Insulin Resistance in Morbid Obesity: Reversal With Intramyocellular Fat Depletion

Aldo V. Greco, Gertrude Mingrone, Annalisa Giancaterini, Melania Manco, Manrico Morroni, Saverio Cinti, Marnie Granzotto, Roberto Vettor, Stefania Camastra, and Ele Ferrannini

Disclosures

Diabetes. 2002;51(1) 

In This Article

Abstract and Introduction

Obesity is a frequent cause of insulin resistance and poses a major risk for diabetes. Abnormal fat deposition within skeletal muscle has been identified as a mechanism of obesity-associated insulin resistance. We tested the hypothesis that dietary lipid deprivation may selectively deplete intramyocellular lipids, thereby reversing insulin resistance. Whole-body insulin sensitivity (by the insulin clamp technique), intramyocellular lipids (by quantitative histochemistry on quadriceps muscle biopsies), muscle insulin action (as the expression of Glut4 glucose transporters), and postprandial lipemia were measured in 20 morbidly obese patients (BMI = 49 ± 8 [mean ± SD] kg · m-2) and 7 nonobese control subjects. Patients were restudied 6 months later after biliopancreatic diversion (BPD; n = 8), an operation that induces predominant lipid malabsorption, or hypocaloric diet (n = 9). At 6 months, BPD had caused the loss of 33 ± 10 kg through lipid malabsorption (documented by a flat postprandial triglyceride profile). Despite an attained BMI still in the obese range (39 ± 8 kg · m-2), insulin resistance (23 ± 3 µmol/min per kg of fat-free mass; P < 0.001 vs. 53 ± 13 of control subjects) was fully reversed (52 ± 11 µmol/min per kg of fat-free mass; NS versus control subjects). In parallel with this change, intramyocellular—but not perivascular or interfibrillar—lipid accumulation decreased (1.63 ± 1.06 to 0.22 ± 0.44 score units; P < 0.01; NS vs. 0.07 ± 0.19 of control subjects), Glut4 expression was restored, and circulating leptin concentrations were normalized. In the diet group, a weight loss of 14 ± 12 kg was accompanied by very modest changes in insulin sensitivity and intramyocellular lipid contents. We conclude that lipid deprivation selectively depletes intramyocellular lipid stores and induces a normal metabolic state (in terms of insulin-mediated whole-body glucose disposal, intracellular insulin signaling, and circulating leptin levels) despite a persistent excess of total body fat mass.

Obesity is associated with type 2 diabetes, cardiovascular complications, and premature death in both men and women [1]. Morbidity and risk of premature death are directly related to the amount and distribution of excess body fat [2]. Mainstays of obesity treatment include caloric restriction, increased physical activity, and cognitive restructuring therapy [3]. In obese women, moderate weight loss (10% of initial body weight) has been shown to reduce mortality by 20% [4]. Most obese patients, however, find it difficult to comply with low-energy diets, particularly in the long run. Morbidly obese patients who do not respond to weight control programs and those who have disabling joint disease, pulmonary insufficiency, hypertension, or diabetes are eligible for surgical treatment. Bariatric surgery usually produces substantial weight loss, often achieving a stable near-normal weight [5,6]. In obese patients with diabetes, biliopancreatic diversion (BPD) [7] induces a normalization of insulin sensitivity that persists for up to 2 years [8,9].

Insulin resistance is common in obesity [10,11], as evidenced by low rates of whole-body glucose uptake during euglycemic-hyperinsulinemic clamping [12]. Weight loss has been shown to improve insulin-mediated glucose disposal by enhancing both oxidation and storage of glucose in skeletal muscle [13,14,15]. The mechanisms whereby weight loss, by diet or surgery, improves insulin resistance are incompletely understood. Recently, attention has focused on the content, localization, and composition of fat within skeletal muscle as determinants of insulin resistance. Several studies have reported an inverse relationship between insulin action and the fatty-acid composition of skeletal muscle phospholipids [16], muscle triglyceride levels [17,18,19,20], and saturated fatty acids in muscle triglycerides [21]. Less information is available on the localization, intracellular or interfibrillar, of lipids in human skeletal muscle and its specific impact on insulin action. Muscle attenuation on computed tomography scans, believed to reflect intramuscle lipid content, has been reported to be accentuated in obese women [22] and to be reciprocally related to insulin sensitivity [20]. Proton magnetic resonance spectroscopy has been validated against a chemical extraction method and used to establish a reciprocal relationship between intramyocellular lipid accumulation and insulin sensitivity in healthy individuals [23]. The accuracy of this approach in obese patients or obese patients with diabetes has not been established, however. By quantitative histochemistry, Phillips et al. [18] found an inverse relationship between intracellular lipids in the gastrocnemius of nondiabetic women and muscle glycogen synthase activity but not insulin sensitivity. In another ex vivo study using histochemistry, lipid accumulation was demonstrated within muscle fibers of the vastus lateralis in obese individuals [24].

The relation of intramyocellular fat depots to total body fat and their physiological regulation are not well known. In rats fed a high-fat diet, acute dietary lipid withdrawal is associated with an improvement of muscle insulin resistance [25]. Likewise, reducing tissue lipid availability in rats by peroxisome proliferator–activated receptor- agonism has been reported to enhance insulin sensitivity [26]. On these grounds, it has been hypothesized that selective depletion of intracellular fat depots in skeletal muscle is the key metabolic change that leads to reversal of insulin resistance independent of fat mass (FM) loss. To test this hypothesis, we measured insulin sensitivity and the distribution of intramuscle fat in a group of morbidly obese patients in whom BPD caused chronic lipid malabsorption, and compared the results with those of patients in whom weight loss was achieved by conventional caloric restriction.

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