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  • 1
    ISSN: 1432-0428
    Keywords: Diabetes mellitus ; insulin resistance ; insulin receptor ; Rabson-Mendenhall syndrome ; insertion mutation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have studied the structure and function of the insulin receptor in a patient (PK) with severe insulin resistance and Rabson-Mendenhall syndrome. Insulin binding to cultured fibroblasts from PK was almost not detectable and insulin-induced insulin receptor autophosphorylation and glucose uptake was abolished. The structure of the receptor gene was analysed by sequencing amplified products of the 22 exons with the flanking intron regions directly as well as after subcloning in pUCBM20 plasmids. Two mutant alleles of the insulin receptor gene were detected. One allele contains in-frame 12 additional base pairs in exon 3 coding for the amino acids Leu-His-Leu-Val located between Asp-261 and Leu-262 in the receptor's extracellular domain, being the first report of an insertion mutation of the insulin receptor gene. In the other allele Arg-86 in exon 2 is changed into a stop codon. Therefore, PK is compound heterozygous at the insulin receptor locus. Direct cDNA sequencing indicates that both mutant alleles are expressed in the patient's fibroblasts. Studies of the parents' fibroblasts revealed that PK inherited the insertion mutation from the father and the nonsense mutation from the mother. Insulin binding to fibroblasts of the mother was reduced (63 % of control cells) and hormone binding to the father's cells shows a larger reduction (37 % of control cells), but less severe than the patient's cells (11 % of control). This investigation provides further evidence that the Rabson-Mendenhall syndrome is causally related to mutations in the insulin receptor gene.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 62 (1984), S. 193-202 
    ISSN: 1432-1440
    Keywords: Diuretics ; Beta-blockers ; Alpha-adrenergic drugs ; Plasma lipids ; Triglyceride and cholesterol metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Hypertension, hyperlipidaemia and cigarette smoking are major risk factors in coronary heart disease. Since many antihypertensive drugs alter plasma lipid levels it is a subject of current discussion that these agents may increase associated coronary risk and therefore offset the beneficial effects of lowering blood pressure. The purpose of this paper is to review clinical and experimental data in the literature on the influence of antihypertensive drugs on lipid metabolism. The thiazides hydrochlorothiazide and chlorthalidone cause an elevation of plasma triglycerides and very low density lipoprotein (VLDL) but have little effect on total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL). The unspecific beta-blockers, e.g. propranolol, do not affect total cholesterol and LDL but increase total triglycerides and VLDL and decrease HDL. The changes of plasma lipids and lipoproteins caused by cardio-selective beta-blockers, e.g. atenolol and metoprolol, and unspecific beta-blockers with intrinsic sympathomimetic activity (ISA), e.g. oxprenolol and pindolol, appear to be qualitatively similar but less pronounced. The alpha1-blocker prazosin reduces total triglycerides and slightly lowers total cholesterol. The concentration of VLDL plus LDL decreases while HDL may increase. Only very few studies have been reported on the effects of other antihypertensive drugs, e.g. clonidine, hydralazine, on plasma lipids. Several experimental studies reveal that antihypertensive agents exert direct effects on triglyceride and cholesterol metabolism. Although the pathophysiological mechanisms and the significance of the alterations of lipid metabolism induced by antihypertensive drugs are not yet clear, the following guidelines for the clinical use of these agents are recommended: (1) before initiating drug treatment in hypertensive patients, blood lipid levels should be measured to exclude a preexisting hyperlipidaemia, (2) during long-term therapy with antihypertensive agents, lipoprotein fractions should be controlled in order to reconsider the therapeutic regime if major alterations of blood lipid levels are observed.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 26 (1984), S. 773-773 
    ISSN: 1432-1041
    Keywords: human mononuclear leukocytes ; cholesterol synthesis ; cimetidine ; histamine action
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 34 (1988), S. 29-33 
    ISSN: 1432-1041
    Keywords: sterol synthesis ; histamine ; human mononuclear leukocytes ; impromidine ; 4-methylhistamine ; H1-/H2-agonists ; H1-/H2-antagonist ; H1-/H2-receptors ; 2-pyridylethylamine ; cimetidine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of histamine on sterol synthesis has been investigated in freshly isolated human mononuclear leukocytes from healthy subjects. Incubation of cells for 6 h in a medium containing lipid depleted serum led to a threefold increase in the incorporation of (14C)-acetate or tritiated water into sterols. Histamine 0.3 µM added to the incubation medium at zero time inhibited this induction by 35% with a sigmoidal log dose-effect curve. The receptors mediating this action were characterised pharmacologically by using selective H1- and H2-agonists and -antagonists. The H2-agonists impromidine and 4-methylhistamine mimicked the effect of histamine on sterol synthesis, the suppression being 42% and 31%, respectively, at a concentration of 1 µM. In contrast, the H1-agonist 2-pyridylethylamine did not affect the pathway. The H2-antagonist cimetidine (10 µM) but not the H1-antagonist mepyramine (10 µM) totally reversed the inhibition of sterol synthesis by histamine. The results provide evidence that sterol synthesis in human mononuclear leukocytes is regulated by histamine, which appears to act predominantly via H2-receptors.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Basic research in cardiology 93 (1998), S. s131 
    ISSN: 1435-1803
    Keywords: Key words Hypertension – insulin resistance – obesity – metabolic syndrome – cholesterol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Several recent studies indicate that type 2 diabetes, arterial hypertension, lipid disorders as well as visceral obesity are coronary risk factors which might belong to a syndrome which is caused by decreased insulin sensitivity with compensatory hyperinsulinaemia. More than 50% of patients with essential hypertension have some degree of insulin resistance, but in contrast to dyslipoproteinaemia and glucose intolerance the causal relation between insulin resistance and elevated arterial blood pressure appears not to be as evident. One explanation is that the link between blood pressure and insulin sensitivity might be mainly related to concomitant obesity. Accordingly, obesity can be associated with an increased activity of the sympathetic nervous system, elevated plasma levels of the vasoconstrictor endothelin-1, and decreased insulin-induced endothelium-dependent vasodilation. Furthermore, adipocytes can secrete vasogenic peptides, such as angiotensinogen. Since insulin resistance is a polygenic disorder, the two basic genetic approaches we follow is to identify genetic defects of insulin action in cells of patients with inherited syndromes of insulin resistance and to characterize molecular mechanisms of insulin regulated gene expression. The results show that insulin can affect the expression rate of various genes, e.g. involved in cholesterol and fatty acid metabolism, by modulating the activity of transcription factors coupled to the MAP kinase cascade and that a genetic postreceptor defect in these intracellular signaling pathways might have a pleiotropic effect on cell metabolism and clinical phenotype.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Der Internist 38 (1997), S. 237-243 
    ISSN: 1432-1289
    Keywords: Schlüsselwörter Adipositas ; Hypertonie ; Insulinresistenz ; Metabolisches Syndrom
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Zum Thema Die Insulinresistenz mit konsekutiver Hyperinsulinämie ist ein Schlüsselphänomen für die überzufällig häufig assoziierte Manifestation koronarer Risikofaktoren, inklusive der Adipositas and arteriellen Hypertonie. Im Gegensatz z.B. zur Dyslipoproteinämie und Glukoseintoleranz ist eine kausale Beziehung zwischen der Insulinresistenz und arteriellen Hypertonie noch nicht direkt gezeigt. Bei dieser Beziehung scheint für die klinische Ausprägung der arteriellen Hypertonie eine begleitende Adipositas von großer Bedeutung zu sein. Mögliche pathophysiologische Mechanismen, wie z.B. erhöhte Sympathikus-Aktivierung, Freisetzung humoraler Faktoren aus dem Fettgewebe und die viszerale Fettverteilung werden diskutiert.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-1289
    Keywords: Schlüsselwörter Hypercholesterinämie ; Therapie ; Dyslipoproteinämie ; KHK ; Prävention ; Cholesterinsynthesehemmer ; Studien ; klinische
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Zusammenfassung In den letzten 4 Jahren haben große klinische Interventionsstudien an über 30000 Probanden gezeigt, daß die medikamentöse Cholesterinsenkung durch Cholesterinsynthesehemmer nicht nur die kardiovaskulären Komplikationen sondern auch die Gesamtsterblichkeit signifikant senken kann. Angiographisch kontrollierte Regressionsstudien haben ebenfalls ergeben, daß die medikamentöse Cholesterinsenkung zu einer drastischen Reduktion kardiovaskulärer Komplikationen führt, aber kaum den angiographischen nachweisbaren Stenosegrad beeinflußt. Diese Studien haben u.a. zu einem neuen Paradigma in der koronaren Herzerkrankung (KHK) bzw. der atherosklerotischen Plaques geführt, d.h. daß die klinische Prognose nicht nur durch den Stenosegrad sondern vielmehr durch die Struktur bzw. Verletzbarkeit der Plaque bestimmt wird. Die vulnerable bzw. instabile Plaque ist durch einen relativ großen lipidreichen Kern und eine dünne fibröse Kappe gekennzeichnet. Reißt diese Kappe ein, kommt es zu einem akuten thrombogenen Geschehen, das in dem plötzlichen Auftreten einer instabilen Angina-pectoris Symptomatik oder eines Myokardinfarktes resultieren kann. Dementsprechend wird zur Zeit intensiv darüber gearbeitet, ob möglicherweise Cholesterinsynthesehemmer (CSE-Hemmer) nicht nur das Plasmacholesterin senken sondern auch Mechanismen, die zu einer Plaque-Stabilisierung beitragen, günstig beeinflussen. So ist zum Beispiel eine effektive Cholesterinsenkung mit einer Verbesserung der endothelialen Dysfunktion und damit der paradoxen Vasokonstriktion assoziiert sowie mit einer dementsprechend verbesserten myokardialen Perfusion und Reduktion myokardialer ischämischer Ereignisse bei Patienten mit klinisch manifester KHK.
    Type of Medium: Electronic Resource
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