Insulin Resistance in Morbid Obesity

Abstract

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 ⅐ 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 ⅐ m ؊2 ), insulin resistance (23 ؎ 3 mol/min per kg of fat-free mass; P < 0.001 vs. 53 ؎ 13 of control subjects) was fully reversed (52 ؎ 11 mol/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.

Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity

“…In obesity and type 2 diabetes, decreased fat metabolism and an accumulation of triacylglycerol has been observed in skeletal muscle, the major site of insulin resistance [2]. In a number of studies, but not all [3], an inverse relationship between insulin sensitivity and intramyocellular triacylglycerol storage has been found [4][5][6][7]. Consistent with this notion, an increase in NEFA concen-trations by lipid infusion leads to decreased insulin sensitivity [8] and increased intramyocellular triacylglycerol stores [2].…”

Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning

“…[11][12][13][14] Consistent with these findings is the inverse relation between intramyocellular lipid content and non-oxidative glucose disposal we found. Further evidence of cause and effect between intramyocellular lipid and insulin resistance came from a study by Greco and colleagues, 29 which showed that selective depletion of intramyocellular fat stores restored normal insulin sensitivity in obese adults, despite a persistent excess of total body fat mass. In our study, sex and ethnicity did not significantly affect the intramyocellular lipid content.…”

Normal mitochondrial function and increased fat oxidation capacity in leg and arm muscles in obese humans

“…13 In sedentary O subjects, a moderate weight loss accompanied by an improved aerobic capacity leads to a normalization of mitochondrial oxidative capacity and insulin resistance. 14 However, when weight loss occurs in the absence of an increase in physical activity level, that is, without improvement in aerobic capacity, insulin resistance is normalized, 2,15 but muscle oxidative capacity remains unaltered. 5,16 In a previous study, a decreased muscle b-hydroxy-acyl-CoA-dehydrogenase (HAD) activity was observed in postobese (PO) subjects, 17 but it is not known whether the obesity-induced attenuation of fat oxidation and/or mitochondrial oxidative capacity is normalized after persistent long-term weight loss.…”