Obesity and Diabetes mellitus, and insulin resistance

Obesity and type 2 diabetes represent a serious threat to the health of the population of almost every country in the world. The World Health Organization estimates that 1.1 million people died as a result of diabetes in 2005, and this is almost certainly an underestimate. Moreover, the figure is expected to increase by 50% during the next ten years.

The increase in the prevalence of type 2 diabetes is closely linked to the upsurge in obesity. About 90% of type 2 diabetes is attributable to excess weight. Furthermore, approximately 197 million people worldwide have impaired glucose tolerance, most commonly because of obesity and the associated metabolic syndrome. This number is expected to increase to 420 million by 2025

In the past 20 years, the rates of obesity have tripled in developing countries that have been adopting a Western lifestyle involving decreased physical activity and over consumption of energy-dense food. Such lifestyle changes are also affecting children in these countries; the prevalence of overweight among them ranges from 10 to 25%, and the prevalence of obesity ranges from 2 to 10%.

Consequently, diabetes is rapidly emerging as a global health care problem that threatens to reach pandemic levels by 2030; the number of people with diabetes worldwide is projected to increase from 171 million in 2000 to 366 million by 2030. This increase will be most noticeable in developing countries, where the number of people with diabetes is expected to increase from 84 million to 228 million. According to the WHO, Southeast Asia and the Western Pacific region are at the forefront of the current diabetes epidemic, with India and China facing the greatest challenges. In these countries, the incidence and prevalence of type 2 diabetes among children are also increasing at an alarming rate, with potentially devastating consequences

Type 2 diabetes mellitus is strongly associated with overweight in both genders in all ethnic groups. The risk of type 2 diabetes mellitus increases with the degree and duration of overweight and with a more central distribution of body fat.

The relationship between increasing BMI and the risk of diabetes is shown in the Nurses Health Study. The risk of diabetes was lowest in individuals with a BMI less than 22 kg/m2 . As BMI increased, the relative risk increased, such that at a BMI of 35 kg/m2, the relative risk increased 40-fold, or 4000%. A similar strong curvilinear relationship was observed in men in the Health Professionals Follow-Up Study. The lowest risk in men was associated with a BMI less than 24 kg/m2, slightly higher than that for the women in the Nurses Health Study. At a BMI above 35 kg/m2, the age-adjusted relative risk for diabetes in nurses increased to 60.9, or more than 6000%.

Weight gain also increases the risk of diabetes. Up to 65% of cases of type 2 diabetes mellitus can be attributed to overweight. Of the 11.7 million cases of diabetes, overweight may account for two thirds of diabetic deaths. Using the BMI at age 18 yr, a 20-kg weight gain increased the risk for diabetes 15-fold, whereas a weight reduction of 20 kg reduced the risk to almost zero. In the Health Professionals Follow-Up Study, weight gain was also associated with an increasing risk of noninsulin-dependent diabetes mellitus, whereas a 3-kg weight loss was associated with a reduction in relative risk. Weight gain appears to precede the onset of diabetes.

In the Health Professionals Follow-Up Study, relative risk of developing diabetes increased with weight gain as well as with increased BMI. In long-term follow-up studies, the duration of overweight and the change in plasma glucose during an oral glucose tolerance test also were strongly related. When overweight was present for less than 10 yr, plasma glucose was not increased. With longer durations, of up to 45 yr, a nearly linear increase in plasma glucose occurred after an oral glucose tolerance test. The risk of diabetes is increased in hypertensive individuals treated with diuretics or -blocking drugs, and this risk is increased in overweight subjects.

In the Swedish Obese Subjects Study, Sjostrom et al observed that diabetes was present in 13-16% of obese subjects at baseline. Of those who underwent gastric bypass and subsequently lost weight, 69% who initially had diabetes went into remission, and only 0.5% of those who did not have diabetes at baseline developed it during the 2 yr of follow-up. In contrast, in the obese control group that lost no weight, the cure rate was low (16%), and the incidence of new cases of diabetes was 7.8%.

Weight loss or moderating weight gain over years reduces the risk of developing diabetes. This is most clearly shown in the Health Professionals Follow-Up Study, in which relative risk declined by nearly 50% with a weight loss of 5-11 kg. Type II diabetes was almost nonexistent with a weight loss of more than 20 kg or a BMI below 20 kg/m2

Both increased insulin secretion and insulin resistance result from obesity. The relationship of insulin secretion to BMI has already been noted. A greater BMI correlates with greater insulin secretion.

Increased visceral fat enhances the degree of insulin resistance associated with obesity and hyperinsulinemia. Together, hyperinsulinemia and insulin resistance enhance the risk of the comorbidities.

There is, therefore, an urgent need for new approaches to address obesity and type 2 diabetes and their associated complications. In particular, understanding the various processes from abnormal regulation of energy metabolism through to dysfunction of molecular mechanisms - will pave the way for the development of new treatment strategies.