Joseph Proietto

Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial.

CONTEXT Observational studies suggest that surgically induced loss of weight may be effective therapy for type 2 diabetes. OBJECTIVE To determine if surgically induced weight loss results in better glycemic control and less need for diabetes medications than conventional approaches to weight loss and diabetes control. DESIGN, SETTING, AND PARTICIPANTS Unblinded randomized controlled trial conducted from December 2002 through December 2006 at the University Obesity Research Center in Australia, with general community recruitment to established treatment programs. Participants were 60 obese patients (BMI >30 and <40) with recently diagnosed (<2 years) type 2 diabetes. INTERVENTIONS Conventional diabetes therapy with a focus on weight loss by lifestyle change vs laparoscopic adjustable gastric banding with conventional diabetes care. MAIN OUTCOME MEASURES Remission of type 2 diabetes (fasting glucose level <126 mg/dL [7.0 mmol/L] and glycated hemoglobin [HbA1c] value <6.2% while taking no glycemic therapy). Secondary measures included weight and components of the metabolic syndrome. Analysis was by intention-to-treat. RESULTS Of the 60 patients enrolled, 55 (92%) completed the 2-year follow-up. Remission of type 2 diabetes was achieved by 22 (73%) in the surgical group and 4 (13%) in the conventional-therapy group. Relative risk of remission for the surgical group was 5.5 (95% confidence interval, 2.2-14.0). Surgical and conventional-therapy groups lost a mean (SD) of 20.7% (8.6%) and 1.7% (5.2%) of weight, respectively, at 2 years (P < .001). Remission of type 2 diabetes was related to weight loss (R2 = 0.46, P < .001) and lower baseline HbA1c levels (combined R2 = 0.52, P < .001). There were no serious complications in either group. CONCLUSIONS Participants randomized to surgical therapy were more likely to achieve remission of type 2 diabetes through greater weight loss. These results need to be confirmed in a larger, more diverse population and have long-term efficacy assessed. TRIAL REGISTRATION actr.org Identifier: ACTRN012605000159651.

Evaluating the glucose tolerance test in mice

The objective of this study was to determine the optimal conditions under which to assess glucose tolerance in chow- and high-fat-fed C57BL/6J mice. Mice were fed either chow or high-fat diet for 8 wk. Variables tested were fasting duration (0-, 3-, 6-, and 24-h and overnight fasting), route of administration (intraperitoneal vs. oral) load of glucose given (2, 1, or 0.5 g/kg and fixed 50-mg dose), and state of consciousness. Basal glucose concentrations were increased in high-fat- compared with chow-fed mice following 6 h of fasting (9.1 +/- 0.3 vs. 7.9 +/- 0.4 mmol/l P = 0.01). Glucose tolerance was most different and therefore significant (P = 0.001) in high-fat-fed mice after 6 h of fasting (1,973 +/- 96 vs. 1,248 +/- 83 mmol.l(-1).120 min(-1)). The difference in glucose tolerance was greater following an OGTT (142%), in contrast to an IPGTT, with a 127% difference between high fat and chow. We also found that administering 2 g/kg of glucose resulted in a greater level of significance (P = 0.0008) in glucose intolerance in high-fat- compared with chow-fed mice. A fixed dose of 50 mg glucose regardless of body weight was enough to show glucose intolerance in high-fat- vs. chow-fed mice. Finally, high-fat-fed mice showed glucose intolerance compared with their chow-fed counterparts whether they were tested under conscious or anesthetized conditions. We conclude that 2 g/kg glucose administered orally following 6 h of fasting is best to assess glucose tolerance in mice under these conditions.

Estrogen deficiency causes central leptin insensitivity and increased hypothalamic neuropeptide Y.

OBJECTIVE: Altered fat distribution is a consequence of menopause, but the mechanisms responsible are unknown. Estrogen insufficiency in humans can be modeled using ovariectomized rats. We have shown that increased adiposity in these rats is due to reduced physical activity and transient hyperphagia, and can be reversed with 17β-estradiol treatment. The aims of this study were to examine whether this altered energy balance is associated with circulating leptin insufficiency, central leptin insensitivity, decreased hypothalamic leptin receptor (Ob-Rb) expression, and/or increased hypothalamic neuropeptide Y (NPY).METHODS: Plasma leptin levels, adipose tissue ob gene expression, energy balance responses to i.c.v. leptin, hypothalamic Ob-Rb expression and NPY concentration in five separate hypothalamic regions were measured in adult female rats after either ovariectomy or sham operations.RESULTS: Obesity was not associated with hypoleptinemia or decreased ob gene expression in ovariectomized rats; however, it was associated with insensitivity to central leptin administration. Food intake was less suppressed and spontaneous physical activity was less stimulated by leptin. This was not due to decreased hypothalamic Ob-Rb expression. NPY concentration in the paraventricular nucleus of the hypothalamus was elevated in the ovariectomized rats, consistent with leptin insensitivity; however this effect was transient and disappeared as body fat and leptin levels increased further and hyperphagia normalized.CONCLUSION: Impaired central leptin sensitivity and overproduction of NPY may contribute to excess fat accumulation caused by estrogen deficiency.

Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes

The prevalence of type 2 diabetes is rapidly increasing, with severe socioeconomic impacts. Excess lipid deposition in peripheral tissues impairs insulin sensitivity and glucose uptake, and has been proposed to contribute to the pathology of type 2 diabetes. However, few treatment options exist that directly target ectopic lipid accumulation. Recently it was found that vascular endothelial growth factor B (VEGF-B) controls endothelial uptake and transport of fatty acids in heart and skeletal muscle. Here we show that decreased VEGF-B signalling in rodent models of type 2 diabetes restores insulin sensitivity and improves glucose tolerance. Genetic deletion of Vegfb in diabetic db/db mice prevented ectopic lipid deposition, increased muscle glucose uptake and maintained normoglycaemia. Pharmacological inhibition of VEGF-B signalling by antibody administration to db/db mice enhanced glucose tolerance, preserved pancreatic islet architecture, improved β-cell function and ameliorated dyslipidaemia, key elements of type 2 diabetes and the metabolic syndrome. The potential use of VEGF-B neutralization in type 2 diabetes was further elucidated in rats fed a high-fat diet, in which it normalized insulin sensitivity and increased glucose uptake in skeletal muscle and heart. Our results demonstrate that the vascular endothelium can function as an efficient barrier to excess muscle lipid uptake even under conditions of severe obesity and type 2 diabetes, and that this barrier can be maintained by inhibition of VEGF-B signalling. We propose VEGF-B antagonism as a novel pharmacological approach for type 2 diabetes, targeting the lipid-transport properties of the endothelium to improve muscle insulin sensitivity and glucose disposal.

Of mice and men: the evolving phenotype of aromatase deficiency

We are rapidly becoming aware of the importance of estrogen in maintaining virtually all facets of male health. In order for estrogens to be synthesized endogenously, the enzyme responsible for their synthesis from androgens, aromatase, must be functional. The seven known men in whom aromatase is nonfunctional all have a mutation in either exon V or IX of the CYP19 gene, which encodes aromatase. Collectively, these men are reported to have undetectable estrogen; normal to high levels of testosterone and gonadotropins; tall stature with delayed skeletal maturation and epiphyseal closure; osteoporosis; impaired lipid and insulin metabolism; and impaired reproductive function. The aromatase knockout mouse presents with a phenotype that is similar in many aspects and provides a valuable tool with which to examine and manipulate the actions of estrogen. By studying the naturally occurring aromatase-deficient humans, together with studies of the aromatase-knockout mouse, we are expanding our understanding of the essential role of estrogen in male physiology.

Pharmacotherapy for obesity.

Pharmacotherapy for the management of obesity is primarily aimed at weight loss, weight loss maintenance and risk reduction, and has included thyroid hormone, amphetamines, phentermine, amfepramone (diethylpropion), phenylpropanolamine, mazindol, fenfluramines and, more recently, sibutramine and orlistat. These agents decrease appetite, reduce absorption of fat or increase energy expenditure.Primary endpoints used to evaluate anti-obesity drugs most frequently include mean weight loss, percentage weight loss and proportion of patients losing ≥5% and ≥10% of initial body weight. Secondary endpoints may include reduction in body fat, risk factors for cardiovascular disease and the incidences of diseases such as diabetes mellitus.Most pharmacotherapies have demonstrated significantly greater weight loss in patients on active treatment than those receiving placebo in short-term (≤1 year) randomised controlled trials of pharmacological treatment in conjunction with a calorie-controlled diet or lifestyle intervention. The evidence of long-term efficacy is limited to sibutramine (2 years) and orlistat (4 years). These are the only drugs currently approved for the long-term management of obesity in adults. Sibutramine recipients randomised following 6 months’ treatment to either sibutramine or placebo demonstrated significantly better weight maintenance at 2 years than those taking placebo (p < 0.001), with ≥10% loss of initial bodyweight in 46% of patients. For patients taking orlistat, weight loss was 2.2kg greater than those on placebo at 4 years (p < 0.001), with significantly more patients achieving ≥10% loss of initial bodyweight (26.2% and 15.6%, respectively; p < 0.001).Other drugs that have been evaluated for weight loss include ephedrine, the antidepressants fluoxetine and bupropion, and the antiepileptics topiramate and zonisamide. Two clinical trials with fluoxetine both reported no significant difference in weight loss compared with placebo at 52 weeks. Clinical trials evaluating ephedrine, bupropion, topiramate and zonisamide have demonstrated significantly greater weight loss than placebo but have been limited to 16–26 weeks’ treatment.A major obstacle to the evaluation of the clinical trials is the potential bias resulting from low study completion rates. Completion rates varied from 52.8% of phentermine recipients in a 9-month study, to 40% of fenfluramine recipients in a 24-week comparative study with phentermine and 18% of amfepramone recipients in a 24-week study. One-year completion rates range from 51% to 73% for sibutramine and from 66% to 85% for orlistat. Other potential sources of bias include run-in periods and subsequent patient selection based on compliance or initial weight loss.Several potential new therapies targeting weight loss and obesity through the CNS pathways or peripheral adiposity signals are in early phase clinical trials. Over the next decade the drug treatment of obesity is likely to change significantly because of the availability of new pharmacotherapies to regulate eating behaviours, nutrient partitioning and/or energy expenditure.

The defence of body weight: a physiological basis for weight regain after weight loss.

Although weight loss can usually be achieved by restricting food intake, the majority of dieters regain weight over the long-term. In the hypothalamus, hormonal signals from the gastrointestinal tract, adipose tissue and other peripheral sites are integrated to influence appetite and energy expenditure. Diet-induced weight loss is accompanied by several physiological changes which encourage weight regain, including alterations in energy expenditure, substrate metabolism and hormone pathways involved in appetite regulation, many of which persist beyond the initial weight loss period. Safe effective long-term strategies to overcome these physiological changes are needed to help facilitate maintenance of weight loss. The present review, which focuses on data from human studies, begins with an outline of body weight regulation to provide the context for the subsequent discussion of short- and long-term physiological changes which accompany diet-induced weight loss.

Safety of Drug Therapies Used for Weight Loss and Treatment of Obesity

Some of the medications used for weight loss in the management of obesity have been associated with unacceptable morbidity and mortality. Safety concerns have led to the withdrawal of aminorex, followed by the fenfluramines in 1997, and phenylpropanolamine (norephedrine) in 2000. Aminorex was associated with an increased prevalence of primary pulmonary hypertension (PPH), fenfluramines with an increased prevalence of PPH and valvulopathy, and phenylpropanolamine with an increased risk of haemorrhagic stroke.Several studies have investigated the safety of the fenfluramines, yet the benefit-risk profile has not been conclusively quantified. This is due to several deficiencies in the published studies, including a lack of data on the baseline prevalences of comorbid conditions in obese subjects, and potential confounders and biases in the study designs. Although several studies and systematic reviews support an increased risk of PPH and valvulopathy in patients who have taken fenfluramines, without knowledge of the background prevalence it is not possible to determine if the exposure preceded the outcome. The population at higher risk of these adverse effects includes those taking higher doses or with a longer duration of exposure to fenfluramines and those with pre-existing cardiac disease or a genetic predisposition. Patients exposed to fenfluramines continue to be monitored, with some follow-up studies indicating no overall worsening in valvulopathy over time.There are limited efficacy and safety data for amfepramone (diethylpropion) and phentermine and their approval for the management of obesity is limited to short-term use. Orlistat and sibutramine are the only currently approved medications for long-term management of obesity. Although the benefit-risk profiles of sibutramine and orlistat appear positive, sibutramine continues to be monitored because of long-term safety concerns.The safety and efficacy of currently approved drug therapies have not been evaluated in children and elderly patient populations and there is limited information in adolescents, whilst the long-term safety of current and potential new drug therapies in adults will require several years of postmarketing surveillance to fully elucidate their adverse effect profiles.

Aromatase-deficient (ArKO) mice accumulate excess adipose tissue.

Aromatase is the enzyme which catalyses the conversion of C19 steroids into C18 estrogens. We have generated a mouse model wherein the Cyp19 gene, which encodes aromatase, has been disrupted, and hence, the aromatase knockout (ArKO) mouse cannot synthesise endogenous estrogens. We examined the consequences of estrogen deficiency on accumulation of adipose depots in male and female ArKO mice, observing that these animals progressively accrue significantly more intra-abdominal adipose tissue than their wildtype (WT) litter mates, reflected in increased adipocyte volume and number. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared to WT controls, as were elevated insulin levels, although blood glucose was unchanged. Associated with these changes, the livers of ArKO animals were characterised by a striking accumulation of lipid droplets. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.

Effect of temperature on muscle metabolism during submaximal exercise in humans.

To study the effect of temperature on muscle metabolism during submaximal exercise, six endurance‐trained men had one thigh warmed and the other cooled for 40 min prior to exercise using water‐perfused cuffs. One cuff was perfused with water at 50‐55°C (HL) with the other being perfused with water at 0°C (CL). With the cuffs still in position, subjects performed cycling exercise for 20 min at a work load corresponding to 70% VO2,peak (where VO2,peak is peak pulmonary oxygen uptake) in comfortable ambient conditions (20‐22°C). Muscle biopsies were obtained prior to and following exercise and forearm venous blood was collected prior to and throughout the exercise period. Muscle temperature (Tmus) was not different prior to treatment, but treatment resulted in a large difference in pre‐exercise Tmus (difference = 6·9 ± 0·9°C; P < 0·01). Although this difference was reduced following exercise, it was nonetheless significant (difference = 0·4 ± 0·1°C; P < 0·05). Intramuscular [ATP] was not affected by either exercise or muscle temperature. [Phosphocreatine] decreased (P < 0·01) and [creatine] increased (P < 0·01) with exercise but were not different when comparing HL with CL. Muscle lactate concentration was not different prior to treatment nor following exercise when comparing HL with CL. Muscle glycogen concentration was not different when comparing the trials before treatment, but the post‐exercise value was lower (P < 0·05) in HL compared with CL. Thus, net muscle glycogen use was greater during exercise with heating (208 ± 23 vs. 118 ± 22 mmol kg−1 for HL and CL, respectively; P < 0·05). These data demonstrate that muscle glycogen use is augmented by increases in intramuscular temperature despite no differences in high energy phosphagen metabolism being observed when comparing treatments. This suggests that the increase in carbohydrate utilization occurred as a direct effect of an elevated muscle temperature and was not secondary to allosteric activation of enzymes mediated by a reduced ATP content.