogenic dyslipidemia (increase TG, decrease HDL-cholesterol, increase Apo-B, increase small dense LDL), hypertension, prothrombotic state (increase PAI-1, increase F-VII, increase fibrinogen, increase vWF, increase adhesion molecules), endothelial dysfunction, hyperuricemia, and increased hsC-RP and cytokines. The metabolic syndrome-X may lead to the development of T2DM and coronary heart disease (CHD); insulin resistance plays pivotal roles in the progression of such a syndrome and cardiovascular diseases. Improvement of Insulin Resistance, therefore, is most likely to reduce the high cardiovascular event rate in T2DM. It has been generally accepted that Insulin Resistance (detected by HOMA-R) and Acute Insulin Response = AIR (by HOMA-B) are both usually present in T2DM. The Thiazolidinedions (TZDs) are Insulin Sensitizers (e.g Rosiglitazone = ROS, Pioglitazone = PIO) introduced into clinical practice in 1997; clinical evidence data showed that TZDs improved both HOMA-R, and HOMA-B. PPARgamma can be activated by TZDs and it appears to be fundamental to the pathophysiology of diabetes mellitus i.e increase GLUT-4, increase glucokinase, decrease PEPCK, increase GLUT-4, and decreases production by fat cell of several mediators that may cause insulin resistance, such as TNFalpha and resistin. PPARgamma also mediates increased production of Adiponectin and the insulin signaling intermediate PI3K, and both actions lead to increase insulin sensitivity. A "dual PPARgamma-PPARalpha agonists" (e.g PIO, but ROS poorly activate PPARalpha) might lower glucose and modulate lipids. Thus, PIO, as a stronger "dual PPARgamma-PPARalpha agonists", shows an important therapeutic pathway in diabetes mellitus and cardiovascular diseases, even in metabolic syndrome. Current evidence suggests a close relationship between activation of PPARgamma and restoration of insulin sensitivity by reductions in TNFalpha and FFAs, and the enhancement of insulin stimulation of PI3-K Pathway and also increase adiponectin & decrease resistin.
 ...
PMID:New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer). 1711 68

Two strongly correlated polymorphisms located within the gene of the glucokinase regulator protein (GKRP), rs780094 and rs1260326, are associated with increased plasma triglyceride levels and provide a genetic model for the long-term activation of hepatic glucokinase. Because pharmacological glucokinase activators are evaluated for the treatment of diabetes, the aim of the study was to assess if these polymorphisms could provide evidence for an increased cardiovascular risk of long-term glucokinase activation. Therefore, these polymorphisms were tested in 3 500 patients of the Ludwigshafen Risk and Cardiovascular Health study, which was designed to assess cardiovascular risk factors. The two variants were associated with a significant increase of both plasma triglycerides (p<0.0001) and VLDL triglyceride levels (p<0.0001). Plasma free fatty acid concentrations were also significantly elevated (p<0.0078). LDL and HDL cholesterol levels were unchanged. No association was found with respect to coronary stenosis, myocardial infarction, left ventricular wall hypertrophy, and hypertension. In conclusion, long-term genetic glucokinase activation by the GKRP polymorphisms was not associated with an increased cardiovascular risk in the study population.
 ...
PMID:Glucokinase-activating GCKR polymorphisms increase plasma levels of triglycerides and free fatty acids, but do not elevate cardiovascular risk in the Ludwigshafen Risk and Cardiovascular Health Study. 2035 98


1 2 Next >>