Treating obesity in type 2 diabetes — although challenging — can substantially improve patient outcome.
Of the estimated 15 million people with type 2 diabetes in the United States, only 7 to 8 million are actually diagnosed with this form of diabetes.Type 2 diabetes is three times more prevalent in obese individuals than non-overweight persons, and 80% of people with type 2 diabetes are also obese. Obesity affects approximately 58 million adults (one-third of the U.S. population) and contributes to the development of cardiovascular disease, hypertension, hypercholesterolemia, and type 2 diabetes.Other serious health conditions associated with obesity include respiratory problems, sleep apnea, arthritis, and some cancers. Mortality rate also increases in obese persons and steadily rises as the degree of obesity increases.
The cause of type 2 diabetes is still unknown, although much research is currently being done to elucidate its underlying etiology and pathology. Type 2 diabetes is characterized by obesity and insulin resistance. Insulin resistance, or the inability of insulin to exert its biologic effect in the body, is suspected to be involved with the pathogenesis of type 2 diabetes. Obesity is a known risk factor for the development of type 2 diabetes, and the two conditions are often present in the same patient. The underlying cause of obesity is poorly understood, and many factors may play a role in its manifestation. Excess lipid deposition occurs when energy intake exceeds energy expenditure. How or why this occurs in a certain individual is not known. Obviously, excess food intake results in obesity, but how decreased energy expenditure occurs metabolically is less understood.
Obesity is commonly defined as a body mass index (BMI) over 25 kg/m[BMI = (kg/(height in meters)]. Health risks increase as BMI increases above 27 kg/m.The various causes of obesity are listed in TABLE 1.
| Table 1. Potential Causes of Obesity |
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Cushing’s syndrome |
Insulin’s Effect on Fat Metabolism
Adipocytes, or fat cells, are present in all mammals. They serve as a reservoir for energy and help to maintain body temperature. Insulin acts to increase hepatic fatty acid synthesis; once insulin facilitates glucose transport into cells, the glucose is used to synthesize free fatty acids and alpha-glycerol phosphate. Alpha-glycerol phosphate provides the glycerol to fatty acid molecules that are used to synthesize triglycerides. The triglycerides are then taken up into adipocytes and stored. Insulin also decreases the action of hormone-sensitive lipase, the enzyme required to hydrolyze triglycerides stored in fat. Insulin is critically needed for normal fat metabolism. In patients with type 2 diabetes, fat and lipid metabolism is abnormal and leads to hypertriglyceridemia, hyperlipidemia, and obesity.
Obesity and Insulin Resistance
Obesity contributes to the development of insulin resistance which leads to the development of overt type 2 diabetes. When the tissues of the body are resistant to the biological actions of insulin, excess insulin production (hyperinsulinemia) by pancreatic beta-cells occurs. Unfortunately, in the insulin-resistant state, insulin is less effective in assisting glucose uptake by the tissues and more and more insulin is needed to keep blood glucose levels in the normal range. In the obese individual, both decreased numbers and less responsive insulin receptors (receptor defects) may be present. It is also possible that intracellular defects occur in the tissues (post receptor defects) of people with insulin resistance. Over time, the pancreas becomes less able to produce insulin, and type 2 diabetes develops when the pancreatic beta-cells burnout (are no longer able to produce insulin).
The pattern of fat distribution may also play a role in the development of insulin resistance and type 2 diabetes. A study of 792 men discovered that those with increased waist to hip ratios (truncal or central obesity) were more likely to develop diabetes than those with normal ratios. Study subjects in the highest 5% of waist to hip ratios, meaning they had large bellies compared to their waist size, were 16.6 times more at risk of developing diabetes than those in the lowest 20% of ratios. No study subjects in the lowest 20% of body mass index (BMI) developed diabetes, while 21.4% in the upper 5% of the body mass index (BMI) distribution developed diabetes over the 13.5 years that they were studied. Individuals who tend to carry their weight in their hips or buttocks are less likely to be insulin resistant or to develop diabetes.
Individuals with central obesity tend to develop the following set of clinical conditions: atherosclerosis (e.g., coronary artery disease, peripheral vascular disease), hypertension, and dyslipidemia. This combination of conditions is referred to as syndrome X. These potential co-morbidities must be addressed when treating obese patients with type 2 diabetes.
Shortfalls of Leptin Replacement
Obesity has long been thought to be caused by a metabolic or hormonal defect, deficiency, excess, or some combination thereof. The discovery of leptin, also known as the “fat-melting hormone,” in 1994 gave physicians and patients hope for an obesity treatment. Certain strains of mice contain a genetic mutation that results in an absolute leptin deficiency. Because they are leptin deficient, they are obese. When these mice are supplemented with leptin, weight reduction occurs.
Scientists hoped that replacing leptin in obese humans would also stimulate weight loss. However, leptin replacement therapies have produced negligible clinical results. In fact, many obese humans already have increased levels of leptin. No weight changes occur when more leptin is added. Researchers are investigating the possibility that these people are leptin-insensitive.