Background: Metabolic flexibility (MF) – the ability to switch from fat to carbohydrate oxidation in response to a glucose load - is impaired in insulin resistance and type 2 diabetes (T2D). We have demonstrated that impaired MF occurs in healthy subjects with a family history of T2D (FH+) compared  to  no  family  history  (FH-),  suggesting  MF  is  impaired  before  whole-body  insulin resistance or glucose intolerance [1].  The causes of impaired MF are unknown.

Aim: To identify vascular and metabolic correlates of MF in FH+ and FH- individuals.

Methods: We recruited people with different degrees of MF - healthy control (Con; 7 FH-, 9 FH+) and T2D (13 FH+, 4 FH-). Participants underwent an oral glucose challenge (OGC, 50g glucose) after a 12-h fast. Using indirect calorimetry, MF was calculated as ΔRER area under the curve (AUC) from fasting though 1-hr of the OGC. Body composition was determined using dual-energy x-ray absorption, and vascular measures were determined by Doppler ultrasound and Mobil-O-Graph PWA Monitor.

Results:  We  confirmed  that  FH+  had  impaired  MF  compared  to  FH-  in  both  Con  and  T2D subjects. In addition to the expected impairments in T2D subjects in fasting blood glucose, glucose tolerance, % body fat, and % trunk fat (p<0.05), MF in Con (FH+/-) subjects showed significant negative correlations with % body fat and certain vascular measures (e.g. diastolic BP, peripheral pulse pressure) but not others (e.g. brachial artery dilation) or glucose tolerance (Table 1). These correlations were absent in T2D, suggesting early changes in MF are associated with adiposity, and specific alterations in vascular function. 

Conclusions: Adiposity and selective vascular dysfunction are early risk factors associated with impaired MF and occur despite normal glucose tolerance in healthy subjects. Further studies into the mechanisms of these associations may yield important information about risk factors for T2D.