Optimal dose and timing of insulin Aspart to mimic first phase insulin response in patients with recently onset type 2 diabetes.

OBJECTIVE: To assess the optimal dose and timing of subcutaneous injection of insulin Aspart (IAsp) in relation to meal to mimic first phase insulin response in patients with recently diagnosed type 2 diabetes. DESIGN AND METHODS: Twenty patients were randomised in a double blind, double dummy design to four standard meal tests with pre-meal injection of insulin Aspart 0.08 IU/kg BW 30 min before the meal, insulin Aspart 0.04 IU/kg BW 30 or 15 min before the meal and placebo. RESULTS: All three insulin regimes significantly reduced postprandial glucose increment (area under the curve AUC(-30 to 240 min)) and peak plasma glucose increment (DeltaC(max)) compared with placebo. Postprandial glucose increment AUC(-30 to 240 min) but not DeltaC(max) was significantly lower with IAsp 0.08 IU/kg BW as compared to IAsp 0.04IU/kg BW, (p<0.03 and p=0.18). One patient experienced hypoglycaemia after injection of IAsp 0.08 IU/kg BW. No difference in postprandial glucose profile was demonstrated whether IAsp 0.04 IU/kg BW was administrated 15 or 30 min before mealtime. CONCLUSIONS: IAsp 0.04IU/kg BW injected subcutaneously 15 or 30 min before meal reduced the postprandial blood glucose increment without risk of hypoglycaemia in patients with recently diagnosed type 2 diabetes. Doubling of the IAsp dose significantly reduced the postprandial glucose increment but increased the risk of hypoglycaemia.

A combined abnormality in heart rate variation and QT corrected interval is a strong predictor of cardiovascular death in type 1 diabetes.

OBJECTIVE: Long-term diabetes is associated with excess morbidity and mortality, and cardiovascular autonomic neuropathy and QTc interval abnormalities are both predictive of early cardiovascular death in diabetes. We aimed to investigate the effect of these risk factors in a large cohort of type 1 diabetic patients followed prospectively for 10 years. MATERIAL AND METHODS: Three-hundred-and-ninety-one type 1 diabetic mellitus patients (240 M and 151 F, age 41.8 years +/- 9.9 (mean +/-SD), duration of DM 27.3 years +/- 8.2) were followed in an outpatient setting. RESULTS: Patients with decreased heart rate variability had an excess overall mortality that diminished after adjusting for conventional cardiovascular risk factors; hazard ratio 2.5 (0.9-6.8; p = 0.071) compared to patients with normal heart rate variability. Likewise, prolonged QTc interval was associated with premature death with an adjusted hazard ratio of 2.3 (1.3-4.0; p = 0.005). In a combined analysis, patients with abnormal values for heart rate variability and QTc had a poorer prognosis compared to patients with normal test values for both parameters (adjusted hazard ratio 6.7 (1.8-25; p = 0.005)). Of the 34 patients with both test values abnormal, 15 died and 14 of these from cardiovascular causes. CONCLUSIONS: We conclude that combined abnormality in heart rate variability and QTc is a strong predictor of mortality in type 1 diabetes independently of conventional risk factors. These results have implications for future screening and treatment programmes for cardiovascular disease in type 1 diabetes.

Impaired first-phase insulin response predicts postprandial blood glucose increment in patients with recently diagnosed type 2 diabetes.

OBJECTIVE: The aim of the study was to evaluate the relationship between postprandial blood glucose and first-phase insulin response and, furthermore, to assess whether the intravenous glucagon stimulation test can be used as a predictor for increased postprandial glucose in patients with recently diagnosed type 2 diabetes. MATERIAL AND METHODS: Twenty patients with diet-treated type 2 diabetes, diagnosed within the past 5 years, were included. In random order, on three different days, the patients underwent: 1) a standardized meal tolerance test, 2) an intravenous glucose tolerance test, and 3) an intravenous glucagon stimulation test. The postprandial blood glucose response was defined as the incremental area under the blood glucose curve 0-240 min after the meal. RESULTS: The first-phase insulin response at an intravenous glucose stimulation test was significantly correlated to the postprandial blood glucose increment (R(2)=0.21, p<0.05) and the maximal increment in plasma glucose concentration (R(2)=0.40, p<0.01) during the meal tolerance test. However, the incremental C-peptide value at 6 min in response to intravenous glucagon stimulation did not correlate to the postprandial blood glucose increment (R(2)=0.09, p=0.14). CONCLUSION: Impaired first-phase insulin response is a significant predictor of the increase in postprandial blood glucose in patients with type 2 diabetes in near normal metabolic control, whereas beta-cell function, assessed by glucagon stimulation test, is not.

Is pancreatic polypeptide response to food ingestion a reliable index of vagal function in type 1 diabetes?

OBJECTIVE: The diagnosis of autonomic neuropathy in diabetic patients is based on cardiovascular reflex tests. Since cardiac function may be affected by arteriosclerosis and cardiomyopathy in type 1 diabetes mellitus, alternative tests reflecting vagal nerve function, in other organ systems, are needed. In this study the pancreatic polypeptide (PP) response to a mixed meal was evaluated in healthy subjects and in recently diagnosed type 1 diabetic patients. MATERIAL AND METHODS: The PP response was studied at different levels of the vagally mediated reflex arch by application of different stimuli: meal ingestion, i.v. edrophonium (a cholinesterase inhibitor) injection and arginine infusion. RESULTS: Meal ingestion (stimulation of cerebral/vagal level) resulted in a significant and similar PP response in the two groups; i.v. edrophonium injection (stimulating at the second neuron level) resulted in a smaller increase in PP concentrations in the type 1 diabetic patients as compared with the healthy subjects, whereas direct PP-cell stimulation by arginine infusion resulted in similar increments in PP concentrations in the two groups. Thus, in recently diagnosed type 1 diabetic patients with no known manifestations of diabetic neuropathy, the cholinergic second neuron function of the vagal arch to the pancreas is impaired, whereas intrinsic PP-cell function is unaffected. CONCLUSIONS: This abnormality in cholinergic second neuron function of the vagal reflex arch and the fact that three of the healthy subjects had no increase in PP concentrations at all during the meal test indicates that PP response to a mixed meal is unsuitable for the diagnosis of autonomic neuropathy in type 1 diabetes. The nature of the defect in the second neuron of the vagal innervation of the pancreas in type 1 diabetes remains to be elucidated.

A low-fat diet improves peripheral insulin sensitivity in patients with Type 1 diabetes.

AIMS: To compare the effects on insulin sensitivity, body composition and glycaemic control of the recommended standard weight-maintaining diabetes diet and an isocaloric low-fat diabetes diet during two, 3-month periods in patients with Type 1 diabetes. METHODS: Thirteen Type 1 patients were included, of whom 10 completed the cross-over study. Ten non-diabetic, matched control subjects were also examined. Body composition was estimated by dual-energy X-ray absorptiometry (DXA) whole-body scanning, diet intake was monitored by 7-day dietary record and insulin sensitivity was measured by the insulin clamp technique at baseline and after each of the diet intervention periods. RESULTS: On an isocaloric low-fat diet, Type 1 diabetic patients significantly reduced the proportion of fat in the total daily energy intake by 12.1% (or -3.6% of total energy) as compared with a conventional diabetes diet (P = 0.039). The daily protein and carbohydrate intake increased (+4.4% of total energy intake, P = 0.0049 and +2.5%, P = 0.34, respectively), while alcohol intake decreased (-3.2% of total energy intake, P = 0.02). There was a significant improvement in insulin sensitivity on the isocaloric, low-fat diet compared with the standard diabetes diet [7.06 +/- 2.16 mg/kg/min (mean +/- sd) vs. 5.52 +/- 2.35 mg/kg/min (P = 0.03)]. However, insulin sensitivity remained 33% lower than in the control subjects (P = 0.021). No significant changes occurred in body weight or body composition. Glycated haemoglobin rose during both diet intervention periods (P = 0.18), with no difference between the two diets. CONCLUSIONS: Change to an isocaloric, low-fat diet in Type 1 diabetic patients during a 3-month period resulted in significant improvement in insulin sensitivity without improvement in glycaemic control. However, insulin sensitivity remained 33% lower than in control subjects.

Left ventricular dysfunction in normotensive Type 1 diabetic patients: the impact of autonomic neuropathy.

AIMS: The pathophysiological mechanisms responsible for increased cardiovascular mortality in diabetic autonomic neuropathy (AN) are largely unknown. The aim was to determine the relative role of AN in the pathogenesis of cardiac diastolic dysfunction and left ventricular hypertrophy in Type 1 diabetes. METHODS: Ten Type 1 diabetic patients with AN, defined by cardiovascular tests (AN+) and 10 age- and sex-matched patients without neuropathy (AN-) as well as 10 healthy subjects (C) participated in the study. Left ventricular diastolic function was assessed by Doppler echocardiography, whilst systolic function was evaluated by cine magnetic resonance (MR) imaging. RESULTS: Doppler echocardiography showed a significant decrease in E/A ratio, i.e. the ratio between peak Early transmitral filling velocity during early diastole (E-wave) and peak transmitral Atrial filling velocity during late diastole (A-wave), in AN+ compared with C (P < 0.01) [0.95 +/- 0.08 (mean +/- sem) (AN+); 1.19 +/- 0.09 (AN-); 1.33 +/- 0.10 (C)]. The E-wave deceleration time was significantly shorter in AN+ compared with AN- and C (P < 0.02) [178 +/- 7 ms (AN+); 203 +/- 9 ms (AN-); 205 +/- 9 ms (C)]. Cine MR imaging showed a significantly greater left ventricular mass index in AN+ compared with C [103 +/- 4 g/m(2) (AN+) vs. 98 +/- 7 (AN-) and 92 +/- 4 g/m(2) (C), P < 0.05]. CONCLUSION: Autonomic neuropathy is associated with left ventricular hypertrophy and diastolic dysfunction in Type 1 diabetic patients.

Body composition in adults with Type 1 diabetes at onset and during the first year of insulin therapy.

AIMS: To describe body composition in patients with Type 1 diabetes at diagnosis and during the first year after initiation of insulin therapy. RESEARCH DESIGN AND METHODS: In 10 (eight male and two female) newly onset Type 1 patients, age 31.5 +/- 3.2 years (27-37 years) (sd and range), body mass index (BMI) 20.8 +/- 1.6 (19.2-23.4) kg/m2, body composition was estimated by means of dual-energy X-ray absorptiometry (DXA) whole body scanning supplemented by estimation of total body water (TBW) (isotope dilution technique with 3H2O) at diagnosis and after 1, 3, 6 and 12 months of insulin therapy. RESULTS: During the first year after onset of diabetes body weight (BW) increased 4.3 +/- 2.9 (0.1-8.3) kg (P = 0.0012) distributed as a 13.3% (1.6 kg) increase in total fat mass (FM) and 4.9% (2.5 kg) increase in lean body soft tissue mass (LBM). The self-reported weight loss at onset was 6.3 +/- 2.5 kg (1.5-10.0 kg). Compared with two reference populations the Metropolitan Life Insurance Co. and a healthy age and sex-matched local DXA scanned group the initial body composition data demonstrated BW 6.2 kg below ideal weight and a significant reduction of the FM (25% or -0.87 sd), whereas LBM was within the expected range. CONCLUSIONS: During the first year after onset of Type 1 diabetes the mean increase in BW is 6.5% with a 13.3% increase in FM and a 4.9% increase in LBM. Self-reported data on premorbid BW suggest an approximately 10% reduction in BW at onset of Type 1 diabetes. Compared with a healthy reference population initial body composition data demonstrate a 25% reduction of the FM, whereas only a minor and non-significant reduction in the LBM is encountered. These data indicate that uncontrolled diabetes is rather a fat catabolic state than, as previously believed, a protein catabolic state.

Minor long-term changes in weight have beneficial effects on insulin sensitivity and beta-cell function in obese subjects.

AIM: To evaluate the long-term effect of changes in body composition induced by weight loss on insulin sensitivity (SI), non-insulin mediated glucose disposal, glucose effectiveness (SG)and beta-cell function. DESIGN: Glucose metabolism was evaluated before and after participation in a two-year weight loss trial of Orlistat vs. placebo, combined with an energy and fat restricted diet. SUBJECTS: Twelve obese patients (11 women, 1 man), age 45.8 +/- 10.5 years, body weight (BW) 99.7 +/- 13.3 kg, BMI 35.3 +/- 2.8 kg/m(2). MEASUREMENTS: At inclusion and 2 years later an oral glucose tolerance test (OGTT) and a frequently sampled intravenous glucose tolerance test (FSIGT) were performed. Body composition was estimated by a dual-energy X-ray absorptiometry (DXA) whole body scanning. RESULTS: The patients obtained varying changes in BW ranging from a weight loss of 17.8 kg to a weight gain of 6.0 kg. Corresponding changes in fat mass (FM) varied from a 40% reduction to a19% increase. A significant decrease in both fasting (p = 0.038) and 2 h (p = 0.047) blood glucose at OGTT was found. The improvement in insulin sensitivity (SI) estimated by means of Bergmans Minimal Model, was significantly and linearly correlated to change in total FM (r = - 0.83,p = 0.0026). A multiple regression analysis showed that changes in truncal FM was the strongest predictor of change in S(I) explaining 67% of the variation. First phase insulin response (AIRg)remained unchanged whereas insulin disposition index increased significantly (p = 0.044). At inclusion five patients had impaired glucose tolerance of which four, who lost weight, were normalized at the retest 2 years later. CONCLUSION: In obese subjects long-term minimal or moderate changes in weight were found to be linearly associated with changes in insulin sensitivity. In obese subjects with impaired glucose tolerance even a minor weight loss was able to normalize glucose tolerance.

[The effect of sibutramine for the maintenance of weight loss. A randomized controlled clinical trial]. / Effekt af sibutramin til vaegttabsvedligeholdelse. En randomiseret klinisk kontrolleret undersøgelse.

INTRODUCTION: Sibutramine is a tertiary amine that has been shown to induce dose-dependent weight loss and enhance the effects of a low-calorie diet for up to a year. We did a randomised, double-blind trial to assess the usefulness of sibutramine in maintaining substantial weight loss over 18 months. METHODS: Eight European centres recruited 605 obese patients (BMI 30-45 kg/m2) for a 6-month period of weight loss with sibutramine (10 mg/day) in combination with an individualised dietary deficit programme of 600 kcal/day based on the measured resting rates of energy expenditure. Of these 605, 467 (77%) patients with more than a 5% weight loss were then randomly assigned to 10 mg/day sibutramine (n = 352) or placebo (n = 115) for a further 18 months. Sibutramine was increased up to 20 mg/day if a weight regain occurred. RESULTS: One hundred and forty-eight (42%) subjects in the sibutramine group and 58 (50%) in the placebo group dropped out. Of the 204 subjects receiving sibutramine who completed the trial, 89 (43%) maintained 80% or more of their original weight loss, compared with nine (16%) of the 57 subjects in the placebo group (odds ratio 4.64, p < 0.001). Substantial decreases were seen over the first six months in triglycerides, VDL cholesterol, insulin, C peptide, and uric acid; changes, which were sustained in the sibutramine group, but not in the placebo group. Concentrations of HDL cholesterol rose substantially in the second year: overall increases were 20.7% (sibutramine) and 11.7% (placebo, p < 0.001). Twenty (3%) patients were withdrawn because of raised blood pressure; in the sibutramine group, from baseline to two years systolic blood pressure rose by 0.1 mmHg (SD 12.9), diastolic blood pressure by 2.3 mmHg (9.4), and pulse rate by 4.1 beats/min (11.9). CONCLUSION: This individualised management programme achieved a weight loss in 77% of obese patients and a sustained weight loss in most patients continuing therapy for two years. Changes in the concentrations of HDL cholesterol, VDL cholesterol, and triglyceride, but not in the LDL cholesterol, exceed those expected either from a weight loss alone or when induced by other selective therapies for low concentrations of HDL cholesterol relating to coronary heart disease.

Predictors of weight loss and maintenance during 2 years of treatment by sibutramine in obesity. Results from the European multi-centre STORM trial. Sibutramine Trial of Obesity Reduction and Maintenance.

BACKGROUND: In this report we assess pre-treatment determinants of weight loss and maintenance outcome in The Sibutramine Trial of Obesity Reduction and Maintenance (STORM), a 2 y randomized, double-blind, placebo-controlled, European multicenter study examining the effect of sibutramine (Sib) on inducing and maintaining weight loss in obese subjects. MATERIAL: A total of 605 obese patients (BMI: 30-45 kg/m2) of both gender were included from eight European centers and treated for 24 months. The patients were treated for the initial 6 months by Sib (10 mg/day) and a low-fat low-energy, individualized diet (600 kcal/day deficit). The 467 patients who achieved >5% weight loss after 6 months were randomized 3∶1 to Sib (10 mg/day) (Sib/Sib) and placebo (Sib/Pla) for weight maintenance over a further 18 months. MAIN OUTCOME AND ANALYSES: Pre-treatment individual characteristics were assessed as predictors of 6 months weight loss (kg) and 24 months weight maintenance using simple and multivariate correlation and regression analyses. RESULTS: In univariate analyses, the 6 month weight loss (n=505) was positively associated with pre-treatment body weight (r=0.27), height (r=0.18), fat-free mass (r=0.21) (all P<0.001), fat mass (r=0.13, P<0.03), and resting metabolic rate (r=0.13, P<0.003). However, no relation was found with age, gender, smoking status, age at onset of obesity, or number of previous slimming attempts. The same predictors were found for weight change to endpoint in the Sib/Sib group (n=350), while no predictors were identified in the Sib/Pla (n=114). In the multivariate regression analysis only pre-treatment body weight predicted weight loss at 6 months (P<0.001). Weight change (kg) to 24 month was predicted by: 4.34+0.07*body weight (kg)-4*treatment (Sib=1, Pla=0)-0.06*age (y), (r2=8%, P<0.001). CONCLUSION: Only pre-treatment body weight seems to be an important independent predictor of 6 months weight loss and 24 month weight maintenance in this study on diet and Sib. As only 8% of the variation in 24 months weight change could be explained by the predictors, the clinical value of this information is limited.

Gene expression of a truncated and the full-length growth hormone (GH) receptor in subcutaneous fat and skeletal muscle in GH-deficient adults: impact of GH treatment.

In humans at least two GH receptors are significantly expressed. One is the full-length receptor (GHR); the other is a truncated form (GHRtr), that lacks most of the intracellular domain. This receptor may inhibit the action of the full-length receptor. Circulating GH-binding protein (GHBP) is a proteolytically cleaved product from both of these receptors. The clinical relevance of the different receptor types is unknown. We examined the gene expression of GHR and GHRtr in human adipose tissue and skeletal muscle and the influence of GH treatment on this expression. Furthermore, we studied the relationship of circulating GHBP and body composition to GHR and GHRtr gene expression. Eleven adult GH-deficient patients were studied before and after 4 months of GH substitution therapy. Abdominal fat obtained by liposuction and femoral muscle biopsies were taken at baseline and after 4 months. Gene expression of GHR and GHRtr in adipose tissue and skeletal muscle was determined and expressed relative to the expression of beta-actin. Gene expression of GHR in abdominal sc adipose tissue was not altered, whereas the expression of GHRtr increased significantly. In skeletal muscle inverse changes were seen in the expression of messenger ribonucleic acid (mRNA) levels for the two GH receptor forms: expression of GHR increased significantly, whereas mRNA levels for GHRtr decreased. As expected, body composition changed with reduction of body fat mass after 4 months of GH treatment. Levels of circulating GHBP decreased significantly. We conclude that GH treatment in GH-deficient adults changes the expression of mRNA for GHR and GHRtr in adipose tissue and skeletal muscle. Whether these changes are responsible for the observed changes in body composition in response to GH treatment and the observed changes in levels of circulating GHBP, however, needs further elucidation.

Neuroendocrine responses to hypoglycaemia decrease within the first year after diagnosis of type 1 diabetes.

Neuroendocrine responses (adrenaline, noradrenaline and pancreatic polypeptide (PP)) to hypoglycaemia are often diminished in long-term diabetic patients, but the role of autonomic nervous system changes in these reductions is not yet fully clarified. In order to establish whether such changes in neuroendocrine responses occur early in the course of diabetes, we investigated the responses to insulin-induced hxypoglycaemia during the first year of type 1 diabetes. Autonomic and somatic nerve function tests were performed concomitantly. Six type 1 diabetes patients were studied 3 and 12 months after diagnosis of diabetes. Hypoglycaemia was induced by i.v. insulin infusion after an overnight normalization of blood glucose. Autonomic nerve function was evaluated by cardiovascular tests, and somatic nerve function by nerve conduction velocities A 50% reduction was found in adrenaline (p < 0.025) and noradrenaline (p < 0.05) responses to hypoglycaemia; PP, too, was significantly diminished at 12 months compared with 3 months after diagnosis of type 1 diabetes. Rate of glucose recovery did not differ at month 12 compared with month 3. Cardiovascular autonomic nerve function tests did not change and remained within the normal range throughout the study. Altered neuroendocrine responses to hypoglycaemia may occur early in the course of type 1 diabetes. These are unlikely to be due to structural changes (i.e. autonomic neuropathy), but rather to changes in central nervous system activity patterns, i.e. a higher threshold (i.e. a lower blood glucose level) for hypothalamic activation of the sympathoadrenal system.

The effect of 30 months of low-dose replacement therapy with recombinant human growth hormone (rhGH) on insulin and C-peptide kinetics, insulin secretion, insulin sensitivity, glucose effectiveness, and body composition in GH-deficient adults.

The aim of the present study was to evaluate the long-term (30 months) metabolic effects of recombinant human GH (rhGH) given in a mean dose of 6.7 microg/kg x day (= 1.6 IU/day), in 11 patients with adult GH deficiency. Glucose metabolism was evaluated by an oral glucose tolerance test and an iv (frequently sampled iv glucose tolerance test) glucose tolerance test, and body composition was estimated by dual-energy x-ray absorptiometry. Treatment with rhGH induced persistent favorable changes in body composition, with a 10% increase in lean body mass (P < 0.001) and a 12% reduction of fat mass (P < 0.002); however, the glucose tolerance deteriorated significantly, and three patients developed impaired glucose tolerance. Fasting insulin level (P < 0.003) and the homeostasis model assessment insulin resistance score increased significantly, indicating a deterioration in insulin sensitivity; whereas the insulin sensitivity index, calculated from the frequently sampled iv glucose tolerance test, only decreased slightly. The clearance of C-peptide and insulin increased 100% and 60%, respectively, and the prehepatic insulin secretion was tripled during rhGH treatment; but related to the impairment in glucose tolerance, beta-cell response was still inappropriate. Our conclusion is that long-term rhGH-replacement therapy in GH deficiency adults induced a significant deterioration in glucose tolerance, profound changes in kinetics of C-peptide, and insulin and prehepatic insulin secretion, despite an increase in lean body mass and a reduction of fat mass. Therefore, rhGH treatment may precipitate diabetes in some patients already susceptible to the disorder.

Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency.

BACKGROUND: Calcium and vitamin D homeostasis seem to be abnormal in patients with exocrine pancreatic dysfunction resulting from cystic fibrosis. Only a few studies have evaluated and described bone mineral metabolism in patients with chronic pancreatitis and pancreatic insufficiency. METHODS: Thirty-two patients with chronic pancreatitis and residual exocrine pancreatic function (group 1) and 26 patients with pancreatic exocrine insufficiency (i.e., meal-stimulated intraduodenal lipase <10% of lowest normal range and steatorrhea) (group 2) were studied. Serum levels of total calcium, phosphate, 25 (OH)D, 1.25(OH)2D, alkaline phosphatase, and parathyroid hormone were measured. Bone mineral density (BMD), bone mineral content (BMC), lean body mass (LBM), and fat mass (FM) were measured using a dual-energy X-ray absorptiometry (DXA) scanner. RESULTS: Alcohol was a causative factor in 79% of the patients. Fifty-six percent in group 1 and 69% in group 2 had Z-scores of the BMD < -1. The mean Z-score was -1.16 +/- 1.29 in group 1 and -1.32 +/- 0.90 in group 2. The mean Z-score of the BMC was -1.02 +/- 1.17 vs -1.39 +/- 0.987. In both groups mean 25 (OH)D and mean 1.25(OH)2D were below reference range. Plasma concentrations of albumin-corrected calcium, alkaline phosphatase, and parathyroid hormone were in the upper range of the reference range. Mean Z-scores of LBM were -0.69 +/- 1.34 in group 1 vs -1.01 +/- 1.12 in group 2 and Z-scores of FM were -0.27 +/- 1.70 in group 1 vs -0.95 +/- 1.01 in group 2 (p <0.05). CONCLUSION: Patients with chronic pancreatitis, in particular patients with advanced disease and steatorrhea, are at risk of developing significant bone loss. Despite normal body mass index the patients are characterized by loss of lean body mass and fat mass. The present study shows that these patients have decreased serum levels of vitamin D metabolites and low bone mass.

Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance.

BACKGROUND: Sibutramine is a tertiary amine that has been shown to induce dose-dependent weight loss and to enhance the effects of a low-calorie diet for up to a year. We did a randomised, double-blind trial to assess the usefulness of sibutramine in maintaining substantial weight loss over 2 years. METHODS: Eight European centres recruited 605 obese patients (body-mass index 30-45 kg/m2) for a 6-month period of weight loss with sibutramine (10 mg/day) and an individualised 600 kcal/day deficit programme based on measured resting metabolic rates. 467 (77%) patients with more than 5% weight loss were then randomly assigned 10 mg/day sibutramine (n=352) or placebo (n=115) for a further 18 months. Sibutramine was increased up to 20 mg/day if weight regain occurred. The primary outcome measure was the number of patients at year 2 maintaining at least 80% of the weight lost between baseline and month 6. Secondary outcomes included changes in uric acid concentrations and glycaemic and lipid variables. Analysis was by intention to treat. FINDINGS: 148 (42%) individuals in the sibutramine group and 58 (50%) in the placebo group dropped out. Of the 204 sibutramine-treated individuals who completed the trial, 89 (43%) maintained 80% or more of their original weight loss, compared with nine (16%) of the 57 individuals in the placebo group (odds ratio 4.64, p<0.001). Patients had substantial decreases over the first 6 months with respect to triglycerides, VLDL cholesterol, insulin, C peptide, and uric acid; these changes were sustained in the sibutramine group but not the placebo group. HDL cholesterol concentrations rose substantially in the second year: overall increases were 20.7% (sibutramine) and 11.7% (placebo, p<0.001). 20 (3%) patients were withdrawn because of increases in blood pressure; in the sibutramine group, systolic blood pressure rose from baseline to 2 years by 0.1 mm Hg (SD 12.9), diastolic blood pressure by 2.3 mm Hg (9.4), and pulse rate by 4.1 beats/min (11.9). INTERPRETATION: This individualised management programme achieved weight loss in 77% of obese patients and sustained weight loss in most patients continuing therapy for 2 years. Changes in concentrations of HDL cholesterol, VLDL cholesterol, and triglyceride, but not LDL cholesterol, exceed those expected either from weight loss alone or when induced by other selective therapies for low concentrations of HDL cholesterol relating to coronary heart disease.

The effect of the deterioration of insulin sensitivity on beta-cell function in growth-hormone-deficient adults following 4-month growth hormone replacement therapy.

The purpose of the present study was to evaluate the combined effect of GH treatment on body composition and glucose metabolism, with special focus on beta-cell function in adult GHD patients. In a double-blind placebo-controlled design, 24 GHD adults (18M/6F), were randomized to 4 months treatment with biosynthetic GH 2 IU/m2s.c. daily (n =13) or placebo (n =11). At inclusion and 4 months later an oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT) and dual-energy X-ray absorptiometry (DXA) whole-body scanning were performed. During the study period, body weight decreased 1.6 kg from 94.0 +/- 18.7 to 92.4 +/- 19.4 kg (mean +/- SD) (P<0.05) in the GH-treated group, but remained unchanged in the placebo group. Fat mass decreased from 32.4 +/- 9.6 to 28.1 +/- 10.5 kg (P<0.001), whereas lean body mass increased from 58.3 +/- 11.5 to 61.0 +/- 11.7 kg (P<0.01) in the GH-treated group. Treatment with GH for 4 months resulted in a significant increase in fasting blood glucose (before GH 5.0 +/- 0.3 and after 5.4 +/- 0.6 mmol/l, P<0.05), fasting plasma insulin (before GH 38.4 +/- 30.2 and after 55.3 +/- 34.7 pmol/l, P<0.02) and fasting proinsulin (before 8. 1 +/- 6.7 and after 14.6 +/- 16.1 pmol/l, P<0.05). The insulin sensitivity index SI, estimated by Bergmans Minimal Model, decreased significantly [before GH 1.1 +/- 0.7 and after 0.4 +/- 0.2 10(-4)(min x pmol/l), P<0.003]. The non-insulin-dependent glucose uptake (glucose effectiveness SG did not change (before GH 0.017 +/- 0.005 and after 0.015 +/- 0.006 min-1, NS). Insulin secretion was enhanced during GH therapy, but insufficiently to match the changes in SI, resulting in a higher blood glucose level during an OGTT. Blood glucose at 120 min was 5.5 and 6.3 mmol/l before and after GH treatment, respectively (P = 0.07). One patient developed impaired glucose tolerance. Short-term GH replacement therapy in a dose of about 2 IU/m2 daily in GHD adults induces a reduction in insulin sensitivity, despite favourable changes in body composition, and an inadequate enhancement of insulin secretion.

Long-term effects of growth hormone (GH) on body fluid distribution in GH deficient adults: a four months double blind placebo controlled trial.

OBJECTIVE: Short-term growth hormone (GH) treatment normalises body fluid distribution in adult GH deficient patients, but the impact of long-term treatment on body fluid homeostasis has hitherto not been thoroughly examined in placebo controlled trials. To investigate if the water retaining effect of GH persists for a longer time we examined the impact of 4 months GH treatment on extracellular volume (ECV) and plasma volume (PV) in GH deficient adults. DESIGN: Twenty-four (18 male, 6 female) adult GH deficient patients aged 25-64 years were included and received either GH (n=11) or placebo (n=13) in a double blind parallel design. METHODS: Before and at the end of each 4 month period ECV and PV were assessed directly using 82Br- and 125I-albumin respectively, and blood samples were obtained. RESULTS: During GH treatment ECV increased significantly (before: 20.48+/-0.99 l, 4 months: 23.77+/-1.38 l (P<0.01)), but remained unchanged during placebo administration (before: 16.92+/-1.01 l, 4 months: 17.60+/-1.24 l (P=0.37)). The difference between the groups was significant (P<0.05). GH treatment also increased PV (before: 3.39+/-0.27 l. 4 months: 3.71+/-0.261 (P=0.01)), although an insignificant increase in the placebo treated patients (before: 2.81+/-0.18 l, 4 months: 2.89+/-0.20 l (P=0.37)) resulted in an insignificant treatment effect (P=0.07). Serum insulin-like growth factor-I increased significantly during GH treatment and was not affected by placebo treatment. Plasma renin (mIU/l) increased during GH administration (before: 14.73+/-2.16, 4 months: 26.00+/-6.22 (P=0.03)) and remained unchanged following placebo (before: 20.77+/-5.13, 4 months: 20.69+/-6.67 (P=0.99)) leaving no significant treatment effect (P=0.08). CONCLUSION: The long-term impact of GH treatment on body fluid distribution in adult GH deficient patients involves expansion of ECV and probably also PV. These data substantiate the role of GH as a regulator of fluid homeostasis in adult GH deficiency.