Insulin Action and Its Disturbances in Disease - part 10 ppt

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/m 2 or 28 kg/m 2 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 and its metabolites are unaffected by the presence of renal dysfunction. 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/m 2 in the presence of co-morbidities or >30 kg/m 2 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 into a small upper pouch with a capacity of about 15 ml, which communicates with 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 is effective at limiting intake of solid food, but liquids can 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/m 2 ). 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/m 2 ) and 20 BMI units in super-obese patients (BMI > 50 kg/m 2 ). 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. Although not a true insulin sensitizer, metformin treatment lower plasma insulin 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 Troglitazone Pioglitazone Rosiglitazone O O S N CH 3 HO H 3 C CH 3 CH 3 O O N O S N O O Et N O S N O O N CH 3 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 PHARMACOLOGICAL TREATMENT OF INSULIN RESISTANCE 547 genes are also controlled by insulin, and TZDs amplify or mimic certain genomic effects of insulin on adipocytes. Activation of PPAR-γ is associated with control of the production, transport and utilization of glucose. The increased glucose transport has been attributed to increased production of the glucose transporter isoforms GLUT1 and GLUT4, and translocation of GLUT4 into the plasma membrane. Increased glucose trans- porter production and translocation into the plasma membrane in skeletal muscle and fat will contribute to improved glucose disposal and reduce glucose toxic- ity. Glucose toxicity will be further reduced by increased glucose disposal and decreased hepatic glucose production. The PPAR-γ receptor is also expressed in several other tissues, including vascular tissue. TZDs lower circulating triglyceride and non-esterified fatty acid concentrations, which may also contribute to improved insulin sensitivity 65 via the glucose fatty acid (Randle) cycle. Because free fatty acids are involved in lipid metabolism and also have deleterious effects on the vasculature, this reduction in plasma free fatty acids may have a beneficial effect on cardio- vascular disease. The lipid-lowering effect of TZDs appears to be independent of their glucose-lowering and their insulin-lowering effects, 66 and this effect has been attributed to decreased hepatic very low density lipoprotein (VLDL) synthesis and increased peripheral clearance, together with reduced lipolysis. It is important to note that TZDs have effects on numerous other genes, which may also be related to the effects seen on glycaemic control and insulin resis- tance. For example, they reduce circulating TNF-α , which may be related to the development of obesity-linked insulin resistance. TZDs also reduce serum leptin, but increase the circulating levels of the antidiabetic, anti-inflammatory and anti-atherogenic agent adiponectin. Rosiglitazone Rosiglitazone (Figure 18.3) is rapidly absorbed and food does not affect absorp- tion significantly. 67 It is highly bound to plasma proteins (99.8 per cent) and metabolized by the liver. It is given in doses of 4–8 mg as single or divided doses. There is virtually no unchanged drug secreted in the urine or faeces. In the UK it is licensed for use as monotherapy, or in combination with a sulfony- lurea or metformin. Rosiglitazone is contraindicated for use in patients with heart failure, and with insulin therapy in the UK, but is used in combination with insulin in the USA. It is also contraindicated in patients with impaired liver function (ALT > 2.5 × normal). Monitoring of liver enzymes is recommended, every two months for the first year and periodically thereafter. Adverse effects related to rosiglitazone therapy include significant increase in body weight (see below) and a decrease in haemoglobin and haematocrit. In controlled clinical trials with rosiglitazone given as monotherapy, dose- dependent reduction in fasting plasma glucose and glycated haemoglobin have 548 THERAPEUTIC STRATEGIES FOR INSULIN RESISTANCE been reported; 68–72 study duration varied in these studies from 8 to 52 weeks. Drug-na ¨ ıve patients show a better response to therapy than those previously treated with other oral agents. 70 A study of combination treatment of sulfony- lureas with either 2 or 4 mg of rosiglitazone has been published. 73 In a study of 574 subjects, patients were randomized to continuing sulfonylurea therapy or the addition of either 2 or 4 mg of rosiglitazone to their therapy. Rosiglitazone, at both doses, in combination with sulfonylurea was associated with significant reduction in HbA 1c from baseline. Furthermore, the percentage of patients who achieved HbA 1c reduction of >0.7 per cent was 19 per cent in the control group versus 60 per cent in those receiving 4 mg of rosiglitazone with sulfonylurea. In addition to sulfonylureas, rosiglitazone has also been studied in combination with metformin. Fonseca et al., reported a mean reduction of 0.56–0.78 per cent in HbA 1c from baseline after 26 weeks of rosiglitazone therapy in combi- nation with metformin. 74 During this period there was a 0.45 per cent increase in HbA 1c from baseline in those receiving metformin alone. In addition to improving glycaemic parameters, rosiglitazone improves endo- genous insulin secretion and significantly reduces NEFA levels. 73, 74 Insulin resistance, measured using homeostasis model assessment (HOMA), was shown to be significantly reduced in patients with type 2 diabetes taking rosiglita- zone 4–8 mg/day monotherapy over 12–52 weeks. There was no significant change in patients taking placebo or glibenclamide. 75 Similarly, rosiglitazone 2–8 mg/day in combination with a sulfonulurea or metformin for 26 weeks resulted in significant reductions in insulin resistance (HOMA) versus no sig- nificant changes with sulfonylurea or metformin alone. 76 Rosiglitazone may reduce insulin-resistance-related cardiovascular disease risk in type 2 diabetes patients. 77 Euglycaemic clamp data substantiate these results: the insulin sen- sitivity index was significantly increased (by 78 per cent from baseline) in 33 patients with type 2 diabetes mellitus receiving rosiglitazone 8 mg/day. 78 These effects appear to be sustained with continued treatment for at least 24 months. 79 Indeed, rosiglitazone has also been shown to improve β-cell function by up to 94 per cent as assessed by mathematical modelling of fasting glucose and insulin data (HOMA). 80 Furthermore, it is reported that open-label extension studies indicate no deterioration of glycaemic control in patients taking rosigli- tazone during the 2 years of follow-up. If confirmed, this could prove to be a major advantage in the treatment of type 2 diabetes and insulin resistance as the progression of this disease is characterized by failing β-cell function. Pioglitazone Pioglitazone (Figure 18.3), like rosiglitazone, mediates its effects through im- proved peripheral glucose disposal and reduced hepatic glucose production. 81 Pioglitazone absorption from the gut is delayed when taken with food but with- out alteration of its clinical efficacy. 73 Pioglitazone undergoes extensive hepatic PHARMACOLOGICAL TREATMENT OF INSULIN RESISTANCE 549 metabolism via the CYP2C8 system. Secondary pathways include CYP3A4, CYP2C9 and CYP1A1/2. 74, 80 Time to peak plasma concentration is 2.5 h for 15 mg/day and 3 h for 30 mg/day, with an elimination half-life of 3.3 and 4.9 h, respectively. Pioglitazone can be administered once daily at a dose of 15–45 mg. Clinical trials have examined its effects during monotherapy and in combination. Clinical efficacy in terms of reducing HbA 1c levels was shown in a double- blind dose-ranging study in which 399 patients were randomized to receive pioglitazone (7.5, 15, 30 or 45 mg/day) or placebo for 26 weeks. Mean HbA 1c levels decreased significantly (p<0.05 versus placebo) with pioglitazone 15, 30 or 45 mg/day in both previously treated and untreated patients. 81 In another ran- domized double-blind study, involving 197 patients with type 2 diabetes mellitus, pioglitazone 30 mg/day for 16 weeks significantly reduced mean HbA 1c (adjusted change versus placebo =−1.37 per cent; p<0.05), and fasting plasma glucose and triglyceride levels. 82 Similar effects on glycaemic control using pioglitazone as monotherapy have been reported by others. 83 In a double-blind study of 560 patients with poorly controlled type II dia- betes mellitus on sulfonylurea therapy, 84 addition of pioglitazone therapy (15 or 30 mg/day) for 16 weeks significantly decreased HbA 1c levels (by 0.9 and 1.3 per cent, respectively; p<0.05) and fasting blood glucose levels (by 2.2 and 3.2 mmol/l respectively; p<0.05), relative to sulfonylurea plus placebo. Furthermore, combination treatment of pioglitazone (30 mg/day) and metformin (>2 g/day in 40 per cent of patients) for 16 weeks significantly decreased HbA 1c and fasting glucose levels in a double-blind study in 328 patients with type 2 diabetes. 85 Administration of pioglitazone 30 mg/day has no significant affects on the pharmacodynamic characteristics of warfarin, glipizide, metformin or digoxin. 74 Lack of induction or inhibition of hepatic enzyme systems was also indicated by data showing no statistically or clinically significant effect of pioglitazone on the pharmacokinetics of ethinyloestradiol/norethindrone or ethinyloestradiol/oestrone as used in oral contraceptive or hormone replacement therapy regimens. 1 How- ever, adverse effects reported include headache, sinusitis, myalgia, tooth disorders and pharyngitis. 2 In the UK, although licensed for use as monotherapy as an alternative to metformin (if intolerant of metformin) and also in combination with metformin or sulfonylurea, their use is restricted within the National Health Service by current guidelines. It has been recommended that their use is confined to those patients inadequately controlled on oral monotherapy and who are unable to tolerate or have contraindications to conventional drug combination therapy of metformin and a sulfonylurea. These guidelines seriously limit the current clinical use of TZDs in the UK. Several studies have clearly shown an advantage for the glitazones in drug-na ¨ ıve type 2 diabetic patients. 69, 70 The same research shows the complementary effect of the three major classes of oral hypoglycaemic agents. Their effects are synergistic and particularly effective in combination 550 THERAPEUTIC STRATEGIES FOR INSULIN RESISTANCE therapy. 84 The combination of TZDs with insulin in insulin-resistant patients is a logical strategy but under current guidelines it is not recommended because of potential problems, including fluid retention. Thiazolidinediones and weight gain Weight gain is associated with both thiazolidinediones. There were initial con- cerns that weight gain with TZD use may have an adverse impact on glycaemic control, and that the increase in the absolute number of fat cells may lead to refractory obesity. However, increases in body weight with TZD use are posi- tively correlated with reductions in HbA 1c and weight gain appears to stabilize after the initial reductions in HbA 1c . Significant variability in the adipose tis- sue distribution of PPAR-γ may be responsible for the observation that TZDs have a site-specific effect on differentiation of human preadipocytes, with the effect being markedly enhanced in subcutaneous fat, with less effect in visceral fat. 86, 87 Several studies have attempted to elucidate the mechanisms behind the apparent paradox of TZDs improving insulin sensitivity while simultaneously causing weight gain. These include increased appetite and a decrease in serum leptin, 88 although not all studies have shown this effect. Fat redistribution may also explain the weight gain seen with TZDs. Fat redistribution may be explained by induced remodelling of abdominal fat tissue, characterized by differentiation of preadipocytes into small fat cells in subcutaneous fat depots and apoptosis of differentiated large adipocytes (hyper- trophic adipocytes) in visceral and/or subcutaneous fat depots. Indeed, several studies have demonstrated that the weight gain with TZDs is associated with an increase in subcutaneous adipose tissue and a concomitant decrease in visceral fat content. This altered fat distribution also improves insulin sensitivity. Carey et al. 89 reported that 16 weeks therapy with rosiglitazone (8 mg daily), in patients with type 2 diabetes, increased subcutaneous fat by eight per cent (p = 0.02 versus placebo) and decreased intrahepatic fat by 45 per cent (p = 0.04 versus placebo). In another study by Kelley et al., 90 rosiglitazone improved insulin sen- sitivity and led to a 10 per cent reduction in visceral fat. These beneficial effects of fat redistribution have also been seen with pioglitazone. 91 Fluid retention is another potential mechanism by which TZDs lead to weight gain, although the precise cause remains unclear. Peripheral oedema is particu- larly a problem when TZDs are used in combination with insulin, 2 and this is one reason why TZDs are not licensed for use in combination with insulin in the UK, although they are in the USA. Fluid retention and the potential precipitation of congestive cardiac failure in patients with underlying heart disease represent the major concern of most health care providers. Because of increases in plasma volume, rosiglitazone and pioglitazone should be used cautiously in patients with signs of impaired cardiac function, such as peripheral oedema. Although in animal studies TZDs have been reported to cause cardiac hypertrophy, in INSULIN SENSITIZERS AND CARDIOVASCULAR RISK FACTORS 551 echocardiographic clinical studies (a 52 week study using rosiglitazone, and a 26 week study with pioglitazone) in patients with type 2 diabetes no deleterious alterations in cardiac structure or function were observed. 92, 93 Apart from fluid retention, lack of compliance with diet is another factor that contributes to weight gain. In addition, weight gain appears to be greatest when TZDs are used in combination with insulin or sulphonylureas and least when used as monotherapy or in combination with metformin. Therefore, previous glycaemic control and type of concomitant therapy may prove to be to the bases for predicting which patients are most likely to gain weight. Education about diet and exercise at time of prescription, low-calorie diets and concomitant use of metformin are strategies to minimize weight gain in individuals given TZDs. 18.9 Insulin sensitizers and cardiovascular risk factors Most patients with obesity and the insulin resistance syndrome exhibit a spec- trum of clinical abnormalities (Table 18.1) that play an important role in the pathogenesis of atherosclerosis (Figure 18.1). It has therefore been proposed that drugs that directly improve insulin sensitivity, such as metformin and the TZDs, may correct other abnormalities of the insulin resistance syndrome in addition to improving hyperglycaemia. Thus, treatment of patients with type 2 diabetes with these agents may confer benefits beyond the lowering of glucose. Metformin Metformin is frequently perceived as a drug that induces weight loss. However, data from the UKPDS showed no change in the weight of patients taking met- formin throughout the study. 53 In the Diabetes Prevention Program, 18 metformin did not cause a greater weight loss than that seen with placebo, and there was a minimal change in weight during the 4 years of the study. This contrasted with the lifestyle-change group, in which participants lost an average of 5.6 kg. Thus, metformin appears to be weight neutral in the long term. To date, metformin is the only drug that has been shown to decrease car- diovascular events in patients with type 2 diabetes, independently of glycemic control. 53 More importantly, the UKPDS demonstrated that patients who were obese and randomized to receive metformin had a significantly reduced rate (30 per cent reduction) of cardiovascular disease events and mortality compared with those receiving conventional therapy when analysed on an intention-to- treat basis. 53 Although the reason for this difference is not clear, it may be related to moderate effects exerted by metformin on the insulin resistance syn- drome; metformin treatment lowers plasma insulin levels and corrects many of the non-traditional risk factors associated with the insulin resistance syndrome. 94 Metformin has a favorable, albeit modest, effect on plasma lipids, particularly lowering levels of triglycerides and LDL cholesterol; however, it has little if any [...]... extracellular α-subunits and two transmembrane β-subunits The binding of the ligand to the IR α-subunits stimulates the tyrosine kinase activity intrinsic to the β-subunits Structural biology studies reveal that the two α-subunits jointly participate in insulin binding and that the kinase domains in the two β-subunits are juxtaposed in order to permit autophosphorylation of tyrosine residues as the first... studies indicate that PTEN plays a negative role in insulin signalling and its inhibition improves insulin sensitivity SHIP2 is another negative regulator of insulin signalling Overexpression of SHIP2 protein decreases insulin- dependent PI(3,4,5)P3 production as well as insulin- stimulated Akt activation, GSK3 inactivation and glycogen synthase activation.99 The inhibitory effects of SHIP2 on insulin signalling... cell fates during embryonic development.71 In the insulin signalling pathway, GSK-3 is active in the absence of insulin; it phosphorylates (and thereby inhibits) glycogen synthase and several other substrates Insulin binding to the IR activates a phosphorylation cascade, leading to inhibitory phosphorylation of GSK-3 by Akt Thus, insulin activates glycogen synthase, in part, by promoting its dephosphorylation... residues) including insulin receptor substrate (IRS) proteins 1–4, Shc and Gab 1, each of which provides specific docking sites for other signalling proteins containing Src homology 2 (SH2) domains .10 These events lead to insulin- mediated activation of glucose transport and glycogen synthesis through activation of downstream signalling molecules including phosphatidylinositol-3-kinase (PI-3-kinase) and Akt... vascular smooth muscle cell migration intima–media thickness cardiac output microalbuminuria plasma activator inhibitor-1 (PAI-1) fibrinogen C-reactive protein interleukin-6 cell adhesion molecules PAI-1 CONCLUSIONS 553 the glucose-lowering or insulin- lowering effects.97 Improving insulin sensitivity has the potential to lower blood pressure in patients with insulin resistance and/ or diabetes A study of 24... availability and improves insulin action and glucoregulation in the rat Diabetes 43, 1203–1 210 61 Young, P W., Cawthorne, M A and Coyle, P J et al (1995) Repeat treatment of obese mice with BRL 49653, a new and potent insulin sensitiser, enhances insulin action in white adipocytes: association with increased insulin binding and cell surface GLUT4 as measured by photoaffinity labeling Diabetes 44, 108 7 109 2... 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Because many cardiovascular risk factors are linked with insulin. 49653, a new and potent insulin sensitiser, enhances insulin action in white adipocytes: association with increased insulin binding and cell surface GLUT4 as measured by photoaffinity labeling. Diabetes