1930-P: Heterogeneity of Skeletal Muscle (SM) Insulin Resistance (IR) in Type 1 Diabetes (T1D)

Abstract

In addition to a severe deficiency of insulin secretory capacity, systemic IR has also been identified as contributing to the pathophysiology of T1D. This study was undertaken to examine the contribution of SM, the major site for insulin-stimulated glucose uptake, to the IR of T1D, and more specifically, the role of impaired glucose transport. During euglycemic insulin infusion, dynamic PET imaging of SM was done using [18F]fluorodeoxyglucose (FDG), the metabolism of which is restricted to transport/phosphorylation. PET images were co-registered with calf MRI to assess and compare FDG uptake (Patlak K) in soleus (SO) SM (largely oxidative, type 1 fiber) and in tibialis anterior (TA) SM (largely glycolytic, type 2 fiber) to determine the respective severity of IR in these two types of SM. Systemic IR was assessed as glucose disposal rate (GDR) during the clamps. Participants (n=10) with T1D with no evidence of coronary artery or renal disease were recruited from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, a 30-year prospective study of childhood onset T1D. Mean HbA1c in T1D was 7.6±1.3%. Nondiabetic healthy controls (n=13) of comparable age (40.4 years) and BMI (24.1 kg/m2) as the T1D group (43.1 years, 24.3 kg/m2) were studied. Systemic IR was evident in T1D, with GDR reduced by ∼25% (4.95 vs. 6.60 mg/kg-FFM, p=0.06). SM IR was clearly present in oxidative SO SM in T1DM, as values for K were reduced by nearly 50% (0.0075 vs. 0.0126 mL/cm3-minutes, p<0.01). Yet intriguingly, there was no evidence of IR in the glycolytic muscle TA in T1D (0.0077 vs. 0.0087 mL/cm3-minutes); K was not different in either muscle group in T1D, though K for SO was greater than in TA in controls. Systemic GDR correlated with both SO (r=0.59, p=0.003) and TA (0.54, p=0.007) FDG uptake (K). Our findings confirm systemic IR in T1D, indicate the contribution of impaired glucose transport/phosphorylation within SM to IR in T1D, and raise the novel hypothesis that SM IR in T1DM predominately involves oxidative type SM. Disclosure K.V. Williams: None. C.M. Shay: None. J. Price: None. T.J. Orchard: Consultant; Self; Boehringer Ingelheim International GmbH. D. Kelley: Consultant; Self; Kallyope, Regeneron Pharmaceuticals, Takeda Pharmaceutical Company Limited. Other Relationship; Self; Merck & Co., Inc. Funding National Institutes of Health (DK071487)