BaillieÁre's Clinical Endocrinology and Metabolism Vol. 13, No. 2, pp. 221±237, 1999
3 Obesity and diabetes King Sun Leong
BMedSci (Hons), MRCP
Clinical Lecturer in Medicine
John P. Wilding
DM, MRCP
Senior Lecturer in Medicine and Honorary Consultant Physician Diabetes and Endocrinology Research Group, University Clinical Departments, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UK
Obesity, particularly truncal obesity, is closely correlated to the prevalence of diabetes and cardiovascular disease. Plasma leptin, tumour necrosis factor-a and non-esteri®ed fatty acid levels are all elevated in obesity and play a role in causing insulin resistance. Diabetic glycaemic control and insulin resistance improve with reductions in obesity, but the treatment of obesity is dicult, and sustained weight reduction rarely occurs with dietary management alone. Hypocaloric diets should be combined with education and low-impact exercise, as well as behavioural techniques used to encourage long-term changes. Weight-reducing drugs have a role in the management of obesity but only as part of such a total package. Newer anti-obesity drugs such as orlistat and sibutramine are well tolerated and have been shown to improve glycaemic control in diabetes. It is probable that drugs developed in the future will act at dierent sites in the pathways regulating body weight, but they may have to be used in combination. Key words: Type 2 diabetes; obesity; leptin; tumour necrosis factor-a; non-esteri®ed fatty acids; uncoupling proteins; orlistat; sibutramine.
The association between obesity and diabetes, particularly Type 2 (non-insulin dependent) diabetes, is not new and has been known for several hundred years. This association has constantly been demonstrated in both cross-sectional1,2 and prospective3,4 studies. Obesity plays a major role in the aetiology of Type 2 diabetes, the world-wide prevalence of which continues to rise and is set to reach 180 million in the year 2010.5 Diabetes and obesity are independently associated with increased morbidity and mortality from cardiovascular disease. As the prevalence of obesity continues to rise6,7, its contribution to the overall burden of cardiovascular disease is set to increase. Studies from developed countries have estimated the economic burden of obesity to lie between 2% and 7% of health-care costs.8±11 These ®gures are, however, likely to be an underestimate because of the diculties of attributing speci®c costs to associated obesity and the exclusion of indirect costs from most of these analyses. In contrast, there are few data on the economic bene®ts of treating obesity. 1521-690X/99/020221+17 $12.00/00
c 1999 Harcourt Publishers Ltd. *
222 K. S. Leong and J. P. Wilding
DEFINITION OF OBESITY Obesity can be de®ned as the state in which the accumulation of fat has occurred to such an extent that the health of the individual is impaired. In addition to the overall weight, the distribution of fat around the body is also important. Generally speaking, there are two types of fat distribution: the android (apple shape), in which fat is distributed around the abdomen and viscera (truncal obesity), and the gynoid (pear shape), in which fat is distributed more peripherally, especially around the hips and buttocks. The former distribution is normally found in men and the latter in women, and it is truncal obesity that is generally associated with ill-health.12
MEASUREMENTS OF OBESITY The body mass index (BMI) is a simple method of estimating adiposity and is calculated as the weight in kilograms divided by the square of the height in metres (kg/m2). Raised BMI levels are associated with increasing risks for developing Type 2 diabetes13 (Figure 1), and dierent classi®cations of BMI have been devised by the World Health Organization14 (see Table 1). The BMI is, however, a relatively insensitive measure of obesity as there can be varying degrees of truncal obesity within the same BMI range. The waist-to-hip ratio (WHR) is the ratio of the waist circumference (measured halfway between the lowest ribs and the iliac crest) to the hip circumference measured at the greater trochanters. The normal WHR is less than 0.95 for men and less than 0.80 for women15, and a raised WHR has been associated with an increased risk of cardiovascular mortality12 (Figure 2). However, such measurements can be dicult to perform as it may be dicult to locate the anatomical landmarks in an obese person. The measurements of waist circumference alone is simpler and can also predict the risk of cardiovascular disease.13,16 A waist circumference of over 94 cm in men and 80 cm in women predicts a BMI greater than 25 in such individuals with a sensitivity and speci®city of 96%.16 Furthermore, an American study showed that waist circumference was associated with diabetes in the top 20% (Figure 3) of the study group compared with only 5% using the WHR.13 Other methods used to measure abdominal fat include computerized tomography and magnetic resonance scanning, but these two methods are mainly used in a research setting. The possible interactions between obesity and diabetes are shown in Figure 4 and will be discussed in detail later.
Table 1. Risk of co-morbidity with increasing body mass index (after Kahn and Porte, 199617). Classi®cation Normal Pre-obese Obese, class I Obese, class 2 Obese, class 3
Body Mass Index 18.5±24.9 25.0±29.9 30.0±34.9 35.0±39.9 540.0
Risk of co-morbidity Average Increased Moderate Severe Very severe
Figure 1. Eect of measuring body mass index on the risk of developing diabetes (after Chan et al, 199413).
Obesity and diabetes 223
224 K. S. Leong and J. P. Wilding
Figure 2. Probability of ischaemic heart disease in relation to tertiles of body mass index (BMI) and waist-tohip ratio (WHR) (after Larsson et al, 198412).
Figure 3. Increasing waist circumference as a risk factor for developing diabetes (after Chan et al, 199413).
INSULIN RESISTANCE, BETA-CELL DYSFUNCTION AND OBESITY Non-esteri®ed fatty acids and insulin resistance Insulin is produced and secreted by the beta-cells in the islets of Langerhans in the pancreas, its main actions being the regulation of carbohydrate, protein and lipid metabolism. Type 2 diabetes is a multifactorial disease, which results from a combination of insulin resistance and beta-cell failure.17 In the liver, insulin inhibits gluconeogenesis and glycogen breakdown, as well as increasing glycogen storage. In the peripheral tissues, insulin acts on both skeletal muscle and fat. Glucose uptake is mediated by GLUT-4 (a glucose transporter protein)18, which is acutely induced by insulin. In muscle, glucose is either metabolized
Obesity and diabetes 225
Figure 4. Interactions between obesity and diabetes. SNS sympathetic nervous system; NEFA nonesteri®ed fatty acids; TNFa tumour necrosis factor-a.
to form ATP or stored as glycogen, and in adipose tissues, glucose is involved in lipogenesis via its conversion to glycerol-3-phosphate, which is then combined with non-esteri®ed fatty acids (NEFAs) to form triglycerides. An important role of insulin is also to prevent the breakdown of triglycerides (lipolysis), which liberates NEFAs. The control of lipolysis is very sensitive to insulin, and lipolysis is inhibited even with basal concentrations of insulin in normal individuals. However in obese subjects, the NEFA level is elevated, and in Type 2 diabetic patients there is both hyperglycaemia and elevated NEFA levels. Raised NEFA levels impair glucose metabolism by reducing insulin-stimulated glucose uptake, particularly in skeletal muscle.19 In the liver, increased levels of NEFA interfere with the Randle (glucose±fatty acid) cycle to increase hepatic glucose output.20 In normal individuals, NEFAs also stimulate insulin production.21 It is therefore possible that in obese individuals predisposed to Type 2 diabetes, the stimulation of insulin by NEFA will eventually fail. Sympathetic activity and obesity Plasma catecholamine levels as a measure of sympathetic activity are dicult to interpret22, and surrogate measures such as microneurography to measure muscle sympathetic nerve activity (MSNA) and measurements of heart rate variability have been used instead. An increased level of MSNA is seen in obese subjects23,24, rising with an increasing percentage of body fat. Using heart rate variability, a decrease in cardiac parasympathetic activity has also been shown in obese subjects25, re¯ecting an overdominance of the sympathetic nervous system. Increased sympathetic activity may contribute to increased cardiovascular mortality and morbidity in obese subjects. The link between increased sympathetic activity and obesity is complex, but hyperinsulinaemia seems likely to contribute signi®cantly. Insulin levels are elevated in the obese, especially those with truncal obesity26, and this may be the result of insulin
226 K. S. Leong and J. P. Wilding
resistance. Furthermore, insulin has been shown to stimulate the sympathetic nervous system27, its level rising after food intake. Sympathetic activity increases after food ingestion28, and the amount of food ingested is higher in obese subjects. All these factors, therefore, contribute to the increase in sympathetic activity seen in obese subjects. Beta-cell dysfunction Hyperglycaemia in the presence of insulin resistance alone would tend to cause hyperinsulinaemia in order to maintain normoglycaemia.29 However, when beta-cell dysfunction supervenes, insulin secretion is inadequate, and Type 2 diabetes develops. It is thought that insulin resistance precedes beta-cell dysfunction by several years.30 The cause of beta-cell dysfunction remains unknown, but there is some suggestion that the defect may be partly inherited31 and that malnutrition in early life may be a further contributing factor (the thrifty phenotype hypothesis).32 Furthermore, both chronic hyperglycaemia and a raised NEFA level may contribute to further beta-cell dysfunction.21,33 Amylin, a protein co-secreted with insulin34, has been observed to accumulate in the islet cells in the form of amyloid ®brils. This may contribute to betacell dysfunction in subjects with insulin resistance. Leptin Leptin, the product of the ob gene35, is produced by adipocytes. The main role of leptin is to regulate food intake and energy expenditure36,37 by reducing food intake and increasing sympathetic nervous system out¯ow, therefore inducing weight loss. These processes are mediated in part by reducing the neuropeptide Y level in the hypothalamus.37 The leptin level is positively correlated with BMI and percentage body fat in both humans and rats.38,39 Independent of percentage body fat, leptin is also positively correlated with insulin resistance40 and tumour necrosis factor-a (TNFa) level.41 Animal and in vitro experiments have demonstrated that leptin can impair the production of insulin42±44 and reduce the eects of insulin on the liver45,46, but it is not clear whether leptin aects the handling of insulin in adipocytes and muscle.47±50 Leptin may also cause insulin resistance by stimulating the sympathetic nervous system. Animal studies have shown that leptin increases noradrenaline turnover and sympathetic activity not only to brown adipocytes but also to the kidney, hindlimb and adrenal glands.51 In humans, leptin levels have been positively correlated with muscle sympathetic nerve activity52, and it is possible that leptin may contribute to the increased sympathetic activity observed in obesity. Uncoupling proteins Uncoupling proteins (UCPs) are found in the mitochondria of various tissues and act to uncouple oxidative ATP phosphorylation, a process known as futile cycling, in order to release heat. There are three isoforms of UCP: UCP-1, UCP-2 and UCP-3. UCP-1 is found in brown adipose tissue, UCP-2 in various organs including the liver, muscle and white adipose tissue, and UCP-3 in muscle and brown adipose tissue.53 In humans, the main heat-producing tissues are muscle, viscera and fat. There is very little brown adipose tissue in humans; it is found only in neonates and disappears with age.
Obesity and diabetes 227
In rodents, brown adipose tissue persists into adulthood, thermogenesis in rodents being produced by the activation of b3-adrenoceptors (b3-ARs) by sympathetic nerves. This increases cAMP production and stimulates lipolysis within brown adipose tissue cells, as well as increasing the expression of UCP-1.54 The selective b3-agonist BRL 35135 has been shown to stimulate b3-ARs and increase thermogenesis in rodents.55 The situation in man is more complex in that the human b3-AR is very dierent from the rodent b3-AR. This poor selectivity of drugs for the human b3-AR has led to signi®cant adrenergic side-eects in humans with early compounds because of the activation of other adrenergic receptors. Newer selective b3-agonists are being developed that should be active in man, but whether these will be eective at stimulating thermogenesis and causing weight loss remains to be seen. Rodent studies have shown that b3-AR agonists increase the production of dierent isoforms of UCP from various tissues56 and that white adipose tissue may be also involved in the thermogenic process.55 Leptin may regulate energy expenditure by aecting the expression of UCPs: in rodents, the administration of leptin increases the expression of UCP mRNA in both brown and white adipose tissue. The novel antidiabetic thiazolidinedione drugs in rodents also increase UCP. The administration of pioglitazone to lean and fatty Wistar rats has been shown to increase the expression of UCP-3, without an eect on UCP-2.57 This may be one mechanism by which thiazolidinediones increase energy expenditure. The genetics of UCPs may also help us to understand why certain populations are prone to obesity. In a study, on Pima Indians, there was a suggestion that polymorphisms in the UCP-2 and UCP-3 genes could lead to variations in metabolic rate and thus to obesity.58 Whereas it is fairly certain that UCP isofroms regulate thermogenesis to diering extents, the exact physiological function of the UCPs remains unknown, and further studies are required in this area. INSULIN SIGNALLING Insulin exerts its eect by binding to its own speci®c receptor. The receptor is activated by phosphorylation, in turn activating a cascade of intracellular mediators such as the insulin receptor substrate group.59 It is therefore possible that factors associated with obesity may cause insulin resistance by interfering with insulin signalling. TNFa a TNFa, also known as cachexin, is a cytokine produced in response to in¯ammation. Studies in obese animals60 and humans61 have shown that the production of TNFa from adipose cells is twice that of non-obese subjects. Moreover, the expression of TNFa in muscle cells from Type 2 diabetic subjects is signi®cantly greater than that in nondiabetic controls.62 TNFa has been shown to impair insulin action in fat and muscle by reducing the tyrosine kinase activity of the insulin receptor.63 Insulin resistance caused by TNFa is likely to be a chronic process: no alteration in insulin resistance has been demonstrated with the short-term exposure of skeletal muscle cells to TNFa.64 Insulin resistance in adipose cells is seen after 3±5 days' exposure to TNFa65,66 and is thought to be mediated via a decrease in GLUT-4 level. Chronic exposure to an elevated endogenous level of TNFa may therefore play an aetiological role in the insulin resistance that ultimately leads to Type 2 diabetes.
228 K. S. Leong and J. P. Wilding
Tyrosine phosphatase-1b b enzyme The protein tyrosine phosphatase-1b (PTP-1b) enzyme causes dephosphorylation of the activated insulin receptor and reduces the action of insulin. Rodents lacking in the gene coding for this enzyme have increased insulin sensitivity compared with rodents which are heterogeneous or homozygous for the gene.67 A possible explanation is that the length of time of phosphorylation of the insulin receptor is increased, thereby increasing the action of insulin. Furthermore, when rats lacking the PTP-1b gene were fed a high-fat diet, they were resistant to obesity and remained insulin sensitive compared with wild-type littermates. The reasons for this resistance to dietaryinduced obesity is not clear from current data, but the role of this gene in regulating body weight and insulin sensitivity will undoubtedly be intensively investigated in the near future. GENETICS OF OBESITY AND TYPE 2 DIABETES Obesity is a multifactorial disease, both genes and the environment playing important roles in its pathogenesis. Obesity tends to aggregate in families, and the strength of this aggregation is higher in those with morbid obesity.68 Studies looking at adoptees have demonstrated a correlation between the BMI of the adult adoptee and that of the biological parent69, while there was no correlation to that of the adoptive parents. It has been estimated that 25±40% of the obese phenotype can be accounted for by genetic heritability.70 Gene linkage studies have identi®ed several loci that may be linked to obesity, but these seem to dier from population to population. So far, 28 chromosomal regions that may be associated with the obese phenotype have been identi®ed.71 The genetics of Type 2 diabetes is heterogeneous and, despite numerous studies using animal models72, very little is known about the genes causing Type 2 diabetes. The main genes identi®ed so far are those involved in maturity-onset diabetes of the young and diabetes±deafness syndromes73,74, neither of which, unlike the majority of cases of Type 2 diabetes, are generally associated with obesity. ENVIRONMENTAL FACTORS IN TYPE 2 DIABETES AND OBESITY Malnutrition in utero and early childhood is associated with impaired glucose tolerance and Type 2 diabetes.75 It has been suggested that poor nutrition in utero or early childhood may induce insulin resistance and beta-cell dysfunction in middle age. This may cause diabetes, particularly if obesity supervenes and further increases insulin resistance. This concept is known as the `thrifty phenotype' hypothesis. The association between insulin resistance in adult life and decreased fetal growth has been shown in another study76, but the association between impaired insulin secretion in adult life and decreased fetal growth has not been demonstrated.77 In 1962, the existence of `thrifty genes' was proposed.78 These `thrifty genes' are thought to increase fat deposition when food is abundant, therefore increasing fat stores, which can then be utilized in times of famine. Those who have these `thrifty genes' will have a survival advantage over those who do not and will be able to survive famine and pass the genes on to the next generation. However, in westernized societies where food is abundant and the lifestyle sedentary, the `thrifty genes' will
Obesity and diabetes 229
predispose to obesity and also Type 2 diabetes. This is thought to be one mechanism contributing to the high incidence of obesity and Type 2 diabetes in Pima Indians when food became abundant.79
TREATMENT OF THE OBESE PATIENT WITH TYPE 2 DIABETES Epidemiological data and retrospective analyses suggest that weight loss in patients with Type 2 diabetes can improve survival. For example, one retrospective study calculated that each kilogram of weight loss was associated with a 3±4 month improvement in survival.80 It has been theoretically estimated that between 64% and 77% of cases of Type 2 diabetes could have been avoided if no person in the WHO MONICA study had had a BMI above 25.81 The prevention of obesity is thus important as diabetes is notoriously dicult to treat.82 Bene®ts of weight loss in diabetes The bene®ts of weight reduction in diabetes are clear. One study83 showed that Type 2 diabetic patients who lost more than 10% of their initial weight showed the most improvement in their diabetic glycaemic control. Those who lost between 5% and 10% had a moderate improvement, and those who lost less than 5% did not show a change. Patients in this study who achieved more than 14 kg of weight loss had a nearnormalization of their glycated haemoglobin (HbA1c) values. Improvements in insulin sensitivity and dyslipidaemia (a reduction in triglyceride and LDL cholesterol levels, and an increase in HDL cholesterol)84, as well as reductions in blood pressure85 and left ventricular mass86, have also been seen with weight reduction. A reduction in the activity of the sympathetic nervous system also occurs with weight loss87,88, and this has been attributed to increased insulin sensitivity. Perhaps the best evidence for the bene®t of weight loss comes from a retrospective study of morbidly obese (BMI 4 40) patients who had undergone gastric reduction surgery.89 The mean weight lost 12 months after surgery was 50 kg (a 70% reduction of excess body weight), and 90% of those who were glucose intolerant initially became normoglycaemic. Surgery has been proposed as a treatment for those with morbid obesity in whom conservative treatment has failed, and an ongoing prospective study is currently addressing the question of whether such procedures improve outcome in terms of diabetes, hypertension, ischaemic heart disease and death.90 The indications for gastric surgery are shown in Figure 5.91 In addition to weight reduction, exercise also improves insulin sensitivity92 by increasing glucose uptake into skeletal muscle. In addition, those who have successfully lost weight and have maintained their weight loss report an improvement in their quality of life93, with increased energy, mobility and con®dence. Most patients achieve weight loss within 3±6 months, but the majority regain the weight in the long term. The emphasis thus has to be on weight maintenance after the initial period. Interventions that encourage walking and do not require regular attendance at gymnasiums are most likely to lead to a sustainable weight loss.94 Exercise in obese subjects does not have to be intense. Prolonged low-intensity exercise (such as brisk walking for 30±60 minutes a day) can be equally bene®cial and is easier to maintain.94 Other strategies such as the regular encouragement and involvement of the whole family can improve compliance to diet and exercise (Figure 6).
230 K. S. Leong and J. P. Wilding
Figure 5. Indications for gastric surgery in morbid obesity (after Kolanowski, 19979).
Figure 6. Factors that improve compliance to exercise (adapted from Hillsdon et al, 1996).94
Conventional diet The mainstay of obesity management is dietary and lifestyle modi®cation to maintain a hypocaloric diet of between 500 and 600 kcal a day less than the base-line energy intake. The base-line energy intake is calculated from standard formulae95 as obese subjects tend to underestimate their dietary intake. The diet recommended for Type 2 diabetic patients does not dier from that for the general public96, being designed to be low in fat and rich in complex carbohydrates. The daily energy intake should comprise over 55% complex carbohydrates, less than 30% fat and 10±15% protein. Special `diabetic' food should be avoided ± they are unnecessary and they contain sorbitol, which can lead to diarrhoea. They are also expensive and do not oer any signi®cant bene®t over other low-sugar foods. A combination of an exercise regimen and a hypocaloric diet may result in a greater weight loss than is seen with either intervention alone, and furthermore, the weight loss can be sustained for over 2 years.97 Weight loss in any intervention programme should be gradual, at around 0.5±0.6 kg a week. Very-low calorie diets Very-low calorie diets (VLCDs) provide fewer than 800 kcal per day, usually containing between 300 and 400 kcal per day. Patients embarking on such diets should be under medical supervision.98 This technique is normally used for short-term weight reduction, the weight loss on these diets ranging from 1.5 to 2.5 kg per week. Such a diet is sometimes also used to replace one or two main meals a day, which makes it easier to adhere to. In the obese Type 2 patient, VLCDs can reduce hyperglycaemia
Obesity and diabetes 231
and diabetic symptoms within a few days99, but the weight loss is not maintained once the diet has been discontinued. VLCDs should normally be recommended for patients with a BMI level of more than 40 who have concurrent medical problems or impending surgery. PHARMACOLOGICAL TREATMENT OF OBESITY IN THE OBESE TYPE 2 DIABETIC PATIENT Drugs used for the treatment of obesity The reduction of obesity is the cornerstone of good diabetes management, orlistat (tetrahydrolipstatin) currently being the only anti-obesity drug licensed in the UK. Despite the huge prevalence of obesity in the Type 2 diabetic population, there is a lack of information on the long-term eects of these drugs in the obese diabetic patient. If drugs are to be used, however, they are likely to be used in conjunction with other oral hypoglycaemic therapy. Furthermore, it is also probable that antiobesity drugs will be required long term. Orlistat A logical approach to reducing energy intake is to reduce the absorption of fat, which has the highest energy content of all nutrients (9 kcal/g). The absorption of fat depends on pancreatic lipase; orlistat binds covalently to gastric and pancreatic lipase. It is not absorbed systemically100, and decreases dietary fat absorption by 25±35%. In one multicentre study on obese Type 2 diabetic patients, the use of orlistat resulted in a 6.2% weight loss from base-line compared with 4.2% in those using placebo101 over a year. Improvements in HbA1c and fasting glucose levels were also seen. The main side-eects, including oily rectal discharge with ¯atus, faecal urgency, and fatty stools, were related to fat malabsorption. These side-eects tended to lessen with compliance to a low-fat diet. Another study using orlistat in non-diabetic obese subjects over a 2-year period demonstrated both weight loss and an improvement in insulin sensitivity.102 A theoretical problem using orlistat is the malabsorption of fat-soluble vitamins (A, D, E and K). One study showed that the absorption of vitamin E was reduced in subjects taking 120 mg orlistat three times daily103, but that absorption of vitamin A was unaected. The long-term eects of orlistat are currently unknown, the longest clinical trial at present having lasted for 2 years. Vitamin supplementation when using orlistat may thus be prudent in the long term. Sibutramine Sibutramine is a centrally acting serotonin and noradrenaline reuptake inhibitor. Animal studies have shown that sibutramine reduces food intake104 by enhancing satiety, and there is evidence that thermogenesis is increased in brown adipose tissue, which is mediated by the sympathetic nervous system.105 This reduction of food intake is reversed partially or completely by the pre-treatment of rats with 5-hydroxytryptamine and noradrenaline antagonists. Sibutramine has an ecacy similar to that of dexfen¯uramine, but at present does not seem to carry the same liability for sideeects, for example cardiac valvular defects.106 The weight reduction of sibutramine is dose dependent.107
232 K. S. Leong and J. P. Wilding
Sibutramine also works synergistically with ¯uoxetine (a serotonin and noradrenaline reuptake inhibitor used for depression), resulting in further weight loss mediated via a reduction in food intake and increased thermogenesis.105 Fluoxetine on its own does not have any of these eects. The side-eects seen with sibutramine are slight and include a dry mouth, constipation and insomnia.106 In a study using sibutramine with obese Type 2 diabetic patients, there was a weight loss of 2.4 kg compared with 0.1 kg in patients on placebo.108 This was associated with a mean fall of HbA1c of 0.4%. Reductions in triglycerides, cholesterol and LDL, and increases in HDL, levels have also been demonstrated.109 TREATMENT OF DIABETES IN THE OBESE TYPE 2 DIABETIC PATIENT The recent UK Prospective Diabetes Study has shown that good glycaemic control is important in the treatment of Type 2 diabetes.110 Type 2 patients treated intensively with insulin or sulphonylureas showed a 25% reduction in microvascular complications, and there was also a trend towards fewer myocardial infarctions, but this did not reach signi®cance (p 0.052). Bene®t was also seen in patients intensively treated with metformin, who had greater falls in diabetes-related end-points and all-cause mortality compared with those on sulphonylurea or insulin.111 Furthermore, there were less weight gain and fewer hypoglycaemic episodes in patients on metformin compared with those on the insulin or sulphonylureas. In the obese Type 2 patient, metformin should therefore be the ®rst-line oral hypoglycaemic agent. The aims of treatment of the obese Type 2 diabetic patient have been summarized in Figure 7. CONCLUSION Obesity is a major health hazard and plays a central role in the pathogenesis and aetiology of diabetes. The newer anti-obesity drugs may help in the management of
Figure 7. Aims of treatment in obese Type 2 diabetes (World Health Organization Study Group, 199714; UK Prospective Diabetes Study Group, 1998110,111).
Obesity and diabetes 233
obesity and perhaps delay the onset of diabetes. However, drug therapy is only one facet of treatment. Education and changes in lifestyle remain the key issues in obesity management. Obesity clearly is a problem that will not disappear, and concerted eorts will be required from physicians, the pharmaceutical industry and also the media to publicize the health hazards of obesity and to promote `healthy lifestyles'.
REFERENCES 1. Morris RD, Rimm DL, Hartz AJ et al. Obesity and heredity in the etiology of non-insulin-dependent diabetes mellitus in 32,662 adult white women. American Journal of Epidemiology 1989; 130: 112±121. 2. Skarfors ET, Selinus KI & Lithell HO. Risk factors for developing non-insulin dependent diabetes: a 10 year follow up of men in Uppsala. British Medical Journal 1991; 303: 755±760. 3. Haner SM, Stern MP, Mitchell BD et al. Incidence of type II diabetes in Mexican Americans predicted by fasting insulin and glucose levels, obesity, and body-fat distribution. Diabetes 1990; 39: 283±288. 4. Charles MA, Fontbonne A, Thibult N et al. Risk factors for NIDDM in white population. Paris prospective study. Diabetes 1991; 40: 796±799. 5. World Health Organization. Prevention of diabetes mellitus. 844. Geneva: WHO, 1997. 6. Mathus-Vliegen EMH. Overweight. I: Prevalences and trends. Nederlands Tijdschrift voor Geneeskunde 1998; 142: 1982±1989. 7. Dobson AJ, Evans A, Ferrario M et al. Changes in estimated coronary risk in the 1980s: data from 38 populations in the WHO MONICA Project. Annals of Medicine 1998; 30: 199±205. 8. National Health and Medical Research Council. Economic issues in the prevention and treatment of overweight and obesity. Acting on Australia's Weight: A Strategic Plan for the Prevention of Overweight and Obesity, pp 85±95. Canberra: Australian Government Publishing Service, 1997. 9. Levy E, Levy P, Le Pen C & Basdevant A. The economic cost of obesity: the French situation. International Journal of Obesity 1995; 19: 788±792. 10. Seidell JC. Obesity in Europe ± causes, costs, and consequences. International Journal of Risk and Safety in Medicine 1995; 7: 103±110. 11. Wolf AM & Colditz GA. The costs of obesity. American Journal of Clinical Nutrition 1992; 55: 503S±507S. 12. Larsson B, Svardsudd K, Welin L et al. Abdominal adipose tissue distribution, obesity and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913. British Medical Journal 1984; 288: 1401±1404. * 13. Chan JM, Rimm EB, Colditz GA et al. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994; 17: 961±969. 14. World Health Organization Study Group. De®ning the problem of overweight and obesity. In Report of a WHO Consultation on Obesity. Obesity: Preventing and Managing the Global Epidemic, pp 7±16. Geneva: WHO, 1997. 15. Food and Nutrition Board. Criteria for evaluating weight management programs. In Thomas PR (ed.) Nature and Problem of Obesity pp 10±11. Washington, DC: National Academy Press, 1995. 16. Han TS, Van Leer EM, Seidell JC & Lean MEJ. Waist circumference action levels in the identi®cation of cardiovascular risk factors: prevalence study in a random sample. British Medical Journal 1995; 311: 1401±1405. 17. Kahn SE & Porte D Jr. Pathophysiology of type II (non-insulin dependent) diabetes mellitus: implications for treatment. In Porte D Jr & Sherwin RS (eds) Diabetes mellitus; theory and practice pp 487±512. New York: Appleton and Lange, 1996. 18. Kruszynska YT. Normal metabolism: the physiology of fuel homeostasis. In Pickup J & Williams G (eds) Textbook of Diabetes, 2nd edn, ch. 11. Oxford: Blackwell Science, 1997. 19. Bonadonna RC, Croop LC, Zych K et al. Dose-dependent eect of insulin of plasma free fatty acid turnover oxidation in humans. American Journal of Physiology 1990; 259: E736±E750. 20. Randle PJ, Garland PB, Hales CN & Newholme CA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963; 1: 785±789. * 21. Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997; 46: 3±10. 22. Macdonald IA. Advances in our understanding of the role of the sympathetic nervous system. International Journal of Obesity 1995; 19 (supplement 7): S2±S7. 23. Spraul M, Ravussin E, Fontvieille AM et al. Reduced sympathetic nervous activity. A potential mechanism predisposing to body weight gain. Journal of Clinical Investigation 1993; 92: 1730±1735.
234 K. S. Leong and J. P. Wilding 24. Grassi G, Cattaneo BM, Seravalle G et al. Obesity and the sympathetic nervous system. Blood Pressure 1996; 5 (supplement 1): 43±46. 25. Kageyama T, Nishikido N, Honda Y et al. Eects of obesity, current smoking status, and alcohol consumption on heart rate variability in male white-collar workers. International Archives of Occupational and Environmental Health 1997; 69: 447±454. 26. Peiris AN, Struve MF, Mueller RA et al. Glucose metabolism in obesity: in¯uence of body fat distribution. Journal of Clinical Endocrinology and Metabolism 1988; 67: 760±767. 27. Anderson EA, Balon TW, Homan RP et al. Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans. Hypertension 1992; 19: 621±627. 28. Fagius J & Berne C. Increase in muscle nerve sympathetic activity in humans after food intake. Clinical Science 1994; 86: 159±167. 29. Lillioja S, Nyomba BL, Saad MF et al. Exaggerated early insulin release and insulin resistance in a diabetes-prone population: a metabolic comparison of Pima Indians and Caucasians. Journal of Clinical Endocrinology and Metabolism 1991; 73: 866±876. 30. DeFronzo RA. Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview. Diabetologia 1992; 35: 389±397. 31. O'Rahilly SP, Nugent Z, Rudenski AS et al. Beta-cell dysfunction, rather than insulin insensitivity, is the primary defect in familial type 2 diabetes. Lancet 1986; 2: 360±364. 32. Hales CN & Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992; 35: 595±601. 33. Yki-Jarvinen H. Glucose toxicity. Endocrine Reviews 1992; 13: 415±431 (review). 34. Scherbaum WA. The role of amylin in the physiology of glycemic control. Experimental and Clinical Endocrinology and Diabetes 1998; 106: 97±102. 35. Zhang Y, Proenca R, Maei M et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425±432. 36. Flier JS. Leptin expression and action: new experimental paradigms. Proceedings of the National Academy of Sciences of the US 1997; 94: 4242±4245. 37. Schwartz MW & Seeley RJ. Neuroendocrine responses to starvation and weight loss. New England Journal of Medicine 1997; 336: 1803±1811. 38. Maei M, Halaas J, Ravussin E et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Medicine 1995; 1: 1155±1161. * 39. Considine RV, Sinha MK, Heiman ML et al. Serum immunoreactive-leptin concentrations in normalweight and obese humans. New England Journal of Medicine 1996; 334: 292±295. 40. Segal KR, Landt M & Klein S. Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men. Diabetes 1996; 45: 988±991. 41. Mantzoros CS, Moschos S, Avramopoulos I et al. Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans. Journal of Clinical Endocrinology and Metabolism 1997; 82: 3408±3413. 42. Emilsson V, Liu YL, Cawthorne MA et al. Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes 1997; 46: 313±316. 43. Koyama K, Chen G, Wang MY et al. Beta cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy. Diabetes 1997; 48: 1276±1280. 44. Ookuma M, Ookuma K & York DA. Eects of leptin on insulin secretion from isolated rat pancreatic islets. Diabetes 1998; 47: 219±223. 45. Cohen B, Novick D & Rubinstein M. Modulation of insulin activities by leptin. Science 1996; 274: 1185±1188. 46. Wang Y, Kuropatwinski KK, White DW et al. Leptin receptor action in hepatic cells. Journal of Biological Chemistry 1997; 272: 16216±16223. 47. Muller G, Ertl J, Gerl M & Preibisch G. Leptin impairs metabolic actions of insulin in isolated rat adipocytes. Journal of Biological Chemistry 1997; 272: 10585±10593. 48. Walder K, Filippis A, Clark S et al. Leptin inhibits insulin binding in isolated rat adipocytes. Journal of Endocrinology 1997; 155: R5±R7. 49. Furnsinn C, Brunmair B, Furtmuller R et al. Failure of leptin to aect basal and insulin-stimulated glucose metabolism of rat skeletal muscle in vitro. Diabetologia 1998; 41: 524±529. 50. Ranganathan S, Ciaraldi TP, Henry RR et al. Lack of eect of leptin on glucose transport, lipoprotein lipase, and insulin action in adipose and muscle cells. Endocrinology 1998; 139: 2509±2513. 51. Haynes WG, Sivitz WI, Morgan DA et al. Sympathetic and cardiorenal actions of leptin. Hypertension 1997; 30: 619±623. * 52. Snitker S, Pratley RE, Nicolson M et al. Relationship between muscle sympathetic nerve activity and plasma leptin concentration. Obesity Research 1997; 5: 338±340. 53. Ricquier D & Bouillaud F. The mitochondrial uncoupling proteins. MeÂdeÂcine/Sciences 1998; 14: 889±897.
Obesity and diabetes 235 54. Stock M. Energy balance and animal models of obesity. In Kopelman PG & Stock M (eds) Clinical Obesity pp 50±72. Oxford: Blackwell Science, 1998. 55. Emilsson V, Summers RJ, Hamilton S et al. The eects of the beta3-adrenoceptor agonist BRL 35135 on UCP isoform mRNA expression. Biochemical and Biophysical Research Communications 1998; 252: 450±454. 56. Savontaus E, Rouru J, Boss O et al. Dierential regulation of uncoupling proteins by chronic treatments with beta3-adrenergic agonist BRL 35135 and metformin in obese fa/fa zucker rats. Biochemical and Biophysical Research Communications 1998; 246: 899±904. 57. Matsuda J, Hosoda K, Itoh H et al. Increased adipose expression of the uncoupling protein-3 gene by thiazolidinediones in Wistar fatty rats and in cultured adipocytes. Diabetes 1998; 47: 1809±1814. 58. Walder K, Norman RA, Hanson RL et al. Association between uncoupling protein polymorphisms (UCP2±UCP3) and energy metabolism/obesity in Pima Indians. Human Molecular Genetics 1998; 7: 1431±1435. 59. White MF. The IRS-signalling system: a network of docking proteins that mediate insulin action. Molecular and Cellular Biochemistry 1998; 182: 3±11. * 60. Hotamisligil GS, Shargill NS & Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87±91. 61. Hotamisligil GS, Arner P, Caro JF et al. Increased adipose tissue expression of tumor necrosis factoralpha in human obesity and insulin resistance. Journal of Clinical Investigation 1995; 95: 2409±2415. 62. Saghizadeh M, Ong JM, Garvey WT et al. The expression of TNF alpha by human muscle. Relationship to insulin resistance. Journal of Clinical Investigation 1996; 97: 1111±1116. 63. Hotamisligil GS, Budavari A, Murray D & Spiegelman BM. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. Journal of Clinical Investigation 1994; 94: 1543±1549. 64. Nolte LA, Hansen PA, Chen MM et al. Short-term exposure to tumor necrosis factor-alpha does not aect insulin-stimulated glucose uptake in skeletal muscle. Diabetes 1998; 47: 721±726. 65. Stephens JM & Pekala PH. Transcriptional repression of the GLUT4 and C/EBP genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha. Journal of Biological Chemistry 1991; 266: 21839±21845. 66. Stephens JM, Lee J & Pilch PF. Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. Journal of Biological Chemistry 1997; 272: 971±976. 67. Elchebly M, Payette P, Michaliszyn E et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1b gene. Science 1999; 283: 1544±1548. 68. Lee JH, Reed DR & Price RA. Familial risk ratios for extreme obesity: implications for mapping human obesity genes. International Journal of Obesity 1997; 21: 935±940. 69. Sorensen TI. The genetics of obesity. Metabolism: Clinical and Experimental 1995; 44: 4±6. 70. Bouchard C. Genetics of human obesity: recent results from linkage studies. Journal of Nutrition 1997; 127: 1887S±1890S. 71. Perusse L & Chagnon YC. Summary of human linkage and association studies. Behavior Genetics 1997; 27: 359±372. 72. Froguel P. Tracking down genes to cure diabetes: an achievable task for the 21st century? Diabetes and Metabolism 1997; 23 (supplement 2): 8±13. 73. Kahn CR, Vicent D & Doria A. Genetics of non-insulin-dependent (type-II) diabetes mellitus. Annual Review of Medicine 1996; 47: 509±531. 74. Velho G & Froguel P. Genetic determinants of non-insulin-dependent diabetes mellitus: strategies and recent results. Diabetes and Metabolism 1997; 23: 7±17. 75. Hales CN, Barker DJ, Clark PM et al. Fetal and infant growth and impaired glucose tolerance at age 64. British Medical Journal 1991; 303: 1019±1022. 76. Phillips DI, Barker DJ, Hales CN et al. Thinness at birth and insulin resistance in adult life. Diabetologia 1994; 37: 150±154. 77. Phillips DI, Hirst S, Clark PM et al. Fetal growth and insulin secretion in adult life. Diabetologia 1994; 37: 592±596. 78. Neel JV. Diabetes mellitus: a thrifty genotype rendered detrimental by `progress'. American Journal of Human Genetics 1962; 14: 353±362. 79. Knowler WC, Pettitt DJ, Bennett PH & Williams RC. Diabetes mellitus in the Pima Indians: genetic and evolutionary considerations. American Journal of Physical Anthropology 1983; 62: 107±114. 80. Lean ME, Powrie JK, Anderson AS & Garthwaite PH. Obesity, weight loss and prognosis in type 2 diabetes. Diabetic Medicine 1990; 7: 228±233. 81. World Health Organization. WHO MONICA Project: Geographical variations in the major risk factors of coronary heart disease in men and women aged 35±64 years. World Health Statistics Quarterly 1988; 41: 115±140.
236 K. S. Leong and J. P. Wilding 82. Garner DM & Wooley SC. Confronting the failure of behavioral and dietary treatments for obesity. Clinical Psychology Review 1991; 11: 729±780. * 83. Wing RR, Koeske R, Epstein LH et al. Long-term eects of modest weight loss in type II diabetic patients. Archives of Internal Medicine 1987; 147: 1749±1753. 84. Dattilo AM & Kris-Etherton PM. Eects of weight reduction on blood lipids and lipoproteins: a metaanalysis. American Journal of Clinical Nutrition 1992; 56: 320±328. 85. Goldstein DJ. Bene®cial health eects of modest weight loss. International Journal of Obesity and Related Metabolic Disorders 1992; 16: 397±415. 86. Karason K, Wallentin I, Larrson B & Sjostrom L. Eects of obesity and weight loss on left ventricular mass and relative wall thickness: survey and intervention study. British Medical Journal 1997; 315: 912±916. 87. Saris S. Eects of energy restriction and exercise on the sympathetic nervous system. International Journal of Obesity 1995; 19 (supplement 7): S17±S23. 88. Grassi G, Seravalle G, Compton MM et al. Body weight reduction, sympathetic nerve trac, and arterial barore¯ex in obese normotensive humans. Circulation 1998; 97: 2037±2042. 89. Pories WJ, Swanson MS, MacDonald KG et al. Who would have thought it? An operation proves to be the most eective therapy for adult-onset diabetes mellitus. Annals of Surgery 1995; 222: 339±350. 90. Sjostrom L, Narbro K & Sjostrom D. Costs and bene®ts when treating obesity. International Journal of Obesity 1995; 19: S9±S12. 91. Kolanowski J. Surgical treatment for morbid obesity. British Medical Bulletin 1997; 53: 433±444. 92. Krotkiewski M, Lonroth P, Mandroukas K et al. The eects of physical training in insulin secretion and eectiveness on glucose metabolism in obesity and type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1985; 28: 881±890. 93. Klem ML, Wing RR, McGuire MT et al. A descriptive study of individuals successful at long-term maintenance of substantial weight loss. American Journal of Clinical Nutrition 1997; 66: 239±246. 94. Hillsdon M & Thorogood M. A systematic review of physical activity promotion strategies. British Journal of Sports Medicine 1996; 30: 84±89. 95. Frost G, Masters K, King C et al. A new method of energy prescription to improve weight loss. Journal of Human Nutrition and Dietetics 1991; 4: 369±373. 96. Ha T & Lean ME. Diet and lifestyle modi®cation in the management of non-insulin dependent diabetes mellitus. In Pickup J & Williams G (eds) Textbook of Diabetes, 2nd edn pp 37.1±37.18. Oxford: Blackwell Science, 1997. 97. Skender ML, Goodrick GK, Del Junco DJ et al. Comparison of 2-year weight loss trends in behavioral treatments of obesity: diet, exercise, and combination interventions. Journal of the American Dietetic Association 1996; 96: 342±346. 98. National task force on the prevention and treatment of obesity. Very low calorie diets. Journal of the American Medical Association 1993; 270: 967±974. 99. Uusitupa MI, Laakso M, Sarlaund H et al. Eects of a very low calorie diet on metabolic control and cardiovascular risk factors in the treatment of obese non-insulin dependent diabetics. American Journal of Clinical Nutrition 1990; 51: 768±773. 100. Guerciolini R. Mode of action of orlistat. International Journal of Obesity and Related Metabolic Disorders 1997; 21 (supplement 3): S12±S23. *101. Hollander PA, Elbein SC, Hirsch IB et al. Role of orlistat in the treatment of obese patients with type 2 diabetes: a 1-year randomized double-blind study. Diabetes Care 1998; 21: 1288±1294. *102. Sjostrom L, Rissanen A, Andersen T et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet 1998; 352: 167±172. 103. Melia AT, Koss-Twardy SG & Zhi J. The eect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers. Journal of Clinical Pharmacology 1996; 36: 647±653. 104. Ryan DH, Kaiser P & Bray GA. Sibutramine: a novel new agent for obesity treatment. Obesity Research 1995; 3 (supplement 4): 553S±559S. 105. Heal DJ, Aspley S & Prow MR et al. Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to dierentiate it from d-amphetamine and d-fen¯uramine. International Journal of Obesity 1998; 22: S18±S29. 106. Luque CA, Rey JA & Fernandez A. Focus on sibutramine: a new anorectic agent for the treatment of obesity. Hospital Formulary 1997; 32: 1025±1039. 107. Bray GA, Ryan DH, Gordon D et al. A double-blind randomized placebo-controlled trial of sibutramine. Obesity Research 1996; 4: 263±270. 108. Griths J, Byrnes AE & Frost G. Sibutramine in the treatment of overweight non-insulin dependent diabetics. International Journal of Obesity 1995; 19 (supplement 2): 144 (abstract). 109. Lean ME. Sibutramine ± a review of clinical ecacy. International Journal of Obesity and Related Metabolic Disorders 1997; 21 (supplement 1): S30±S36.
Obesity and diabetes 237 *110. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837±853. *111. UK Prospective Diabetes Study (UKPDS) Group. Eect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854±865.