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Biomedical subjects

D R Matthews

Publications and source records attributed to D R Matthews.

At least 55 records · Page 3Linked to original sources
PubMed1999

Microaneurysms in the development of diabetic retinopathy (UKPDS 42). UK Prospective Diabetes Study Group.

AIMS/HYPOTHESIS: To determine whether microaneurysms, in the absence of other lesions, have a predictive role in the progression of diabetic retinopathy in Type II (non-insulin-dependent) diabetes mellitus. METHODS: Retinal photographs taken at diagnosis in patients participating in the United Kingdom Prospective Diabetes Study, and thereafter at 3 yearly intervals, were assessed using a modified Early Treatment of Diabetic Retinopathy grading system for lesions of diabetic retinopathy and end points of vitreous haemorrhage and photocoagulation. The number of microaneurysms in each eye was recorded. RESULTS: The changes between diagnosis and later photographs were analysed in 2424 patients at 6 years, 1236 at 9 years and 414 at 12 years. Of the 2424 patients studied in the 6 year cohort 1809 had either no retinopathy or microaneurysms only at entry. In these patients the presence of microaneurysms alone and also the number of microaneurysms had a high predictive value for worsening retinopathy at 3, 6, 9, and 12 years after entry into the study (e. g. at 6 years chi(2) for trend = 75 on 1 df, p < 0.001). The predictive value of the presence or absence of microaneurysms and their number at 3 years from diagnosis and subsequent worsening retinopathy was similar to that at entry. CONCLUSION/INTERPRETATION: Microaneurysms are important lesions of diabetic retinopathy and even one or two microaneurysms in an eye should not be regarded as unimportant.

Aneurysm↗
PubMed1999

Lipid profile, glucose tolerance and insulin sensitivity after more than four years of growth hormone therapy in non-growth hormone deficient adolescents.

OBJECTIVE: To study the effects of long-term (> 4 years) growth hormone (GH) therapy on insulin sensitivity, glucose tolerance and lipid profile in non-GH deficient adolescents at completion of their growth. SUBJECTS: Thirty non-GH deficient (15 'idiopathic' short stature, 8 intrauterine growth retardation, 7 partial GH deficiency in childhood but normal on retesting) were recruited, median (range) age 16.9 years (15-20.3) prior to ceasing their GH therapy. Their median (range) duration of GH treatment was 7.9 years (4-11). Insulin sensitivity was also recorded in 10 normal controls with a median (range) age of 20.5 years (18.4-22.3). METHODS: Insulin sensitivity was assessed by a short insulin tolerance test in 18 patients on GH therapy and controls. It was repeated in 14 patients six months after stopping their GH therapy. A 3-h standard oral glucose tolerance test (OGTT) was performed in 19 patients on GH therapy, and repeated after 6 months off GH in 10 patients. Fasting lipids were also measured. RESULTS: Insulin sensitivity index was significantly lower in the patients on GH therapy than in the controls, (median (range)) 3.7%/min (1.2-5.3) and 5.3%/min (3.8-6.2), respectively. Six months after termination of GH therapy, insulin sensitivity increased significantly from 3.6%/min (1.2-5) to 4. 8%/min (2.8-5.6). Fasting plasma insulin decreased significantly off GH therapy from 10.1 to 3.6 mU/l. The area under the insulin curve during the OGTT was also significantly higher on GH therapy. Apart from one patient with impaired glucose tolerance on GH treatment, plasma glucose concentrations remained within the normal range. No lipid abnormalities were recorded. CONCLUSIONS: These data suggest that long-term GH therapy may cause insulin resistance in non GH deficient adolescents, but usually with neither impaired glucose tolerance nor hyperlipidaemia.

Adolescent↗
PubMed1999

The relative roles of continuous growth hormone-releasing hormone (GHRH(1-29)NH2) and intermittent somatostatin(1-14)(SS) in growth hormone (GH) pulse generation: studies in normal and post cranial irradiated individuals.

OBJECTIVES: Pulsatile GH release in humans is thought to involve the coordinated interaction of growth hormone-releasing hormone (GHRH) and somatostatin (SS). Disordered GH secretion is seen in most patients following high dose (> 30 Gy) cranial irradiation in childhood and could result from dysregulation of these hypothalamic hormones or reflect direct pituitary damage. We have used a peptide 'clamp' to assess the relative roles of continuous GHRH and intermittent SS in GH pulse generation in healthy volunteers and short-and long-term survivors of childhood brain tumours. DESIGN: Randomized controlled study. PATIENTS: 12 adult male long-term survivors of childhood brain tumours (median age 17.0 years (15.2-19. 7); 12.2 years (5.8-14.0) postradiotherapy, > 30Gy whole brain irradiation) with 9 matched control volunteers and 6 short-term survivors of childhood brain tumours (median age 6.4 years (5.9-7. 7); 2.5 years (1.7-3.6) post radiotherapy, > 30Gy whole brain irradiation) with 6 matched controls (studies of spontaneous GH release alone). MEASUREMENTS: Serum GH concentrations in 24 h spontaneous GH profiles and during three 'clamp' studies: continuous GHRH(1-29)NH2 (60 ng/kg/minutes, subcutaneous infusion, 24 h); intermittent SS(1-14) withdrawal (20microg/m2/hour, intravenous infusion, 3 h on/1 h off, 2-3 cycles over 8-12 h); intermittent SS and continuous GHRH combined (2-3 cycles over 8-12 h). Data were analysed by spectral analysis, 'peak' and 'trough' determination and serial array averaging. RESULTS: In normal adults, discrete pulsatility was seen in all profiles of spontaneous GH secretion. Continuous GHRH amplified peak GH concentrations (median basal peak 21.1 mU/l vs. GHRH 62.0 mU/l, P = 0.008) whilst pulse timing remained unaffected. Rebound GH release following SS withdrawal alone was variable. Combining continuous GHRH with intermittent SS produced regular GH responses upon SS withdrawal (20.3 mU/l; range 2. 3-105.4). Heterogeneous patterns of spontaneous GH release were seen in the irradiated subjects. Spontaneous peak GH release was reduced in the children following irradiation (Irradiation 14.9 mU/l vs. Control 25.1 mU/l, P = 0.007). Peak GH concentrations were significantly amplified by GHRH in half of them. Adult long-term survivors had lower spontaneous GH concentrations and continuous GHRH amplified GH release in most subjects (Spontaneous 4.2 mU/l vs. GHRH 6.5 mU/l, P = 0.008) but peak concentrations remained far less than those of controls. Combining intermittent SS with continuous GHRH regularized GH release in many patients but the GH responses remained attenuated (4.6 mU/l; 2.5-17.5). CONCLUSION: GH pulsatility can be generated in normal volunteers by the combination of continuous GHRH and intermittent SS and provides indirect evidence for a role for GHRH in GH synthesis and replenishment of stored GH pools at times of high SS tone. Patterns of GH release in short-and long-term survivors of childhood brain tumours are heterogeneous suggesting that combined hypothalamic deficiencies of GHRH and SS occur following high dose radiotherapy. The attenuated GH release seen in long-term survivors compared to controls suggests that GH secretory dysfunction does not simply reflect reduced GHRH and SS secretion, and that trophic effects or pituitary damage may be important with time.

Adolescent↗
PubMed1999

Suppression of the nocturnal rise in growth hormone reduces subsequent lipolysis in subcutaneous adipose tissue.

BACKGROUND: The aim of this study was to examine the effect of the nocturnal rise in growth hormone (GH) concentration on lipolysis in adipose tissue the following morning. METHODS: Eight healthy subjects were studied on two occasions (control vs. suppression of GH secretion) and six were studied on a third occasion (control vs. replacement of GH). Lipolysis in the whole body was assessed by measurement of systemic glycerol turnover. Lipid metabolism in the subcutaneous adipose tissue of the anterior abdominal wall was studied by measurement of arterio-venous differences. RESULTS: Suppression of the nocturnal rise in GH did not affect systemic glycerol turnover. However, in subcutaneous abdominal adipose tissue it led to a significant reduction in the veno-arterial differences in nonesterified fatty acid (NEFA, P = 0.041) and glycerol (P = 0. 014) concentrations, reflecting a reduction in intracellular lipolysis (P = 0.011). Although arterialized plasma triacylglycerol (TG) concentrations were reduced in the absence of the nocturnal GH pulse, the extraction of TG in subcutaneous abdominal adipose tissue remained unchanged. CONCLUSION: We conclude that the normal nocturnal rise in plasma GH concentration leads to site-specific regulation of lipolysis in adipose tissue on the following day, with preferential fat mobilization from central depots.

Adipose Tissue↗
PubMed1999

Glycaemic control and familial factors determine hyperlipidaemia in early childhood diabetes. Oxford Regional Prospective Study of Childhood Diabetes.

AIMS: To determine whether abnormal lipid levels in children with Type 1 diabetes mellitus are the result of poor metabolic control or may in part be determined by genetic factors. METHODS: Non-fasting lipid levels were measured in 141 children with Type 1 diabetes (age range 7.7-19 years) 3 years after diagnosis, and in 192 of their parents. Glycosylated haemoglobin and the urinary albumin-creatinine ratio (three urine samples) were estimated in each child annually. RESULTS: The children had a mean total cholesterol of 4.46 +/- 1.25 mmol/l (+/- SD) and a median triacylglycerol of 1.18 mmol/l (range 0.32-4.7). A total of 15.3% of the population had a total cholesterol > 5.2 mmol/l and 17.9% had a triacylglycerol > 1.7 mmol/l; in 5.6% both total cholesterol and triacylglycerol were greater than these cut-off points. Total cholesterol, triacylglycerol and very low density lipoprotein-cholesterol were significantly correlated to glycaemic control. However, total cholesterol was also significantly related to parental total cholesterol either as analysed separately or as mean parental total cholesterol (r = 0.37, P = 0.0001). In stepwise multiple regression analysis both mean parental total cholesterol (P = 0.001) and HbA1c (P = 0.015) were significant determinants of the child's total cholesterol. The children studied were being followed prospectively for the development of microalbuminuria and there was a weak association across tertiles of total cholesterol, linking higher levels to the development of microalbuminuria (P < 0.05). CONCLUSIONS: We conclude that both glycaemic control and familial factors may be important determinants of lipid levels in young people with diabetes. Both may contribute to the subsequent risk of cardiovascular disease and possibly the development of incipient diabetic nephropathy.

Adolescent↗
PubMed1999

INS VNTR allelic variation and dynamic insulin secretion in healthy adult non-diabetic Caucasian subjects.

AIMS: To elucidate the relationship between the human insulin gene INS VNTR regulatory polymorphism and insulin secretion. The polymorphism arises from tandem repetition of 14-15 bp oligonucleotides. In Caucasians, repeat number varies from 26 to over 200, with two main and discrete allele size classes: class I (26-63 repeats) and class III (141-209 repeats). Class I allele homozygosity is associated with elevated risk of developing Type 1 diabetes, while the class III allele has been associated with increased risk of Type 2 diabetes, polycystic ovary syndrome (PCOS) and with larger size at birth, which may influence development of adult disease. METHODS: Thirty-one healthy adult subjects with normal glucose tolerance, underwent an intravenous glucose tolerance test with one minute sampling. Seventeen subjects were homozygous for class I alleles (14 excluding individuals carrying alleles associated with parent-of-origin effects and heterogeneity in allele transmission) and 14 homozygous for class III alleles. The groups were well matched. RESULTS: No significant differences in amount or rate of insulin secretion, or beta cell function were detected between the two groups. There was a difference in pattern of pulsatile insulin secretion with more 9-minute oscillations in class I homozygotes (P<0.026). The after-load glucose concentration was also higher in subjects with class I alleles (P<0.03). CONCLUSIONS: These results warrant further analysis of possible association between allelic variation of the INS VNTR and the pulsatility of insulin secretion.

Adult↗
PubMed1999

Peak and trough growth hormone (GH) concentrations influence growth and serum insulin like growth factor-1 (IGF-1) concentrations in short children.

OBJECTIVE: Growth hormone (GH) is secreted in a pulsatile fashion promoting growth and a number of diverse metabolic actions. The precise components of the pulsatile signal involved in growth regulation are unclear. DESIGN: A retrospective analysis of 24 h serum GH concentration profiles to evaluate the relative contribution of peak and trough serum GH concentrations to growth regulation, GH response to insulin induced hypoglycaemia (ITT) and serum insulin like growth factor-1 (IGF-1) concentration. PATIENTS: Fifty short prepubertal children (age 5.2-11.9 years). MEASUREMENT: Analysis of the hormone profile by a concentration distribution method that determines the concentration at or below which the serum GH concentrations in the 24 hour profile spend a percentage of the total time. The method generates an estimate of the observed concentrations (OC) below which 95% and 5% of the values in the time series lie: OC 95 (peaks) and OC5 (troughs). RESULTS: Twenty six of the children were growing at a normal rate for short children with a height velocity standard deviation score (HVSDS) between +0.4 and -0.8 whereas twenty four were growing more slowly (HVSDS between -0.9 to -3.9). The former group had a mean peak GH response to ITT of 27.3 (11.1) mU/l whereas the latter had a mean value of 8.7 (6.5) mU/l. There was no relationship between (peak and trough GH concentration) and the age of the individual or body mass index. Peak GH levels were positively related to HVSDS and serum IGF-1 values (r = 0.44; P = 0.002 and r = 0.53; P = 0.002, respectively). GH trough levels were inversely related to these measurements (r = -0.29; P = 0.05; and r = -0.46; P = 0.002, respectively). Further analysis showed that individuals with the slowest growth rates and lowest IGF-1 concentrations had the lowest peak and highest trough GH concentrations (ANOVA F = 6.0; P = 0.002). Similarly, the peak GH response to ITT was lowest in those individuals with high troughs and low peaks (ANOVA F = 9.99; P < 0.001). CONCLUSIONS: These results suggest that the peak values of a GH concentration profile influence growth rate and the IGF-1 axis whereas elevated trough values have the greatest influence on growth rate and IGF-1 values when GH peaks are low.

Analysis of Variance↗
PubMed1999

A sexually dimorphic pattern of growth hormone secretion in the elderly.

In rodents, the sexually dimorphic pattern of pulsatile GH secretion is an important determinant of growth, liver enzyme function and insulin-like growth factor I (IGF-I) expression. Whether this difference is present in humans at different ages is unclear. We studied GH secretory patterns in the elderly by constructing 24-h serum GH profiles in 45 male and 38 female (age, 59.4-73.0 yr) volunteers and related patterns to IGF-I, IGF-binding protein-3 (IGFBP-3), and GH-binding protein levels; body mass index; and waist/hip ratio. Serum GH concentrations were measured in samples drawn at 20-min intervals and analyzed using a sensitive chemiluminescent assay (Nichols Institute Diagnostics: sensitivity, 0.036 mU/L). The 24-h serum GH profiles were analyzed using a concentration distribution method to determine GH peak and trough levels, spectral analysis, and assessment of serial irregularity by approximate entropy (ApEn). There was a highly significant difference in mean 24-h serum GH concentrations in females compared to males (males, 0.88 mU/L; females, 1.31 mU/L; P = 0.009) as a result of significantly higher trough GH levels (males, 0.04 mU/L; females, 0.16 mU/L; P < 0.001). Peak values were not significantly different. Serum IGF-I levels were significantly higher in males (males, 162.4 ng/mL; females, 87.8 ng/ mL; P < 0.001). Peak GH values were related to serum IGF-I levels (males: r = 0.39; P = 0.009; females: r = 0.5; P = 0.002), whereas trough GH levels were not. IGFBP-3 levels were similar and related to GH peaks only in males (r = 0.32; P = 0.03). GH was secreted with a dominant periodicity of 200 min in males and 280 min in females (P < 0.025). The proportion of time taken up by regular oscillatory activity was less in females (females, 11.1%; males, 14.7%; P = 0.01). GH secretion assessed by ApEn was more disordered in females (males, 0.60; females, 0.81; P < 0.001), and increasing disorder was associated with lower IGF-I levels. Body mass index was negatively related to GH in both sexes. In males, trough values were the major determinant (r = -0.31; P = 0.04), whereas in females, the peak value was the major determinant (r = 0.35; P = 0.04). Trough GH levels were inversely related in both sexes to waist/hip ratio (males: r = -0.40; P = 0.006; females: r = -0.44; P = 0.006) and to increasing secretory disorder (ApEn; r = -0.46; P < 0.001). These data demonstrate a sexually dimorphic pattern of GH secretion in the elderly.

Aged↗
PubMed1998

Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23)

OBJECTIVE: To evaluate baseline risk factors for coronary artery disease in patients with type 2 diabetes mellitus. DESIGN: A stepwise selection procedure, adjusting for age and sex, was used in 2693 subjects with complete data to determine which risk factors for coronary artery disease should be included in a Cox proportional hazards model. SUBJECTS: 3055 white patients (mean age 52) with recently diagnosed type 2 diabetes mellitus and without evidence of disease related to atheroma. Median duration of follow up was 7.9 years. 335 patients developed coronary artery disease within 10 years. OUTCOME MEASURES: Angina with confirmatory abnormal electrocardiogram; non-fatal and fatal myocardial infarction. RESULTS: Coronary artery disease was significantly associated with increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, and increased triglyceride concentration, haemoglobin A1c, systolic blood pressure, fasting plasma glucose concentration, and a history of smoking. The estimated hazard ratios for the upper third relative to the lower third were 2.26 (95% confidence interval 1.70 to 3.00) for low density lipoprotein cholesterol, 0.55 (0.41 to 0.73) for high density lipoprotein cholesterol, 1.52 (1.15 to 2.01) for haemoglobin A1c, and 1.82 (1.34 to 2.47) for systolic blood pressure. The estimated hazard ratio for smokers was 1.41 (1.06 to 1.88). CONCLUSION: A quintet of potentially modifiable risk factors for coronary artery disease exists in patients with type 2 diabetes mellitus. These risk factors are increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, raised blood pressure, hyperglycaemia, and smoking.

Adult↗
PubMed1998

United Kingdom Prospective Diabetes Study, 30: diabetic retinopathy at diagnosis of non-insulin-dependent diabetes mellitus and associated risk factors.

OBJECTIVES: To report on the prevalence of retinopathy in patients with newly diagnosed non-insulin-dependent diabetes mellitus (NIDDM) and to evaluate the relationship of retinopathy to clinical and biochemical variables. DESIGN: A multicenter, randomized, controlled clinical study of therapy in patients with NIDDM. SETTING AND PATIENTS: Patients were part of the United Kingdom Prospective Diabetes Study, a 23-center study of 2964 white patients who had both eyes photographed and assessed. OUTCOME MEASURES: The presence and severity of diabetic retinopathy were evaluated by sex, and the relationship of retinopathy to medical and biochemical parameters was assessed. RESULTS: Retinopathy, defined as microaneurysms or worse lesions in at least 1 eye, was present in 39% of men and 35% of women. Marked retinopathy with cotton wool spots or intraretinal microvascular abnormalities was present in 8% of men and 4% of women. The severity of retinopathy was related in both sexes to higher fasting plasma glucose levels, higher systolic and diastolic blood pressure, lower serum insulin levels, and reduced beta-cell function. In addition, in men, increased alcohol consumption was related to increased severity of retinopathy, while leaner women had more severe eye lesions. Visual acuity was normal in most patients, but in men there was a trend for those with more severe retinal lesions to have worse visual acuity. CONCLUSIONS: Diabetic retinopathy is common in patients with newly diagnosed NIDDM. Careful ophthalmic assessment at diagnosis is important.

Alcohol Drinking↗
PubMed1998

UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years. UK Prospective Diabetes Study (UKPDS) Group.

Patients with Type 2 (non-insulin-dependent) diabetes mellitus (DM) on sulphonylurea therapy convert to insulin progressively as the sulphonylureas 'fail'. The rate of failure and the features of those who fail have been poorly described. To assess secondary failure rates of sulphonylureas, we report on the responses in 1305 patients with newly diagnosed Type 2 DM randomly allocated to therapy with either chlorpropamide or glibenclamide in the UK Prospective Diabetes Study (UKPDS). These patients were initially treated by diet for 3 months and had a fasting plasma glucose > 6 mmol l(-1); mean age 53 (SD 9) years; BMI 26.8 (SD 5.0) kg m(-2); and median fasting plasma glucose 9.1 (7.6-12.5 quartiles) mmol l(-1). If their fasting plasma glucose subsequently rose above 15.0 mmol l(-1), or they developed hyperglycaemic symptoms, additional hypoglycaemic therapy was given: metformin, ultratard insulin, and soluble insulin as required. By 6 years, 44% had required additional therapy. Of those randomized to glibenclamide, 48% required additional therapy by 6 years, compared with 40% of those allocated to chlorpropamide (p < 0.01). Sixty-one per cent, 39%, and 23%, respectively, of patients with fasting plasma glucose > or = 10.0 mmol l(-1), > or = 7.8 mmol l(-1) to < 10.0 mmol l(-1) and < 7.8 mmol l(-1) at randomization required additional therapy (p < 0.001). In the initial 3 years, non-obese subjects (BMI < 30 kg m(-2)) were more likely to require additional therapy than obese patients (BMI > or = 30 kg m(-2)) (43% vs 53% at 6 years; p < 0.001). Modelled beta-cell function showed that those with lower function were more likely to fail (p < 0.0001). Thus sulphonylureas fail as a therapeutic agent at rates which are dependent both on the phenotype at presentation and perhaps on the agent used initially. Higher failure rates were found in those with higher glucose concentrations, those who were younger, those with lower beta-cell reserve and those randomized to glibenclamide compared with chlorpropamide.

Adult↗
PubMed1998

Insulin, insulin-like growth factor I (IGF-I), IGF-binding protein-1, growth hormone, and feeding in the newborn.

The relationship between GH, insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), and insulin may be critical to the understanding of variation in early growth, especially in the small for gestational age (SGA) baby. To investigate these relationships, we have undertaken 12-h hormone profiles in 26 babies (13 SGA) at a median of 4.5 days of age. GH levels were measured every 10 min; insulin and IGFBP-1 were measured every 20 min. Mean levels of these hormones and IGF-I levels (from a single sample) were related to size at birth. The GH data were analyzed by Pulsar and time series analysis to characterize hormone pulsatility and relationship with feeds. IGF-I levels correlated with birth weight and length (r2 = 0.47; P = 0.004, and r2 = 0.5; P = 0.0005, respectively, after allowing for gestation), whereas mean GH levels were negatively related to birth size (r2 = -0.18; P = 0.04 and r2 = -0.2; P = 0.03 for weight and length, respectively). No direct relationship between mean GH levels and IGF-I was identified. IGF-I levels were higher in appropriate for gestational age (AGA; mean +/- SD, 82+/-61 ng/mL) than in SGA (34+/-22 ng/mL; P = 0.03) babies. Baseline (mean +/- SD, 25.9+/-11.9), mean (33.9+/-14.0), and peak (45.0+/-18.1 microg/L) GH levels were higher in SGA than in AGA babies [17.1+/-8.2 (P = 0.04), 22.5+/-10.4 (P = 0.03), and 30.7+/-15.4 microg/L (P = 0.04), respectively]. Mean IGFBP-1 levels were also higher in SGA than AGA babies (157.4+/-90.7 vs. 62.7+/-43.8 ng/mL; P = 0.01). A positive correlation was identified between changes in insulin and coincident pulses of GH (r = 0.147; P < 0.01), whereas there was an inverse relationship between insulin and IGFBP-1, with a lag time 120 min (r = -0.33; P < 0.0001). In conclusion, these studies indicate that the GH-IGF-I axis is closely related to feeding in the newborn. In SGA babies, low IGF-I and elevated IGFBP-1 reflect the slow growth, but elevated GH and rapid GH pulsatility may be a signal for lipolysis.

Eating↗
PubMed1998

Mid-follicular phase pulses of inhibin B are absent in polycystic ovarian syndrome and are initiated by successful laparoscopic ovarian diathermy: a possible mechanism regulating emergence of the dominant follicle.

The hypothalamic pulse generator of GnRH is recognized to be central to ovulatory function as evidenced by the anovulation of women with hypogonadotrophic hypogonadism due to Kallmann's syndrome or severe anorexia nervosa. LH is released from the anterior pituitary in pulses, the frequency of which is closely entrained with those of GnRH. In contrast, secretion of FSH is influenced by a number of regulatory molecules, including GnRH, estradiol, inhibin, and activin. The close temporal relationship between changes in levels of inhibin B and FSH in the mid-follicular phase suggests that the release of inhibin B by the preovulatory follicle critically regulates pituitary FSH secretion. Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders affecting ovulation, and abnormal ovarian morphology as detected by ultrasonography remains the most sensitive diagnostic marker for this disorder. The etiology of PCOS is unclear, but its effective treatment by both anti-estrogens and by exogenous FSH suggests that a primary disorder of FSH regulation may be central. To investigate the possible role of inhibin B in the pathology of PCOS, serum inhibin B levels were measured in 10 women with PCOS on cycle day 5 of a spontaneous or progestrogen-provoked bleed and compared with levels on cycle day 5 of 10 women with regular ovulatory cycles. The mean serum inhibin B levels in the PCOS patients were significantly higher at 248 (+/- 43.4) pg/mL compared with normal controls, 126 (+/- 18.6) pg/mL (P < 0.01). Ten women with clomiphene resistant PCOS and 5 normal controls consented to undergo serial blood sampling on cycle day 5. Time Series Analysis using a Fourier Transformation to analyze the power spectrum of the data revealed that in normal women there is a distinct periodicity in inhibin B levels with a clear peak detectable every 60-70 min (P < 0.05), whereas in women with ovulatory dysfunction due to PCOS, no such pattern of regular pulsatility was seen. Four women with PCOS whose anovulation was successfully treated with laparoscopic ovarian diathermy (LOD) underwent repeat venous sampling following LOD. Their serum inhibin B levels fell to the upper limit of the normal range (160 +/- 38.5) pg/mL, and pulsatility was initiated. It is possible that inhibin B pulses are being generated directly by the ovary in response to pulses of GnRH in the peripheral circulation, or indirectly in response to FSH pulses arising in the pituitary. The function of inhibin B pulses in the mid-follicular phase of the normal cycle remains to be elucidated, but the absence of the normal pulsatile pattern in women with PCOS, in conjunction with high basal levels of inhibin B arising from the multiple small follicles characteristic of the PCOS ovary, appears to reinforce the development of a large cohort of small, developmentally arrested, and ultimately atretic follicles in these patients. Initiation of normal inhibin B pulsatility by LOD in patients with polycystic ovaries appears to correlate with the post-operative onset of ovular cycles.

Diathermy↗
PubMed1998

Acute effect of fructose on postprandial lipaemia in diabetic and non-diabetic subjects.

We investigated whether the potentiation of postprandial lipaemia by fructose occurs in both non-diabetic subjects and those with non-insulin-dependent diabetes mellitus. Six non-diabetic and six diabetic subjects were studied on two occasions. They were given a meal containing 1 g fat/kg body weight with, on one occasion, 0.75 g fructose/kg body weight, on the other occasion 0.75 g starch/kg body weight. In both groups, plasma glucose and insulin concentrations rose more after starch than after fructose. At 1-2 h after the meal, plasma non-esterified fatty acid concentrations were suppressed more after fructose than after starch, but later they rose more after fructose than after starch. Plasma triacylglycerol concentrations rose more slowly after fructose, but were considerably higher than those after starch from 4-6 h after the meal. There were no differences in post-heparin plasma lipoprotein lipase (EC 3.1.1.34) activity at the end of the test. The potentiation of postprandial lipaemia by fructose was positively related to the fasting plasma insulin concentration, suggesting that insulin-resistant subjects are more prone to this effect. We conclude that the potentiation of postprandial lipaemia by fructose is seen in both diabetic and non-diabetic subjects. Our results suggest that alterations in the dynamics of plasma non-esterified fatty acids might underlie the effects of fructose on triacylglycerol metabolism.

Adult↗
PubMed1997

The stimulation of insulin secretion in non-insulin-dependent diabetic patients by amino acids and gliclazide in the basal and hyperglycemic state.

Sulfonylureas stimulate insulin secretion as their predominant contribution toward decreasing blood glucose in diabetic patients. We studied eight gliclazide-treated, non-insulin-dependent diabetic patients on two occasions with a protocol of basal observation for 30 minutes, a 60-minute infusion of randomized leucine or arginine, and a further 90-minute hyperglycemic clamp. Basal glucose was the same on both occasions (mean, 7.82 mmol/L for leucine v 7.79 for arginine, P = NS), and glucose levels declined to 7.50 and 7.25 mmol/L, respectively, by 30 minutes. After leucine infusion, the decline of glucose continued, but stabilized or reversed with arginine such that by the end of the infusions, glucose levels were 6.63 +/- 0.69 mmol/L for leucine and 7.62 +/- 0.67 for arginine (P < .02). Arginine caused a sharp increase in insulin secretion (from 17.8 mU/L to 43.8 mU/L in 6 minutes) at the onset of the infusion, and thereafter insulin secretion was not significantly different throughout either the amino acid or hyperglycemic clamp periods (mean, 42.1 v 44.7 mU/L, respectively, P = NS). By contrast, the leucine infusion caused little acute change in secretion, but augmented it with time from the basal period (17.2 mU/L) to the end of the infusion (29.4 mU/L). During the hyperglycemic clamp period, there was significant further augmentation of insulin secretion, increasing to 81.6 +/- 16 mU/L at the end of the study. Leucine significantly augmented insulin secretion compared with arginine (81.6 +/- 16 v 54.0 +/- 8.4 mU/L, respectively, P < .002). These data suggest that leucine is a better priming agent for sulfonylurea than arginine. Additive effects on insulin secretion may allow the use of combinations of branched chain amino acids (BCAAs) and sulfonylureas to augment insulin secretion in the presence of hyperglycemia.

Aged↗