Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Strongly Predict Whole-Body Insulin Resistance in the Development of Type 2 Diabetes

Abstract

We aimed to elucidate tissue-specific glucose uptake in the development of whole-body insulin resistance and type 2 diabetes (T2D). We recruited 13 T2D(D), 12 prediabetes (IFG/IGT) (P), and 10 control (C) subjects, matched for age and BMI. Integrated whole-body 18F-FDG PET and MRI was performed during a hyperinsulinemic euglycemic clamp to assess glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and liver correlated positively with the M-value. Muscle and adipose tissue MRglu was lower in both P and D. D had lower liver MRglu than P and C. Brain MRglu was higher in D and P and it was inversely correlated with M-values. The M-value was best predicted by a multivariate model (adjusted r2= 0.85) including muscle (Std.β-Coeff.=0.64, p<0.001), VAT (Std.β-Coeff.=0.18, p<0.05) and brain MRglu (Std.β-Coeff.=-0.33, p<0.001). In the development of T2D, brain glucose uptake is enhanced during hyperinsulinemia in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated brain MRglu were independently associated with whole-body insulin resistance. This suggests that these alterations may contribute to T2D development.Table 1.Table 1M-Value (g/kg lbm/min)MRglu Muscle (μmol/100g/min)MRglu Liver (<μmol/100g/min)MRglu VAT (μmol/100g/min)MRglu SAT (μmol/100g/min)MRgluHeart (μmol/100g/min)MRgluBrain (μmol/100g/min)Control10.82 ± 1.1415.4 ± 1.96.2 ± 0.73.4 ± 0.52 ± 0.480.5 ± 4.815.8 ± 1.4Prediabetes6.33 ± 0.96 **8.8 ± 1.2**6.6 ± 0.82.5 ± 0.4*1.8 ± 0.176.7 ± 9.418.4 ± 0.9*T2D5.12 ± 0.69 **6.7 ± 1.2**3.7 ± 0.6*¤2.1 ± 0.3*1.4 ± 0.2*79.7 ± 7.419.3 ± 1.1* M-ValueMuscleLiverVATSATHeartBrainMuscler=0.884**r=0.335*r=0.712**r=0.596**r=0.156r=-0.437**Liverr=0.403*r=0.335*r=0.462**r=0.557**r=-0.166r=-0.167VATr=0.707**r=0.712**r=0.462**r=0.683**r=0.126r=-0.259SATr=0.574**r=0.596**r=0.557**r=0.683**r=0.064r=-0.058Heartr=0.149r=0.156r=-0.166r=0.126r=0.064r=-0.007Brainr=-0.616**r=-0.437**r=-0.167r=-0.259r=-0.058r=-0.007* p<0.05, ** p<0.01 for comparisons vs. C, or ¤ p<0.for comparison vs. P. Disclosure G.J. Boersma: None. K. Heurling: None. M.J. Pereira: None. E. Johansson: None. M. Lubberink: None. P. Katsogiannos: None. S. Skrtic: Employee; Self; AstraZeneca. J. Kullberg: Stock/Shareholder; Self; Antaros Medical. Board Member; Self; Antaros Medical. Employee; Self; Antaros Medical. H. Ahlström: Stock/Shareholder; Self; Antaros Medical AB. J.W. Eriksson: Employee; Spouse/Partner; Amgen Inc.. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Consultant; Self; Novo Nordisk A/S, Merck Sharp & Dohme Corp.. Research Support; Self; Bristol-Myers Squibb Company.