Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study

Abstract

We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r=0.884, r=0.574, r=0.707 and r=0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r=-0.616). Myocardial MRglu did not differ between groups and did not correlate with the M-values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r=0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r=0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development.

Heterogeneity of Metabolic Defects in Type 2 Diabetes and Its Relation to Reactive Oxygen Species and Alterations in Beta-Cell Mass

“…However, in individuals with impaired fasting glucose (IGF), the brain glucose utilization increases in response to insulin infusion suggesting that the brain glucose metabolism is disturbed even in IFG (Hirvonen et al, 2011). Using whole-body [ 18 F]FDG PET and hyperinsulinemic euglycemic clamp, it was recently demonstrated that the brain glucose utilization is increased in patients with T2D (Boersma et al, 2018). In contrast, the authors found that the glucose utilization was decreased in skeletal muscle, visceral- and adipose tissue, and the liver in patients with T2D (Boersma et al, 2018).…”

“…Using whole-body [ 18 F]FDG PET and hyperinsulinemic euglycemic clamp, it was recently demonstrated that the brain glucose utilization is increased in patients with T2D (Boersma et al, 2018). In contrast, the authors found that the glucose utilization was decreased in skeletal muscle, visceral- and adipose tissue, and the liver in patients with T2D (Boersma et al, 2018).…”

Validation of automated whole-body analysis of metabolic and morphological parameters from an integrated FDG-PET/MRI acquisition

“…Semi-synthetic human insulin (Actrapid, Novo Nordisk, Copenhagen, Denmark) was infused at 56 mU/m 2 body surface/min and a variable glucose infusion (200 mg/ml) was adjusted to maintain a stable plasma glucose level of 5.6 mmol/l. The data collection has previously been described in more detail 18,19 . pet/MR imaging.…”

“…injection of 4 MBq [ 18 F]FDG/kg bodyweight was used. A 10 min dynamic PET scan of the thorax was collected to capture early tracer dynamics of [ 18 F]FDG 13,18 . After this, five whole-body PET scans (from head to toe) were acquired.…”

eBrain: a Three Dimensional Simulation Tool to Study Drug Delivery in the Brain

“…We compared Eq. (1) parameters with diffusion coefficients measured using UV imaging in agarose hydrogels that is used for mimicking subcutaneous tissues 27,28 . Experimental results of insulin diffusion coefficients in different medium conditions ranges between 0.8–2.0 (m 2 /s).…”