P. G. Kopelman

Effect of sibutramine on weight maintenance after weight loss: a randomised trial*

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0.001). 20 (3%) patients were withdrawn because of increases in blood pressure; in the sibutramine group, systolic blood pressure rose from baseline to 2 years by 0.1 mm Hg (SD 12.9), diastolic blood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.

Leptin levels do not change acutely with food administration in normal or obese subjects, but are negatively correlated with pituitary‐adrenal activity

Leptin is a peptide secreted by white adipose tissue which has been shown to have a major influence on body weight regulation, while animal studies have revealed widespread interconnections between leptin and other endocrine systems, especially with insulin. However, its acute regulation has been little studied in the human. We have therefore investigated the effect of a 1000 kcal meal and fasting on the levels of leptin, insulin and cortisol, in both normal and obese subjects.

Central obesity and hyperinsulinaemia in women are associated with polymorphism in the 5‘ flanking region of the human insulin gene

Abstract. presented to the European Association for the Study of Diabetes, September 1990 and the 6th International Congress on Obesity, October 1990

Decreased sex hormone binding globulin (SHBG) and insulin-like growth factor binding protein (IGFBP-1) in extreme obesity

Obesity may be characterized by abnormal sex steroid secretion and reduced sex hormone binding globulin (SHBG) which in turn is related to fat distribution and insulin secretion. Recent in‐vitro and in‐vivo evidence suggests that insulin is the common mechanism regulating the secretion of SHBG and insulin‐like growth factor small binding protein (IGFBP‐1). IGFBP‐1 appears not only to be a carrier for insulin growth factors (IGFs) but also to play an active role in growth processes, independent of growth hormone secretion. We have examined the possible relationship between fasting insulin, SHBG, testosterone, IGF‐1, IGFBP‐1 and fat distribution in 25 extremely obese, menstruating women (mean weight 107 |Mp 3 kg) with normal glucose tolerance. Fat distribution was assessed from measurements of the waist to hip ratio (W/H). The obese women showed an elevated fasting insulin (mean |Mp SEM; 21 |Mp 2 μmo1/1), a normal IGF‐1, but reduced IGFBP‐1 (14.6 |Mp 2, μg/1); in 15 women IGFBP‐1 levels were undetectable by the present assay. In addition, SHBG levels were reduced in the obese women (24|Mp2 nmol/1) but total testosterone values (1.9 |Mp 0.1 nmo1/1) were normal. The elevated fasting insulin levels were positively correlated with increasing upper segment obesity as expressed by a rising W/I‐1 ratio (P < 0.01, r2=0.306) and inversely correlated with SHBG (P <0.01, r2= 0.483). Similarly, reduced SHBG values showed an inverse correlation with increasing W/H ratio (P < 0.001, r2= 0.383). No correlation was found between IGFBP‐1 and W/H ratio but a strong positive correlation was seen between IGFBP‐1 and SHBG (P < 0.001, r2=0.466). Furthermore, an equally significant inverse correlation was found between IGFBP‐1 and insulin levels (P <0.001, r2=0.474). Testosterone and fasting IGF‐1 did not show any correlation with the studied variables. Multivariate analysis suggested that insulin was the strongest factor involved in the regulation of IGFBP‐1 levels, whereas the level of SHBG was primarily determined by IGFBP‐1 concentration and W/H ratio. We conclude that reduced SHBG and IGFBP‐1 found in extreme obesity are inversely correlated to the prevailing hyperinsulinaemia and to increasing upper segment obesity. These findings provide further evidence to support the hypothesis for insulin being an important regulator of both binding proteins, SHBG and IGFBP‐1.

Differential stimulation of corticol and dehydropiandrosterone levels by food in obese and normal subjects: relation to body fat distribution

BACKGROUND It has been previously shown that food intake elevates circulating ACTH and cortisol levels, but no report has been published regarding the changes in circulating dehydroepiandrosterone (DHEA). DHEA was originally described as a weak androgen, but more recently it has been associated with a wide range of metabolic functions. In addition, previous studies have described a hyper‐responsive hypothalamo‐pituitary‐adrenal axis in obese subjects in response to various stimuli, but the specific response to food has not been studied.

trkA and trkC expression is increased in human diabetic skin

Nerve growth factor (NGF) is reduced in epidermal keratinocytes in human diabetic skin, and this decrease has been related to dysfunction of cutaneous sensory fibres. In vitro studies show that keratinocytes express both NGF and its high-affinity receptor, trkA, and that NGF may increase keratinocyte proliferation and its own expression via an autocrine loop. However, the level of trkA expression in vivo by keratinocytes in normal and diabetic skin is unknown. We have therefore measured trkA expression in calf skin biopsies from patients with early subclinical diabetic neuropathy and control subjects, using in situ hybridisation combined with image analysis quantification. Expression of trkC was also studied, as its endogenous ligand neurotrophin-3 (NT-3) is related to NGF, and is present in human epidermis. Hybridisation signal was seen for both trkA and trkC localised throughout the epidermal layer of control skin, with a higher density of silver grain deposition observed for trkA mRNA. However, in diabetic epidermis there was a significant increase (P < 0.001) for both trk A (control, 0.178 +/- 0.013; diabetic, 0.304 +/- 0.032; mean silver grain counts/microm2 +/- SEM) and trkC expression (controls, 0.059 +/- 0.004; diabetics, 0.191 +/- 0.010). The up-regulation of epidermal trk receptors may result from decreased autocrine neurotrophin action, and could represent a compensatory mechanism.

Hyperactivity of the hypothalamo‐pituitary‐adrenal axis in obesity: a study of ACTH, AVP, β‐lipotrophin and Cortisol responses to insulin‐induced hypoglycaemia

OBJECTIVE The purpose of this study was to determine whether alterations in the hypothalamo‐pituitary‐adrenal axis and arginine vasopressin secretion, which have been associated with animal obesity, also occur in man.

Genetic contribution of polymorphism of the GLUT1 and GLUT4 genes to the susceptibility to type 2 (non-insulin-dependent) diabetes mellitus in different populations

Polymorphic variation of genes encoding the glucose transporters glycoproteins (GLUT) may contribute to the genetic susceptibility to type 2 (non-insulin-dependent) diabetes. In this study we evaluated the allele and genotype frequencies of GLUT1 and GLUT4 restriction fragment length polymorphism (RFLP), revealed by digestion withXbaI for GLUT1 andKpnI for GLUT4, in Caucasian, Chinese, Japanese, Asian Indian and American black populations. No differences of theKpnI GLUT4 RFLP were found between control and diabetic subjects in any ethnic group or when all data are combined. In contrast, positive results were found for theXbaI RFLP: (1) most ethnic groups showed an association of allele 1 with type 2 diabetes, and this association was maintained when all groups were analysed together; (2) after stratifying for sex and obesity, this association was significant only for overweight/obese women. This joint analysis suggests that GLUT1 polymorphism may contribute to susceptibility to type 2 diabetes in some populations, and especially in overweight/obese women.

An association between hypothalamic‐pituitary dysfunction and peripheral endocrine function in extreme obesity

Summary. objective The aim was to Investigate a possible relation‐ship between measures of Insulin secretion and glucose disposal and hypothalamic–pituitary function In extreme obesity.

Investigation of obesity

Obesity is the most common nutritional disorder in the developed world and is assuming great significance in the developing world. Although obesity is the condition which results from excess body fat, few definitions are based on measuring or estimating the fat content. Indeed, both clinical practice and population studies depend only on measuring weight and height: weight corrected for the individual’s height is then accepted as a crude indication of the body’s fat content. A widely accepted method for simplifying the tables for weight and height is to calculate the body mass index (BMI) which is the weight in kilograms divided by the height in metres2 measured in indoor clothing without shoes. A normal BMI is between 20 and 25 kg/mZ whereas overweight is defined as a BMI of 25.1-29.9 kg/m2. Obesity is considered as a BMI > 30 kg/m* because a BMI above this level is associated with increasing morbidity and mortality. Obesity as a primary reason or as a secondary complicating factor is possibly the commonest presentation to all medical specialties.