Insulin Resistance in Morbid Obesity
Reversal With Intramyocellular Fat Depletion
- Aldo V. Greco1,
- Gertrude Mingrone1,
- Annalisa Giancaterini1,
- Melania Manco1,
- Manrico Morroni2,
- Saverio Cinti2,
- Marnie Granzotto3,
- Roberto Vettor3,
- Stefania Camastra4 and
- Ele Ferrannini4
- 1Department of Medicine, Catholic University, Rome, Italy
- 2Institute of Normal Human Anatomy, University of Ancona, Ancona, Italy
- 3Department of Medical and Surgical Sciences, University of Padova, Padova, Italy
- 4Metabolism Unit, Department of Internal Medicine and C.N.R. Institute of Clinical Physiology, University of Pisa, Pisa, Italy
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.
Address correspondence and reprint requests to Ele Ferrannini, MD, C.N.R. Institute of Clinical Physiology, Via Savi, 8 I-56100 Pisa, Italy. E-mail:.
Received for publication 21 May 2001 and accepted in revised form 1 October 2001.
BPD, biliopancreatic diversion; FFM, fat-free mass; FM, fat mass; LC-CoA, long-chain fatty acyl-CoA; TBW, total-body water; WHR, waist-to-hip ratio.