Insulin resistance is an early phenotypic feature of nondiabetic first-degree relatives of type 2 diabetic subjects (FDR) (1,2). While intramyocellular lipid (IMCL) is a marker of insulin resistance (3), how it develops is not completely understood. To study early defects accompanying insulin resistance, we characterized a population at high risk of type 2 diabetes (4,5). We studied young, healthy, sedentary, nonsmoking (age <45 years, BMI <36 kg/m2), normolipidemic, and normal glucose tolerant subjects. At-risk FDR subjects (14 female and 5 male) were compared with control subjects without family history of diabetes (12 female and 10 male).

To test the lipid supply hypothesis, we extended previous investigations in FDR (5) to determine whether IMCL is associated with insulin resistance and significantly greater in at-risk compared with control subjects in the prediabetes stage.

IMCL were determined in three muscles of differing fiber composition (biochemical determination of vastus lateralis IMCL obtained from biopsy and soleus and tibialis anterior IMCL from magnetic resonance spectroscopy). Additional metabolic assessments were performed as previously reported (46). IMCL content of soleus and tibialis anterior muscles (ratio between proton resonance areas of intramyocellular CH2 and creatine). Statistical analyses were performed using StatView 5 (SAS Institute, Cary, NC). Results are presented as means ± SE and P value <0.05 was considered significant.

At-risk and control subjects were similar for age, BMI, blood pressure, fasting glucose, leptin, adiponectin, and circulating lipid levels (4). At-risk subjects were 25% more insulin resistant than control subjects (51.8 ± 3.9 vs. 64.9 ± 4.6 μmol · min−1 · kg−1 fat-free mass, P = 0.04) (4).

IMCL triglyceride levels were slightly higher in the at-risk group in soleus (10.3 ± 1.1 vs. 8.6 ± 1.0 IMCH2-to-creatine ratio, P = 0.25) and similar in tibialis anterior (5.6 ± 0.8 vs. 5.0 ± 0.8 IMCH2-to-creatine ratio, P = 0.45) and vastus lateralis muscles (35.9 ± 5.2 vs. 32.1 ± 5.8 μmol/g dry weight, P = 0.63). As reported by Krssak and Roden (7), IMCL content of tibialis anterior was the best (and only) predictor of insulin sensitivity by euglycemic clamp in the entire cohort (tibialis anterior r = −0.39, P = 0.015; vastus lateralis r = 0.21, P = 0.20; soleus r = 0.07, P = 0.67) and also in the at-risk group alone (r = −0.58, P = 0.009). There was no significant sex difference in IMCL content (data not shown).

Thus, using an appropriate human model of early insulin resistance in prediabetes (healthy but insulin resistant, normoglycemic, normolipidemic diabetic relatives compared with matched subjects with no diabetic family history), ICML content in three different muscles was not significantly increased, nor related overall to insulin sensitivity (46).

While our findings differ from Petersen et al. (8), we studied three muscles with two different methods (5,6) at an earlier stage of insulin resistance. However, as our subjects are mildly insulin resistant, possibly very small differences in muscle triglyceride levels may be undetectable by either state-of-the-art method. The implication remains that such small triglyceride accumulation is more likely to be secondary to a (putative) mitochondrial impairment (as proposed by Petersen et al.) than to be the primary cause for whole-body insulin insensitivity. In other words, increased muscle triglyceride appears unlikely to be the primary cause of established whole-body insulin resistance.

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