Effect of thiazolidinediones on body weight in patients with diabetes mellitus

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Abstract

Treatment of diabetes mellitus with medications, including insulin, sulfonylureas, and thiazolidinediones (TZDs), often leads to weight gain through a variety of mechanisms. Weight gain can have adverse consequences for patients with type 2 diabetes, many of whom are overweight or obese, because obesity is linked to insulin resistance and other medical consequences such as cardiovascular disease. TZDs improve glycemic control and insulin sensitivity in patients with type 2 diabetes, despite their potential to cause weight gain. Studies have attempted to elucidate the mechanisms behind the apparent paradox of TZDs improving insulin sensitivity while causing weight gain. Data indicate that with TZD treatment, there is a favorable shift in fat distribution from visceral to subcutaneous adipose depots that is associated with improvements in hepatic and peripheral tissue sensitivity to insulin. Although weight gain may occur with TZD therapy, it is not inevitable. A weight-management program combining a low-calorie, low-sodium diet with education and behavior modification has been shown to be effective in patients with type 2 diabetes being treated with TZDs. Further research is needed to define the optimal dietary modifications that can be used universally in TZD-treated patients to minimize weight gain while effectively treating insulin resistance and hyperglycemia.

Section snippets

Body fat distribution and insulin resistance

Although insulin resistance is associated with obesity, recent evidence suggests that insulin resistance is more closely related to the distribution of body fat rather than the overall fat mass.4, 5 Central obesity (fat around the waist) reflects an increase in intra-abdominal visceral fat. Data suggest that adipocytes in visceral fat are metabolically more active than in subcutaneous fat, releasing greater amounts of fat products such as free fatty acids (FFAs).6 Furthermore, because visceral

Effects of diabetes treatments on obesity

Many of the medications used to treat diabetes have been reported to cause weight gain, potentially causing distress to patients who are trying to lose weight. A variety of mechanisms contribute to this weight gain (Table 1). Severe hyperglycemia induces a catabolic state, and its correction leads to rebuilding of muscle and fat mass. This is particularly true with the use of insulin, whether exogenous or endogenous (i.e., stimulation by secretagogues). In addition, even mild degrees of

Mechanism of weight gain with thiazolidinediones

TZDs are ligands of peroxisome proliferator-activated receptor–γ (PPAR-γ), which is highly expressed in adipose tissue and plays an important role in the differentiation of adipocytes.26 The beneficial effects of TZDs on glucose metabolism are believed to be mediated by their binding to PPAR-γ, an activity likely to stimulate adipogenesis.27 The TZDs have a site-specific effect on differentiation of human preadipocytes; this effect is markedly enhanced in subcutaneous fat, with less effect in

Use of thiazolidinediones in obese patients

Clinical trials of TZDs have been conducted in a wide variety of patients with and without overt diabetes. Most of these trials included patients with moderate to severe obesity, and the mean body mass index (BMI) was approximately 30 to 35 in clinical trials conducted in the United States. Buch and coworkers45 reported their experience with the addition of rosiglitazone to insulin therapy for 24 weeks; their 8 subjects were massively obese patients (mean BMI, 42) with poorly controlled type 2

Weight loss/maintenance in patients treated with thiazolidinedione

Several strategies have been used to induce weight loss in patients with diabetes. The weight-loss agents sibutramine and orlistat have been studied as monotherapy and in combination with antidiabetic therapies in patients with type 2 diabetes. Such combinations cause weight loss while decreasing the need for insulin or secretagogue therapy46, 47, 48, 49, 50; however, these weight-loss agents have not been studied in combination with TZDs. Another option is use of low-calorie packaged or liquid

Summary

Obesity plays a pivotal role in the development of insulin resistance and is common in patients with type 2 diabetes. Strategies to manage body weight should be part of all diabetic treatment plans. However, through a variety of mechanisms, most medications used to treat diabetes tend to provoke weight gain, and this can be problematic for patients who are attempting to lose weight. Currently available data indicate that TZDs improve insulin sensitivity and cause a favorable redistribution of

Summary statements

  • Weight gain occurs with most treatments for diabetes.

  • Weight gain may be associated with TZDs, but it is not inevitable, and it can be controlled with dietary methods.

  • TZDs improve insulin sensitivity and cause a favorable redistribution of fat.

  • The combination of metformin with a TZD does not cause additional weight gain and may have an additive effect on insulin sensitivity.

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