To investigate the short-term effects of insulin on feeding, 14 fasting, young adults received 15... more To investigate the short-term effects of insulin on feeding, 14 fasting, young adults received 150-min euglycemic intravenous infusions of control (C), low-dose (LD, 0.8 mU.kg-1.min-1), and high-dose (HD, 1.6 mU.kg-1.min-1) insulin and ate freely from a buffet meal during the last 30 min. Steady-state preprandial plasma insulin concentrations were 5.9 +/- 0.7 (C), 47 +/- 2 (LD), and 95 +/- 6 (HD) microU/ml and increased 56-59 microU/ml during the meal. No effect of treatment type of hunger or fullness ratings, duration of eating, or the weight, energy content (1,053 +/- 95 kcal, C; 1,045 +/- 101 kcal, LD; 1,066 +/- 107 kcal, HD; P = 0.9), and composition of food eaten was observed. On a fourth study day, 12 of the subjects received an intravenous infusion of glucose only (Glc) that was identical to the glucose infusion on their HD insulin day. Mean venous glucose concentration was 9.3 +/- 0.5 mmol [P < 0.001 vs. C (5.3 +/- 0.1), LD (5.2 +/- 0.2), and HD (5.2 +/- 0.2)], and plasma insulin increased to 45 +/- 2.3 microU/ml at the start and 242 +/- 36 microU/ml at the end of the meal. Energy intake during the meal was (approximately 15%) reduced (1,072 +/- 97 kcal, C; 1,086 +/- 102 kcal, LD; 1,088 +/- 105 kcal, HD; 919 +/- 115 kcal, Glc; P < 0.05 Glc vs. C, LD, and HD). Plasma insulin normally increases to approximately 100 microU/ml after a mixed meal in lean subjects. Therefore, in the absence of altered blood glucose concentrations, physiological concentrations of insulin are unlikely to play a role in meal termination and the short-term control of appetite.
To determine whether the satiating effects of nutrients in the small intestine are lower in obese... more To determine whether the satiating effects of nutrients in the small intestine are lower in obese than in nonobese people, 9 healthy, obese men [age: 18-33 y; body mass index (BMI; in kg/m 2 ) 30.4-40.8] and 11 healthy, nonobese men (age: 18-33 y; BMI: 19.1-26.4) received an intraduodenal infusion of saline (control), lipid (11.97 kJ/min, or 2.86 kcal/min), or glucose (11.97 kJ/min) for 120 min on separate days. Fullness, hunger, and nausea were assessed by visual analogue scales. After the infusions, a meal was offered and food intake was quantified. There was no difference in appetite ratings between the obese and nonobese subjects during the infusions, in the amount or macronutrient composition of food eaten after the infusions, or in the time taken to eat the meals. Both the lipid and glucose infusions were associated with greater fullness than the control infusion. The energy content of the food eaten was less after the lipid infusion than after either the control or glucose infusion (P < 0.01); lipid infusion suppressed energy intake by 22% compared with the control infusion and by 15% compared with the glucose infusion. Suppression of energy intake after intraduodenal nutrient infusions was due to slower eating (P < 0.01). Intraduodenal infusions of fat suppressed appetite and food intake more than did equienergetic infusions of carbohydrate in both obese and nonobese young men, and the responses to intraduodenal fat and glucose were not affected by obesity. The latter observation suggests that established obesity is not associated with reduced small-intestinal responses to dietary fat or carbohydrate.
To determine the effects of acute hyperglycaemia on anorectal motor and sensory function in patie... more To determine the effects of acute hyperglycaemia on anorectal motor and sensory function in patients with diabetes mellitus. In eight patients with Type 1, and 10 patients with Type 2 diabetes anorectal motility and sensation were evaluated on separate days while the blood glucose concentration was stabilized at either 5 mmol/l or 12 mmol/l using a glucose clamp technique. Eight healthy subjects were studied under euglycaemic conditions. Anorectal motor and sensory function was evaluated using a sleeve/sidehole catheter, incorporating a barostat bag. In diabetic subjects hyperglycaemia was associated with reductions in maximal (P<0.05) and plateau (P<0.05) anal squeeze pressures and the rectal pressure/volume relationship (compliance) during barostat distension (P<0.01). Hyperglycaemia had no effect on the perception of rectal distension. Apart from a reduction in rectal compliance (P<0.01) and a trend (P=0.06) for an increased number of spontaneous anal sphincter relaxa...
The difficulty of recruiting older people to clinical trials is well described, but there is limi... more The difficulty of recruiting older people to clinical trials is well described, but there is limited information about effective ways to screen and recruit older people into trials, and the reasons for their reluctance to enrol. This paper examines recruitment efforts for a community-based health intervention study that targeted older adults. One year randomized control trial. Undernourished men and women, aged ≥ 65 years and living independently in the community were recruited in three Australian states. Participants were allocated to either oral testosterone undecanoate and high calorie oral nutritional supplement or placebo medication and low calorie oral nutritional supplementation. Hospital admissions, functional status, nutritional health, muscle strength, and other variables were assessed. 4023 potential participants were identified and 767 were screened by a variety of methods: hospital note screening, referrals from geriatric health services, advertising and media segments/...
American journal of physiology. Endocrinology and metabolism, 2002
Arginine stimulates growth hormone (GH) secretion, possibly by inhibiting hypothalamic somatostat... more Arginine stimulates growth hormone (GH) secretion, possibly by inhibiting hypothalamic somatostatin (SS) release. Insulin-like growth factor I (IGF-I) inhibits GH secretion via effects at the pituitary and/or hypothalamus. We hypothesized that if the dominant action of IGF-I is to suppress GH release at the level of the pituitary, then the arginine-induced net increase in GH concentration would be unaffected by an IGF-I infusion. Eight healthy young adults (3 women, 5 men) were studied on day 2 of a 47-h fast for 12 h (35th-47th h) on four occasions. Saline (Sal) or 10 microg. kg(-1). h(-1) recombinant human IGF-I was infused intravenously for 5 h from 37 to 42 h of the 47-h fast. Arginine (Arg) (30 g iv) or Sal was infused over 30 min during the IGF-I or Sal infusion from 40 to 40.5 h of the fast. Subjects received the following combinations of treatments in random order: 1) Sal + Sal; 2) Sal + Arg; 3) IGF-I + Sal; 4) IGF-I + Arg. Peak GH concentration on the IGF-I + Arg day was ~4...
Comparative biochemistry and physiology. Part C, Pharmacology, toxicology & endocrinology, 1999
Nitric oxide (NO) synthase inhibitors reduce food intake in rodents and chickens, suggesting that... more Nitric oxide (NO) synthase inhibitors reduce food intake in rodents and chickens, suggesting that NO may stimulate feeding. We used two competitive, non-selective inhibitors of NO synthase (NOS), (NG-monomethyl-L-arginine ester [L-NMMA] and NG-nitro-L-arginine methyl ester [L-NAME]), to evaluate the role of NO mechanisms in the control of food intake in a marsupial model previously used in studies of appetite regulation. Adult male Sminthopsis crassicaudata (n = 11-16, 15 +/- 0.3 g, mean +/- S.E.M.) received L-NMMA (50, 100, 200 and 1000 mg/kg), L-NAME (50, 100 and 200 mg/kg), L-arginine (L-arg) the precursor of NO (1000 and 2000 mg/kg), L-NAME (200 mg/kg) in combination with L-arg (2000 mg/kg), or saline (0.9%). All drugs were administered intraperitoneally after 24 h of food deprivation, after which food was immediately made available ad libitum. Food intake was measured 0, 0.5, 1, 2, 4 and 24 h after treatments. In addition, we studied the effect of acute L-NAME administration on...
There is a loss of lean body mass (LBM) with increasing age. A low LBM has been associated with i... more There is a loss of lean body mass (LBM) with increasing age. A low LBM has been associated with increased adverse effects from prescribed medications such as chemotherapy. Accurate assessment of LBM may allow for more accurate drug prescribing. The aims of this study were to develop new prediction equations (PEs) for LBM with anthropometric and biochemical variables from a development cohort and then validate the best performing PEs in validation cohorts. PEs were developed in a cohort of 188 healthy subjects and then validated in a convenience cohort of 52 healthy subjects. The best performing anthropometric PE was then compared to published anthropometric PEs in an older (age≥50 years) cohort of 2287 people. Best subset regression analysis was used to derive PEs. Correlation, Bland-Altman and Sheiner & Beal methods were used to validate and compare the PEs against dual X-ray absorptiometry (DXA)-derived LBM. The PE which included biochemistry variables performed only marginally be...
Sarcopenia is the presence of low muscle mass and low muscle function. The aim of this study was ... more Sarcopenia is the presence of low muscle mass and low muscle function. The aim of this study was to establish cutoffs for low muscle mass using three published methods and to compare the prevalence of sarcopenia in older Australians. Gender specific cutoffs levels were identified for low muscle mass using three different methods. Low grip strength was determined using established cutoffs of <30 kg for men and <20 kg for women to estimate the prevalence of sarcopenia. Gender specific cutoffs levels for low muscle mass identified were (a) <6.89 kg/m(2) for men and <4.32 kg/m(2) for women, <2 standard deviation (SD) of a young reference population; (b) <7.36 kg/m(2) for men and <5.81 kg/m(2) for women from the lowest 20% percentile of the older group; and (c) <-2.15 for men and <-1.42 for women from the lowest 20% of the residuals of linear regressions of appendicular skeletal mass, adjusted for fat mass and height. Prevalence of sarcopenia in older (65 years...
Journal of the American Medical Directors Association, 2015
Sarcopenia is the presence of low muscle mass and poor physical function. We have developed an an... more Sarcopenia is the presence of low muscle mass and poor physical function. We have developed an anthropometric prediction equation (PE). We compared the accuracy of our previously developed anthropometric prediction equation (PE) to dual absorptiometry x-ray (DXA) in predicting low muscle mass and sarcopenia. Cross-sectional study design. Community dwelling. Men and women aged 65 years and older. Gender-specific low muscle mass cutoffs were identified using the lowest 20% of the skeletal muscle index (SMI) where muscle mass was determined using PE in 611 men and 375 women aged 65 years and older. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PE derived low muscle mass were compared with DXA-derived low muscle mass. The cohort was randomized into a development and validation group to identify various cutoffs for low muscle mass via the PE method and test its performance against the DXA method. The PE cutoff for low muscle mass was...
In Australia, enzyme replacement therapy (ERT) for Fabry Disease (FD), both Agalsidase alfa (Repl... more In Australia, enzyme replacement therapy (ERT) for Fabry Disease (FD), both Agalsidase alfa (Replagal, Shire HGT) and beta (Fabrazyme, Genzyme), is funded and monitored through a specific government program. Agalsidase beta supply has been rationed by Genzyme since 2009 due to manufacturing issues. Consequently, the Australian Fabry Disease Advisory Committee has treated patients on Agalsidase beta at 50% of their usual dose from mid-2009, with a further reduction to 30% for some patients from late 2009. To determine the clinical effect of Agalsidase beta dose reduction in the Australian FD patient cohort. A questionnaire assessing FD symptoms was administered to 40 patients on long-term ERT. Clinical data from The Fabry Registry for patients receiving Agalsidase alfa or beta, for at least 2 years prior to the time of enforced Agalsidase beta dose reduction, were reviewed. Disease burden and quality of life (QOL) were graded using the Disease Severity Scoring System, Mainz Severity ...
Since diabetes mellitus is a frequent manifestation of haemochromatosis the prevalence of the dis... more Since diabetes mellitus is a frequent manifestation of haemochromatosis the prevalence of the disease was investigated in 418 patients attending a diabetic clinic. 21 (5%) patients had a persistently high serum ferritin (men, over 400 micrograms/l; women, over 300 micrograms/l) and 5 of these had transferrin saturations consistently over 55%. Idiopathic haemochromatosis was confirmed by liver biopsy in 4 patients, all of whom had a hepatic iron index greater than 2.0. The prevalence rate of previously unrecognised idiopathic haemochromatosis was thus 9.6 per 1000 (general population prevalence 1 in 250), suggesting that screening of diabetic patients for this genetic disease may be more cost-effective than screening in the general population.
Journal of the American Medical Directors Association, 2012
Diabetes mellitus elderly older people position statement consensus recommendations a b s t r a c... more Diabetes mellitus elderly older people position statement consensus recommendations a b s t r a c t Diabetes mellitus is a highly prevalent metabolic condition in ageing societies associated with high levels of morbidity, multiple therapies, and functional deterioration that challenges even the best of health care systems to deliver high-quality, individualized care. Most international clinical guidelines have ignored the often-unique issues of frailty, functional limitation, changes in mental health, and increasing dependency that characterize many aged patients with diabetes. A collaborative Expert Group of the IAGG and EDWPOP and an International Task Force have explored the key issues that affect
The Journal of Clinical Endocrinology & Metabolism, 1997
To determine the effect of aging on the suppression of GH secretion by insulin-like growth factor... more To determine the effect of aging on the suppression of GH secretion by insulin-like growth factor (IGF)-I, we studied 11 healthy young adults (6 men, 5 women, mean Ϯ SD: 25.2 Ϯ 4.6 yr old; body mass index 23.7 Ϯ 1.8 kg/m 2 ) and 11 older adults (6 men, 5 women, 69.5 Ϯ 5.8 yr old; body mass index 24.2 Ϯ 2.5 kg/m 2 ). Saline (control) or recombinant human IGF-I (rhIGF-I) (2 h baseline then, in sequence, 2.5 h each of 1, 3, and 10 g/kg⅐h) was infused iv during the last 9.5 h of a 40.5-h fast; serum glucose was clamped within 15% of baseline. Baseline serum GH concentrations (mean Ϯ SE: 3.3 Ϯ 0.7 vs. 1.9 Ϯ 0.5 g/L, P ϭ 0.02) and total IGF-I concentrations (219 Ϯ 15 vs. 103 Ϯ 19 g/L, P Ͻ 0.01) were higher in the younger subjects. In both age groups, GH concentrations were significantly decreased by 3 and 10 g/kg⅐h, but not by 1 g/kg⅐h rhIGF-I. The absolute decrease in GH concentrations was greater in young than in older subjects during the 3 and 10 g/kg⅐h rhIGF-I infusion periods, but both young and older subjects suppressed to a similar GH level during the last hour of the rhIGF-I infusion (0.78 Ϯ 0.24 g/L and 0.61 Ϯ 0.16 g/L, respectively). The older subjects had a greater increase above baseline in serum concentrations of both total (306 Ϯ 24 vs. 244 Ϯ 14 g/L, P ϭ 0.04) and free IGF-I (8.5 Ϯ 1.4 vs. 4.2 Ϯ 0.6 g/L, P ϭ 0.01) than the young subjects during rhIGF-I infusion, and their GH suppression expressed in relation to increases in both total and free serum IGF-I concentrations was significantly less than in the young subjects. We conclude that the ability of exogenous rhIGF-I to suppress serum GH concentrations declines with increasing age. This suggests that increased sensitivity to endogenous IGF-I negative feedback is not a cause of the decline in GH secretion that occurs with aging. (J Clin
The Journal of Clinical Endocrinology & Metabolism, 1992
Page 1. 0021-972X/92/7406-1378$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright... more Page 1. 0021-972X/92/7406-1378$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright 0 1992 by The Endocrine Society Vol. 74, No. 6 Printed in USA Oral Administration of Growth Hormone (GH)-Releasing Peptide Stimulates GH Secretion in Normal Men* ...
The Journal of Clinical Endocrinology & Metabolism, 1994
Modifications were made to a commercially available human (h) GH chemiluminescence assay (Nichols... more Modifications were made to a commercially available human (h) GH chemiluminescence assay (Nichols Luma Tag hGH assay), which improved its sensitivity to 0.002 micrograms/L. The results of this assay had a high correlation with those of the Nichols hGH immunoradiometric assay (IRMA; r = 0.91; P &lt; 0.001). The addition of recombinant hGH-binding protein (0.1-10 nmol/L) to standards and serum samples caused a dose-responsive reduction in measured GH in both the chemiluminescence assay and the IRMA; at physiological concentrations of hGH-binding protein, a 10-20% reduction was observed. Fifteen normal young adults (nine men and six women) underwent a standard 100-g oral glucose tolerance test, and plasma GH was measured from 30 min before until 5 h after glucose ingestion. GH was measurable in all samples with the chemiluminescence assay, but fell below the sensitivity of the IRMA in 59% of the samples. There was no difference between baseline or peak glucose levels in male and female subjects, but serum GH concentrations (mean +/- SD) measured by the enhanced sensitivity chemiluminescence assay were lower in male than female subjects at both baseline (0.12 +/- 0.08 vs. 2.3 +/- 2.3 micrograms/L; P &lt; 0.01) and the postglucose GH nadir (0.029 +/- 0.014 vs. 0.25 +/- 0.23 micrograms/L; P &lt; 0.01). The high correlation between baseline and nadir GH (r = 0.82; P &lt; 0.001) and the equivalent fractional decline in mean GH levels in men and women after glucose administration (67 +/- 17% vs. 84 +/- 8%; P = 0.06) suggest that the lower GH levels in men after glucose treatment are due to lower baseline values and not to a greater suppressive effect of glucose.
The Journal of Clinical Endocrinology & Metabolism, 1996
L-692,429 ([L]) is a GH-releasing peptide mimetic that stimulates GH secretion when administered ... more L-692,429 ([L]) is a GH-releasing peptide mimetic that stimulates GH secretion when administered acutely. To determine the effect of its continuous administration, six older adults (four men and two women, aged 64-82 yr) received i.v. transfusions of 1) saline for 24 h (control), 2) [L] (0.05 mg/kg.h) for 24 h (low dose), and 3) [L] (0.1 mg/kg.h) for 12 h, then saline for 12 h (high dose), followed on all admissions by saline for 2.5 h. GHRH (1 microgram/kg, i.v.) was given 30 min before the end of each 24-h treatment. Blood was collected every 10 min for GH measurement, and GH secretion was assessed by deconvolution analysis. Pulsatile GH secretion continued throughout both [L] infusions. During the first 12 h (when comparison of both doses was possible), [L] exerted a dose-dependent stimulatory effect on mean GH concentrations, from 0.6 +/- 0.1 (control, mean +/- SE), to 1.2 +/- 0.2 (low dose [L]) and 2.3 +/- 0.5 microgram/L (high dose [L]; P &lt; 0.05, high dose vs. control), and on calculated GH secretory rates [1.6 +/- 0.3 (control), 2.5 +/- 0.3 (low dose [L]), and 5.8 +/- 0.7 microgram/L distribution vol.h (high dose [L]); P &lt; 0.05, high dose vs. control]. GH secretory pulse height and area increased significantly in a dose-responsive manner, without significant changes in GH secretory pulse number, half-duration of pulses, or GH half-life. GH concentrations remained elevated during the second 11.5 h of low dose [L] infusion. Over the 23.5-h period before GHRH administration, mean GH concentrations and secretion rates were significantly higher than control values with high dose, but not low dose, [L]. Low dose [L] enhanced the peak GH response to GHRH (17.4 +/- 3.5 micrograms/L) compared to the control value (8.4 +/- 2.8 micrograms/L; P &lt; 0.05). We conclude that the administration of [L] to healthy older adults by continuous i.v. infusion enhances pulsatile GH secretion by increasing the mass of GH secreted per pulse, but not the number of secretion pulses, and increases the GH response to GHRH.
The Journal of Clinical Endocrinology & Metabolism, 1996
Aging is associated with declining activity of the GH axis, possibly contributing to adverse body... more Aging is associated with declining activity of the GH axis, possibly contributing to adverse body composition changes and increased incidence of cardiovascular disease. The stimulatory effects on the GH-insulin-like growth factor I (IGF-I) axis of orally administered MK-677, a GH-releasing peptide mimetic, were investigated. Thirty-two healthy subjects (15 women and 17 men, aged 64-81 yr) were enrolled in a randomized, double blind, placebo-controlled trial. They received placebo or 2, 10, or 25 mg MK-677, orally, once daily for 2 separate study periods of 14 and 28 days. At baseline and on day 14 of each study period, blood was collected every 20 min for 24 h to measure GH, PRL, and cortisol. Attributes of pulsatile GH release were assessed by 3 independent algorithms. MK-677 administration for 2 weeks increased GH concentrations in a dose-dependent manner, with 25 mg/day increasing mean 24-h GH concentration 97 +/- 23% (mean +/- SE; P &amp;amp;lt; 0.05 vs. baseline). This increase was due to an enhancement of preexisting pulsatile GH secretion. GH pulse height and interpulse nadir concentrations increased significantly without significant changes in the number of pulses. With 25 mg/day MK-677 treatment, mean serum IGF-I concentrations increased into the normal range for young adults (141 +/- 21 microgram/L at baseline, 219 +/- 21 micrograms/L at 2 weeks, and 265 +/- 29 micrograms/L at 4 weeks; P &amp;amp;lt; 0.05). MK-677 produced significant increases in fasting glucose (5.4 +/- 0.3 to 6.8 +/- 0.4 mmol/L at 4 weeks; P &amp;amp;lt; 0.01 vs. baseline) and IGF-binding protein-3. Circulating cortisol concentrations did not change, and PRL concentrations increased 23%, but remained within the normal range. Once daily treatment of older people with oral MK-677 for up to 4 weeks enhanced pulsatile GH release, significantly increased serum GH and IGF-I concentrations, and, at a dose of 25 mg/day, restored serum IGF-I concentrations to those of young adults.
Journal of Clinical Endocrinology & Metabolism, 1998
To determine the time course of recovery of GH release from insulin-like growth factor I (IGF-I) ... more To determine the time course of recovery of GH release from insulin-like growth factor I (IGF-I) suppression, 11 healthy adults (18-29 yr) received, in randomized order, 4-h i.v. infusions of recombinant human IGF-I (rhIGF-I; 3 microg/kg-h) or saline (control) from 25.5-29.5 h of a 47.5-h fast. Serum GH was maximally suppressed within 2 h and remained suppressed for 2 h after the rhIGF-I infusion; during this 4-h period, GH concentrations were approximately 25% of control day levels [median (interquartile range), 1.2 (0.4-4.0) vs. 4.8 (2.8-7.9) microg/L; P &lt; 0.05]. A rebound increase in GH concentrations occurred 5-7 h after the end of rhIGF-I infusion [7.6 (4.6 -11.7) vs. 4.3 (2.5-6.0) microg/L; P &lt; 0.05]. Thereafter, serum GH concentrations were similar on both days. Total IGF-I concentrations peaked at the end of the rhIGF-I infusion (432 +/- 43 vs. 263 +/- 44 microg/L; P &lt; 0.0001) and remained elevated 18 h after the rhIGF-I infusion (360 +/- 36 vs. 202 +/- 23 microg/L; P = 0.001). Free IGF-I concentrations were approximately 140% above control day values at the end of the infusion (2.1 +/- 0.4 vs. 0.88 +/- 0.3 microg/L; P = 0.001), but declined to baseline within 2 h after the infusion. The close temporal association between the resolution of GH suppression and the fall of free IGF-I concentrations, and the lack of any association with total IGF-I concentrations suggest that unbound (free), not protein-bound, IGF-I is the major IGF-I component responsible for this suppression. The rebound increase in GH concentrations after the end of rhIGF-I infusion is consistent with cessation of an inhibitory effect of free IGF-I on GH release.
To determine the effects of acute hyperglycaemia on appetite and food intake in Type 1 diabetes m... more To determine the effects of acute hyperglycaemia on appetite and food intake in Type 1 diabetes mellitus.
To investigate the short-term effects of insulin on feeding, 14 fasting, young adults received 15... more To investigate the short-term effects of insulin on feeding, 14 fasting, young adults received 150-min euglycemic intravenous infusions of control (C), low-dose (LD, 0.8 mU.kg-1.min-1), and high-dose (HD, 1.6 mU.kg-1.min-1) insulin and ate freely from a buffet meal during the last 30 min. Steady-state preprandial plasma insulin concentrations were 5.9 +/- 0.7 (C), 47 +/- 2 (LD), and 95 +/- 6 (HD) microU/ml and increased 56-59 microU/ml during the meal. No effect of treatment type of hunger or fullness ratings, duration of eating, or the weight, energy content (1,053 +/- 95 kcal, C; 1,045 +/- 101 kcal, LD; 1,066 +/- 107 kcal, HD; P = 0.9), and composition of food eaten was observed. On a fourth study day, 12 of the subjects received an intravenous infusion of glucose only (Glc) that was identical to the glucose infusion on their HD insulin day. Mean venous glucose concentration was 9.3 +/- 0.5 mmol [P &amp;amp;lt; 0.001 vs. C (5.3 +/- 0.1), LD (5.2 +/- 0.2), and HD (5.2 +/- 0.2)], and plasma insulin increased to 45 +/- 2.3 microU/ml at the start and 242 +/- 36 microU/ml at the end of the meal. Energy intake during the meal was (approximately 15%) reduced (1,072 +/- 97 kcal, C; 1,086 +/- 102 kcal, LD; 1,088 +/- 105 kcal, HD; 919 +/- 115 kcal, Glc; P &amp;amp;lt; 0.05 Glc vs. C, LD, and HD). Plasma insulin normally increases to approximately 100 microU/ml after a mixed meal in lean subjects. Therefore, in the absence of altered blood glucose concentrations, physiological concentrations of insulin are unlikely to play a role in meal termination and the short-term control of appetite.
To determine whether the satiating effects of nutrients in the small intestine are lower in obese... more To determine whether the satiating effects of nutrients in the small intestine are lower in obese than in nonobese people, 9 healthy, obese men [age: 18-33 y; body mass index (BMI; in kg/m 2 ) 30.4-40.8] and 11 healthy, nonobese men (age: 18-33 y; BMI: 19.1-26.4) received an intraduodenal infusion of saline (control), lipid (11.97 kJ/min, or 2.86 kcal/min), or glucose (11.97 kJ/min) for 120 min on separate days. Fullness, hunger, and nausea were assessed by visual analogue scales. After the infusions, a meal was offered and food intake was quantified. There was no difference in appetite ratings between the obese and nonobese subjects during the infusions, in the amount or macronutrient composition of food eaten after the infusions, or in the time taken to eat the meals. Both the lipid and glucose infusions were associated with greater fullness than the control infusion. The energy content of the food eaten was less after the lipid infusion than after either the control or glucose infusion (P < 0.01); lipid infusion suppressed energy intake by 22% compared with the control infusion and by 15% compared with the glucose infusion. Suppression of energy intake after intraduodenal nutrient infusions was due to slower eating (P < 0.01). Intraduodenal infusions of fat suppressed appetite and food intake more than did equienergetic infusions of carbohydrate in both obese and nonobese young men, and the responses to intraduodenal fat and glucose were not affected by obesity. The latter observation suggests that established obesity is not associated with reduced small-intestinal responses to dietary fat or carbohydrate.
To determine the effects of acute hyperglycaemia on anorectal motor and sensory function in patie... more To determine the effects of acute hyperglycaemia on anorectal motor and sensory function in patients with diabetes mellitus. In eight patients with Type 1, and 10 patients with Type 2 diabetes anorectal motility and sensation were evaluated on separate days while the blood glucose concentration was stabilized at either 5 mmol/l or 12 mmol/l using a glucose clamp technique. Eight healthy subjects were studied under euglycaemic conditions. Anorectal motor and sensory function was evaluated using a sleeve/sidehole catheter, incorporating a barostat bag. In diabetic subjects hyperglycaemia was associated with reductions in maximal (P<0.05) and plateau (P<0.05) anal squeeze pressures and the rectal pressure/volume relationship (compliance) during barostat distension (P<0.01). Hyperglycaemia had no effect on the perception of rectal distension. Apart from a reduction in rectal compliance (P<0.01) and a trend (P=0.06) for an increased number of spontaneous anal sphincter relaxa...
The difficulty of recruiting older people to clinical trials is well described, but there is limi... more The difficulty of recruiting older people to clinical trials is well described, but there is limited information about effective ways to screen and recruit older people into trials, and the reasons for their reluctance to enrol. This paper examines recruitment efforts for a community-based health intervention study that targeted older adults. One year randomized control trial. Undernourished men and women, aged ≥ 65 years and living independently in the community were recruited in three Australian states. Participants were allocated to either oral testosterone undecanoate and high calorie oral nutritional supplement or placebo medication and low calorie oral nutritional supplementation. Hospital admissions, functional status, nutritional health, muscle strength, and other variables were assessed. 4023 potential participants were identified and 767 were screened by a variety of methods: hospital note screening, referrals from geriatric health services, advertising and media segments/...
American journal of physiology. Endocrinology and metabolism, 2002
Arginine stimulates growth hormone (GH) secretion, possibly by inhibiting hypothalamic somatostat... more Arginine stimulates growth hormone (GH) secretion, possibly by inhibiting hypothalamic somatostatin (SS) release. Insulin-like growth factor I (IGF-I) inhibits GH secretion via effects at the pituitary and/or hypothalamus. We hypothesized that if the dominant action of IGF-I is to suppress GH release at the level of the pituitary, then the arginine-induced net increase in GH concentration would be unaffected by an IGF-I infusion. Eight healthy young adults (3 women, 5 men) were studied on day 2 of a 47-h fast for 12 h (35th-47th h) on four occasions. Saline (Sal) or 10 microg. kg(-1). h(-1) recombinant human IGF-I was infused intravenously for 5 h from 37 to 42 h of the 47-h fast. Arginine (Arg) (30 g iv) or Sal was infused over 30 min during the IGF-I or Sal infusion from 40 to 40.5 h of the fast. Subjects received the following combinations of treatments in random order: 1) Sal + Sal; 2) Sal + Arg; 3) IGF-I + Sal; 4) IGF-I + Arg. Peak GH concentration on the IGF-I + Arg day was ~4...
Comparative biochemistry and physiology. Part C, Pharmacology, toxicology & endocrinology, 1999
Nitric oxide (NO) synthase inhibitors reduce food intake in rodents and chickens, suggesting that... more Nitric oxide (NO) synthase inhibitors reduce food intake in rodents and chickens, suggesting that NO may stimulate feeding. We used two competitive, non-selective inhibitors of NO synthase (NOS), (NG-monomethyl-L-arginine ester [L-NMMA] and NG-nitro-L-arginine methyl ester [L-NAME]), to evaluate the role of NO mechanisms in the control of food intake in a marsupial model previously used in studies of appetite regulation. Adult male Sminthopsis crassicaudata (n = 11-16, 15 +/- 0.3 g, mean +/- S.E.M.) received L-NMMA (50, 100, 200 and 1000 mg/kg), L-NAME (50, 100 and 200 mg/kg), L-arginine (L-arg) the precursor of NO (1000 and 2000 mg/kg), L-NAME (200 mg/kg) in combination with L-arg (2000 mg/kg), or saline (0.9%). All drugs were administered intraperitoneally after 24 h of food deprivation, after which food was immediately made available ad libitum. Food intake was measured 0, 0.5, 1, 2, 4 and 24 h after treatments. In addition, we studied the effect of acute L-NAME administration on...
There is a loss of lean body mass (LBM) with increasing age. A low LBM has been associated with i... more There is a loss of lean body mass (LBM) with increasing age. A low LBM has been associated with increased adverse effects from prescribed medications such as chemotherapy. Accurate assessment of LBM may allow for more accurate drug prescribing. The aims of this study were to develop new prediction equations (PEs) for LBM with anthropometric and biochemical variables from a development cohort and then validate the best performing PEs in validation cohorts. PEs were developed in a cohort of 188 healthy subjects and then validated in a convenience cohort of 52 healthy subjects. The best performing anthropometric PE was then compared to published anthropometric PEs in an older (age≥50 years) cohort of 2287 people. Best subset regression analysis was used to derive PEs. Correlation, Bland-Altman and Sheiner & Beal methods were used to validate and compare the PEs against dual X-ray absorptiometry (DXA)-derived LBM. The PE which included biochemistry variables performed only marginally be...
Sarcopenia is the presence of low muscle mass and low muscle function. The aim of this study was ... more Sarcopenia is the presence of low muscle mass and low muscle function. The aim of this study was to establish cutoffs for low muscle mass using three published methods and to compare the prevalence of sarcopenia in older Australians. Gender specific cutoffs levels were identified for low muscle mass using three different methods. Low grip strength was determined using established cutoffs of <30 kg for men and <20 kg for women to estimate the prevalence of sarcopenia. Gender specific cutoffs levels for low muscle mass identified were (a) <6.89 kg/m(2) for men and <4.32 kg/m(2) for women, <2 standard deviation (SD) of a young reference population; (b) <7.36 kg/m(2) for men and <5.81 kg/m(2) for women from the lowest 20% percentile of the older group; and (c) <-2.15 for men and <-1.42 for women from the lowest 20% of the residuals of linear regressions of appendicular skeletal mass, adjusted for fat mass and height. Prevalence of sarcopenia in older (65 years...
Journal of the American Medical Directors Association, 2015
Sarcopenia is the presence of low muscle mass and poor physical function. We have developed an an... more Sarcopenia is the presence of low muscle mass and poor physical function. We have developed an anthropometric prediction equation (PE). We compared the accuracy of our previously developed anthropometric prediction equation (PE) to dual absorptiometry x-ray (DXA) in predicting low muscle mass and sarcopenia. Cross-sectional study design. Community dwelling. Men and women aged 65 years and older. Gender-specific low muscle mass cutoffs were identified using the lowest 20% of the skeletal muscle index (SMI) where muscle mass was determined using PE in 611 men and 375 women aged 65 years and older. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PE derived low muscle mass were compared with DXA-derived low muscle mass. The cohort was randomized into a development and validation group to identify various cutoffs for low muscle mass via the PE method and test its performance against the DXA method. The PE cutoff for low muscle mass was...
In Australia, enzyme replacement therapy (ERT) for Fabry Disease (FD), both Agalsidase alfa (Repl... more In Australia, enzyme replacement therapy (ERT) for Fabry Disease (FD), both Agalsidase alfa (Replagal, Shire HGT) and beta (Fabrazyme, Genzyme), is funded and monitored through a specific government program. Agalsidase beta supply has been rationed by Genzyme since 2009 due to manufacturing issues. Consequently, the Australian Fabry Disease Advisory Committee has treated patients on Agalsidase beta at 50% of their usual dose from mid-2009, with a further reduction to 30% for some patients from late 2009. To determine the clinical effect of Agalsidase beta dose reduction in the Australian FD patient cohort. A questionnaire assessing FD symptoms was administered to 40 patients on long-term ERT. Clinical data from The Fabry Registry for patients receiving Agalsidase alfa or beta, for at least 2 years prior to the time of enforced Agalsidase beta dose reduction, were reviewed. Disease burden and quality of life (QOL) were graded using the Disease Severity Scoring System, Mainz Severity ...
Since diabetes mellitus is a frequent manifestation of haemochromatosis the prevalence of the dis... more Since diabetes mellitus is a frequent manifestation of haemochromatosis the prevalence of the disease was investigated in 418 patients attending a diabetic clinic. 21 (5%) patients had a persistently high serum ferritin (men, over 400 micrograms/l; women, over 300 micrograms/l) and 5 of these had transferrin saturations consistently over 55%. Idiopathic haemochromatosis was confirmed by liver biopsy in 4 patients, all of whom had a hepatic iron index greater than 2.0. The prevalence rate of previously unrecognised idiopathic haemochromatosis was thus 9.6 per 1000 (general population prevalence 1 in 250), suggesting that screening of diabetic patients for this genetic disease may be more cost-effective than screening in the general population.
Journal of the American Medical Directors Association, 2012
Diabetes mellitus elderly older people position statement consensus recommendations a b s t r a c... more Diabetes mellitus elderly older people position statement consensus recommendations a b s t r a c t Diabetes mellitus is a highly prevalent metabolic condition in ageing societies associated with high levels of morbidity, multiple therapies, and functional deterioration that challenges even the best of health care systems to deliver high-quality, individualized care. Most international clinical guidelines have ignored the often-unique issues of frailty, functional limitation, changes in mental health, and increasing dependency that characterize many aged patients with diabetes. A collaborative Expert Group of the IAGG and EDWPOP and an International Task Force have explored the key issues that affect
The Journal of Clinical Endocrinology & Metabolism, 1997
To determine the effect of aging on the suppression of GH secretion by insulin-like growth factor... more To determine the effect of aging on the suppression of GH secretion by insulin-like growth factor (IGF)-I, we studied 11 healthy young adults (6 men, 5 women, mean Ϯ SD: 25.2 Ϯ 4.6 yr old; body mass index 23.7 Ϯ 1.8 kg/m 2 ) and 11 older adults (6 men, 5 women, 69.5 Ϯ 5.8 yr old; body mass index 24.2 Ϯ 2.5 kg/m 2 ). Saline (control) or recombinant human IGF-I (rhIGF-I) (2 h baseline then, in sequence, 2.5 h each of 1, 3, and 10 g/kg⅐h) was infused iv during the last 9.5 h of a 40.5-h fast; serum glucose was clamped within 15% of baseline. Baseline serum GH concentrations (mean Ϯ SE: 3.3 Ϯ 0.7 vs. 1.9 Ϯ 0.5 g/L, P ϭ 0.02) and total IGF-I concentrations (219 Ϯ 15 vs. 103 Ϯ 19 g/L, P Ͻ 0.01) were higher in the younger subjects. In both age groups, GH concentrations were significantly decreased by 3 and 10 g/kg⅐h, but not by 1 g/kg⅐h rhIGF-I. The absolute decrease in GH concentrations was greater in young than in older subjects during the 3 and 10 g/kg⅐h rhIGF-I infusion periods, but both young and older subjects suppressed to a similar GH level during the last hour of the rhIGF-I infusion (0.78 Ϯ 0.24 g/L and 0.61 Ϯ 0.16 g/L, respectively). The older subjects had a greater increase above baseline in serum concentrations of both total (306 Ϯ 24 vs. 244 Ϯ 14 g/L, P ϭ 0.04) and free IGF-I (8.5 Ϯ 1.4 vs. 4.2 Ϯ 0.6 g/L, P ϭ 0.01) than the young subjects during rhIGF-I infusion, and their GH suppression expressed in relation to increases in both total and free serum IGF-I concentrations was significantly less than in the young subjects. We conclude that the ability of exogenous rhIGF-I to suppress serum GH concentrations declines with increasing age. This suggests that increased sensitivity to endogenous IGF-I negative feedback is not a cause of the decline in GH secretion that occurs with aging. (J Clin
The Journal of Clinical Endocrinology & Metabolism, 1992
Page 1. 0021-972X/92/7406-1378$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright... more Page 1. 0021-972X/92/7406-1378$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright 0 1992 by The Endocrine Society Vol. 74, No. 6 Printed in USA Oral Administration of Growth Hormone (GH)-Releasing Peptide Stimulates GH Secretion in Normal Men* ...
The Journal of Clinical Endocrinology & Metabolism, 1994
Modifications were made to a commercially available human (h) GH chemiluminescence assay (Nichols... more Modifications were made to a commercially available human (h) GH chemiluminescence assay (Nichols Luma Tag hGH assay), which improved its sensitivity to 0.002 micrograms/L. The results of this assay had a high correlation with those of the Nichols hGH immunoradiometric assay (IRMA; r = 0.91; P &lt; 0.001). The addition of recombinant hGH-binding protein (0.1-10 nmol/L) to standards and serum samples caused a dose-responsive reduction in measured GH in both the chemiluminescence assay and the IRMA; at physiological concentrations of hGH-binding protein, a 10-20% reduction was observed. Fifteen normal young adults (nine men and six women) underwent a standard 100-g oral glucose tolerance test, and plasma GH was measured from 30 min before until 5 h after glucose ingestion. GH was measurable in all samples with the chemiluminescence assay, but fell below the sensitivity of the IRMA in 59% of the samples. There was no difference between baseline or peak glucose levels in male and female subjects, but serum GH concentrations (mean +/- SD) measured by the enhanced sensitivity chemiluminescence assay were lower in male than female subjects at both baseline (0.12 +/- 0.08 vs. 2.3 +/- 2.3 micrograms/L; P &lt; 0.01) and the postglucose GH nadir (0.029 +/- 0.014 vs. 0.25 +/- 0.23 micrograms/L; P &lt; 0.01). The high correlation between baseline and nadir GH (r = 0.82; P &lt; 0.001) and the equivalent fractional decline in mean GH levels in men and women after glucose administration (67 +/- 17% vs. 84 +/- 8%; P = 0.06) suggest that the lower GH levels in men after glucose treatment are due to lower baseline values and not to a greater suppressive effect of glucose.
The Journal of Clinical Endocrinology & Metabolism, 1996
L-692,429 ([L]) is a GH-releasing peptide mimetic that stimulates GH secretion when administered ... more L-692,429 ([L]) is a GH-releasing peptide mimetic that stimulates GH secretion when administered acutely. To determine the effect of its continuous administration, six older adults (four men and two women, aged 64-82 yr) received i.v. transfusions of 1) saline for 24 h (control), 2) [L] (0.05 mg/kg.h) for 24 h (low dose), and 3) [L] (0.1 mg/kg.h) for 12 h, then saline for 12 h (high dose), followed on all admissions by saline for 2.5 h. GHRH (1 microgram/kg, i.v.) was given 30 min before the end of each 24-h treatment. Blood was collected every 10 min for GH measurement, and GH secretion was assessed by deconvolution analysis. Pulsatile GH secretion continued throughout both [L] infusions. During the first 12 h (when comparison of both doses was possible), [L] exerted a dose-dependent stimulatory effect on mean GH concentrations, from 0.6 +/- 0.1 (control, mean +/- SE), to 1.2 +/- 0.2 (low dose [L]) and 2.3 +/- 0.5 microgram/L (high dose [L]; P &lt; 0.05, high dose vs. control), and on calculated GH secretory rates [1.6 +/- 0.3 (control), 2.5 +/- 0.3 (low dose [L]), and 5.8 +/- 0.7 microgram/L distribution vol.h (high dose [L]); P &lt; 0.05, high dose vs. control]. GH secretory pulse height and area increased significantly in a dose-responsive manner, without significant changes in GH secretory pulse number, half-duration of pulses, or GH half-life. GH concentrations remained elevated during the second 11.5 h of low dose [L] infusion. Over the 23.5-h period before GHRH administration, mean GH concentrations and secretion rates were significantly higher than control values with high dose, but not low dose, [L]. Low dose [L] enhanced the peak GH response to GHRH (17.4 +/- 3.5 micrograms/L) compared to the control value (8.4 +/- 2.8 micrograms/L; P &lt; 0.05). We conclude that the administration of [L] to healthy older adults by continuous i.v. infusion enhances pulsatile GH secretion by increasing the mass of GH secreted per pulse, but not the number of secretion pulses, and increases the GH response to GHRH.
The Journal of Clinical Endocrinology & Metabolism, 1996
Aging is associated with declining activity of the GH axis, possibly contributing to adverse body... more Aging is associated with declining activity of the GH axis, possibly contributing to adverse body composition changes and increased incidence of cardiovascular disease. The stimulatory effects on the GH-insulin-like growth factor I (IGF-I) axis of orally administered MK-677, a GH-releasing peptide mimetic, were investigated. Thirty-two healthy subjects (15 women and 17 men, aged 64-81 yr) were enrolled in a randomized, double blind, placebo-controlled trial. They received placebo or 2, 10, or 25 mg MK-677, orally, once daily for 2 separate study periods of 14 and 28 days. At baseline and on day 14 of each study period, blood was collected every 20 min for 24 h to measure GH, PRL, and cortisol. Attributes of pulsatile GH release were assessed by 3 independent algorithms. MK-677 administration for 2 weeks increased GH concentrations in a dose-dependent manner, with 25 mg/day increasing mean 24-h GH concentration 97 +/- 23% (mean +/- SE; P &amp;amp;lt; 0.05 vs. baseline). This increase was due to an enhancement of preexisting pulsatile GH secretion. GH pulse height and interpulse nadir concentrations increased significantly without significant changes in the number of pulses. With 25 mg/day MK-677 treatment, mean serum IGF-I concentrations increased into the normal range for young adults (141 +/- 21 microgram/L at baseline, 219 +/- 21 micrograms/L at 2 weeks, and 265 +/- 29 micrograms/L at 4 weeks; P &amp;amp;lt; 0.05). MK-677 produced significant increases in fasting glucose (5.4 +/- 0.3 to 6.8 +/- 0.4 mmol/L at 4 weeks; P &amp;amp;lt; 0.01 vs. baseline) and IGF-binding protein-3. Circulating cortisol concentrations did not change, and PRL concentrations increased 23%, but remained within the normal range. Once daily treatment of older people with oral MK-677 for up to 4 weeks enhanced pulsatile GH release, significantly increased serum GH and IGF-I concentrations, and, at a dose of 25 mg/day, restored serum IGF-I concentrations to those of young adults.
Journal of Clinical Endocrinology & Metabolism, 1998
To determine the time course of recovery of GH release from insulin-like growth factor I (IGF-I) ... more To determine the time course of recovery of GH release from insulin-like growth factor I (IGF-I) suppression, 11 healthy adults (18-29 yr) received, in randomized order, 4-h i.v. infusions of recombinant human IGF-I (rhIGF-I; 3 microg/kg-h) or saline (control) from 25.5-29.5 h of a 47.5-h fast. Serum GH was maximally suppressed within 2 h and remained suppressed for 2 h after the rhIGF-I infusion; during this 4-h period, GH concentrations were approximately 25% of control day levels [median (interquartile range), 1.2 (0.4-4.0) vs. 4.8 (2.8-7.9) microg/L; P &lt; 0.05]. A rebound increase in GH concentrations occurred 5-7 h after the end of rhIGF-I infusion [7.6 (4.6 -11.7) vs. 4.3 (2.5-6.0) microg/L; P &lt; 0.05]. Thereafter, serum GH concentrations were similar on both days. Total IGF-I concentrations peaked at the end of the rhIGF-I infusion (432 +/- 43 vs. 263 +/- 44 microg/L; P &lt; 0.0001) and remained elevated 18 h after the rhIGF-I infusion (360 +/- 36 vs. 202 +/- 23 microg/L; P = 0.001). Free IGF-I concentrations were approximately 140% above control day values at the end of the infusion (2.1 +/- 0.4 vs. 0.88 +/- 0.3 microg/L; P = 0.001), but declined to baseline within 2 h after the infusion. The close temporal association between the resolution of GH suppression and the fall of free IGF-I concentrations, and the lack of any association with total IGF-I concentrations suggest that unbound (free), not protein-bound, IGF-I is the major IGF-I component responsible for this suppression. The rebound increase in GH concentrations after the end of rhIGF-I infusion is consistent with cessation of an inhibitory effect of free IGF-I on GH release.
To determine the effects of acute hyperglycaemia on appetite and food intake in Type 1 diabetes m... more To determine the effects of acute hyperglycaemia on appetite and food intake in Type 1 diabetes mellitus.
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