Summary and Discussions on Other Models

The World Health Organization defines obesity as a disease in which excess body fat has accumulated to such an extent that health may be adversely affected. Obesity is a chronic disease with important health and psychological consequences.⁹ The adverse health consequences of obesity include insulin resistance (an integral part of type 2 diabetes mellitus), type 2 diabetes mellitus, dyslipidaemia, hypertension, coronary heart disease, hyperuricaemia, osteoarthritis and even malignancies such as cancer of the breast (in post menopausal woman), endometrium and colon.9,16,19,34,48,96 The Body Mass Index (BMI) has long been established as the preferred method of measuring adiposity in epidemiological studies⁹⁷, and for most populations a good correlation

exits between BMI, percentage body fats for all ages and both sexes. Appropriate cut off points for the WHO classification of adults, and children according to BMI are now available96, 98, 99. Generalized obesity can be estimated clinically by using the BMI, also called the Quetelet Index, which is the ratio of weight in kilogram to the square of the height in meters.⁹⁶ An individual is obese if BMI is greater than or equal to 30kg/m².⁹⁹

Obesity has become a global health problem affecting more than 1.3 billion adults in both developed and developing countries¹⁰⁰. In South Africa, it has been suggested that urbanization is associated with an increased risk of becoming overweight or obese.^101,102 There is a genetic and environmental component to overweight and obesity. Considerable attention has been paid to the secular changes in food intake and physical activity that underlie the recent rise in the prevalence of obesity.103,104,105 However, there are compelling evidences that inter-individual differences in susceptibility to obesity have strong genetic determinants¹⁰⁶. In the past decade, there have been major advances in the understanding of the molecular constituents of the pathways that control mammalian energy homeostasis.¹⁰⁶ Six human obesity syndromes that arise from genetic defects have been described and several patients with congenital leptin deficiency have been identified.¹⁰⁶ Individuals with the above mentioned defects present with hyperphagia, severe disabling obesity, impaired T-cell mediated immunity and hypogonadotrophic hypogonadism.¹⁰³ In clinical trials of daily subcutaneous injections of recombinant human Leptin, sustained beneficial effects on appetite, fat mass, hyperinsulinaemia and hyperlipidaemia were observed¹⁰³. Two thousand severely obese children were recruited to the Genetics of Obesity Study (GOOS) using a candidate gene approach. Several loss of function mutations in the melanocortin 4 receptor (MC4R), which causes a dominantly inherited syndrome that accounts for up to 5% of patients with severe, early onset obesity, were found. The above has been also found to be the commonest obesity syndrome

today.¹⁰³ The characterization of these syndromes and of patient with mutations in the gene encoding the Leptin receptor, pro-opiomelanocortin (POMC) and pro-hormone convertase – 1, has provided a better mechanistic understanding of the regulation of appetite and body weight in humans. This will have implications for treatment of overweight and obesity with related metabolic disorders. Environmental factors, particularly diets which contain high carbohydrates, have been implicated in a study to be a cause or predisposing factor to overweight and obesity¹⁰⁷. Whilst genetic factors are important in the aetiology of overweight and obesity, it is clearly the changing lifestyle that is fuelling the current epidemic.

The effect of stress in early life leading to obesity, metabolic syndrome and type 2 diabetes mellitus has been proven¹⁰³ Stress activates the central and peripheral components of the stress system that is the hypothalamic-pituitary-adrenal (HPA) axis and the arousal/sympathetic system. The principal effectors of the stress system are the corticotrophin-releasing hormone (CRH), arginine, vasoprin, the propiomelanocortin-derived peptides, melanocyte stimulating hormone, endorphin, the glucocorticoidS, and the cathecholamines norepinephrine and epinephrine. The developing brain undergoes rapid growth and is characterized by high turnover of neuronal connections during the prenatal and early extra-uterine life. These processes and, hence, brain plasticity, slow down during childhood and puberty and plateau in young adulthood. Hormonal actions in early life, can be organizational to an extent, that is, it can have effects that can last the entire life of the individual. Hormones of the stress system as well as the sex steroids have such effects which influence the behaviour and certain physiologic functions of the individual for life.¹⁰³ Exposure of the developing brain to severe and/or prolonged stress may result in hyperactivity/hyper reactivity of the stress system. This will result to amygdala hyper function (fear reaction), decreased activity of the hippocampus (defective glucocorticoid negative feedback and cognition). The

mesocorticolimbic dopaminergic system is also affected, leading to (dysthymia, novelty speaking, addictive behaviours), suppression of reproductive growth, thyroid and immune functions, hyper-activation of the HPA axis (Hypercotisolism) and changes in pain perception. These changes may be accompanied by abnormal childhood, adolescent and adult behaviours, including excessive fear (inhibited child syndrome) and addictive behaviours, dysthymia and/or depression and gradual development of components of metabolic syndrome X including severe obesity, diabetes mellitus type 2, and essential hypertension.¹⁰³ Although the link between overweight and obesity with metabolic mortality and deaths is established, the association between BMI and all other causes of mortality is uncertain, as is the optimum BMI. The BMI associated with lowest all causes mortality is 20 – 24.9 for white adults. The greater mortality at low BMI is partly explained by the association of smoking and pre-existing illness with low body weight. The link between BMI and mortality weakens with increasing age,¹⁰⁰ partly because of the increasing prevalence of diseases that increase mortality and also cause weight loss, and partly because harmful visceral fat deposition is greater at lower BMI. Collaborative analyses of baseline BMI versus mortality in 57 prospective studies with 894 576 participants, mostly in Western Europe and North America, showed that, for each 5kg/m² increase BMI, overall mortality increased by 30% ( a hazard ratio of 1.29). For each 5kg/m², mortality was increased by 40% for vascular diseases, 20% for respiratory diseases, 60-120% for diabetes mellitus, renal and hepatic diseases, and 10% for cancer.¹⁰⁰ Overweight and obesity are therefore associated with increased risks for metabolic disorders.¹⁰⁸ Obesity in adults is associated with increased risks of diabetes mellitus and coronary heart disease. A study in Israel has provided data from adolescence into adulthood. A total of 37 674 men in the Israeli army were examined from the age of 17. Mean total follow up was for 17.4 years during which 1173 men developed type 2 diabetes mellitus and 327 coronary diseases. After adjustment for age, family

history for diabetes mellitus, blood pressure, physical activity, fasting blood glucose, and triglyceride level the risk of type 2 diabetes mellitus was significantly increased in participants with the adolescent BMI within the top 30% (BMI 22.35 - 25.07). The increase in risk compared with the first decile (method of splitting up a set of ranked data into 10 equally large sub sections or percentiles taken in tens) for BMI was 47% in the eight decile, 79% in the ninth, and 176% in the tenth. For the angiographically proved coronary disease, the increase in risk (compared with the first BMI decile) rose from 71% in the second decile (BMI 18.12% - 19.00) to 585% in the tenth decile (BMI 25.07 - 35.99). Adjustment for BMI in adulthood eliminates the increased risk for diabetes mellitus associated with a higher BMI in adolescence but not the increase risk for coronary disease. Increase in the risk for type 2 diabetes is mainly associated with the raised BMI near the time of diagnosis of diabetes. The process whereby increased weight leads to diabetes may occur very quickly than those relating increased weight to coronary heart disease.¹⁰⁹

Body Mass Index is positively associated with increased risk of type 2 diabetes mellitus in both sexes in many ethnic groups.^110-112 In Africans, the BMI has been found to be lower in rural people¹¹³ than in their urban counterparts.¹¹⁴ Centralized distribution of body fat (referred to as abdominal or central obesity), determined by waist circumference (WC) and waist Hip Ratio (WHR) has been implicated as a risk for diabetes type 2.^110,113

About 75% of patients with diabetes are overweight or obese⁹⁶.In Europe and North America, the risk for type 2 diabetes mellitus begins to increase from BMI 22 kg/m² in women and 24 kg/m² in men; in Asian populations, the risk begins to increase at BMI of 1-2kg/m² lower than the threshold in Europe and North America. In men aged 40-75 years followed for five years, the risk for diabetes was 6.4 fold greater in those who had a BMI of 27 kg/m² at 40 years and, independently, 3.5 fold greater in those who gained 9kg from that age. The relative risk of developing diabetes

increases by 25% for every 1 kg/m² increase in BMI above 22 kg/m². With the onset of obesity occurring earlier in life, the average age of onset of type 2 diabetes mellitus is also falling: from 52 to 46 years between 1994 and 2000 in the USA.96,100,108,112. Central or upper body fats distribution, as measured by waist circumference, is an independent risk factor for the development of type 2 diabetes mellitus.¹¹² Visceral fat distribution is associated with insulin resistance, which is present at the level of the peripheral tissues (muscle and adipose tissue) and the liver.¹⁰³ Insulin resistance and hyperinsulinaemia are characteristic features of obesity.¹⁰³ Insulin resistance is primarily caused by post-receptor defects (impaired autophosphorylation of tyrosine kinase, the enzyme responsible for glucose transport, oxidation and storage) and to a lesser extent, a receptor defect. High levels of tumour necrosis factor alpha in obese individuals are inversely related to low levels of adiponectin, have been shown to inhibit autophosphorylation of tyrosine kinase and could have an important role to play in the development of insulin resistance. Initially, insulin resistance is compensated for by increase insulin secretion and pancreatic beta-cells, to maintain normal glucose homeostasis at the expense of hyperinsulineamia. When the beta-cells ‘burn out’

and insulin secretion cannot match the increasing insulin resistance, impaired glucose tolerance and frank diabetes mellitus develops.^103,112 The rate of conversion from impaired glucose tolerance to type 2 diabetes mellitus varies in different studies and ranges from 1.5% per year in the 10 year follow up of the United Kingdom to 7% per year in Seattle and Asians in Madras.^53,60. The clinical hallmark of insulin resistance is the skin condition, acanthosis nigricans, a darkening and ridging of the skin seen on the neck, knuckles, knees and elbows.

Central obesity is a measure of visceral fat deposit and can be defined by parameters such as the waist circumference (WC), and waist to hip ratio (WHR) ^{115,116, 117}. Other sophisticated tools that can be used to measure intra-abdominal fat include CT Scan, magnetic resonance imaging (MRI)

and Dual Energy X-ray absorptiometry; these have been found to correlate well with anthropometric indices.^118,119

A study of African-Americans showed that deposition in both visceral and subcutaneous tissue depot correlates with insulin resistance and type 2 diabetes.¹¹⁹ Stern et al¹²⁰ also showed that BMI correlates with insulin resistance. In a strict sense, obesity can be defined as an excess of body fat relative to the amount of non adipose tissue in the individual. In clinical practice, it is not infrequently equated with overweight. Moderate deposition of fat can occur in the individual who is not overweight, and muscular hypertrophy may cause an appreciable increase in weight with only a minimum accumulation of adipose tissue in the body.¹²¹ The distinction between overweight and obesity is not often easy, and different criteria have been used by many authors in obtaining cut-off points on weight and weight for height charts at which overweight in the individual subject becomes obesity.¹²² In Nigeria, Johnson T.O in 1970¹²³ in a survey among randomly selected urban adult Nigerians in Lagos, compared the weights of his subject to similar American average weight tables. He found overweight and obesity to be commoner in female than in males, a finding that is similar to the study done by Puepet et al¹²¹ in 2002. Both studies found out that weight reduction of 5 to 10% can substantially improve blood pressure, serum lipid level and glucose tolerance.

Puepet et al¹²⁴ studied some metabolic abnormalities in type 2 diabetes patients in Jos and found that BMI and WHR, which are indices of obesity, were significantly higher in diabetics than control subjects (P<0.05 obese). Fadupin et al¹²⁵ working among Nigerian diabetic patients in Ibadan found that 83% of the patients were either overweight or obese using BMI > 30kg/m². In a study of hypertension in type 2 diabetes in Jos, Agaba et al¹²⁶ found that 40 out of 152 of the patients were obese. In summary, overweight and obesity have been reported in various studies as

risk factors for diabetes type 2, and interventions are required since they constitute modifiable risk factors.