INSULIN RESISTANCE AND IMPAIRED MITOCHONDRIAL FUNCTION IN OBESE ADOLESCENT GIRLS

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 690-701-Obesity Pathophysiology
Translational
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-694
Meghan Slattery*1, Miriam Bredella1, Martin Torriani2, Hena Thakur2 and Madhusmita Misra2
1Massachusetts General Hospital/Harvard Medical School, Boston, MA, 2Massachusetts General Hospital, Boston, MA
BACKGROUND: Mitochondrial dysfunction (MDF) plays a central role in development of muscle insulin resistance (IR). Decreased oxidative capacity due to MDF is reported to cause accumulation of intramyocellular lipid (IMCL) in skeletal muscle, which then interferes with insulin signaling. Conversely, MDF has been reported in women with T2DM compared to BMI matched obese subjects despite similar IMCL, suggesting that the association between MDF and IR is IMCL independent. There are limited data regarding the relationship between mitochondrial function, IR and IMCL in obese adolescents. Markers of mitochondrial function and IMCL can be assessed non-invasively using dynamic phosphorous magnetic resonance spectroscopy (31P-MRS) and 1H-MRS respectively. The use of an MR compatible lower leg exercise machine allows investigation of in-vivo mitochondrial function by measuring phosphocreatine (PCr) kinetics, namely Tau (PCr recovery time constant) and ViPCr (1/tau normalized for PCr depletion), during recovery from exercise. 

OBJECTIVES:We assessed mitochondrial function and IMCL in obese adolescent girls with and without IR to determine (i) whether girls with IR have impaired mitochondrial function, and (ii) whether impaired mitochondrial function in girls with higher IR is related to higher IMCL.

METHODS: We examined 22 obese girls (mean BMI 38.5±7.53 kg/m2) 13-21 years old (mean age 16.6±2.4; mean bone age 16.9±1.3) for IR (defined as HOMA-IR>4).  We compared mitochondrial function, IMCL in the tibialis anterior and soleus muscles, and MRI measures of visceral, subcutaneous and total adipose tissue (VAT, SAT and TAT) in girls with HOMA-IR>4 (IR group) vs. HOMA-IR<4 [insulin sensitive (IS) group]. Serum lipids and waist to hip ratio (W/H) were also measured.        

RESULTS: Girls with IR (N=8) did not differ from the IS group (N=14) for age, bone age, weight, VAT or IMCL.  However, the IR group had higher W/H (p=0.002), SAT (p=0.04) and TAT (p=0.047).  In addition, the IR group had lower log ViPCr (1.9±1.0 vs. 2.7±0.6 mmol/min; p=0.04) and higher log TAU (3.8±0.6 vs. 3.5±0.2 secs; p=0.05), indicative of impaired mitochondrial function.  We found similar results for log ViPCr (2.0±0.8 vs. 2.9±0.6 mmol/min; p=0.02) when IR and IS groups were dichotomized by HOMA-IR above or below the median (3.35). Using this categorization, the IR group had lower HDL (40.6±5.6 vs. 47.8±10.0 mg/dL; p=0.049), and higher VLDL (23.3±7.5 vs.15.5±7.9 mg/dL; p=0.03) and triglycerides (116.4±37.4 vs. 77.2±39.7 mg/dL; p=0.03) than the IS group.  There were no differences between groups for total cholesterol or LDL.   

CONCLUSION:  Obese girls with increased IR have impaired mitochondrial function. This association is not mediated by IMCL alterations.  Further studies are necessary to determine whether there is a causal relation between impaired mitochondrial function and IR in obesity and mediators of this relationship.

Nothing to Disclose: MS, MB, MT, HT, MM

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Supported by an investigator initiated grant from Genentech L4716N