Management of Obesity

The fact that Type 2 diabetes does not inevitably occur in both of a pair of monozygotic twins clearly indicates that environment, as well as heredity, has a part to play in the development of Type 2 diabetes. Furthermore, since Type 2 diabetes is not, in most cases, a monogenic and environment is likely to be complex and variable from individual to individual. Genetic differences may explain in part why, for example, some patients with Type 2 diabetes achieve improved glucose control through weight loss and / or exercise and others do not.

There is every reason to suppose that manipulation of the metabolic environment through weight loss should be able to prevent, or at the very least delay, the development of diabetes, even in people with a strong genetic predisposition.

Pharmacological Treatment

There are several approaches to treat obesity pharmacologically :

Food intake may be reduced by centrally acting appetite – suppressant drug, which fall into three broad categories; those acting via adrenergic pathways, serotonergic pathways or dopaminergic pathways. All have been shown to reduce appetite and food intake, but cardiovascular side effects may present problems. Dopaminergic stimulation is associated with mood enhancement and dependency; amphetamines and functionally related drugs stimulate this mechanism, therefore should not be used for weight management. Drugs with catecholaminergic activity include structural amphetamine derivatives, such as diethylpropion, phentolamine, phenylpropanolamine and mazindol, (amphetamine and phenmetrazine are no longer available because of strong stimulatory properties and addictive potential).

Another approach to modifying food intake is to reduce the activity of enzymes involved in absorption of nutrients – glucosidase inhibitors inhibit enzymes in the brush border membranes, which delays carbohydrate breakdown and absorption, leading to an improvement in glycaemic control, these are agents that inhibit fat absorption or digestion. Tetrahydrolipostatin has been useful in conjunction with dietary modification in obese non-diabetic subjects.

Increasing Energy Expenditure

In animals, B3 -- adrenergic agonists have been found to stimulate energy expenditure and decrease body weight without reducing food intake, research on the activation of brown adipose tissue led to the discovery of the ß lipolytic adrenoceptor, which stimulates thermogenesis. The recently developed atypical B3 – adrenergic agonists are undergoing clinical trials, but none are licensed yet. Sibutramine is a new anti- obesity agent, a serotonin and noradrenaline re-uptake inhibitor (SNRI). It appears to cause weight loss via effects on reducing food intake and there is some evidence of elevation of metabolic rate. It is hoped that sibutramine, which has been extensively studied in clinical trials, will provide a safe and effective new adjunct for dietary and behavioural approaches to involve and maintain weight loss.

Other Areas Of Research

There are currently a number of peptides (including cholecystokinin, glucagon like peptides and neurotensin) with appetite modifying properties, which are undergoing extensive studies. Also, the recent discovery of leptin and neuropeptide Y are considered to be important advances in obesity research.

Conclusions

While the search goes on for the genes that cause ‘diabesity’ is clear that the most effective strategy currently at our disposal of the prevention of Type 2 diabetes is to avoid weight gain during adult life and to lose excess weight when necessary, this applies to populations as a whole and most especially to those with central obesity or a family history of diabetes.

For those who already have IGT or diagnosed disease, the message is the same. Weight loss can improve Glucose tolerance, increase insulin sensitivity, improve the lipid profile and decrease the need for hypoglycaemic agents. Weight loss has already been shown to reduce mortality from cardiovascular disease in obese individuals in general. There is every reason to support that it will also do so in patients with diabetes, thus diminishing one of the most common and lethal complications of the disease. Indeed, the preliminary evidence indicates that weight loss can significantly prolong life.

One of the most encouraging findings is that weight loss does not have to be very great in order to produce significant health benefits. We have seen that a weight loss of just 2-4 kg can be enough to reduce blood glucose, and a more substantial loss may achieve normoglycaemia. A weight loss of 10 kg has been calculated to be enough to eliminate excess mortality. Modest losses like this are more readily achieved than the ideal weight and represent a more realistic target for patients. The combination of a low-fat, reduced energy diet with increased physical activity is likely to have the most beneficial effect.

Losing weight is never easy, even for people whose health is immediately and obviously in danger. Long-term lifestyle changes are most likely to be achieved where continued support and counselling are available from a skilled practitioner. Pharmacological treatment and fat substitutes may also be useful in helping patients to lose weight and reduce the fat content of their diet. For the most severely obese, surgery may be a viable option.

Sustained effort on the part of both patient and physician will be needed to achieve and maintain weight loss in Type 2 diabetes, however, starting with the first few kilos, these efforts can result in a healthier, longer and more active life.