Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries

OBJECTIVE Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinaemia and insulin resistance. Previous reports of lipid abnormalities in the syndrome have produced conflicting results which may, in part, be related to the lack of appropriate controls for the obese women with PCOS. Only one study has related lipid levels to insulin sensitivity. The objective of this study was to assess lipids and lipoproteins in women with PCOS, to compare the results with weight matched controls, and to relate the findings to indices of insulin secretion and action, and to menstrual history. DESIGN A cross-sectional study of insulin sensitivity and lipids in a cohort of PCO subjects compared to weight and ethnic group matched controls. PATIENTS AND METHODS We have therefore investigated glucose tolerance, plasma lipids and lipoproteins in 19 lean (LP) and 55 obese (OP) patients with PCO and compared the results with those in 22 lean (LC) and 15 obese (OC) control women. Insulin sensitivity was measured in the same subjects with a short insulin (0.05 U/kg i.v. insulin) tolerance test (LP, n = 18; OP, n = 20; LC, n = 19; OC, n = 11). RESULTS Results are expressed as mean ± SEM or median (interquartile range). Fasting plasma glucose levels were similar in the four groups but the plasma glucose area was higher after oral glucose (75 g) in both the lean and obese PCOS groups than in their controls (LC 32.4 ± 0.7 vs LP 35.2 ± 1.2, P < 0.01; OC 34.7 ± l.8 vs OP 37.8 ± 1.5 mmol/l/3 h, P < 0.01). Insulin sensitivity was significantly reduced in obese PCOS women (LC 196 ± 9 vs LP 179 ± 9, NS; OC 168 ± 12 vs OP 133 ± 9 mmol/l/min, P < 0.01). Total serum cholesterol levels were similar in the four groups but HDL₂-cholesterol was reduced in both obese and lean PCOS (LC 0.42 (0.38–0.62), LP 0.31 (0.26–0.44), P < 0.05; OC 0.34 (0.21–0.47), OP 0.21 (0.12–0.32) mmol/l, P < 0.01). Total HDL-cholesterol was decreased significantly only in the obese PCOS group. Body mass index correlated significantly and negatively with total HDL-cholesterol and with HDL₂-cholesterol levels both within the PCOS group and the control women. Using multiple regression insulin insensitivity contributes significantly beyond BMI to the low HDL-cholesterol in women with polycystic ovaries. CONCLUSION Polycystic ovary syndrome is associated with biochemical risk factors for premature vascular disease, which cannot be explained by obesity alone.     

Hyperinsulinaemia,obesity, and syndrome X

Abstract. Objective . The major aim of this study was to compare various aspects of carbohydrate, insulin, and lipoprotein metabolism, serum uric acid concentration, and blood pressure in normal subjects stratified on the basis of both plasma insulin concentration and degree of obesity. The hypothesis to be tested was that hyperinsulinaemia, per se, was associated with relative glucose intolerance, higher triglyceride and uric acid concentrations, lower high-density lipoprotein cholesterol concentration and higher blood pressure, irrespective of degree of obesity. Design . This represents a case-control study, in which normal volunteers were subdivided into four equal groups based upon degree of obesity and plasma insulin response to a 74 g oral glucose challenge. Setting . The study was performed in the out-patient clinic of a university hospital. Subjects . Sixty-four individuals were recruited for this study, subdivided into four groups based upon their plasma insulin concentration and body mass index. Subjects were classified as hyperinsulinaemic if their plasma insulin concentrations in response to an oral glucose challenge were more than two standard deviations above the mean of 732 volunteers previously studied [1]. Obesity was defined as a body mass index of > 30 kg m^-2, and individuals were classified as non-obese if their body mass index was < 27.0 kg m^-2. Based upon these criteria, four experimental groups were created: (i) non-obese hyperinsulinaemic (NOB hyper); (ii) obese hyperinsulinaemic (OB hyper); (iii) non-obese normo-insulinaemic (NOB normo); and (iv) obese normo-insulinaemic (OB normo). Main outcome measures . Subject groups were compared on the basis of the integrated plasma glucose response to a 75 g oral glucose challenge, fasting plasma triglyceride, cholesterol, high-density lipoprotein cholesterol, and uric acid concentrations, and blood pressure. Results . Mean (± standard error of the mean) integrated plasma glucose response area for 2 h following a 75 g oral glucose load was significantly higher (13.4 ± 0.4 vs. 11.0 ± 0.4 mmol 1^-1, P < 0.001) in the hyperinsulinaemic group, as were the fasting triglyceride levels (2.4 ± 0.2 vs. 1.4 ± 0.1 mmol 1^-1, P < 0.001) and uric acid (5.3 ± 0.2 vs. 4.4 ± 0.2 mmol 1^-1, P < 0.05) concentrations. In contrast, high-density lipoprotein concentrations were lower in the hyperinsulinaemic group (1.06.0.05 vs. 1.32 ± 0.05 mmol 1^-1, P < 0.001). In addition, blood pressure was higher in the hyperinsulinaemic group (136 ± 5/87 ± 2 vs. 123 ± 2/82 ± 1 mmHg, P < 0.05). Furthermore, when each of the two groups were divided into obese (n = 16) and non-obese (n = 16) groups, all of the differences outlined above persisted. These changes were independent of age, gender distribution, generalized and abdominal obesity, cigarette smoking, and estimated physical activity. Conclusions . The cluster of changes subsumed under the heading of syndrome X are closely associated with hyperinsulinaemia (and presumably insulin resistance), and can be discerned irrespective of degree of obesity.     

The effect of cisapride on oral and intravenous glucose tolerance in normal subjects

Cisapride is used widely for the treatment of diabetic gastroparesis. There is some evidence that cisapride may influence insulin secretion. The aim of this study was to evaluate the effect of cisapride on plasma concentrations of glucose, insulin and C-peptide in response to oral and intravenous glucose loads. Twelve normal subjects took cisapride and placebo, each for 10 days using a randomized, double-blind, crossover design. In each treatment phase, the plasma glucose, insulin and C-peptide response to intravenous (0.5 g/kg) and oral (75 g) glucose loads was evaluated on separate days. Gastric emptying of the oral glucose load was also measured. After the intravenous glucose load, plasma concentrations of C-peptide were higher (P < 0.01) on cisapride when compared with placebo (e.g. peak C-peptide 2.08 ± 0.25 nmol/L vs 1.78 ± 0.22 nmol/L, P < 0.01) while there was no significant difference in plasma glucose or insulin. Cisapride had no effect on the rate of gastric emptying of the oral glucose load. Mean plasma concentrations of insulin and C-peptide were higher after oral glucose on cisapride than placebo, but these differences were not significantly different. These observations indicate that cisapride may increase glucose-stimulated insulin secretion.     

The effect of gemfibrozil on lipid profile and glucose metabolism in hypertriglyceridaemic well-controlled non-insulin-dependent diabetic patients

We assessed the efficacy of gemfibrozil therapy on lipid profile and glucose metabolism in a large cohort of (type 2) non-insulin-dependent diabetic patients. We enrolled 217 type 2 diabetic patients with plasma triglyceride concentrations equal to or above 2 mmol/l: 110 were randomized to gemfibrozil (600 mg twice daily) and 107 to placebo treatment in a double blind fashion. Each treatment was followed for 20 weeks. To assess postprandial glucose metabolism and insulin secretion, at time 0 and 20 weeks, a standard meal containing 12.5 g of proteins, 40.1 g of carbohydrate, 10 g of lipids was given. No differences in demographic characteristics were observed between patients randomized either to gemfibrozil or to placebo therapy. No differences were observed in total cholesterol and LDL-cholesterol concentration changes between the baseline observations and week 20 of both treatments. At variance, both treatments significantly increased HDL cholesterol. Gemfibrozil treatment significantly decreased plasma triglyceride concentration from 316±84 to 214±82 mg/dl (P < 0.001), whereas with placebo triglyceride levels increased from 318 + 93 to 380 + 217 mg/dl. No changes were observed in non-esterified fatty acid concentrations or in fasting plasma glucose concentrations, in HbA_1C values, insulin and C-peptide concentrations. Gemfibrozil treatment: 1) significantly reduces circulating triglyceride concentration; 2) does not significantly affect cholesterol concentration; 3) does not worsen glucose metabolism. Received: 13 July 1998 / Accepted in revised form: 24 February 1999     

The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries

OBJECTIVE Insulin insensitivity is a recognized feature of polycystic ovary syndrome (PCOS) but previous studies have suggested that circulating insulin concentrations are normal in hyperandrogenaemic women with regular cycles. The aim of this study was to examine the relationship between insulin sensitivity and menstrual pattern in women with PCO. DESIGN A cross-sectional study of insulin sensitivity in a cohort of PCO subjects with oligomenorrhoea compared to women with PCO and regular menstrual cycles and a group of normal control subjects. SUBJECTS Seventy-two women with polycystic ovaries on ultrasonography were studied. PCO subjects had clinical and/or biochemical evidence of hyperandrogenism; 53 had oligo/amenorrhoea (olig) and 19 had regular menses (reg). Results were compared with 31 control subjects. The groups were matched for age, weight and ethnic origin. METHODS Glucose and insulin responses to 75 g oral glucose were measured. Insulin sensitivity was assessed by the decline in plasma glucose following intravenous insulin (0.05 U/kg). RESULTS Glucose area (mean±SEM) after oral glucose was increased slightly in both PCO groups compared with controls (olig 37.6±1.4, reg 36.0±1.8, control 33.7±0.9 mmol/l h, both P < 0.01). Insulin area median (interquartile range) in response to glucose was significantly greater in the oligomenorrhoeic group (346 (239–734) mU/l h), compared with both PCO with regular cycles (246 (148–355), P<0.01) and controls (221 (147–277), P<001). Insulin sensitivity was reduced (P< 0.01) in the oligomenorrhoeic group (147 ±9.2 /imol/l min) compared to controls (185 ±7.4) but was normal in PCO with regular cycles (182 ±12.5). Insulin sensitivity did not correlate significantly with plasma testosterone or with SHBG levels, but plasma insulin concentrations correlated negatively with SHBG levels (fasting insulin vs SHBG, r= -0.47, P<0.01; insulin area vs SHBG, r= -0.47, P<0.01). CONCLUSIONS Insulin insensitivity in polycystic ovary syndrome occurs when there is oligo/amenorrhoea but not when the menstrual cycle is regular. This is consistent with PCO and insulin insensitivity being separate abnormalities which when combined are associated with anovulation.     

Effect of glucocorticoid replacement therapy on glucose tolerance and intermediary metabolites in hypopituitary adults

BACKGROUND AND OBJECTIVES Excess Impaired glucose tolerance and diabetes mellitus have been reported in hypopituitary adults on conventional replacement therapy Including glucocorticoids. We investigated the effect of the glucocorticoid component on glucose tolerance and intermediary metabolites in hypopituitary adults. DESIGN A 3-hour 75-g oral glucose tolerance test (OGTT) was performed on two study days, at least one week apart. On one study day, the glucocorticoid replacement morning dose was taken 60 minutes before the OGTT, and on the other it was left until after the OGTT. All other pituitary replacement therapies were kept unchanged on the two study days. PATIENTS Eight hypopituitary adults (3 males and 5 females; aged 46–76 years) on conventional replacement therapy were studied. Their duration of hypopituitarism was mean (range) 15 (5–31) years. Their mean body mass index (BMI) was 28·4 (24·1–35·1) kg/m². Their total daily cortisol dose was 26 (15–30) mg. MEASUREMENTS Plasma glucose, insulin, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate were measured at 30-minute intervals and plasma cortisol levels were measured hourly. RESULTS Fasting glucose and insulin concentrations were similar on the glucocorticoid day (GD) and the non-glucocorticoid day (NGD) (glucose (mean ± SD) 4·9 ± 0·9 vs 4·4 ± 0·5 mmol/l, insulin (median (range) 5 (1-17) vs 2 (1-15) mU/l, respectively). Post-glucose glycaemia was higher on the GD than on the NGD with a significantly higher glucose area under the curve (AUC) (45·0 ± 82 vs 38·9 ± 11·7 mmol/l h, P < 0·05). Post-glucose insulinaemia was also higher on the GD than on the NGD with significantly higher insulin AUC (270 (47-909) vs 207 (46-687)mU/l h, P < 0·02). Impaired glucose tolerance was found in three patients on the GD, one of whom continued to have impaired glucose tolerance on the NGD. The areas under the curves of NEFA, glycerol and 3-hydroxybutyrate were not significantly different on the two days. On the NGD, plasma cortisol levels were undetectable (<50nmol/l) in all patients and on the GD the median (range) peak was 500 (330–740) nmol/l dropping to 125 (60-330) nmol/l at 180 minutes. The difference in glucose AUC between the two days correlated with the maximal plasma cortisol levels (Spearman's p= 0·83, P < 0·01). CONCLUSIONS Glucocorticoid replacement therapy taken pre-prandially In hypopituitary adults induces mild elevations In circulating glucose and insulin levels even with acceptable plasma cortisol concentrations. Optimal regimens for glucocorticoid replacement require more study.     

Overnight metabolic fuel deficiency in patients treated conventionally for hypopituitarism

BACKGROUND Hormone replacement in hypopituitary adults attempts to reproduce normal physiology. Conventional regimens fail to mimic normal hormone profiles over 24 hours. OBJECTIVE To investigate the metabolic consequences of conventional hormone replacement in hypopituitary adults by measuring circulating levels of the major fuels, glucose, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate (3-OHB) over 24 hours in hypopituitary subjects and controls. SUBJECTS Ten GH and adrenocorticotrophin deficient hypopituitary adults on conventional replacement and 13 controls matched for age, sex and body mass index were studied. The patients received replacement with hydrocortisone twice daily (at 0730 and 1730 h; mean (range) daily dose 22 (10–30) mg/24 h) but not with GH. Other hormones were replaced as clinically necessary. MEASUREMENTS Circulating glucose, NEFA, glycerol and 3-OHB levels were measured over 24 hours together with concentrations of cortisol (total and free), GH and insulin, and urinary free cortisol. RESULTS Levels of glucose, NEFA and 3-OHB were lower in patients than controls (mean ± SEM) (4.3 ± 0.1 vs 5.3 ± 0.1 mmol/l, P = 0.0001; 291 ± 46 vs 448 ± 48 μmol/l, P = 0.015; 78 ± 8 vs 136 ± 24 μmol/l, P = 0.035, respectively) before breakfast. This decrease in glucose, NEFA and 3-OHB was observed in the patient group throughout the night, from midnight to breakfast. For NEFA, the decrease persisted throughout the 24 hours. Glycerol did not differ significantly in patients and controls. Integrated levels of total and free plasma cortisol, and 24-hour urine cortisol excretion, were normal in patients but total and free plasma cortisol concentrations overnight were markedly decreased (overnight area under the curve (AUC) of total cortisol: 440 ± 154 vs 1593 ± 267 nmol/l h, P = 0.0024; overnight AUC of free cortisol: 24 ± 8 vs 161 ± 26 nmol/l h, P = 0.0001). GH levels were low throughout the whole 24 hours in the patient group (24-hour AUC: 10.6 ± 5.1 vs 74.6 ± 19.6 mU/l h, P = 0.008). CONCLUSIONS Hypopituitary adults on conventional hormone replacement regimens have low concentrations of metabolic fuels, glucose, non-esterified fatty acids and 3-hydroxybutyrate throughout the night, possibly related to GH deficiency or to decreased overnight circulating cortisol levels. This overnight fuel deficiency may underlie the mechanism for the non-specific symptoms, such as fatigue and headache in the early morning, which are frequent in this group of patients.     

Elevated fibrinogen levels decrease following treatment of acromegaly

OBJECTIVE Acromegaly is associated with increased morbidity and mortality from cardiovascular disease and from stroke in particular. Fibrinogen is an established risk factor for stroke and myocardial infarction and high levels of plasminogen activator inhibitor-1 (PAl-1) activity were predictive of a recurrent myocardial infarction. The aim of this study was to analyse fibrinogen and PAI-1 activity in patients with acromegaly before and after treatment. PATIENTS Twenty patients with acromegaly were compared with healthy controls matched for sex (12 men, 8 women), age (mean 53±7 years), body mass index (mean 26.5±2.5kg/m²) and smoking. Fibrinogen was also compared with a random population sample of men and women (n=392), aged 25–64 years, from the WHO's MONICA Project, Go¨teborg, Sweden. RESULTS The acromegalic patients had a higher lean body mass of 65±11 vs 59±11 kg (P<0.05), lower body fat of 17±8 vs 25±10kg (P<0.01), higher plasma fibrinogen of 4.0±0.9 vs 2.4±0.5g/l (P<0.001) and plasma insulin of 15±14 vs 7±2mU/l (P<0.01), serum triglycerides of 1.5±0.5 vs 1.2±0.5mmol/l (P<0.05), as well as serum insulin-like growth factor-I (IGF-I) levels of 742±271 vs 168±51μg/l (P<0.001) compared with the matched controls. PAI-1 activity was similar, as was total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting blood glucose and blood pressure for acromegalic patients compared with controls. All the acromegalic patients had higher fibrinogen levels (P<0.001) than the population mean. Plasma fibrinogen correlated positively with serum IGF-I in acromegaly (r=0.55, P<0.05). Fibrinogen decreased to a mean value of 3.2±0.3 g/l on treatment. CONCLUSION Acromegaly is associated with high fibrinogen levels which may be one explanation for the increased risk of cardiovascular events, and stroke in particular, in this disease. Fibrinogen levels decreased following treatment of acromegaly.     

A reduced serum level of total osteocalcin in men predicts the development of diabetes in a long-term follow-up cohort

Background Osteocalcin (OC), an osteoblast‐specific protein, has been demonstrated to affect glucose metabolism in both animals and humans. Studies in animals have shown an effect of undercarboxylated OC (ucOC) on beta‐cell proliferation and insulin resistance. It remains unclear whether OC is associated with the future development of diabetes in humans, as well as the relative importance of ucOC vs OC. Objective The aim of this study was to examine serum OC and its post‐translational forms as potential biomarkers for future the development of type 2 diabetes. Methods This was a nested case–control study using data from the Electricity Generating Authority of Thailand (EGAT). We identified 63 men without diabetes in the exploratory cohort at baseline who developed type 2 diabetes (DM) during the 10‐year follow‐up period from 1998–2008, and also 63 men age‐ and BMI‐matched for a non‐diabetes control group (non‐DM). Serum N‐mid OC and ucOC were measured in baseline blood samples. Logistic regression models were used to explore and identify baseline factors, including OC and ucOC, that predicted the subsequent development of diabetes. Results The mean age and BMI were similar in both non‐DM and DM groups (47·2 ± 0·5 vs 47·8 ± 0·8 years and 25·2 ± 0·5 vs 25·9 ± 0·5 kg/m², respectively). Only baseline mean serum N‐mid OC (15·2 ± 0·5 vs 13·0 ± 0·5 μg/l, P < 0·05) and fasting plasma glucose (4·92 ± 0·04 vs 5·28 ± 0·07 mmol/l, P < 0·05) were significantly different between the two groups. Multiple logistic regression analysis showed that baseline serum N‐mid OC and glucose, but not ucOC, were independent risk factors for the development of diabetes in this long‐term study cohort. Conclusions Circulating total OC is associated with incident diabetes in men. Further studies to evaluate the potential utility of OC as a biomarker to predict the development of type 2 diabetes are warranted.     

Increased secretion of 32,33 split proinsulin after intravenous glucose in glucose-tolerant first-degree relatives of patients with non-insulin dependent diabetes of European, but not Asian, origin

OBJECTIVE The aetiology of non-Insulin dependent diabetes Is unknown, but defective insulin Secretion is a feature. The disease also has a strong genetic basis and first-degree relatives of patients have an increased risk of future diabetes. To investigate whether β-cell dysfunction is an early feature of the disease, we studied insulin secretion In healthy first-degree relatives of patients with non-insulin dependent diabetes. DESIGN Each subject underwent a 1-hour intravenous glucose tolerance test (0·3 g/kg). PATIENTS Seventeen first-degree relatives of patients (10 of European and 7 of Asian (Indian subcontinent) origin) with normal glucose tolerance were compared with 17 matched control subjects with no family history of diabetes. MEASUREMENTS Plasma immunoreactive insulin (IRI) was measured by radiouimmunoassay, and specific insulin, intact and 32,33 split proinsulin were measured by specific immunoradiometric assays (IRMA) for the 1st phase (0–10 minutes) and 2nd phase (10–60 minutes) responses. Glucose and Intermediary metabolites were measured enzymatically. RESULTS Fasting concentrations of IRI, IRMA insulin, intact and 32,33 split proinsulin were similar in relatives and controls In each group. Fasting glucose levels were similar In European relatives and controls but lower in Asian relatives compared to their controls (mean±SE 4·9 ± 0·2 vs 5·5 ± 0·2 mmol/l, P < 0·05). Following Intravenous glucose, European relatives had similar IRI and glucose levels to their controls. Secretion of 32,33 split proinsulin was increased in European relatives compared to their controls, significantly so for 2nd phase secretion (1st phase median (range): 71 (7-352) vs 55 (17-118) pmol/l min, NS; 2nd phase: 433 (115-1459) vs 234 (55-745) pmol/l min, P < 0·05). Secretion of IRMA insulin and intact proinsulin were similar in European relatives and controls (IRMA insulin: 1st phase 2757 (700-10969) vs 2830 (632-4682) pmol/l min; 2nd phase 6387 (3006-15 865) vs 5284 (2060-18605) pmol/l min; intact proinsulin: 1st phase 31 (13-113) vs 32 (16-72) pmol/l min; 2nd phase: 174 (87-737) vs 159 (97-298) pmol/l min). European relatives had a greater percentage of proinsulin-like molecules (intact + 32,33 split proinsulin) to total insulin (sum of IRMA insulin + intact + 32,33 split proinsulin) during the 2nd phase of secretion (9·1 (5·0–11·8) vs 5·9 (4·3-12·6)%, P < 0·05). In contrast, Asian relatives had similar Secretion of IRI, IRMA Insulin, intact and 32,33 split proinsulin to their controls. Glucose disappearance (K_G) was similar in relatives and controls within each ethnic group (Europeans: relatives 725 ± 101 vs controls 668 ± 47/min; Asian: relatives 610 ± 97 vs controls 783 ± 936/min). Asian relatives had higher fasting circulating glycerol (65 ± 7 vs 44 ± 4 μmol/l, P < 0·05), non-esterlfied fatty acid (569 ± 59 vs 375 ± 64 μmol/l, P < 0·05) and 3-hydroxybuiyrate levels (147 (44-187) vs 35 (21-57) μmol/l, P < 0·01) than their controls and this persisted following intravenous glucose. This difference was not observed In the European group. CONCLUSION First-degree relatives of European patients with NIDDM possess early signs of β-cell dysfunction, with Increased and disproportionate secretion of 32,33 split proinsuiln after intravenous glucose, whilst glucose tolerance Is still normal.     

Impact of 2 weeks high dose growth hormone treatment on basal and insulin stimulated substrate metabolism in humans

OBJECTIVE Short-term, high dose growth hormone (GH) treatment has been advocated in many catabolic disease states. It is likely that some of the anabolic effects of GH are mediated through activation of lipolysis, but the metabolic impact of therapeutically relevant GH exposure is not known in detail. The present study was accordingly designed to assess the effects of such GH exposure on basal and insulin stimulated intermediary metabolism. DESIGN, PATIENTS AND MEASUREMENTS Six healthy young females were examined following daily injections of GH (12 IU/day) or saline for 2 weeks in a placebo controlled design. Each study consisted of a 3 hour basal period and a 2 hour hyperinsulinaemic euglycaemic clamp. RESULTS GH treatment caused (1) increased levels of IGF-I (382 ± 46 vs 294 ± 22 /μg/l, P < 0 05) and (2) increased basal values of free fatty acids (714 ±40 (GH) vs 634 ±64 (placebo) μmol/l, P<0 05), 3-hydroxybutyrate (118 3 ± 42 8 (GH) vs 57 7 ± 21 6 (placebo) μmol/l, P < 0 05), glycerol (54–3 ±8–2 (GH) vs 41–4 ±8–4 (placebo) μmol/l, P<0 05) and forearm uptake of 3-hydroxybutyrate, together with increments of plasma glucose (5 28 ±0–11 (GH) vs 4 87±0 16 (placebo) mmol/l, P<0 05). Basal forearm uptake of glucose, isotopically determined glucose turnover and serum levels of GH, insulin and C-peptide were unaltered. During the clamp GH treatment was associated with (1) a 40% decrease in the administered amount of glucose (M-value) (P<0 05) and (2) a 70% decrease in forearm glucose uptake (P<0 05). Indirect calorimetry revealed a 15% increase in resting energy expenditure (P<0 05) and a decreased basal respiratory exchange ratio (0 75 (GH) vs 0 80 (placebo), P<0 05), presumably reflecting increased lipid oxidation. CONCLUSIONS Administration of GH in a therapeutic dose for 2 weeks, despite apparently normal daytime levels of major metabolic hormones, induces significant increases in circulating lipid fuel substrates, increased energy expenditure and lipid oxidation, together with insulin resistance. Such effects should be considered when applying GH treatment schedules clinically.     

PLASMA TUMOR NECROSIS FACTOR α LEVELS AND INSULIN SENSITIVITY IN HYPERTENSIVE SUBJECTS

Recent studies have shown that tumor necrosis factor-alpha (TNFα), secreted by macrophage, adipocyte and muscle cells, are associated with insulin resistance syndrome i.e., hyperinsulinemia, hypertriglyceridemia and decreased high density lipoprotein (HDL) cholesterol levels. However, it is unclear whether plasma TNFα levels relate to insulin resistance syndrome in subjects with essential hypertension who are also characterized by an insulin resistance state. We recruited 85 nondiabetic subjects (45 men and 40 women) with essential hypertension and 85 nondiabetic subjects who were matched for age, sex and body mass index (BMI) to determine their fasting plasma glucose, insulin and lipoprotein concentrations, their glucose and insulin responses to an oral glucose challenge, and their degrees of insulin resistance. Fasting plasma leptin and TNFα levels were measured by radioimmunoassay and chemiluminescent enzyme immunometric assay respectively. Total body fat mass was assessed by the bioelectrical impedance method. The results showed that fasting plasma leptin levels were similar between hypertensive and normotensive subjects (7.9±0.6 vs 7.4±0.7 ng/ml, p=0.190). Fasting plasma TNFα concentrations were not different between subjects with hypertension and normotension (10.5±0.5 vs 9.8±0.4 pg/ml, p=0.360). Fasting plasma TNFα concentrations were not different across three subgroups of the insulin resistance both in hypertensive patients (8.4±0.4 vs. 10.9±1.6 vs. 9.9±1.0 pg/ml, p=0.297) and normotensive subjects (9.2±0.7 vs. 9.3±0.9 vs. 9.7±0.9 pg/ml, p=0.875). Fasting plasma TNFα values showed significantly positive correlations with triglyceride concentrations (p<0.03) but negative correlation with HDL cholesterol concentrations (p<0.04) in normotensive but not in hypertensive individuals. These relations persisted even after adjustment for BMI and total fat mass. In conclusion, our data indicated that circulating levels of TNFα did not differ between hypertensive subjects and normotensive controls. Plasma TNFα concentrations correlated positively with fasting plasma triglyceride levels and negatively with HDL cholesterol concentrations in normotensive but not in hypertensive subjects. The influence of TNFα on carbohydrate and lipoprotein metabolism in hypertensive patients deserves further investigations.     

IMPAIRMENT OF INSULIN SECRETION DURING EXPERIMENTAL POTASSIUM DEPLETION IS NOT CORRECTED BY THE PROSTAGLANDIN SYNTHESIS INHIBITOR, INDOMETHACIN

The effect of potassium depletion on glucose tolerance, plasma insulin and plasma glucagon was studied in six normal young female subjects. Negative potassium balance was induced by a diet low in potassium, together with frusemide (40 mg/day), for 3 days. Studies were performed during a period of potassium depletion and were repeated during potassium depletion in five subjects taking indomethacin (150 mg/day), an inhibitor of prostaglandin biosynthesis. Mean plasma potassium concentration was reduced from 4·2 ± 0·1 mmol/l to 3·3 ± 0·1 mmol/l, and was 3·2 ± 0·1 mmol/l during administration of indomethacin. Potassium depletion had no significant effect on the levels of plasma glucose, either fasting or following a 100 g oral glucose load, although the peak rise in plasma glucose after oral glucose was delayed (from 30 to 60 min). There was a decrease in the fasting plasma insulin concentration from 10·0 ± 1·3 mu/l to 6·7 ± 0·6 mu/l and a significant suppression of the early (30 min) insulin response to oral glucose from 126·0 ± 23·5 mu/l to 74·0 ± 19·2 mu/l. The insulin: glucose ratio during the first 60 min following oral glucose was significantly decreased from 43·7 ± 7·3 mu insulin/mmol glucose to 30·6 ± 7·3 mu insulin/mmol glucose. Furthermore, the suppression of plasma glucagon secretion that normally follows oral glucose was not observed. Administration of indomethacin during potassium depletion had no significant effect on plasma glucose, insulin or glucagon concentrations. These data indicate that short-term potassium depletion in normal young females impairs the early insulin response to oral glucose but does not significantly alter overall glucose tolerance. Failure of an indomethacin effect suggests that the defect in insulin secretion may not be mediated by an increased synthesis of prostaglandins.     

Serum lipoproteins in acromegaly before and 6-15 months after transsphenoidal adenomectomy

OBJECTIVES Acromegaly is a rare disorder characterized by over-secretion of GH, most often because of a pituitary adenoma. The disease is associated with disturbances in lipoprotein metabolism and an increased cardiovascular mortality. The aim of the present study was to investigate whether treatment of acromegaly results in changes in serum concentrations of lipids and apolipoproteins, Including lipoprotein(a) (Lp(a)). DESIGN Fourteen patients with clinical features of acromegaly and Increased GH secretion were studied 1-10 months before and 6-15 months after transsphenoidal adenomectomy in an open study. PATIENTS Three patients had diabetes mellitus before surgery and two of these patients had normalized serum glucose levels post-operatively. Mean and baseline plasma GH levels were determined from 24-hour GH profiles. Serum samples were taken in the morning after an overnight fast. All patients were normocholesterolaemic, and four patients were hypertriglyceridaemic before treatment. RESULTS Mean plasma GH levels decreased from 34·5 ±7·4 to 2·1 ±0·4 μ/l (mean ±SEM). Serum IGF-I, insulin and free T3 levels decreased and serum SHBG concentrations Increased post-operatively. There was no effect of treatment on serum cholesterol concentrations, but serum triglyceride concentrations decreased. Serum apollpoprotein (apo) B and apoE levels were unaffected by treatment. Serum apoA-I levels increased and Lp(a) levels decreased post-operatively. CONCLUSIONS Successful treatment of acromegaly, resulting in normal mean GH values (< 5mU/l) and/or normal responsiveness to TRH, have beneficial effects on serum lipoproteins with increased serum apoA-I levels and decreased serum levels of triglycerides and Lp(a). These effects seem to be independent of improvement In glucose tolerance, since patients with diabetes mellitus before surgery and normal fasting blood glucose levels post-operatively had similar lipoprotein responses to treatment as those with normal fasting blood glucose levels before surgery.     

The effect of recombinant IGF-I on anterior pituitary function in healthy volunteers

OBJECTIVE Insulin-like growth factor-I is the mediator of many of the actions of GH and is a potent metabolic regulator. Recombinant IGF-I (rhIGF-I) is of potential value in the treatment of syndromes associated with either GH or insulin resistance. This study was designed to assess the effects of subcutaneous (s.c.) rhIGF-I on anterior pituitary function. DESIGN Double-blind, placebo controlled, randomized cross-over study. The interval between investigations was 2 weeks. SUBJECTS Twelve normal volunteers received on one occasion a single S.C. dose of 40 μg/kg rhIGF-I and on the other, placebo. MEASUREMENTS Circulating levels were measured, over 24 hours, of GH, LH, FSH, PRL, TSH, cortisol, ACTH, glucose, IGF-I, IGF-II, Insulin, C-peptide; IGF binding proteins by Western ligand blotting; total IGF bioactivity using FRTL-5 thyroid cells; and glucose by the glucose oxidase method. RESULTS Recombinant IGF-I Increased AUC for plasma IGF-I, measured by radioimmunoassay (rhIGF-I mean 7065 ± SEM 33 vs 3895 ± 204 μg/l, P < 0·0001) and IGF bioactivity (22·5 ± 3·4 vs 14·2 ± 1·8 U/ml, P < 0·001) but plasma IGF-II fell (9308 ± 403 vs 11052 ± 451 μg/l, P < 0·0001). There was no biochemical or clinical evidence of hypoglycaemia and no difference in mean glucose levels. No difference existed in AUC for GH, LH, FSH, ACTH and cortisol between rhIGF-I and placebo; additionally, pulse number and amplitude for GH and LH were unaffected. TSH fell following rhIGF-I (33·0 ± 3·36 vs 42·5 ± 5·98 mU h/l, P= 0·01). Both mean plasma C-peptlde (0·73 ± 0 06 vs 0·91 ± 0±05 nmol/l, P= 0·03), and insulin (10·81 ± 1·02 vs 15·36 ± 1·18 mU/l, P= 0·03) were lower following rhIGF-I. There was no change In IGFBPs. CONCLUSION A single injection of 40 μg/kg of subcutaneous rhIGF-I does not cause hypoglycaemia. IGF bioactivity was increased without inhibition of GH secretion. The only change observed in anterior pituitary function was a fall in plasma TSH.     

Circulating leptin concentrations in polycystic ovary syndrome: relation to anthropometric and metabolic parameters

OBJECTIVE To determine the relation between metabolic and anthropometric parameters and circulating leptin concentrations in women with polycystic ovary syndrome (PCOS). DESIGN AND PATIENTS Correlation of fasting serum leptin concentrations with anthropometric measures and multiple metabolic parameters including insulin and glucose responses to a 2-hour 75-g oral glucose tolerance test (OGTT) in 85 women with PCOS (17–36 years, body mass index (BMI) 29.9 ± 0.9 kg/m², mean ± SD) and 18 control women (25–47 years, BMI 25 ± 1.7 kg/m²). Diagnostic criteria for PCOS: characteristic ovarian morphology on ultrasound plus at least two of (1) elevated serum testosterone; (2) elevated serum androstenedione; and (3) reduced serum SHBG concentrations. MEASUREMENTS Concentrations of androgens, lipids, PRL, gonadotrophins, and leptin were measured in the baseline fasting blood sample from an OGTT. Insulin and glucose were measured throughout OGTT. Serum leptin concentrations were measured by radioimmunoassay. RESULTS Log leptin levels in the PCOS group correlated significantly with BMI (r = 0.85, P < 0.0001) and with 8 other parameters including waist/hip ratio (r = 0.51, P = 0.0005). By stepwise regression analysis, only BMI (P < 0.0001) and plasma high density lipoprotein concentration (P = 0.02) were independently correlated with log leptin levels, both positively. There was no effect of fat distribution, as measured by waist/hip ratio, on leptin concentrations. Comparison of control subjects to a BMI-matched subgroup of 55 PCOS subjects revealed significantly higher circulating concentrations of LH, testosterone, DHEAS, progesterone and androstenedione, and higher glucose and insulin responses to OGTT in the PCOS group. Leptin levels were not different between the PCOS subgroup and control group (14.8 ± 1.3 vs 12.1 ± 2.3 μg/l, mean ± SE, P = 0.26) and the relation of BMI to leptin levels determined by linear regression analysis also did not differ between the two groups. CONCLUSIONS Our results indicate that circulating leptin concentrations in women with PCOS, a condition characterized by hyperandrogenaemia, increased LH concentrations and insulin resistance, are strongly related to BMI and not independently affected by circulating levels of insulin, gonadotrophins or sex hormones.     

Changes in insulin and lipid metabolism in males with asymptomatic hyperuricaemia

Abstract. Objectives. To define the effect of asymptomatic hyperuricaemia on various facets of glucose, insulin, and lipoprotein metabolism. Design. Case control study in health volunteers. Setting. The volunteers for this study were selected on the basis of their laboratory results from a larger population participating in a general survey in one large factory. Subjects. The study population consisted of 40 healthy males: 20 with asymptomatic hyperuricaemia (serum uric acid concentration equal to or greater than 420 mmol l^?1) and 20 with normal serum uric acid concentrations (180–320 mmol l^?1). The two groups were similar in terms of age, general obesity (estimated by body mass index), smoking and alcohol intake, and estimate of work and leisure time activity. Interventions. All subjects received a 75 g oral glucose challenge, with blood taken before and at frequent intervals thereafter. Main outcome measures. Fasting plasma glucose, insulin, and lipid concentrations and plasma glucose and insulin responses to the oral glucose challenge. Results. By selection, mean (± sem ) serum uric acid concentration was higher in the hyperuricaemic individuals (454 ± 7 vs. 274 ± 12 mmol l^?1). In addition, the plasma insulin response to oral glucose was increased in individuals with asymptomatic hyperuricaemia (P < 0.005) as were both systolic (136 ± 3 vs. 126 ± 3 mmHg, P < 0.05) and diastolic (91 ± 1 vs. 82 ± 1, P < 0.01) blood pressure. Furthermore, subjects with asymptomatic hyperuricaemia were dyslipidaemic (higher plasma TG and cholesterol and lower HDL-cholesterol concentrations) as compared to the normouricaemic control group (P < 0.07–0.005). Conclusions. These results provide a possible explanation for the well-known association of hyperuricaemia with coronary heart disease, as well as suggesting that hyperuricaemia be added to the cluster of metabolic and haemodynamic abnormalities associated with insulin resistance and/or hyperinsulinaemia and designated as Syndrome X.     

Beta-blockers in hypertensive non-insulin-dependent diabetics: Comparison between penbutolol and propranolol on metabolic control and response to insulin-induced hypoglycemia

Summary In a single blind randomized study the effects of a 4-week administration of propranolol (160 mg/day) and penbutolol (40 mg/day) on metabolic control and insulin-induced hypoglycemia were tested in 8 non-insulin-dependent diabetics with diastolic blood pressure between 95 and 110 mmHg. The recovery from hypoglycemia was not delayed by either drug; hypoglycemic nadir and Conard’sK did not change significantly. Symptoms of hypoglycemia were inhibited to a lesser extent and pulse rate decrease was lower after penbutololvs baseline (65±2.4vs 77±2.4 beats/min, p<0.01) than after propranololvs baseline (61±1.06vs 77±2.4 beats/min p<0.001). Both drugs produced similar and significant effects on blood pressure both systolic and diastolic. There were no significant effects on fasting plasma glucose concentration, HbA_tc, IRI, urinary C-peptide, triglycerides, total and HDL cholesterol and FFA. IRG decreased after penbutololvs baseline 60 min after insulin injection (170±30.8vs 125±15.4 pmol/l, p<0.05). These results indicate that the use of beta-blockers, in particular penbutolol, for mild to moderate hypertension may be considered the treatment of choice also in non-insulin-dependent diabetics at the therapeutic doses employed.     

Serum concentrations of osteocalcin, procollagen type 1 N-terminal propeptide and beta-CrossLaps in obese subjects with varying degrees of glucose tolerance

Aims To evaluate serum levels of osteocalcin (OC), procollagen type 1 N‐terminal propeptide (P1PN) and beta‐CrossLaps (beta‐CTx) in obese subjects and their relationship with glucose metabolism parameters. Subjects Sixty‐four obese patients classified according to their glucose tolerance. Design Case–control study. Measurements A 75‐g oral glucose tolerance test was performed with determinations of glucose and insulin between 0 and 120 min. Serum concentrations of OC, P1PN and beta‐CTx were quantified in baseline samples. Results Patients with type 2 diabetes (T2D, n = 24) exhibited OC serum levels (2·6 ± 1·0 nm ) significantly lower than those found in subjects with normal glucose tolerance (NGT, n = 20, 3·9 ± 1·5 nm , P < 0·01). We found no significant differences in P1NP and beta‐CTX levels among patients with NGT, prediabetes and T2D. Multiple regression analysis showed that serum OC concentration, but not P1NP or beta‐CTx levels, was independently related to 2‐h plasma glucose. Conclusion Obese patients with T2D showed significantly reduced levels of OC in comparison with patients with lower degrees of glucose tolerance derangement. Our results also suggest that OC was the only bone marker independently related to the degree of glucose metabolism derangement in these patients.     

Effects of Acipimox on the metabolism of free fatty acids and very low density lipoprotein triglyceride

The mechanism of triglyceride lowering by Acipimox, a nicotinic acid analogue, was examined in a group of five moderately hypertriglyceridemic male rhesus monkeys. Two experiments were designed to examine the effect of the drug on lipid and glucose metabolism in nondiabetic, insulin-resistant animals. A single dose of Acipimox (8 mg/kg) given with a meal lowered the plasma free fatty acids (FFA) significantly at 4 h (0.102±0.008 vs 0.154±0.020 g/l; ±SEM;P<0.03); however, FFA concentrations returned to control levels at 6 h. Chronic administration of Acipimox (16 mg/kg q. i. d.) for 2 months produced a 31% reduction in triglyceride concentration (P<0.05) and a significant decrease in low density lipoprotein (LDL)-cholesterol (P<0.04), without changes in insulin action as measured by the hyperinsulinemic euglycemic clamp. Fasting FFA concentrations were not significantly altered by chronic treatment (0.163±0.013 versus 0.140±0.034 g/l). Fatty acid metabolic studies indicated increases in FFA transport (203.7±59.1 versus 136.1±26.6 μEq/min;P<0.05), while FFA fractional clearance rate (FCR) was unchanged. Very low density lipoprotein triglyceride (VLDL-Tg) metabolic experiments, using [³H]glycerol, showed increases in production and FCR with the drug. Increased VLDL-Tg clearance, in spite of increased production of VLDL, appears to be the mechanism by which triglycerides are lowered upon chronic Acipimox administration.