Insulin Action and Its Disturbances in Disease - part 10

542 THERAPEUTIC STRATEGIES FOR INSULIN RESISTANCE range, although these levels were lower than those of placebo-treated patients in some trials. It is therefore recommended the diet should be rich in fruit and vegetables. In addition to this, NICE has recommended that the patient should have already lost 2.4 kg by diet and exercise prior to starting orlistat; their BMI should be above 30 kg/m2 or 28 kg/m2 if they have other co-morbidities. Patients should receive appropriate dietary advice from health professionals. Continuation of treatment beyond 3 months should be accompanied by a weight loss of five per cent from the initial body weight and beyond six months by a loss of 10 per cent.38, 39 Sibutramine Sibutramine is an orally administered, centrally acting weight management agent. It is apparently devoid of amphetamine-like abuse potential. The primary (BTS 54 505) and secondary (BTS 54 354) amine metabolites of sibutramine are pharmacologically active and are thought to induce the natural processes leading to the enhancement of satiety and thermogenesis by inhibiting serotonin and noradrenaline re-uptake. The pharmacological activity of sibutramine does not appear to be a result of increased serotonin release; this differentiates it from the action of dexfen-fluramine, which predominantly causes the release of serotonin and dexamphe-tamine, which predominantly releases dopamine and noradrenaline. This may account for the lack of abuse potential with sibutramine.40 The drug undergoes first pass metabolism to form pharmacologically active primary (M1) and sec-ondary (M2) metabolites. In trials steady state plasma metabolite concentrations were maintained throughout treatment.41 Plasma concentrations of sibutramine anditsmetabolitesareunaffectedbythepresenceofrenaldysfunction.42 However, sibutramine is contraindicated in patients with significant hepatic dysfunction. In most trials sibutramine was administered with a reduced calorie diet and activity advice. Trial data has shown weight loss in up to 77 per cent of patients treated with sibutramine 10 mg/day and a 600 kcal/day deficit diet. There was also sustained weight loss in patients continuing therapy for 2 years.43 At higher doses (up to 30 mg/day), greater initial weight loss has been reported.44 Patients receiving 10–20 mg/day lost 5.0–7.5 kg of body weight over an 8–12 week period, compared with placebo recipients, who lost between 1.5 and 3.5 kg. In individuals with type 2 diabetes, weight loss of more than 10 per cent was achieved by a third of subjects on sibutramine, and this weight loss was associ-ated with improvements in both metabolic control and quality of life.45 However, in the UK, the NICE guidelines state that sibutramine should only be prescribed as part of an overall treatment plan for the management of nutritional obesity in people aged 18–65 years who have either a BMI of >27.0 kg/m2 in the presence of co-morbidities or >30 kg/m2 without associated co-morbidities. The recommended starting dose of sibutramine is 10 mg o.d. with or without food. Sibutramine should be used in conjunction with a reduced calorie diet. SURGICAL MANAGEMENT OF OBESITY 543 If a weight loss of 1.8 kg is not achieved within the first 4 weeks of therapy, either an increase in the dose to 15 mg o.d. or discontinuation of sibutramine should be considered. Dosages higher than 15 mg are not recommended. The most commonly reported adverse effects include headache, dry mouth, anorexia, insomnia and constipation. Statistically significant increases in blood pressure and heart rate (compared with placebo) were observed in obese patients without hypertension who received sibutramine. Blood pressure monitoring is therefore required before, and at regular intervals during, therapy. Treatment with sibu-tramine is not recommended for individuals whose blood pressure before the start of therapy is >145/90 mm Hg. It should be discontinued if it rises above this level or if the increase is greater than 10 mm Hg.38 Sibutramine should not be given to patients with poorly controlled hypertension, and it is also con-traindicated for patients with coronary heart disease, congestive cardiac failure, arrhythmia, stroke or severe renal or hepatic impairment.40 18.7 Surgical management of obesity Surgery as a treatment for obesity is not new. Techniques such as jaw wiring and stapled gastroplasty have been used for some time with variable results and complications. In some carefully selected patients newer surgical techniques (performed by a surgeon with experience in this field) can achieve a weight loss of up to 60 per cent. There are two approaches, either restrictive or malabsorptive surgical techniques. Many procedures involve a combination of these. Techniques to restrict intake include the stapled gastroplasty, an operation devised by Mason in 1982. It involves dividing the stomach by a line of staples intoasmallupperpouchwithacapacityofabout15 ml,whichcommunicateswith the main body of the stomach via a stoma about 9 mm in diameter (Figure 18.2). When the patient eats or drinks, the pouch rapidly fills and stops further ingestion. This procedure iseffective at limitingintakeof solidfood, but liquidscan be taken fairly easily. Over time the pouch tends to stretch, thus allowing more intake. The procedure is relatively safe because the bowel is not cut open and food is nor-mally digested and absorbed. The average weight loss at 1 year is 28.8 kg. More recently, extra-gastric banding has been used. Again this restricts the capacity of the stomach but it is achieved by wrapping an inextensible material around the outside. This can be done by either open or laproscopic techniques. In a multi-centre study of 70 consecutive patients the excess weight loss in morbidly obese patients was 59 per cent (pre-op mean BMI = 45.2 kg/m2).46 This approach to weight loss has been shown to have associated improvement in insulin sensitivity and β-cell function. In a series of 254 patients who underwent adjustable gas-tric banding paired data from pre-operative and 1 year follow-up biochemistry showed marked improvement in insulin resistance.47 Malabsorptive procedures include the gastric bypass, bilio-pancreatic diver-sion and jejuno-ileal bypass. The current gold standard is the Roux en Y gastric 544 THERAPEUTIC STRATEGIES FOR INSULIN RESISTANCE Figure 18.2 Cartoons show the principles of the bilio-pancreatic bypass and lap-band pro-cedures for bariatric surgery (illustrations kindly supplied by Robert, E. Brolin, M. D., New Jersey Bariatrics, www.njbariatricspc.com) bypass (Figure 18.2). This can have results of greater than 50 per cent weight loss in over 80 per cent of patients, corresponding to a fall of 15 BMI units in morbidly obese patients (BMI > 40 kg/m2) and 20 BMI units in super-obese patients (BMI > 50 kg/m2).48 An ongoing intervention study, the Swedish Obe-sity Study (SOS), enrolled over 2000 surgically treated patients and a similar number of matched controls. After 2 years follow-up the surgically treated patients had lost an average of 28 kg and the incidence of diabetes was reduced by 90 per cent.49 Complications from surgery in this high risk group include immediate cardiorespiratory complications with pulmonary embolus accounting for the majority of deaths. Abdominal wall complications occur in 6–10 per cent. Later complications include pouch dilation/erosion of the bands or staple line disruption, diarrhoea and the dumping syndrome. Nutritional complications are very common after bypass techniques and many patients require iron, folate and B12 supplementation.50 18.8 Pharmacological treatment of insulin resistance Metformin Metformin is the only biguanide available for clinical use. Although metformin has a small effect as a peripheral insulin sensitizer, it primarily works by PHARMACOLOGICAL TREATMENT OF INSULIN RESISTANCE 545 reducing hepatic gluconeogenesis and hepatic glycogenolysis, and by enhancing insulin-stimulated glucose uptake and glycogenesis by skeletal muscle.51 This effect may be mediated through stimulation of AMP-activated protein kinase.52 It does not cause hypoglycaemia or weight gain, which is extremely advantageous for many patients with associated obesity. Following the results of metformin in the United Kingdom Prospective Diabetes Study (UKPDS), it has become the first line pharmacological treatment for type 2 diabetes in overweight individu-als in the United Kingdom.53 Beneficial effects for metformin in patients with insulin resistance but without type 2 diabetes have also been shown. Althoughnotatrueinsulinsensitizer,metformintreatmentlowerplasmainsulin levels and corrects many of the non-traditional cardiovascular risk factors associ-ated with the insulin resistance syndrome. Various studies have used metformin in patients with polycystic ovarian syndrome with positive effects both on weight and sex-hormone-binding globulin, androgens and insulin resistance above that of diet alone.54, 55 Patients with acanthosis nigricans given metformin have also shown a reduction in hyperinsulinaemia, body weight and fat mass and improved insulin sensitivity.56 Patients with impaired glucose tolerance but not overt dia-betes have been treated with metformin and diet in various studies. It has been shown that metformin also improves insulin resistance in these individuals and in some studies there appears to be an anti-obesity effect.57, 58 However, the use of metformin does not appear to alter the long term susceptibility of developing type 2 diabetes above the use of diet and lifestyle modifications alone.19 Side-effects in the gut include bloating, flatulence, diarrhoea and epigastric discomfort, which are common at the start of therapy. These can be minimized by starting at a low dose of 500 mg once or twice daily with meals. These side-effects resolve with time in many patients and the dose can be increased to a therapeutic level of 1 g twice daily. The drug is contraindicated in patients with renal impairment as it is excreted unchanged in the urine and excess accu-mulation causes hyperlactataemia and the risk of the rare complication of lactic acidosis. Other conditions leading to tissue hypoxia, for example severe heart failure or advanced liver disease, also exclude the use of metformin. Thiazolidinediones Thiazolidinediones (TZDs) are novel compounds chemically and functionally unrelated to other oral blood-glucose-lowering agents. The antihyperglycaemic effects of TZDs were noticed by actions of ciglitazone on obese and diabetic animals in the early 1980s. Many agents in this class have followed, including troglitazone, pioglitazone and rosiglitazone. A thiazolidine-2-4-dione structure is common to all agents of this class, but they possess different side-chains that influence their pharmacological actions and potential for adverse effects. Trogli-tazone was introduced for clinical use in 1997 in Japan, the United States and United Kingdom, but its use was voluntarily suspended in the United Kingdom 546 THERAPEUTIC STRATEGIES FOR INSULIN RESISTANCE O CH3 N H3C O O S Troglitazone CH3 O HO CH3 O Et N Pioglitazone S N O O O CH3 S N Rosiglitazone N N O O Figure 18.3 Structure of rosiglitazone and pioglitazone as distinct from troglitazone in December 1997 following reports of side-effects on the liver and subsequently it was withdrawn worldwide due to problems with idiosyncratic hepatotoxicity. It is the α-tocopherol moiety on the side-chain of troglitazone that was thought to be implemented in hepatotoxicity (Figure 18.3). Thiazolidinediones (TZDs) have emerged as an important therapeutic drug class in the management of type 2 diabetes mellitus. Administration of a thi-azolonedione results in increased insulin sensitivity in insulin-resistant mam-mals.59–61 This is thought to be associated with increased insulin gene expression in both skeletal muscle and adipose tissue and increased intrinsic activity of glu-cose transporters.62 The actions of the TZDs are mediated through binding and activation of the peroxisome proliferator-activated receptor (PPAR) γ, a nuclear receptor that has a regulatory role in the differentiation of cells, particularly adipocytes.63, 64 Since TZDs mediate their effects via gene transcription, the maximal therapeutic effect is seen 6–8 weeks after start of therapy. PPAR-γ is expressed mainly in white and brown adipocytes, where it is complexed to the retinoid X receptor (RXR) within the nucleus. Being lipophilic, TZDs enter the cells and bind to PPAR-γ with high affinity. This causes a conformational change in the PPAR-γ–RXR complex, which displaces a co-repressor and allows activation of regulatory sequences of DNA, which in turn controls expression of specific genes. Thus, increased expression of insulin-sensitive genes, through the activation of PPAR-γ, is perceived as the main mechanism by which TZDs reduce insulin resistance. At least some of these ... - tailieumienphi.vn