Isotretinoin 5 mg daily for low-grade adult acne vulgaris--a placebo-controlled, randomized double-blind study.

BACKGROUND: Despite acne persisting into adulthood in up to 50% of the population, very few therapeutic studies have been performed in this age group. OBJECTIVES: To assess the efficacy of 5 mg/day isotretinoin in adult acne. METHODS: An investigator initiated, industry-sponsored, randomized, double-blind, placebo-controlled, parallel-group clinical study of isotretinoin 5 mg/day in the treatment of low-grade adult acne for 16 weeks followed by an open-label phase of 16 weeks. Group 1 received 32 weeks of 5 mg isotretinoin/day; Group 2 first received 16 weeks of placebo, followed by 16 weeks open-label 5 mg isotretinoin/day. Patients were followed for a further 10 weeks off treatment. The primary end-point was the difference in acne lesion count and disability score after 16 weeks isotretinoin compared to placebo. Secondary end-points included differences in these counts/scores after 32 weeks of isotretinoin compared to baseline, and after 10 weeks off treatment, compared to end of treatment (week 32). RESULTS: There were highly significant differences (P < 0.0001) in acne lesion count, Dermatology Life Quality Index and self-assessment after 16 weeks of isotretinoin, compared to placebo (both per protocol and intention to treat). Acne lesions fell significantly, within 4 weeks of 5 mg isotretinoin/day (Group 1) and continued to fall during 32 weeks of treatment [acne lesion count (mean ± SD): 11.3 ± 8.1 (baseline), 3.6 ± 5.5 (week 16), 1.3 ± 3.1 (week 32), P < 0.0001)]. There was a similar significant reduction in acne lesion count in Group 2, but only from week 20, 4 weeks after starting open-label 5 mg isotretinoin. Adverse effects were minimal. CONCLUSIONS: Isotretinoin 5 mg/day is effective in reducing the number of acne lesions, and improving patients dermatologic quality of life, with minimal adverse effects.

A randomised trial of enteric-coated nutrient pellets to stimulate gastrointestinal peptide release and lower glycaemia in type 2 diabetes.

AIMS/HYPOTHESES: Glucagon-like peptide-1 (GLP-1), an important mediator of postprandial glycaemia, could potentially be stimulated by delivering small quantities of nutrient to a long length of distal gut. We aimed to determine whether enteric-coated pellets, releasing small amounts of lauric acid throughout the ileum and colon, could reduce glycaemic responses to meals in type 2 diabetes, associated with stimulation of GLP-1. METHODS: Eligible patients, who had type 2 diabetes controlled by diet or metformin, were each studied on two occasions in a hospital setting. After an overnight fast, patients consumed 5 g active pellets (47% lauric acid by weight) or placebo with breakfast (T = 0 min) and lunch (T = 240 min), in a crossover design with order randomised by the hospital pharmacy and allocation concealed by numbered containers. Patients and investigators making measurements were blinded to the intervention. Blood was sampled frequently for blood glucose (the primary outcome) and hormone assays. RESULTS: Eight patients were randomised (four to receive either intervention first), and all completed the study without adverse effects. Blood glucose was lower after breakfast (T = 0-240 min, area under the curve (AUC) 2,075 ± 368 vs 2,216 ± 163 mmol/l × min) and lunch (T = 240-480 min, AUC 1,916 ± 115 vs 2,088 ± 151 mmol/l × min) (p = 0.02 for each) after active pellets than after placebo. Plasma GLP-1 concentrations were higher after breakfast (p = 0.08) and lunch (p = 0.04) for active pellets. While there were no differences in insulin or glucose-dependent insulinotropic polypeptide concentrations, glucagon concentrations were higher after breakfast and lunch (p = 0.002 for each) for active pellets. CONCLUSIONS/INTERPRETATION: Delivering small amounts of nutrient to the ileum and colon can stimulate substantial endogenous GLP-1 release and attenuate postprandial glycaemia. This novel approach has therapeutic potential in type 2 diabetes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000600842. FUNDING: The study was funded by Meyer Nutriceuticals.

Effects of variations in duodenal glucose load on glycaemic, insulin, and incretin responses in type 2 diabetes.

AIMS: Postprandial glucagon-like peptide-1 (GLP-1) secretion and the 'incretin effect' have been reported to be deficient in Type 2 diabetes, but most studies have not controlled for variations in the rate of gastric emptying. We evaluated blood glucose, and plasma insulin, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) responses to intraduodenal glucose in Type 2 diabetes, and compared these with data from healthy controls. METHODS: Eight males with well-controlled Type 2 diabetes, managed by diet alone, were studied on four occasions in single-blind, randomized order. Blood glucose, and plasma insulin, GLP-1, and GIP were measured during 120-min intraduodenal glucose infusions at 1 kcal/min (G1), 2 kcal/min (G2) and 4 kcal/min (G4) or saline control. RESULTS: Type 2 patients had higher basal (P < 0.0005) and incremental (P < 0.0005) blood glucose responses to G2 and G4, when compared with healthy controls. In both groups, the stimulation of insulin and GLP-1 by increasing glucose loads was not linear; responses to G1 and G2 were minimal, whereas responses to G4 were much greater (P < 0.005 for each) (incremental area under the GLP-1 curve 224 ± 65, 756 ± 331 and 2807 ± 473 pmol/l.min, respectively, in Type 2 patients and 373 ± 231, 505 ± 161 and 1742 ± 456 pmol/l.min, respectively, in healthy controls). The GLP-1 responses appeared comparable in the two groups. In both groups there was a load-dependent increase in plasma GIP with no difference between them. CONCLUSIONS: In patients with well-controlled Type 2 diabetes, blood glucose, insulin and GLP-1 responses are critically dependent on the small intestinal glucose load, and GLP-1 responses are not deficient.

The nitric oxide synthase inhibitor, Ng-nitro-L-arginine-methyl-ester, attenuates the delay in gastric emptying induced by hyperglycaemia in healthy humans.

The aim of this study was to determine whether the nitric oxide (NO) synthase inhibitor, N(g)-nitro-L-arginine-methyl-ester (L-NAME), reverses the effects of acute hyperglycaemia on gastric emptying and antropyloroduodenal (APD) motility. The study had a four-way randomized crossover (hyperglycaemia vs euglycaemia; L-NAME vs placebo) design in a clinical laboratory setting. Seven healthy volunteers [four males; age 30.3 +/- 3.8 years; body mass index (BMI) 23.6 +/- 1.2 kg m(-2)] were the study subjects. After positioning a transnasal manometry catheter across the pylorus, the blood glucose concentration was maintained at either 15 or 5 mmol L(-1) using a glucose/insulin clamp. An intravenous infusion of L-NAME (180 microg kg(-1 )h(-1)) or placebo (0.9% saline) was commenced (T = -30 min) and continued for 150 min. At T = -2 min, subjects ingested a drink containing 50 g of glucose made up to 300 mL with water. Gastric emptying was measured using 3D ultrasound, and APD motility using manometry. Hyperglycaemia slowed gastric emptying (P < 0.05), and this effect was abolished by L-NAME. L-NAME had no effect on gastric emptying during euglycaemia. Hyperglycaemia suppressed fasting antral motility [motility index: 3.9 +/- 0.8 (hyperglycaemia) vs 6.5 +/- 0.6 (euglycaemia); P < 0.01]; l-NAME suppressed postprandial antral motility [motility index: 3.6 +/- 0.2 (L-NAME) vs 5.1 +/- 0.2 (placebo); P < 0.001]. Postprandial basal pyloric pressure was higher during hyperglycaemia (P < 0.001), and lower after administration of L-NAME (P < 0.001). Slowing of gastric emptying induced by hyperglycaemia is mediated by NO, and may involve the modulation of tonic pyloric activity.

Relation between calcium absorption and serum calcitriol in normal men: evidence for age-related intestinal resistance to calcitriol.

OBJECTIVE: To obtain information on the causes of age-related bone loss in men and the concomitant decline in calcium absorption. DESIGN: Cross-sectional study. SETTING: Adelaide, South Australia, Australia. SUBJECTS: A total of 95 healthy, Caucasian men (age range 27-87 y). RESULTS: Calcium absorption declined with age (r=-0.46, P<0.0001), as did 24-h urine calcium, phosphate and creatinine (r>-0.21, P<0.05 for all); serum calcitriol and 25 hydroxyvitamin D did not change with age. Calcium absorption was related to serum calcitriol (r=0.20, P=0.05). An inverse relation between the residual deviations in calcium absorption, after allowing for its dependence on calcitriol, and age (F=5.4, P<0.005) was observed. The 24-h urinary calcium, phosphate and creatinine were all related to calcium absorption (r>0.41, P<0.0001). Forearm bone density fell with age (r=-0.45, P<0.0001) but was not related to calcium absorption, or markers of bone turnover. CONCLUSIONS: In healthy Caucasian males (i) calcium absorption falls, but serum calcitriol does not change with age, (ii) the relation between calcium absorption and serum calcitriol changes with age, indicative of an intestinal resistance to calcitriol and (iii) calcium absorption is a significant determinant of 24-h urinary calcium excretion.

Effects of lipase inhibition on gastric emptying of, and on the glycaemic, insulin and cardiovascular responses to, a high-fat/carbohydrate meal in type 2 diabetes.

AIMS/HYPOTHESES: We examined the effects of lipase inhibition with orlistat on (i) gastric emptying of, and (ii) the glycaemic, glucagon-like peptide-1 (GLP-1) and cardiovascular responses to, a high-fat/carbohydrate meal in type 2 diabetic patients. METHODS: Eight type 2 diabetic patients, who were aged 62 years (median range: 49-68 years) and managed by diet alone, consumed a meal containing 65 g powdered potato, 20 g glucose reconstituted with 200 ml water (labelled with 20 MBq (99m)Tc-sulphur-colloid) and 45 g margarine. They did this on two separate occasions, with and without 120 mg orlistat, and while in the seated position with their back against a gamma camera. Venous blood samples for measurement of blood glucose, plasma insulin and GLP-1 were obtained immediately before the meal and at regular intervals afterwards. Blood pressure (systolic and diastolic) and heart rate were measured using an automated device. RESULTS: Gastric emptying of the meal was faster after orlistat than without orlistat (50% emptying time [mean +/- SEM], 61+/-8 min vs 98+/-5 min; p=0.0001). In the first 60 min after the meal blood glucose (p=0.001) and plasma insulin (p=0.01) concentrations were higher in patients who had taken orlistat; between 60 and 180 min plasma GLP-1 (p=0.02) concentrations were lower after orlistat than without orlistat. Between 0 and 30 min systolic blood pressure (p=0.003) was lower, and heart rate (p=0.03) greater in subjects who had taken orlistat than in those who had not. CONCLUSIONS/INTERPRETATION: Inhibition of fat digestion by orlistat may-as a result of more rapid gastric emptying-exacerbate postprandial glycaemia and the postprandial fall in blood pressure in patients with type 2 diabetes after ingestion of meals containing fat and carbohydrate.

Effect of lipase inhibition on gastric emptying of, and the glycemic and incretin responses to, an oil/aqueous drink in type 2 diabetes mellitus.

This study examined the effects of the lipase inhibitor, orlistat, on gastric emptying of, and the glycemic and incretin hormone responses to, a drink containing oil and glucose components in patients with type 2 diabetes. Seven patients (aged 58 +/- 5 yr), managed by diet alone, consumed 60 ml olive oil (labeled with 20 MBq (99m)Tc-V-thiocyanate) and 300 ml water containing 75 g glucose (labeled with 6 MBq (67)Ga-EDTA), on two occasions, with and without 120 mg orlistat, positioned in the left lateral decubitus position with their back against a gamma camera. Venous blood samples, for measurement of blood glucose and plasma insulin, glucagon-like peptide-1 and glucose-dependent insulintropic polypeptide were obtained immediately before, and after, the drink. Gastric emptying of both oil (P < 0.001) and glucose (P < 0.0005) was faster after orlistat compared with control. Postprandial blood glucose (P < 0.001) and plasma insulin (P < 0.05) were substantially greater after orlistat compared with control. In contrast, plasma glucagon-like peptide-1 (P < 0.005) and glucose-dependent insulintropic polypeptide (P < 0.05) were less after orlistat. In conclusion, inhibition of fat digestion, by orlistat, may exacerbate postprandial glycemia, as a result of more rapid gastric emptying and a diminished incretin response.

Bone density and bone-related biochemical variables in normal men: a longitudinal study.

BACKGROUND: The objective of this study was to determine the pattern of forearm bone loss and its relationship to markers of bone turnover and sex steroids in normal men. This was a longitudinal study over a median interval of 41 months. The study was conducted in Adelaide, Australia. Study participants were 123 healthy male subjects, between the ages of 20 and 83 years. METHODS: Fat-corrected forearm bone mineral content (fcBMC), markers of bone formation (alkaline phosphatase, osteocalcin, procollagen type 1 C-terminal extension peptide) and bone resorption (collagen type I cross-linked telopeptide, hydroxyproline/creatinine, pyridinoline/creatinine, and deoxypyridinoline/creatinine), calculated serum bioavailable testosterone, and serum estradiol were measured. RESULTS: The mean time-weighted rate of change in forearm fcBMC was -0.33% +/- 0.72 (SD) per year. Bone loss commenced after 30 years of age and increased with age (p <.001), particularly after age 70 years. There was no relationship between the rate of change in fcBMC and either markers of bone turnover or serum sex steroids. CONCLUSIONS: In normal men, bone loss increases with age; there does not appear to be any relationship between this loss and either markers of bone turnover or levels of free androgen or estrogen.

Effects of dose and timing of calcium supplementation on bone resorption in early menopausal women.

Bone resorption follows a circadian rhythm that peaks at night, reflecting the circadian rhythm of serum parathyroid hormone. Our previous studies in early postmenopausal women have established that 1000 mg of calcium given at 9 p. m. reduced bone resorption markers overnight, but not during the day. In contrast, 1000 mg given as a divided dose (500 mg doses at 9 a. m. and 9 p. m. each) reduced bone resorption markers during the day, but not during the night. We have now evaluated the effect of 1500 mg of calcium given as a divided dose of 500 mg in the morning and 1000 mg in the evening on bone resorption. We studied 26 healthy women (median age 56 years) whose menopause was less than five years before. On two days, urine was collected from 9 a. m. to 9 p. m. (day collection), and from 9 p. m. to 9 a. m. (night collection); a further fasting (spot) urine sample was obtained at 9 a. m. at the end of the night collection. On the second day, 500 mg of calcium in the carbonate form was taken at 9 a. m. (at the start of the collection) and a further 1000 mg at 9 p. m. (at the start of the second night collection). Calcium supplementation decreased urinary deoxypyridinoline (DPyr/Cr) during the day (p = 0.08) and night (p < 0.05), as well as urinary pyridinoline (Pyr/Cr) both by day (p < 0.05) and night (p < 0.001). There were also decreases in urine hydroxyproline. We conclude that the acute administration of 500 mg of calcium in the morning and 1000 mg in the evening to early postmenopausal women suppresses bone resorption markers during both the day and night.

Predictors of delayed gastric emptying in diabetes.

OBJECTIVE: To define the predictors of the rate of gastric emptying in patients with diabetes. RESEARCH DESIGN AND METHODS: A total of 101 outpatients with diabetes (79 type 1 and 22 type 2) underwent measurements of gastric emptying of a solid/liquid meal (scintigraphy), upper gastrointestinal symptoms (questionnaire), glycemic control (blood glucose concentrations during gastric emptying measurement), and autonomic nerve function (cardiovascular reflexes). RESULTS: The gastric emptying of solid and/or liquid was delayed in 66 (65%) patients. Solid (retention at 100 min 64 +/- 3.2 vs. 50.2 +/- 3.6%, P < 0.005) and liquid (retention at 100 min 22.7 +/- 1.7 vs. 16.0 +/- 1.8%, P < 0.001) gastric emptying was slower in women than in men. Of all upper gastrointestinal symptoms (including nausea and vomiting), only abdominal bloating/fullness was associated with slower gastric emptying (P < 0.005). A multiple regression analysis demonstrated that both abdominal bloating/fullness and female sex were predictors of slower gastric emptying of both solids and liquids. CONCLUSIONS: We conclude that the presence of abdominal bloating/fullness but not any other upper gastrointestinal symptom is associated with diabetic gastroparesis and that gastric emptying is slower in diabetic women than in diabetic men.

Effects of glucose supplementation on gastric emptying, blood glucose homeostasis, and appetite in the elderly.

The aims of this study were to evaluate the effects of dietary glucose supplementation on gastric emptying (GE) of both glucose and fat, postprandial blood glucose homeostasis, and appetite in eight older subjects (4 males, 4 females, aged 65--84 yr). GE of a drink (15 ml olive oil and 33 g glucose dissolved in 185 ml water), blood glucose, insulin, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and appetite (diet diaries, visual analog scales, and food intake at a buffet meal consumed after the GE study) were evaluated twice, after 10 days on a standard or a glucose-supplemented diet (70 g glucose 3 times a day). Glucose supplementation accelerated GE of glucose (P < 0.05), but not oil; there was a trend for an increase in GIP (at 15 min, P = 0.06), no change in GLP-1, an earlier insulin peak (P < 0.01), and a subsequent reduction in blood glucose (at 75 min, P < 0.01). Glucose supplementation had no effect on food intake during each diet so that energy intake was greater (P < 0.001) during the glucose-supplemented diet. Appetite ratings and energy intake at the buffet meal were not different. We conclude that, in older subjects, glucose supplementation 1) accelerates GE of glucose, but not fat; 2) modifies postprandial blood glucose homeostasis; and 3) increases energy intake.

Effects of fedotozine on gastric emptying and upper gastrointestinal symptoms in diabetic gastroparesis.

BACKGROUND: Delayed gastric emptying and upper gastrointestinal symptoms occur frequently in patients with diabetes mellitus. AIM: To evaluate the effects of fedotozine on gastric emptying and gastrointestinal symptoms in diabetic gastroparesis. METHODS: Thirty-one diabetic patients (20 type 1, 11 type 2) with gastroparesis were randomized to receive fedotozine (30 mg as the tartrate) or placebo t.d.s. Measurements of gastric emptying (100 g ground beef labelled with 20 MBq 99mTc-sulphur colloid chicken liver and 150 mL 10% dextrose labelled with 10 MBq 113mIn-DTPA) and gastrointestinal symptoms were performed before and after 12-16 days of treatment. Data are the mean +/- s.d. RESULTS: Of the 31 patients enrolled, two were excluded from analysis. Data from the remaining 29 patients (18 type 1, 11 type 2; 22 female, seven male), aged 42.7 +/- 11.1 years (of whom 14 were randomized to fedotozine and 15 to placebo), were analysed. Fedotozine had no effect on either gastric emptying (solid retention at 100 min; fedotozine: baseline, 84 +/- 15%; treatment, 73 +/- 23% vs. placebo: baseline, 83 +/- 10%; treatment, 70 +/- 20%) or liquid 50% emptying time (fedotozine: baseline, 59 +/- 32 min; treatment, 58 +/- 38 min vs. placebo: baseline, 44 +/- 9 min; treatment, 43 +/- 21 min) or gastrointestinal symptoms (fedotozine: baseline, 4.4 +/- 2.9; treatment, 4.1 +/- 3.9 vs. placebo: baseline, 4.9 +/- 4.2; treatment, 4.8 +/- 3.9). CONCLUSIONS: Fedotozine has no effect on gastric emptying in patients with diabetic gastroparesis.

The relation between bone density, free androgen index, and estradiol in men 60 to 70 years old.

The cause of age-related bone loss in men is poorly understood. Previous studies of the relationship between bone density and serum androgens have yielded inconsistent results, perhaps partly because age is a determinant of both. Recent studies suggest that serum estrogen levels influence bone density in adult men. In order to determine whether bone mineral density (BMD) and bone turnover are associated with serum sex steroids, we investigated 37 normal men within a narrow age range (60-70 years). Bone mineral density at the forearm, hip, and spine, testosterone, sex hormone binding globulin (SHBG), free androgen index (FAI:T/SHBG), estradiol (E), free estradiol index (FEI:E/SHBG), and markers of bone formation (alkaline phosphatase, osteocalcin, procollagen type I C-terminal extension peptide) and bone resorption (hydroxyproline/creatinine [OHPr/Cr], deoxypyridinoline/creatinine [Dpd/Cr], pyridinoline/creatinine, collagen type I cross-linked telopeptide) were measured. Bone mineral density was positively related (r > 0.35, p < 0.05 at all sites) to log FAI, whereas there was no significant relationship between BMD and either serum total testosterone, serum E, or FEI. Bone density at the spine and hip were inversely related to both OHPr/Cr (r > -0.41, p < 0.05 for all sites) and Dpd/Cr (r > -0.36, p < 0.05 for all sites). OHPr/Cr (r = -0.41, p < 0.05) and Dpd/Cr (r = -0.41, p < 0.05) were both inversely related to log FAI. We conclude that BMD and bone turnover in adult men are related to plasma free androgens.

Effects of intraduodenal glucose and fructose on antropyloric motility and appetite in healthy humans.

Oral fructose empties from the stomach more rapidly and may suppress food intake more than oral glucose. The purpose of the study was to evaluate the effects of intraduodenal infusions of fructose and glucose on antropyloric motility and appetite. Ten healthy volunteers were given intraduodenal infusions of 25% fructose, 25% glucose, or 0.9% saline (2 ml/min for 90 min). Antropyloric pressures, blood glucose, and plasma insulin, gastric inhibitory peptide (GIP), and glucagon-like peptide-1 (GLP-1) were measured concurrently; a buffet meal was offered at the end of the infusion. Intraduodenal fructose and glucose suppressed antral waves (P < 0. 0005 for both), stimulated isolated pyloric pressure waves (P < 0.05 for both), and increased basal pyloric pressure (P = 0.10 and P < 0. 05, respectively) compared with saline, without any significant difference between them. Intraduodenal glucose increased blood glucose (P < 0.0005), as well as plasma insulin (P < 0.0005) and GIP (P < 0.005) more than intraduodenal fructose, whereas there was no difference in the GLP-1 response. Intraduodenal fructose suppressed food intake compared with saline (P < 0.05) and glucose (P = 0.07). We conclude that, when infused intraduodenally at 2 kcal/min for 90 min 1) fructose and glucose have comparable effects on antropyloric pressures, 2) fructose tends to suppress food intake more than glucose, despite similar GLP-1 and less GIP release, and 3) GIP, rather than GLP-1, probably accounts for the greater insulin response to glucose than fructose.

Inhibition of bone resorption by divided-dose calcium supplementation in early postmenopausal women.

We have previously shown that a calcium (Ca) supplement of 1000 mg given in the evening reduces the overnight and early morning, but not the daytime, excretion of bone resorption markers in postmenopausal women within five years of the menopause. In the present study, we have looked at the effect of splitting the Ca into two doses of 500 mg each given in the morning and evening. We studied 19 healthy women (median age 53 years) who were all within 5 years of the menopause. On the 2 study days, urine was collected from 9 a.m. to 9 p.m. (day collection), and from 9 p.m. to 9 a.m. (night collection); a further fasting (spot) urine sample was obtained at 9 a.m. at the end of the night collection. The first day was a control day; on the second day the subjects ingested 500 mg Ca as the carbonate at 9 a.m. and 9 p.m. We measured pyridinoline cross-links excretion in all the samples, as well as hydroxyproline in the fasting urine. The Ca supplements lowered urinary excretion of the markers during the day (P < 0.01), had only a marginal effect during the night, but reduced excretion significantly in the fasting urine (P < 0.001). In the whole 24-hour period, the falls in resorption markers were small but comparable to those seen after the ingestion of 1 g of Ca in the evening. We conclude that the acute administration of 0.5 g Ca in the morning and evening reduced the markers of bone resorption in early postmenopausal women during the day but not during the following night, whereas the single 1 g supplement had the reverse effect. Over the 24-hour period, there was nothing to choose between the two regimes. Women at this stage in their life cycle probably require a larger Ca supplement if they are not taking estrogen.

Effect of perimenopause on calcium absorption: a longitudinal study.

OBJECTIVE: Cross-sectional studies suggest that the rise in calcium requirement at the menopause may be attributable, at least in part, to a fall in intestinal calcium absorption. The aim of the present study was to determine the effect of the menopause on intestinal calcium absorption and the relationship between any change in calcium absorption and serum calcitriol. METHODS: Radiocalcium absorption and serum calcitriol were measured in 72 women aged 47.3 (standard error, SE 0.19) years who were initially premenopausal (as judged by menstrual history and serum follicle stimulating hormone (FSH)) and again 18 months later. RESULTS: Calcium absorption fell at the second visit from 0.72 (0.029)/h to 0.64 (0.029)/h (p = 0.003). Serum calcitriol had also fallen at the second visit from 124 (4.2) pmol/l to 111 (4.0) pmol/l (p = 0.007). At that visit, serum FSH exceeded the premenopausal reference range in 11 subjects and the menstrual cycle had become irregular in 24 of them. In the 11 women with raised FSH at the second visit, radiocalcium absorption fell from 0.85/h (0.097) at baseline to 0.57/h (0.049) (p = 0.008), but only from 0.70/h (0.028) to 0.65/h (0.033) (not significant) in the remaining 61. Similarly, radiocalcium absorption fell significantly (p = 0.003) in the 24 women with irregular menses, but not in the remaining 48 who continued to menstruate regularly. These changes in calcium absorption were still significant after correction for changes in calcitriol levels. CONCLUSION: The perimenopause is associated with a fall in calcium absorption, which is only in part attributable to a fall in calcitriol levels.

Relationships between age, dehydro-epiandrosterone sulphate and plasma glucose in healthy men.

BACKGROUND: dehydro-epiandrosterone sulphate (DHEAS) has been reported to ameliorate diabetes mellitus in rats. AIM: we investigated the relationships between plasma glucose, age, serum DHEAS and weight in healthy men. METHODS: we measured the serum DHEAS, fasting plasma glucose, plasma cortisol and body mass index in 169 subjects (mean age 46.5 years). RESULTS: there was a significant decline in serum DHEAS with age (P < 0.0001). Multiple linear regression showed significant relationships with plasma glucose for all measured variables. Age was not a significant determinant of plasma glucose after adjusting for log serum DHEAS, body mass index and log serum cortisol. CONCLUSIONS: a lowered serum DHEAS is paralleled by an elevated plasma glucose within the normal reference interval, and this may contribute to the rise in fasting plasma glucose which occurs with ageing.

Effects of age on concentrations of plasma cholecystokinin, glucagon-like peptide 1, and peptide YY and their relation to appetite and pyloric motility.

BACKGROUND: Aging is associated with a decrease in appetite and a slowing of gastric emptying. The gastrointestinal hormones cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) may mediate these changes. OBJECTIVE: We investigated whether aging influenced the secretion of CCK, GLP-1, and PYY and their effects on appetite and pyloric motility. DESIGN: Eight healthy older (65-80 y) and 7 younger (20-34 y) men received isoenergetic (12.1 kJ/min) intraduodenal infusions of lipid and glucose for 120 min on separate days. Plasma CCK, GLP-1, and PYY concentrations were measured. RESULTS: Plasma CCK concentrations were higher in older than in younger subjects (P = 0.004) as a result of higher baseline values (4.7+/-0.2 compared with 3.2+/-0.2 pmol/L; P < 0.0001) and a greater rise during lipid infusion (increase from baseline: 7.1+/-0.5 compared with 5.3+/-0.6 pmol/L; P = 0.048). Plasma GLP-1 and PYY concentrations were not significantly different between groups. The decrease in hunger during intraduodenal lipid infusion was inversely related to the increase in CCK, GLP-1, and PYY in younger but not older subjects. During intraduodenal lipid infusion, the increase in isolated pyloric pressure wave (IPPW) frequency was positively related to GLP-1 and PYY and the increase in IPPW amplitude was positively related to CCK in older but not younger subjects, whereas the increase in IPPW amplitude and pyloric tone was negatively related to GLP-1 and PYY in younger subjects. CONCLUSIONS: Human aging is associated with increased CCK concentrations, which may contribute to the slowing of gastric emptying, mediated by increased pyloric motility. The role of increased plasma CCK concentrations in mediating the age-related decrease in appetite remains to be established.

Natural history of diabetic gastroparesis.

OBJECTIVE: The major aim of this study was to evaluate the prognosis of diabetic gastroparesis. RESEARCH DESIGN AND METHODS: Between 1984 and 1989, 86 outpatients with diabetes (66 type 1, 20 type 2; 40 male, 46 female) underwent assessment of solid and liquid gastric emptying and esophageal transit (by scintigraphy), gastrointestinal symptoms (by questionnaire), autonomic nerve function (by cardiovascular reflex tests), and glycemic control (by HbAlc and blood glucose concentrations during gastric emptying measurement). These patients were followed up in 1998. RESULTS: Of the 86 patients, solid gastric emptying (percentage of retention at 100 min) was delayed in 48 (56%) patients and liquid emptying (50% emptying time) was delayed in 24 (28%) patients. At follow-up in 1998, 62 patients were known to be alive, 21 had died, and 3 were lost to follow-up. In the group who had died, duration of diabetes (P = 0.048), score for autonomic neuropathy (P = 0.046), and esophageal transit (P = 0.032) were greater than in those patients who were alive, but there were no differences in gastric emptying between the two groups. Of the 83 patients who could be followed up, 32 of the 45 patients (71%) with delayed solid emptying and 18 of the 24 patients (75%) with delay in liquid emptying were alive. After adjustment for the effects of other factors that showed a relationship with the risk of dying, there was no significant relationship between either gastric emptying or esophageal transit and death. CONCLUSIONS: In this relatively large cohort of outpatients with diabetes, there was no evidence that gastroparesis was associated with a poor prognosis.