Multiple metachronous metastasis of adenocarcinoma of the kidneys in crossed ectopy with fusion

OBJECTIVE: Hyperandrogenism in patients with polycystic ovary syndrome has been shown to correlate with hyperinsulinaemia of insulin resistance. We have investigated if basal levels of insulin and the response to the intravenous administration of glucagon can reveal insulin resistance in patients with polycystic ovary syndrome. PATIENTS: Nine obese (BMI > 25 kg/m2) and nine non-obese (BMI 19-25 kg/m2) women with PCOS, chosen from a population of 91 women attending the infertility clinic, and 19 normally cycling women (seven obese, 12 non-obese) were studied. Oligo or amenorrhoea, hirsutism, and 12 or more follicles in a given ovary were selection criteria. MEASUREMENTS: Glucagon, 1 mg, was given intravenously to 18 of the 91 women and to the control subjects. Blood was taken at -5, 0, 5, 10 and 15 minutes for measurements of integrated areas under the response curve for insulin, C-peptide and glucose, respectively. Basal blood samples were drawn for fasting insulin, C-peptide, glucose, testosterone, sex hormone-binding globulin (SHBG), free fatty acids and IGF-I measurements. The free androgen index was calculated according to the formula FAI = testosterone x 100/SHBG. RESULTS: There were no significant differences in maximal increment and area under the response curve for glucose, C-peptide and insulin. FAI was significantly higher in all patients with features of polycystic ovary syndrome. However, fasting insulin levels were significantly higher only in obese patients when compared with obese control subjects and lean patients. CONCLUSIONS: The administration of 1 mg glucagon i.v. did not distinguish patients with polycystic ovary syndrome from control subjects. The mild insulin resistance of polycystic ovary syndrome is related only to obesity and is therefore unlikely to play an important role in the hyperandrogenism associated with the syndrome.     

Polycystic ovary syndrome

Polycystic ovary syndrome is a syndrome and not a disease. It reflects multiple potential etiologies and variable clinical presentations that are reviewed in this article. In addition to menstrual dysfunction and hyperandrogenism, women with polycystic ovary syndrome also may have hypothalamic-pituitary abnormalities, polycystic ovaries on pelvic ultrasonography, infertility, obesity, and insulin resistance. A familial pattern occurs in some cases, suggesting a genetic component to the disorder. The three major pathophysiologic hypotheses that have been proposed to explain the clinical findings of the disorder as well as treatment options are reviewed in this article.     

Insulin stimulation of lactate accumulation in isolated human granulosa-luteal cells: a comparison between normal and polycystic ovaries

Polycystic ovary syndrome (PCOS) is often associated with hyperinsulinaemia and peripheral insulin resistance. Whether the ovary is resistant to insulin is a matter of controversy. The aim was therefore to study the effect of insulin on lactate accumulation, an indicator of glucose metabolism, in granulosa-luteal cells from women with PCOS and from women with normal ovarian function. The cells were obtained from women undergoing clinical in-vitro fertilization-embryo transfer, either from patients with normal ovarian function and tubal or male infertility, or from women with PCOS, with or without tubal factor. The patients were down-regulated with buserelin and stimulated with urofollitrophin and human chorionic gonadotrophin (HCG). Follicle aspiration was performed under ultrasound guidance. Following oocyte recovery the granulosa-luteal cells were isolated, washed and cultured (2-3 x 10(4) viable cells/well) in serum-free Eagle's minimal essential medium for 48 h. After washing, the cells were then cultured in medium containing HCG (0.1-10 IU/ml) or insulin (0.05-0.5 microg/ml) for 24-48 h. Lactate accumulation in the media and cellular protein were analysed. Basal lactate accumulation did not differ in granulosa-luteal cells obtained from normal or PCOS ovaries, and averaged 46 and 49 nmol/g protein/24 h, respectively. A significant stimulation (40-60%) was obtained by HCG in both groups. Insulin caused a dose-dependent increase in lactate in granulosa-luteal cells obtained from normal ovaries (control: 45.5 +/- 6.3; insulin 0.5 microg/ml: 77 +/- 10 nmol/microg protein). Lactate accumulation in granulosa-luteal cells from PCOS ovaries was not altered in the presence of insulin. These results suggest that granulosa-luteal cell glucose metabolism is resistant to insulin in PCOS.     

Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis

Insulin resistance syndrome (IRS) has the potential to explain a large group of common metabolic and cardiovascular disorders [e.g., obesity, non-insulin-dependent diabetes mellitus (NIDDM), hypertension, hyperlipidaemia, hypercoagulability] which are all in themselves cardiovascular risk factors. This contribution firstly reviews the convincing evidence from glucose-clamp studies that all of these conditions are characterised by the presence of combined insulin resistance and hyperinsulinaemia, and secondly examines the relationships of the components of this syndrome to coronary artery disease and to the rational choice of antihypertensive therapy.     

Current concepts of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) may be loosely defined as unexplained hyperandrogenism, with variable degrees of cutaneous symptoms, anovulatory symptoms, and obesity. The vast majority of patients with the full-blown Stein-Leventhal syndrome have functional ovarian hyperandrogenism (FOH). However, FOH often occurs without the LH excess or polycystic ovaries of classic PCOS. Functional adrenal hyperandrogenism (FAH) is often found in the syndrome, but it is less closely associated with anovulatory symptoms than is FOH. The vast majority of FOH seems to arise from abnormal regulation (dysregulation) of ovarian androgen secretion. This typically is due to escape from desensitization to luteinizing hormone (LH); this appears to occur because of a breakdown in the processes that normally coordinate ovarian androgen and oestrogen secretion so as to prevent hyperoestrogenism. Similar dysregulation of adrenal androgen secretion in response to ACTH seems to account for most FAH. Dysregulation of androgen secretion may affect the ovary alone (isolated FOH), the adrenal alone (isolated FAH), or both together. Modest insulin resistance is common in PCOS/FOH, and the resultant hyperinsulinaemia is a major candidate as the cause of the dysregulation. The hyperinsulinaemia may arise from either 'nature' (genetic defects) or 'nurture' (exogenous obesity). Although hyperinsulinaemia alone does not have an obvious effect on steroidogenesis, it may act in genetically predisposed women as a 'second hit' to unmask latent abnormalities in steroidogenesis. The ovary, the adrenal cortex, and several other organs paradoxically function as if responding to the hyperinsulinaemic state in spite of resistance to the effects of insulin on glucose metabolism. PCOS should be viewed as an early manifestation of a hyperinsulinaemic condition that will predispose to cardiovascular and metabolic complications later in life. A subset of PCOS patients appear to have not only insulin resistance but also beta-cell secretory dysfunction, which may indicate a relationship of the disorder to NIDDM. The fundamental genetic defects remain to be elucidated.     

Incidence of NIDDM and the effects of gender, obesity and hyperinsulinaemia in Taiwan

Our aim is to determine non-insulin-dependent diabetes mellitus (NIDDM) incidence in Taiwan and examine its relation to obesity and hyperinsulinaemia in Chinese men and women. A total of 995 men and 1195 women aged 35-74 years free from diabetes in two townships in Taiwan were followed up with a second examination. At baseline general and metabolic data were recorded, and detailed anthropometric parameters and plasma glucose and insulin were assessed. World Health Organisation (WHO) criteria of fasting glucose 7.8 mmol/l or greater was utilized for defining diabetes. The age-standardized incidence rate based on the United States population in 1970 was 9.3/1000 (CI 5.8-12.8) in men and 9.3/1000 (CI 6.2-12.4) in women and the based on the WHO population in 1976 was 8.9/1000 (CI .5-12.3) in men and 8.9/1000 (CI 5.9-11.9) in women for the Chinese who had a mean BMI slightly greater than 24 (kg/m2). The predictability of the plasma glucose level was greater than that of the insulin level and the obesity indices. NIDDM incidence increased approximately threefold with each 0.67 mmol/l increase in plasma glucose level in men and women. The present study demonstrated the essential relationship of not only BMI but also central obesity indices (such as subscapular and waist circumference) to the incidence of NIDDM among men and women and a stronger relationship between NIDDM incidence and obesity in women than in men. The predictive effects of obesity indices and fasting plasma insulin values on NIDDM risk were independent of each other in men. Obesity and hyperinsulinaemia each without the presence of the other can lead to an increased risk of NIDDM. In women the NIDDM incidence increased more than additively in those with both obesity and hyperinsulinaemia compared to those with single obesity or hyperinsulinaemia. A slightly higher incidence of NIDDM in Taiwan than in western countries was found. The importance of obesity is indicated for predicting NIDDM in the community. Hyperinsulinaemia was found to play a significant role in predicting NIDDM incidence independent of obesity in men and synergistically with obesity in women.     

A case of congenital infantile fibrosarcoma of the right hand

BACKGROUND AND AIMS: In recent years it has been proposed that hypertension is part of a cluster of metabolic risk factors (syndrome X) involving hyperlipidaemia and hyperglycaemia, with hyperinsulinaemia as the common link. This study has investigated: (1) the prevalence of the metabolic syndrome and its component variables and their relationship to body mass index (BMI) and non-fasting insulin levels in a general population; and (2) the distribution and clustering of metabolic variables in normotensives and hypertensives. METHODS: Cross-sectional study of 5222 men aged 40-59 years with no history of coronary heart disease (CHD), diabetes mellitus or stroke drawn from general practices in 18 British towns. The men were a subgroup of the 7735 men in the British Regional Heart Study (BRHS) cohort whose baseline non-fasting serum was analysed for insulin, using a specific ELISA method. MAIN OUTCOME MEASURES: Hyperinsulinaemia, hyperglycaemia, high serum total cholesterol, high triglyceride and hyperuricaemia were defined as the top 20% of the distribution in the 5222 men. Low HDL-cholesterol was defined as the bottom 20%. RESULTS: BMI and non-fasting insulin were both significantly and strongly associated with non-diabetic hyperglycaemia, lipid abnormalities (HDL-cholesterol, triglyceride and total cholesterol) and hyperuricaemia. BMI was strongly associated with hypertension whereas non-fasting insulin showed a much weaker relationship which was abolished after adjustment for BMI. However, only 2.9% of men showed the 'full metabolic syndrome' (hypertension, hyperglycaemia and dyslipidaemia) and a large proportion of these men were hyperinsulinaemic (65%) or obese (47%). Dyslipidaemia (any one of low-HDL-cholesterol, high triglyceride or high cholesterol) was common in both normotensives and hypertensives (40.5% vs 46.4%). Hypertensives showed significantly higher levels of total cholesterol, triglyceride, blood glucose, urate and more clustering of hyperglycaemia and dyslipidaemia than normotensives even after adjustment for BMI. CONCLUSION: Hypertensives were more likely to have lipid abnormalities and clustering of risk factors than normotensives even after adjustment for BMI. The metabolic syndrome is more strongly associated with hyperinsulinaemia than with obesity but it is relatively uncommon in men with no history of cardiovascular disease or diabetes. Given the weak relationship between hypertension and hyperinsulinaemia, the latter is unlikely to explain the higher levels of lipid abnormalities and clustering seen in hypertensives. Overweight/obesity may be primarily involved in the pathways to hypertension and lipid abnormalities but the unravelling of these relationships require more specific measures of adipose tissue distribution, composition and function.     

Experimental benefit of moxonidine on glucose metabolism and insulin secretion in the fructose-fed rat

OBJECTIVE: Non-insulin-dependent diabetes mellitus (NIDDM) is often associated with hypertension leading to a specifically high cardiovascular risk in these patients. However, there is evidence that insulin resistance and hyperinsulinaemia are not only characteristic for diabetic patients but also for some non-diabetic populations in which a cluster of cardiovascular risk factors is observed (hypertension, hypertriglyceridaemia, obesity). Therefore, hyperinsulinaemia and insulin resistance have been suggested to be of major pathophysiological importance for the development of this syndrome (syndrome X). Since imidazoline receptors are currently considered to be a specific pharmacological target for blood pressure reduction, it is important to know whether and in which way these compounds affect the glucose homoeostasis and insulin release. DESIGN: The influence of moxonidine on glucose tolerance in vivo was determined in healthy control rats, in rats receiving a high fructose diet for 6 weeks to induce insulin resistance, hyperinsulinaemia and hypertension, and in rats receiving in addition to a high fructose diet moxonidine (1.5 mg/kg body weight daily). In vitro, using isolated pancreatic islets of mice, long-lasting effects (chronic) and immediate (acute) effects of moxonidine on beta-cell function were determined by basal and glucose stimulated insulin release in two different experimental systems: (1) islets were exposed for 24 h (37 degrees C) to various concentrations of moxonidine ranging from 1 nmol/l to 1 mmol/l, followed by a washing procedure to remove excess of moxonidine and then used for the beta-cell function test; (2) islet cultures were incubated again with moxonidine for 24 h (37 degrees C) with either 1 nmol/l or 1 micromol/l. In contrast to the first experiments, however, after the washing procedure moxonidine was added at the same concentration as used for preincubation to test its direct effect on beta-cell function. RESULTS: In healthy control rats acute administration of moxonidine in vivo impaired the glucose tolerance in high dosages, which effectively reduced the blood pressure (>1 mg/kg body weight). This effect was, however, smaller that that observed by clonidine. In fructose-fed rats, moxonidine completely prevented the development of insulin resistance, hyperinsulinaemia and hypertension. In vitro, pancreatic islets preincubated with moxonidine exhibited dose-dependently both stimulatory and inhibitory chronic effects on beta-cell function compared with that in controls. Preincubation of islet cultures with moxonidine at concentrations between 1 nmol/l and 1 mmol/l resulted in a reduction of basal insulin release which was very pronounced at concentrations higher than 100 nmol/l. The results obtained for glucose-stimulated insulin release opposed in part those for basal insulin release, since the preincubation with moxonidine up to 10 micromol/l gave rise to an increased insulin release. An additional direct effect of moxonidine with a marked reduction of glucose-stimulated insulin release was observed, however, when moxonidine was present during the preincubation (24 h) and the functional test at a concentration of 1 nmol/l or 1 micromol/l. CONCLUSIONS: Our data suggest that a causal linkage exist between the development of hypertension and insulin resistance/hyperinsulinaemia in the high fructose diet rat model. Since central activation of imidazoline receptors by moxonidine can prevent this syndrome, it follows that an overactivity of the sympathetic nervous system is of major importance. Suppression of this sympathetic overactivity might be an effective approach to reduce hypertension and the concomitant metabolic defect. Therefore, such an interventional strategy could contribute to reduce the cardiovascular risk of NIDDM patients and patients with other forms of insulin resistance/hyperinsulinaemia such as metabolic cardiovascular syndrome.     

Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome

Recent data in the mouse demonstrate that leptin, a protein hormone produced by fat cells, is required for fertility. In the absence of leptin the mice become obese, diabetic and infertile. Polycystic ovary syndrome (PCOS), a common cause of infertility in women, is associated with obesity and insulin resistance. Because of the increased frequency of PCOS in obese women we tested the hypothesis that alterations in serum leptin concentrations might be associated with PCOS. Immunoreactive leptin concentrations were measured in 58 women with PCOS and 70 regularly menstruating (control) women. As has previously been shown there was a positive correlation between leptin levels and body mass index (BMI). Although the leptin levels in the majority of women with PCOS fell within the control range, 29% of PCOS women had leptin levels above the 99% prediction interval for their BMI and none had low leptin levels. There were also positive correlations of leptin levels with free testosterone and insulin sensitivity in control women. In women with PCOS, 13% and 9.5% exhibited higher than expected leptin concentrations with respect to free testosterone and insulin sensitivity, respectively. Insulin resistant PCOS women had higher leptin levels than controls. The data demonstrate that a substantial proportion of women with PCOS have leptin levels that are higher than expected for their BMI, free testosterone and insulin sensitivity. These results suggest that abnormalities in leptin signaling to the reproductive system may be involved in certain cases of PCOS.     

Impaired ovulation and breast cancer risk

Conflicting results have been reported on the association between breast cancer risk and symptoms of luteal insufficiency, such as irregular or prolonged menstrual cycles and difficulty in becoming pregnant. Studies on the association between breast cancer risk and hormonal markers of impaired ovulation have also yielded conflicting results. Inadequate allowance for body mass and fat distribution may lead to inconsistent results when assessing the association between luteal insufficiency in premenopausal women and breast cancer risk. Ovulatory function is impaired by obesity, especially if it is predominantly abdominal in distribution. The Western diet and lifestyle favour early manifestation of hyperinsulinaemic insulin resistance in genetically-predisposed women. It is commonly associated with obesity which is predominantly abdominal in distribution. In a subset of premenopausal women, the concomitants of hyperinsulinaemia may impair maturation of ovarian follicles by a direct effect of insulin or insulin-like growth factors on ovarian tissue. Even when women are ovulating regularly, obesity may be associated with luteal insufficiency as shown by decreased levels of progestins or other changes in the sex steroid profile. Insulin resistance is likely to be involved and might explain the weak reduction in breast cancer risk associated with overweight in premenopausal Western women, in contrast with the increased risk widely reported in obese post menopausal women.     

Role of GnRH drive in the pathophysiology of polycystic ovary syndrome

Polycystic ovary syndrome may result from multiple mechanisms, but full expression of the PCO syndrome with hyperandrogenic anovulation depends upon sustained LH drive and relative FSH deficiency. We have described possible intrinsic and extrinsic factors capable of modifying the hypothalamic-pituitary-ovarian axis. Available evidence suggests the presence of an intrinsic alteration in GnRH-LH drive. The long-term natural history of HAA is variable and depends on several factors including obesity, aberrations in insulin action, intrinsic ovarian function, and end-organ responsiveness to androgens. Figure 1 presents a conceptualization of the pathogenesis of PCOS diagramming the multiple modulators of its expression. Long-term suppression of androgens when fertility is not desired should modify the full expression of the PCO syndrome. It is important to appreciate that therapy with oral contraceptive agents has few drawbacks and many immediate and potential long-term benefits for women with HAA. This therapy may be of greatest benefit when started in adolescence prior to the progression of obesity, hirsutism, and thecal-stromal hyperplasia. Women with HAA represent a large subgroup of patients who require individualization of their health care with sensitivity to issues surrounding anovulation, obesity, hirsutism, and infertility.     

Gestational diabetes mellitus and subsequent development of overt diabetes mellitus

GDM develops in 1-3% of all pregnancies. Women with GDM are characterized by a relatively diminished insulin secretion coupled with a pregnancy-induced insulin resistance primary located in skeletal muscle tissue. The cellular background for this insulin resistance is not known. The binding of insulin to its receptor and the subsequent activation of the insulin receptor tyrosine kinase have significant importance for the cellular effect of insulin. Thus, the pathogenesis to the insulin resistance was studied by investigating insulin receptor binding and tyrosine kinase activity in skeletal muscle biopsies from women with GDM and pregnant controls. No major abnormalities were found in GDM wherefore it is likely that the insulin resistance is caused by intracellular defects distal to the activation of the tyrosine kinase. Glucose tolerance returns to normal postpartum in the majority of women with GDM. However, previous studies, in populations quite different from a Danish population, have shown that women with previous GDM have a high risk of developing overt diabetes mellitus later in life. Hence, we aimed to investigate the prognosis of women with previous GDM with respect to subsequent development of diabetes and also to identify predictive factors for the development of overt diabets in these women. A follow-up study of diet treated GDM women diagnosed during 1978 to 1985 at the Rigshospital, Copenhagen was performed. Glucose tolerance was evaluated in 241 women (81% of the GDM population) 2-11 years after pregnancy. Abnormal glucose tolerance was found in 34.4% of the women (3.7% IDDM, 13.7% NIDDM, 17% IGT) in contrast to a control group where none had diabetes and 5.3% had IGT. Logistic regression analysis identified the following independent risk factors for later development of diabetes: a high fasting glucose level at diagnosis of GDM, a delivery more than 3 weeks before term, and an abnormal OGTT 2 months postpartum. Low insulin secretion at diagnosis of GDM was also an independent risk factor. The presence of ICA and GAD-autoantibodies in pregnancy was associated with later development of IDDM. In another study the following techniques: hyperinsulinaemic euglycaemic clamp, indirect calorimetry and tritiated glucose infusion were used to evaluate insulin sensitivity in glucose tolerant nonobese women with previous GDM and controls. A decreased insulin sensitivity due to a decreased non-oxidative glucose metabolism in skeletal muscle was found in women with previous GDM. Hence, the activity of three key enzymes in intracellular glucose metabolism (GS, HK and PFK) was studied in skeletal muscle biopsies obtained in the basal state and after 3 h hyperinsulinaemia, with the aim to identify the cellular defects causing the decreased insulin sensitivity. However, no abnormalities in enzyme activity was found. The same group of previous GDM women had a relatively reduced insulin secretion evaluated by the IVGTT. A longitudinal study of 91 GDM women showed a relatively reduced insulin secretion to oral glucose in pregnancy, postpartum as well as 5-11 years later. Thus the present review has shown that even nonobese glucose tolerant women with previous GDM are characterized by the metabolic profile of NIDDM i.e. insulin resistance and impaired insulin secretion. Hence, the combination of this finding together with the significantly increased risk for development of diabetes indicates that all women with previous GDM should have a regular assessment of their glucose tolerance in the years after pregnancy. The first OGTT should be performed around 2 months postpartum in order to diagnose women already diabetic and to identify women with the highest risk for later development of overt diabetes. Women with previous GDM comprise a target group for future intervention trials with the aim to prevent or delay development of NIDDM and IDDM.     

Influence of delayed staging laparotomy after laparoscopic removal of ovarian masses later found malignant

OBJECTIVE: To study the prevalence of cardiovascular risk factors in native urban Asian Indians and to look for the occurrence of clustering of these factors. RESEARCH DESIGN AND METHODS: The study included 953 subjects (532 men and 421 women), aged > or = 40 years, selected from a population survey for diabetes, which was conducted in 1994 in Madras, Tamil Nadu, India. Measurements of anthropometry, blood pressure, plasma lipid profile, glucose tolerance, plasma insulin response, and electrocardiogram were made. Based on the normal ranges derived from the population study, abnormalities in anthropometric values, plasma lipids, and insulin values were determined. Age-adjusted prevalences of the abnormalities were calculated using data from a 1991 urban census in Madras. The expected prevalences of the abnormalities in isolation and in combinations were calculated and compared with the corresponding observed figures. RESULTS: The prevalences of risk factors were in the order of central adiposity > dyslipidemia > hyperinsulinemia (2-h) > glucose intolerance > obesity > hypertension. The age-adjusted prevalence of coronary heart disease (CHD) was 3.9% (3.5% in men and 4.5% in women, NS), and T wave inversion was seen in an additional 10.3%. Isolated prevalences of all factors, except hypertension, were in lower frequency than expected. Combinations of each risk factor with one or two more risk factors occurred more frequently (1.3-4 times) than expected by chance. Impaired glucose tolerance and dyslipidemia showed association with hyperinsulinemia, whereas hypertension did not show such an association. CONCLUSIONS: Clustering of the cardiovascular risk factors or the components of insulin resistance syndrome occurs in the native Asian Indian population. This finding under-scores the need for preventive aspects of metabolic disorders and CHD.     

Role of the beta 3-adrenergic receptor locus in obesity and noninsulin-dependent diabetes among members of Caucasian families with a diabetic sibling pair

Obesity and insulin resistance are important risk factors for the development of noninsulin-dependent diabetes (NIDDM) and are prevalent among predisposed first degree relatives of diabetic individuals. Recent molecular screening and analysis of a common missense mutation of the beta 3-adrenergic receptor gene suggested this locus as a strong candidate for increased obesity, earlier age of diabetes onset, and insulin resistance. To test the hypothesis that the beta 3-adrenergic receptor locus affects diabetes susceptibility, obesity as measured by body mass index, and components of the insulin resistance syndrome, we examined the role of this region in families ascertained for two or more NIDDM siblings. Linkage analysis was conducted using both parametric and nonparametric analyses, including multipoint sibling pair analysis. We found no evidence for linkage to NIDDM as a dichotomous trait and no evidence for linkage to body mass index, waist/hip ratio, insulin levels, or glucose levels as quantitative traits or to reported age of onset among NIDDM individuals. The Trp64 Arg missense mutation was present in 11% of the population. The mutation was not associated with NIDDM, and Arg64 carriers did not have earlier NIDDM onset, higher body mass index, or higher waist/hip ratio than Trp64 homozygotes. Among relatives, Arg64 carriers had significantly lower fasting glucose levels and lower waist/hip ratios than Trp64 homozygotes, but no characteristics of the insulin resistance syndrome. We conclude that the beta 3-adrenergic receptor locus does not play an important role in NIDDM susceptibility or in the insulin resistance syndrome among members of families with a strong predisposition to NIDDM.     

Diabetic nephropathy. Its relationship to hypertension and means of pharmacological intervention

Hypertension and diabetes mellitus are common chronic conditions which frequently coexist. Diabetic nephropathy is a major cause of elevated blood pressure in patients with insulin-dependent diabetes mellitus (IDDM). Diabetic nephropathy, arterial sclerosis, obesity and association of essential hypertension can be the causes of hypertension in patients with non-insulin-dependent diabetes mellitus (NIDDM). Ambulatory blood pressure monitoring has revealed that the nocturnal fall of blood pressure is blunted in patients with diabetic nephropathy. A blunted diurnal blood pressure variation is seen in microalbuminuric diabetic patients and even in some normoalbuminuric patients. Accumulating data suggest that normalisation of blood pressure in hypertensive IDDM patients is most important to minimise the loss of kidney function. Angiotensin converting enzyme (ACE) inhibitors have been reported to be effective in postponing the development of nephropathy and in slowing its progression. Whether only ACE inhibitors have such beneficial renal effects on diabetic nephropathy is under discussion. While many studies have suggested that insulin resistance and hyperinsulinaemia are related to an elevated blood pressure in hypertensive patients, there does not seem to be enough evidence to prove that insulin per se can raise blood pressure in humans. Neither an insulin infusion within a physiological range nor sustained hyperinsulinaemia and insulin resistance (e.g. patients with insulinoma, cystic ovary syndrome) have been associated with an elevated blood pressure. Insulin resistance in some hypertensive patients may be a consequence of a decreased blood flow due to an increased peripheral resistance. Preliminary evidence suggests that low birth weight or impaired fetal growth is related to hypertension and NIDDM. Familial clustering of diabetic nephropathy suggests the contribution of genetic susceptibility and/or environmental inheritance. The frequent association of nephropathy with hypertension has led to research on the genes related to hypertension (ACE, angiotensinogen). Nevertheless, to date no reliable and clinically useful genetic marker has been found. Attempts to correct the metabolic abnormalities derived from diabetes are a new topic in the treatment of diabetic nephropathy. The effects of HMG CoA reductase inhibitors (antihypercholesterolaemic drugs), aldose reductase inhibitors (inhibitors of the polyol pathway) and glycation inhibitors (inhibitors of formation of advanced glycosylation end-products) on diabetic nephropathy have been evaluated in animal studies and in some clinical trials. Thus far, results with HMG CoA reductase and aldose reductase inhibitors have been somewhat conflicting. The potential therapeutic role of glycation inhibition in the treatment of diabetes deserves further study.     

Ureteral occlusion prosthesis

The improving survival rate of patients with childhood cancer has led to a growing awareness of the long-term effects of malignant disease and its treatment. Various endocrine abnormalities have been reported as frequent long-term adverse effects of cancer treatment in childhood, and among these growth hormone (GH) deficiency is the most common one, especially after cranial irradiation. Besides promoting growth, GH has well-established metabolic effects. Patients with GH deficiency tend to be obese, and obesity per se is also associated with insulin resistance which plays a key role in a cluster of metabolic derangements including glucose intolerance, hypertension, lipid abnormalities and atherosclerotic cardiovascular disease. This condition is known as the metabolic syndrome. Our recent observations indicate that a combination of obesity, glucose intolerance, hyperinsulinaemia and an abnormal lipid profile can be observed in long-term survivors of childhood cancer. Every sixth patient had the triad of obesity, hyperinsulinaemia and low HDL cholesterol, whereas this combination was not seen in any of the controls. The survivors with such a high-risk profile for cardiovascular disease had markedly reduced spontaneous GH secretion, and also additional features of the metabolic syndrome, such as higher systolic blood pressure and higher plasma glucose and serum triglyceride levels. Accordingly, decreased GH secretion, or alternatively some other disturbance in the hypothalamic-pituitary axis, emerging as a consequence of cranial radiation, may expose long-term survivors of childhood cancer to premature evolution of the metabolic syndrome. This can have an important impact on the long-term prognosis in these patients, because the syndrome as such results in an increased risk of cardiovascular morbidity and mortality.     

Ethnicity and cardiovascular risk: variations in people of African ancestry and South Asian origin

Mortality from coronary heart disease (CHD), stroke and end-stage renal failure are high in South Asian migrants in the UK. This is associated with high prevalence of diabetes and hypertension. These seem to be manifestations of a metabolic syndrome with insulin resistance (hyperinsulinaemia) and central obesity (based on high waist-to-hip ratio rather than on conventional measures of body mass index). This is associated with sedentary lifestyle, high serum triglycerides and low HDL-cholesterol. Mortality from stroke and end-stage renal failure are high in black migrants to the UK (both Caribbeans and West Africans). However, CHD mortality is low in this group. This pattern of mortality is associated with high prevalence of hypertension and diabetes. This group tends to be obese (particularly women) according to conventional measures of body mass index and to have hyperinsulinaemia, low serum triglycerides and high HDL-cholesterol. Conventional risk factors such as cigarette smoking and hypercholesterolaemia are less prevalent in ethnic minority populations in the United Kingdom and unlikely to explain the differences seen between groups, although each risk factor is likely to contribute to the variation in vascular disease within each group. There is difficulty in reconciling the results of migration studies (eg, from rural to urban environments) pointing to major environmental influences on the changes in cardiovascular risk factors with the consistent pattern of disease of ethnic groups across the world and in subsequent generations, suggesting a certain degree of genetic susceptibility. Important environment-gene interplays might be underlying some of these processes. The detection and management of hypertension and diabetes are still unsatisfactory in inner city areas and show variations by ethnic origin. Strategies for the control of CHD and stroke adopted in European countries directed mostly to white populations may be inappropriate for ethnic minority populations.     

Premature peripheral vascular disease: clinical profile and abnormal lipid peroxidation

Type 2 diabetes is extremely common and increasing in the United States. The pathophysiology of type 2 diabetes is a combination of increased insulin resistance and inadequate secretion. The main risk factors for diabetes are family history, obesity, sedentary lifestyle, ethnic background, age, and a history of gestational diabetes. Diet and exercise, the cornerstones of diabetes management, will improve insulin sensitivity and indirectly augment insulin secretion. Until recently, the only pharmacological approaches to diabetes were sulfonylureas and insulin, which either augment insulin secretion or replace insulin, thus acting only on the insulin side of the equation. Recently, a series of new drugs have become available that are capable of decreasing hepatic glucose output (metformin), slowing postprandial glucose absorption (acarbose), and improving peripheral insulin sensitivity (troglitazone). With these drugs, either alone or in combination, and behavioral therapies, it is now feasible to achieve good to outstanding glycemic control in most individuals with type 2 diabetes.     

The value of certain parameters in the diagnosis and detection of metabolic X syndrome

Authors summarise their 5-year long experiences on 343 patients about diagnostic methods of metabolic syndrome X and offer a simple possibility for screening of the jeopardized individuals. In a group of patients with hypertension and central obesity (group I: with 2 insulin resistant condition), 229 (89%) out of 255 cases met the basic criteria of the syndrome X which were hypertension, central obesity and high insulin levels for the corresponding blood sugar levels during oral glucose tolerance test (probable insulin resistance). Dyslipidemia was missing in 20% of these people. Hyperinsulinism occurred in 85%, glucose intolerance in 53%, presumable insulin resistance in 90% of cases. Insulin resistance was characterised by late hyperinsulinism (90 and 120 min.) during oral glucose tolerance test. This was the case in people with "diabetoid" glucose responses too, suggesting an early failure of glucose tolerance and/or insulin secretion. Components of syndrome X were present with a lower frequency in 24 patients with obesity (group II), in 35 patients with hypertension (group III) and in 29 patients without obesity or hypertension (group IV), as well. According to central obesity and hypertension, syndrome X could be screened by a probability of 90%. This can be helpful in prevention of NIDDM and coronary heart disease.     

Combined oral contraceptives and gonadotropin releasing hormone agonistic analogs in polycystic ovary syndrome: clinical and experimental studies

Polycystic ovary syndrome is a common endocrine disorder, presenting with menstrual irregularities, hirsutism, obesity, infertility and abnormal ovarian morphology. In addition, polycystic ovary syndrome is associated with a self-perpetuating imbalance involving the endocrine system and metabolic pathways, in which carbohydrates, lipids and growth factors are involved. Because of its chronicity, it is considered to be a substantial risk factor for atherogenesis and hormone-dependent neoplasia. The etiology and pathophysiology of the syndrome remain elusive. However, during the last decade, several clues have emerged from human and animal studies that may have significant repercussions in the treatment of polycystic ovary syndrome. Therapeutic maneuvers should be directed towards the dominant abnormalities present in individual patients with polycystic ovary syndrome. Gonadotropin releasing hormone (GnRH) agonists can directly affect the gonadotropin generator and secondary downstream derangements, whereas combined oral contraceptives (COCs) can modify hypothalamic as well as peripheral abnormalities. In view of the fact that GnRH agonistic analogs (GnRH-a) will induce hypoestrogenemia and its sequelae, the add-back strategy of estrogenic supplementation is recommended for preventive reasons and, as it transpires from some studies, for enhancement of GnRH-a effectiveness.