Prevalence of metabolic syndrome, insulin resistance, and microvascular angina pectoris in 500 consecutive patients referred to coronarography.

OBJECTIVE: This work was aimed to evaluate the prevalence of insulin resistance (IR) and metabolic syndrome in a large cohort of 40-60 years old patients with cardiovascular symptoms. METHODS: A total of 500 consecutive males and females referred to coronarography and coronary catheterization, because of spontaneous or after load precordial pain plus denivelisation of ST segment by electrocardiography, were included. Besides standard clinical examinations, ergometry, echocardiography, fundamental laboratory tests, and several other laboratory examinations were also performed, including oral glucose toleration test (OGTT), total and high-density lipoprotein (HDL) cholesterol, triglycerides, apoprotein A1 and B, apolipoprotein (a), uric acid, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), cytokines (tumor necrosis factor α, TNFα, interleukin-1, IL-1, interleukin-6, IL-6), endothelin-1, as well as hormones (insulin, C peptide, leptin, growth hormone, cortisol). RESULTS: In 81.6% of patients, IR syndrome with compensatory hyperinsulinemia was found in a positive correlation with various symptoms of metabolic syndrome, including abdominal obesity, increased body mass index (BMI), dysglycemia, dyslipoproteinemia, coronary stenosis, decreased HDL level, and hypertension. Hirsutism with polycystic ovarian syndrome was found in 52% of examined women with IR. However, a normal coronary angiogram, called as a microvascular form of the angina pectoris (MIV-AP), was found in 14% of predominantly periclimacteric and benign hirsutic females with long-term disorders of menstrual cycle. Since these patients showed the same symptoms as their gender, age, BMI, and degree of coronary stenoses adjusted pairs with the macrovascular form (such as the same levels of several lipids, hormones and obesity measures), our data strongly support the view that MIV-AP might belong to the IR syndrome. CONCLUSIONS: Hyperinsulinemia and high prevalence of various symptoms of metabolic syndrome (MS) were found in high percentage of patients with after load precordial pain who were referred to coronarography. Similarly, in several women, MIV-AP was detected and its affiliation to MS suggested.

[Thyrotoxic heart disease. Part II--aspects of treatment of thyrotoxicosis with cardiac involvement]. / Cor thyreotoxicum. Cast' II.--osobitosti v liecbe tyreotoxikóz s postihnutím srdca.

In the treatment of the thyrotoxic heart a radical, early thyroeliminating procedure should have preference. As the method of first choice a single administration of a whole calculated dose of I131 is recommended without previous medicamentous preparation up to 25-30 mCie which can be administered also in the out-patient department, with subsequent immediate treatment with thyrostatics and beta-blockers till remission of thyrotoxicosis is achieved (6-12 weeks). Total strumectomy after medicamentous preparation in remission of thyrotoxicosis is preferred in large multinodular, iodinated patients and in solitary toxic adenoma where however also partial STE (lobectomy) is possible and radioiodine is equivalent. Its dosage in toxic adenoma and nodular goitre is however in general higher than in diffuse goitre but the incidence of late postadministration hypothyroidism is lower. Fibrillation arrhythmia usually (in ca 60%) recedes spontaneously with the assistance of beta-blockers in remission of thyrotoxicosis. If this does not occur, pharmacological or electric cardioversion is necessary after anticoagulation preparation, because persistence of FA is an important risk factor of cardiac failure and thromboembolic complications. Eurhythmia then usually lasts as long as remission of thyrotoxicosis persists or there is no overdosage of substitution doses of T4 during treatment of hypothyroidism which develops after thyroelimination treatment. Amiodarone is unsuitable, even contraindicated, for treatment of fibrillation arrhythmia in thyrotoxic heart.

[Cor thyreotoxicum. Part I--new findings about its etiopathogenesis and diagnosis. Overview of problems based on 35 years' experience]. / Cor thyreotoxicum. Cast' I.--súcasné novosti v jeho etiopatogenéze a diagnostike. (Prehlad problematiky na základe 35-rocných skúseností).

In the seventies thyrotoxic heart accounted for 3% of all hospitalized cardiac patients and was found on average in 30% of all cases of hyperthyroidism. It presented most frequently by tachyfibrillation and resistant cardiac decompensation. It affected men four times as frequently as women. The incidence correlated with age, toxic nodose goitre, but its development did not correlate with concurrent thyrotoxic rhizomyelic myopathy nor with the extent of deviation of thyroid laboratory parameters (T4, T3, indexes FT4). At present the incidence of thyrotoxic heart declined due to early detection and more adequate diagnosis and treatment of hyperthyroidism, as well as due to the decline of oligosymptomatic toxic nodose goitres even in old age due to preventive iodization of table salt. However, there was an increase of hyperthyroidism induced by amiodarone and other iodine preparations (X-ray contrast materials) associated with primary heart disease and arrhythmias. (Up to 2% of amiodarone treated patients). The ratio of so-called real subclinical thyrotoxicoses in the development of thyrotoxic heart is negligible. Isolated reduction of TSH in hospital screening is a frequent finding but is conditioned most frequently by: a) the 1st stage of the low thyroxin syndrome, b) the 1st stage of subacute thyroiditis, c) the influence of various drugs (iodine preparations, overdosage of T4 substitution, pharmacotherapy with glucocorticoids, dopamine etc.), d) methodical artefacts, e) natural pulsed secretion of TSH etc. Hospital screening of hyperthyroidism and thyrotoxic heart even in older people above 60 years by T4 and/or TSH (2nd generation equipment) is not effective because it is detected in 20% of current hospital admissions and in 60% of those admitted to intensive care unitpathologic values of T4 and/or TSH most frequently without non-thyroid causes (stages of the low thyroxin syndrome) are recorded. This hospital screening has a satisfactory sensitivity but low specificity and in a large number of people calls for further diagnostic steps. Therefore it is more suitable only after clinical examination of the patient to confirm suspected hyperthyroidism to examine FT4 and TSH (IRMA 3rd generation) or possibly supplement FT3 and other aimed tests.

[Thallium scintigraphy of the myocardium in evaluation of patients with insulin resistance syndrome and microvascular angina pectoris]. / Táliová spect scintigrafia myokardu v hodnotení pacientov so syndrómom inzulínovej rezistencie a mikrovaskulárnou anginou pectoris.

Insulin resistance syndrom (IR) is often associated with the syndrome of microvascular angina pectoris (MVAP) or with coronary artery disease (CAD). The authors quantified distribution and washout of 201Tl in heart (C), lungs (L) and liver (H) to evaluate the results 201Tl stress (s) and redistribution SPECT in 50 patients. They compared 2 groups of patients with laboratory verified IR (MVAP and CAD) and control group (CG) of patients with normal coronarography without any symptoms of IR. In Patients with IR and MVAP were found significantly more frequent local perfusion abnormalities then in CG. The index sL/C calculated by ROI analysis is significantly lower in controls, then in CAD. The index sC/H is lower in patients with IR (MVAP significantly) then in CG. The washout of 201Tl in CAD myocardium decreased and in MVAP liver increased. 201thalium scintigraphy is useful for separation of patients with MVAP and local perfusion abnormalities. This findings had probably prognostic value in patients with IR.

[Insulin resistance and the coronary syndrome]. / Inzulínová rezistencia a koronárny syndróm.

The different diseases associated with the insulin resistance syndrome--diabetes mellitus or impaired carbohydrate tolerance, atherogenic lipoprotein phenotype, arterial hypertension and central type of obesity are the main risk factors of atherosclerosis. The reduced sensitivity of target tissues to the metabolic action of insulin (insulin resistance) is considered at present a separate risk factor. The authors analyze on the basis of a group of 210 coronarographic patients the influence of insulin resistance and associated etiopathogenetic risk factors on coronary lesions evaluated by the method of quantitative coronarography. From the results of the investigation ensues that insulin resistance is the most frequent metabolic deviation in patients with coronary disease whereby in the macrovascular group it was found in 74.3% and in the group with microvascular angina pectoris in 64.3% of the patients. Changes in the lipoprotein spectrum were a more frequent and earlier manifestation of insulin resistance than impaired carbohydrate metabolism. The change from functional changes of the vascular wall (impaired endothelium-dependent vasodilatation) to the development of an atheromatous plaque depends on the total number of cholesterol conveying lipoproteins assessed by means of the apoprotein B level and on the capacity of the reverse cholesterol transport, whereby both mechanisms are greatly influenced by insulin sensitivity. The degree of coronary affection evaluated by means of a coronary score, is in patients with manifest diabetes comparable with the affection in patients with insulin resistance without manifest diabetes and these two groups differ very significantly as to the extent and degree of affection from patients with a normal sensitivity to the effect of insulin.

[Occurrence of primary aldosteronism in a group of ambulatory hypertensive patients]. / Výskyt primárneho aldosteronizmu v súbore ambulantných hypertonikov.

Findings pertaining to the diagnosis and treatment of primary aldosteronism are rapidly expanding. In the present work the authors focused attention on the clinical application of some progressive methods. They examined a group of 115 ambulatory patients with arterial hypertension, not suspected of secondary arterial hypertension, in the course of one year. As a screening method of primary aldosteronism they selected the aldosterone renin ratio (ARR). Using this method the authors diagnosed 125 cases of primary aldosteronism, i.e. a 13% prevalence in the examined group. Only in one instance they detected an adenoma by computed tomography (CT), in the remaining patients, i.e. four times, the adenoma was verified by selective catheterization of adrenal veins and assessment of aldosterone and cortisol. The authors did not confirm a more accurate localization of the adenoma by the aldosterone/cortisol ration than when assessing aldosterone only. In two patients adrenalectomy was performed by laparoscopy and this surgical technique, as regards adrenal glands, was implemented for the first time in Slovakia in our department. It has certain advantages over classical adrenalectomy.

[Relation between cytokines (TNF-alpha, IL-1 and 6) and homocysteine in android obesity and the phenomenon of insulin resistance syndromes]. / Vzt'ah cytokínov (TNF-alfa, IL-1 a 6) a homocysteínu k androidnej obezite a k fenoménom syndrómu inzulínovej rezistencie.

TNF-alpha (so-called cachectin), IL-1 and 6 are important regulating agents in the homeostasis of energy in the organism, as among others they control processes of apoptosis and thus also the volume of adipose and muscular tissues. They are produced not only in immunocompetent cells but also in adipocytes and muscle cells. The cytokine system is then activated not only in tumours and infections but elevated values were found also in obesity, NIDDM, in myocardial infarction and in advanced decompensated cardiac patients. By acting on phosphorylation of IRS-1 and PI-3 kinase TNF-alpha promotes significantly insulin resistance, causes deterioration of diabetes, as well as elevated body temperature, sleepiness and anorexia. In a group of 65 patients, mostly with android obesity, in hyperleptinaemic and insulin resistant probands with coronarographically confirmed microvascular angina pectoris (n = 22) or IHD, mostly after a myocardial infarction (n = 43) with one or more significant stenoses on the epicardial coronary arteries in half the patients positive or elevated TNF-alpha was found and in 28% also IL-6. This increase did not correlate however with BMI, the percentage of body fat, IRI and C peptide levels nor with cortisol and leptin levels. Insulin resistant subjects had more frequently elevated homocysteine and Lp(a) values which are further two independent risk factors of atherothrombogenesis. Hyperhomocysteinaemia can be favourably influenced by vitamin fortification of the diet or by administration of folate and pyridoxine (1 tablet per day) involving negligible financial costs.

[Homocysteine--a routine biochemical parameter in cardiovascular diseases?]. / Homocysteín--rutinný biochemický parameter pri kardiovaskulárnych ochoreniach?

An elevated level of total homocysteine (tHcy) in blood-hyperhomocysteinemia, is prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral and peripheral vessels and for thromboembolism (arterial and venous). Elevated total homocysteine confers a graded risk with no threshold, is independent of but may enhance the effect of conventional risk factors. Hyperhomocysteinemia seems to be a particularly strong predictor of cardiovaskular mortality. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe and inexpensive means to reduce an elevated total homocysteine level.

[Relation between levels of leptin, insulin and cortisol in persons with the 5H (X) syndrome]. / Vzt'ah hladín leptínu k hladinám inzulínu a kortizolu u l'udí so syndrómom 5H (X).

Leptin levels in subjects with android obesity with the insulin resistance syndrome (syndrome X, 5H) are in general elevated, as compared with non-obese subjects and correlate with the BMI, with the percentage of body fat, WHR, IRI levels and sex (they are higher in women), as it is the case in the general population. In the elevated leptin level in syndrome 5H (association of hyperinsulinism, hyperglycaemia-NIDDM, hyperlipoproteinaemia with android obesity, arterial hypertension and hirsutism in females with the polycystic ovaries syndrome) participate in a significant way also elevated basal IRI and cortisol levels as well as an elevated postprandial IRI response during oGTT despite the fact that leptin and endothelin-1 levels do not rise significantly during oGTT despite hyperinsulinaemia. Leptin levels were however higher in men (liminally significant in women) with an hyperinsulinaemic response during oGTT, as compared with probands with a normal insulin response. Optimal insulin and glucocorticoid levels are the prerequisite for a rise of leptin because proadipocytes in vitro begin to produce leptin as soon as insulin is added to the medium and this effect is trebled, if cortisol is added. It appears that the insulin and leptin resistance in syndrome 5H are parallel phenomena which potentiate each other. Elevated insulin and cortisol levels maintain elevated leptin levels which in turn enhances the insulin resistance in muscles and at the same time has an impact on the IRI response to postprandial hyperglycaemia. In the background of this insulin and leptin resistance in the majority of subjects with the 5H syndrome there is apparently no actual molecular defect of the hormone and its receptors in target tissues but a possible defect in mechanisms of postreceptor transduction of the hormonal signal. In the hormonal resistance participate moreover also two general and non-specific mechanisms such as: 1. increased consumption or uptake of hormonal receptors by elevated levels of the appropriate hormone ("down regulation" phenomenon), 2. disorders of paracrine endothelial mechanisms of the vascular wall which determine via the control of the inflow in the regional microcirculation the availability of insulin, leptin and metabolic substrates to target tissues. Impaired vasodilatation reserves and the development of paradoxical vascular spasms in response to stimuli which normally cause vasodilatation (strain, administration of acetylcholine, histamine, ATP etc.) are constant, associated phenomena in hyperlipoproteinaemias, arterial hypertension and in type 2 diabetics. These phenomena are the syndrome of insulin resistance and syndrome 5H-X resp. Endothelin-1 levels assessed in the systemic circulation are however due to their short biological half-life and the paracrine action of endothelin-1 not sensitive markers of endothelial dysfunction in syndrome X.

[Functions and dysfunctions of the vascular endothelium]. / Funkcie a dysfunkcie cievneho endotelu.

Endothelium represents a large paracrine gland with an enormous reactive surface. By means of its numerous vasodilation and vasospastic factors it manages the basal and working tonus of vessels and thus also the regional flow and the access of target tissues to hormones and metabolic substrates. It manages also the proliferation and migration of myocytes of the vascular wall and thus its adaptation to overload. The dysfunctional states of endothelium are observed in arterial hypertensions, diabetes, dyslipoproteinaemia, and they grow with age. They are the first stage of atherothrombogenic processes. They manifest themselves by a decreased vasodilation reserve of the vascular wall to strain, insulin and many other stimuli. On the contrary, quite frequently they paradoxically react to physical strain, acetylcholine, histamine, ATP etc. by vascular spasms which can determine vasospastic and microvascular angina pectoris including spasms and occlusions of e.g. coronary arteries in sites of insignificant stenoses with the origin of infarctions. The damaged endothelium, so to explain, conceives these stimuli in accordance with the encoded programme as a stimulus to the protection from haemorrhage during stress (fight or flight) and develops "suicidal" defensive reaction against them which we are nowadays able to modulate by administration of ACE-inhibitors, beta-blockers, hypolipidaemic drugs, inhibitors of cyclooxygenase-1 (30-100 mg of aspirin), Ca-antagonists and antioxidants including numerous non-pharmacological procedures. We can retard or halt the process of atherothrombogenesis and avoid or lower thus the number of sudden vascular ventricular as well as brain episodes, including the congestive heart failures, limb amputations and ischaemic damage of the brain. (Fig. 4, Ref. 70.)

Funkcie a dysfunckie cievneho endotelu.

Endothelium represents a large paracrine gland with an enormous reactive surface. By means of its numerous vasodilation and vasospastic factors it manages the basal and working tonus of vessels and thus also the regional flow and the access of target tissues to hormones and metabolic substrates. It manages also the proliferation and migration of myocytes of the vascular wall and thus its adaptation to overload. The dysfunctional states of endothelium are observed in arterial hypertensions, diabetes, dyslipoproteinaemia and they grow with age. They are the first stage of atherothrombogenic processes. They manifest themselves by a decreased vasodilation reserve of the vascular wall to strain, insulin and many other stimuli. On the contrary, quite frequently they paradoxically react to physical strain, acetylcholine, histamine, ATP etc. by vascular spasms which can determine vasospastic and microvascular angina pectoris including spasms and occlusions of e.g. coronary arteries in sites of insignificant stenoses with the origin of infarctions. The damaged endothelium, so to explain, conceives these stimuli in accordance with the encoded programme as a stimulus to the protection from haemorrhage during stress (fight or flight) and develops "suicidal" defensive reaction against them which we are nowadays able to modulate by administration of ACE-inhibitors, beta-blockers, hypolipidaemic drugs, inhibitors of cyclooxygenase-1 (30--100 mg of aspirin), Ca-antagonists and antioxidants including numerous nonpharmacological procedures. We can retard or halt the process of atherothrombogenesis and avoid or lower thus the number of sudden vascular ventricular as well as brain episodes, including the congestive heart failures, limb amputations and ischaemic damage of the brain. (Fig. 4, Ref. 70.).

[The insulin resistance syndrome and fibrinolysis disorders]. / Syndróm inzulínovej rezistencie a poruchy fibrinolýzy.

The high atherogenic potential of the insulin resistance syndrome can be only partly explained by the association of "classical" risk factors of atherosclerosis which are considered part of it, i.e. impaired carbohydrate tolerance/diabetes mellitus type II, dyslipidaemia, hypertension and obesity. Impaired fibrinolysis due to excessive production of the plasminogen activator inhibitor-1 (PAI-1) are further risk factors which participate in the process of atherogenesis from the beginning of formation of the atheromatous plaque to the thrombotic occlusion of the vascular lumen. The authors present a group of 25 patients with different grades of glucose resistance, evaluated by theinsulin response to a glucose load. The insulin resistant group (n = 15) differed significantly from the non-resistant one (n = 10) as regards body weight and the central type of obesity (< 0.01 and 0.001 resp.) insulin level on fasting and after a load (< 0.0001 and 0.001 resp.), triglyceride levels (< 0.01), the incidence of diabetes or impaired carbohydrate tolerance (66.7 vs. 20%) and hypertension (53.3 vs. 20%), but also as regards the PAI-1 activity (.0001). As regards blood sugar levels, total and HDL cholesterol the groups did not differ. The authors investigated also the relationship between PAI-1 activity and different components of the insulin resistance syndrome in the whole group. The closest correlation was found between the PAI-1 activity and the general insulinaemic response to a glucose load (< 0.001) and between PAI-1 and triglycerides (< 0.001). Based on the presented results it may be stated that hypofibnrinolysis as a result of excessive production of PAI.1 is part of the insulin resistance syndrome and potentiates its high atherogenic risk.

[Leptin and its biological and clinical significance. Is leptin and insulin resistance in the X-5H hormonal metabolic syndrome a parallel or causally-linked phenomenon?]. / Leptín a jeho biologicko-klinický význam. Sú leptínová a inzulínová rezistencia u hormonálne-metabolického syndrómu X-5H pararelné alebo kauzálne zviazané fenomény?

Leptin 167 an amino acid product of the recently discovered obesity gene "ob-gene", is a tissue hormone of adipose tissue. It is a hormonal satiety signal or a signal for terminating food intake. Its level rise after a meal or after administration. Rats with a mutation of the ob-gene have zero or very low leptin levels, are hyperphagic, obese and sterile, develop diabetes as a result of overeating. Administration of recombinant leptin arrests hyperphagia, the body weight declines and sexual function improve partly, in particular in males. It seems that leptin controls not only the function of the hypothalamic satiety centre but also the output of GnRh and other liberins as well as thermoregulation, muscular and sexual activity and thus energy expenditure. In the majority of obese rats and human the leptin levels are significantly higher compared with asthenic individuals, proportionate to the percentage of body fat and BMI. Obesity promotes also insulin resistance and penetration of the H-phenomenon into the phenotype. In the insulin resistance syndrome (5H-X) it may thus be assumed that there is a parallel leptin and insulin resistance, probably of the postreceptor type, and even a causal association, as the "db" gene is identical with the gene for leptin receptors.

[The role of calcium inhibitors in the treatment of arterial hypertension]. / Miesto Ca-inhibitorov v liecbe artériovej hypertenzie.

Base on their own experience with isradipine and results of a multicentric study with amplodipine in the Slovak Republic, as well as based on data in the literature the authors conclude that: 1. In the treatment of arterial hypertension associated in the syndrome of insulin resistance (syndrome X and 5H resp.) with type 2 diabetes, hyperlipiproteinaemia and hyperinsulinism drugs of first choice include ACE-inhibitors and Ca antagonist of the second generation, dihydropiridine type, such as amplodipine, isradipine, fellodipine, nirtendipine etc. ACE inhibitors and Ca antagonist of the dihydropyridine type with prolonged effect have a good tolerance, few undesirable effect, a favourable effect on the decline of BP, regression of hypertrophy of the left ventricle and vascular wall; they do not cause deterioration of insulin resistance and thus do not interfere with compensation of diabetes and associated hyperlipoproteinaemia. 2. ACE inhibitors moreover reduce glomerular filtration and albuminuria and thus retard along with the effect on BP the progression of diabetic nephropathy. 3. In pre-existing hyporeninemic hypoaldosteronism (cca in 18% diabetic subjects) they can however cause dangerous hyperkalinaemia by further inhibition of the damaged renin-angiotensin-aldosterone system. In instances Ca inhibitors are indicated. The latter activate RAAS and do not have an impact on albuminuria. By their effect on the vas deferens they can increase glomerular filtration. 4. Diuretics are not suitable for the treatment of hypertension in X syndrome and the use of beta-blocking agents even with ISA and beta-1-selective preparations in restricted in particular when insulin is administered or other numerous contraindications are present (cardiac failure, bradyarrythmias, bronchitis etc.). Perhaps a combination of ACE-inhibitors and Ca antagonists of the 2nd generation with an alpha-blocking agent or hybrid alpha-beta-blocking agent is a suitable solution.

[The effects of nicotine on leptin levels in patients with android obesity]. / Vplyv nikotínu na hladiny leptínu u androidne obéznych jedincov.

In insulin resistant subjects with android obesity the leptin levels are, as compared with non-obese subjects, elevated in proportion to their BMI, WHR and their percentage of body fat. Generally independent on obesity, leptin levels are significantly higher in women than in men as in women the percentage of adipose tissue is higher. After administration of 2 mg nicotine in Nicorette chewing gum to 36 android obese non-smokers the elevated baseline values of leptin did not change and thus the observation that cigarettes suppress hunger or that smoking promotes weight reduction is untrue or else this effect is not mediated by nicotine stimulation of leptin secretion or formation in adipose tissue, leptin being the adipose tissue hormone which controls food intake, the sensation of satiety and via neuropeptide Y also other hypothalamic functions such as muscular and sexual activity, gonadoliberin output, thermoregulation etc. Leptin thus offers no alibi to smokers. Conversely smoking in android obese hyperinsulinaemic hyperleptinaemic subjects with syndrome X (5H) potentiates significantly the risk of cardiovascular death.

[Initial experience with laparoscopic adrenalectomy]. / Prvé skúsenosti s laparoskopickou adrenalektómiou.

We present the first experience with laparoscopic adrenalectomy, which was in Slovakia introduced to the surgical practice on March 3, 1996. We analyse first seven patients who underwent completed laparoscopic adrenalectomy (five leftsided, two right-sided). Four patients had cortex adenoma (clinically 2 incidentalomas and 2 Cishing syndroma), three patients had cortex hyperplasia (clinically Conn syndroma). Average duration of operation was 120 minutes, there were no postoperative complications. Average postoperative hospital stay was 5 days. Our initial experiences are comparable with that of surgical departments which has more than two-years experiences. Laparoscopic adrenalectomy is a perfect method for the small adrenal tumors and it is better than traditional transabdominal approach.

[The polycystic ovary syndrome and insulin resistance]. / Syndróm polycystických ovárií a inzulínová rezistencia.

The insulin resistance syndrome and the polycystic ovary syndrome (PCOS) appear to have some following coincidences: the existence of subclinical acanthosis nigricans in PCOS hyperinsulinemic women, correlation of insulin levels and free testosterone, insulin-like growth factor I binding protein (IGFIBP), and sex-hormone binding globulin. Insulin and IGFI act synergically with luteinizing hormone increasing the activity of cytochrome P450c17 and its enzymatic activity in the adrenals. The decrease in IGFI level and IGFI receptors in the ovarian granulosa cells reduce the steroids aromatisation. The increased expression of IGFI receptors in the theca cells favours the androgens' synthesis. Long-term insulin therapy results in an increase in ovary volume and the blood androgens levels. The deterioration of insulin resistance in PSOC women progresses also by the reduction of type I of skeletal muscle fibres which are sensitive to insulin, and the increase of type II fibres which are resistant to insulin in hyperandrogenemia. Testosterone deteriorates the skeletal as well as hepatic insulin sensitivity by both its facilitating effect on lipolysis and the increase of free fatty acids. Abdominal obesity seen in PCOS and insulin resistance is composed by adipocytes with glucocorticoid receptors, which after cortisol stimulation activate the lipoprotein lipase and fat accumulation. Gynoid obesity with the preferential aromatisation of steroids is not evolved because of the low estrogens and progesterone levels in PCOS. Low progesterone levels (with anticortisol effect) support the development of abdominal obesity. Ultimately, the early peak of insulin secretion (4-8 min) in PCOS is higher. This fact should testify a certain diabetic disposition. (Ref. 37.)

[Amylin as an additional possible pathogenic factor in NIDDM and the insulin resistance syndrome]. / Amylín ako d'alsí mozný patogenetický clánok NIDDM a syndrómu inzulínovej rezistencie.

The syndrome of insulin resistance comprises the following H-phenomena: 1. Hyperinsulinism compensating the inborn postreceptor insulin resistance, 2. Hyperglycaemia-non-insulin-dependent diabetes mellitus, 3. Hyperlipoproteinaemia with android obesity, 4. Hypertension, 5. Hirsutism with the syndrome of polycystic ovaries as a manifestation of a hyperandrogenic situation in the female organism. Molecular syndromes of this syndrome of insulin resistance are obscure. They are the subject of intensive studies because H-phenomena are an aggregation of the main risk factors of atherogenesis. Recently attention is focused also on amylin--a 37 amino acid peptide with a 50% homologous amino acid sequence with a calcitonin-gene--related peptide (CGRP), which is the product of a gene made up of three introns on the 12th chromosome. Amylin acts in the beta-cells of the pancreas as a co-secretion of insulin. If in excess, it is deposited in the form of an amyloid in the beta-cells. In the early stage of NIDDM it alters the physiological response of the beta-cell to glycaemic stimuli and food, in later stages of the disease, after accumulation, it causes apoptosis of the beta-cell and reduces thus the secretory capacity of the Langerhans islets. It is excreted in the urine and thus, if the glomerular filtration is reduced, it cumulates in the blood stream and thus enhances insulin resistance already in the early stages of chronic renal insufficiency, or in diabetic nephropathy. In type II diabetes similarly as insulin levels also amylin levels are elevated, while in type I diabetes with early autoimmune destruction of the beta-cells the insulin and amylin levels are reduced or even zero. Amylin reduces in the muscle, probably by inhibition of glycogen synthase, the insulin stimulated non-oxidative utilization of glucose into muscle glycogen and conversely by stimulation of phosphorylase it stimulates glycogenolysis and thus also lactate production and gluconeogenesis in the liver which all are anti-insulin effects which intensify the insulin resistance of the main target tissues. Amylin, similarly as CGRP or calcitonin, reduces Ca blood levels and has a vasodilatating effect; it reduces the BP but in different minimal and maximal doses and by a different mechanism and via special receptors because the link of amylin to calcitonin receptors is 100 times lower and does not produce a rise of cAMP in the target cell. The effect on the enhancement of insulin resistance in muscle was proved also by direct measurements using an hyperinsulinaemic euglycaemic clamp. After prolongation of the clamp to more than two hours the effect on insulin resistance disappeared, although the hypocalcinaemic effect persisted. Amylin is able by its biological action to modify the secretion as well as the effectiveness of insulin to pathological values. These two characteristics are typical for impaired glucose tolerance in type II diabetes. Studies are under way to find out whether the effect of amylin is involved directly also in the pathogenesis of the other H-phenomena or only via accentuation of hyperinsulinism. In any case amylin is a new link the role of which in the pathogenesis of NIDDM and the syndrome of insulin resistance awaits evaluation. Due to its effect on gastric evacuation it participates also in the postprandial glycaemic control in particular in type I diabetes where it it begins to be used in therapy. Perhaps it will be possible to administer it in these patients along with insulin to improve diabetes compensation.

[Diabetic nephropathy and isolated hyporeninemic hypoaldosteronism]. / Diabetická nefropatia a izolovaný hyporenínový hypoaldosteronizmus.

Isolated hypoaldosteronism is found in 75% diabetics where the disease has persisted for 10 or more years. Sporadically it is found in congenital autonomous neuropathy, in acute glomerulonephritis, in gouty kidney, tubulointerstitial nephritis, after transplantation of the kidney, on mytomycin etc. During dynamic testing of the response of plasma renin activity and aldosterone to the administration of furosemide and a vertical position in diabetics a significantly reduced response was recorded as compared with non-diabetic hypertonic subjects. In 18.3% no response was observed (decompensated form of IHH). Diabetic hypertonics behaved like control hypertonics on long-term beta-blocker treatment. In the decompensated form of IHH after administration of drugs interfering with the activity of SNS-RAAS activity (ACEI, spirolactone etc.) a hyperkalaemic crisis may develop which threatens the patient with acidosis, dehydration, myoplegia, muscular spasms, however, in particular with fatal disorders of the cardiac rhythm. A similar effect may be exerted also by blockers of prostaglandin synthetase (non-steroid antirheumatics) and other drugs. The cause of IHH in diabetics is the coincidence of several pathogenic factors: 1. hypersecretion of ANF with hyperosmolar hyperglycaemic hypervolaemia and hyperfiltration already at the onset of DN, 2. early development of autonomous neuropathy of the sympathetic nerve, 3. reduced renin and prostaglandin formation already in the early stages of DN, 4. reduced extrarenal isorenin formation, 5. reduced conversion of prorenin into active renin, 6. reduced reactivity of the zona glomerulosa to AII, hyperkalaemia and ACTH for its functional reconstruction as a result of periodic activation of contraregulative hormones by fluctuations of the blood sugar level in diabetic patients, 7. reduced response of the distal renal tubule to aldosterone because of tubulointerstitial changes. IHH is thus another serious but rarely diagnosed late complication of diabetes which depends only partly on the stage of DN. It must be, however, diagnosed and respected with regard to the selection of drugs for the treatment of arterial hypertension and the syndrome of insulin resistance and the 5H syndrome resp., i.e. the association of hyperinsulinism which compensates insulin resistance with hyperglycaemia (NIDDM), hypertension, hyperlipoproteinaemia and hirsutism in women (so-called Stein-Leventhal syndrome).