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Intramyocellular Lipid Is Not Significantly Increased in Healthy Young Insulin Resistant First-Degree Relatives of Diabetic Subjects

¹ Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia
² School of Molecular and Microbial Sciences, University of Sydney, Sydney, Australia
³ Department of General Medicine, Flinders University of South Australia, Adelaide, Australia
⁴ Diabetes Centre, St. Vincent’s Hospital, Sydney, Australia

Address correspondence to Prof. Lesley V. Campbell, Diabetes and Obesity Research Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, Sydney, NSW 2010, Australia. E-mail: l.campbell{at}garvan.org.au.

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 (4–6). 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 (4–6).

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.

References

1. Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, Groop L: Early metabolic defects in persons at increased risk for non-insulin dependent diabetes mellitus. N Engl J Med 321:337–343, 1989[Abstract]
   
2. Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR: Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic patients. Ann Intern Med 13:909–915, 1990
   
3. Lillioja SL, Mott DM, Spraul M, Ferraro R, Foley JE, Ravussin E, Knowler WC, Bennet PH, Bogardus C: Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus: prospective studies of Pima Indians. N Engl J Med 329:1988–1992, 1993[Abstract/Free Full Text]
   
4. Kriketos AD, Greenfield JR, Peake PW, Furler SM, Denyer GS, Charlesworth JA, Campbell LV: Inflammation, insulin resistance, and adiposity. Diabetes Care 27:2033–2040, 2004[Abstract/Free Full Text]
   
5. Kriketos AD, Milner KL, Denyer G, Campbell LV: Is postprandial hypertriglyceridaemia in relatives of type 2 diabetic subjects a consequence of insulin resistance? Eur J Clin Invest 35:117–125, 2005[Medline]
   
6. Gan SK, Kriketos AD, Ellis BA, Maclean EL, Thompson CH, Kraegen EW, Chisholm DJ: Changes in aerobic capacity and visceral fat but not myocyte lipid levels predict increased insulin action after increased exercise in overweight males. Diabetes Care 26:1706–1713, 2003[Abstract/Free Full Text]
   
7. Krssak M, Roden M: The role of lipid accumulation in liver and muscle for insulin resistance and type 2 diabetes mellitus in humans. Rev Endocrin Metab Disord 5:127–134, 2004
   
8. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI: Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350:664–671, 2004[Abstract/Free Full Text]
   

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