FAILURE OF SUPPRESSION OF ENDOGENOUS GLUCOSE PRODUCTION (EGP) DIMINISHED LIPOLYSIS AND FREE FATTY ACID (FFA) OXIDATION IN A POPULATION AT HIGH RISK FOR THE DEVELOPMENT OF TYPE 2 DIABETES
S Forbes1, S Robinson1, MI McCarthy2, IA MacDonald3, P Bannister1, S Venketesan1 & D Johnston1
Type 2 diabetes is associated with insulin resistance, failure to suppress lipolysis and EGP and impaired FFA. It is not known which defect develops first.
Eleven European women with previous gestational diabetes (PGDM) and normal glucose tolerance post-partum, as a high risk group for the development of Type 2 diabetes, and 11 matched controls (BMI 23.8±4.5 kg m-2 versus 24.6±4.9 kg m-2 respectively) were studied. Insulin sensitivity was assessed with the short insulin tolerance test. After an overnight fast, the stable isotopes 6,6-2H2 glucose, 1,1,2,3,3-2 H5 glycerol and 1-13C palmitate, were given for 4 hours. Adrenaline 25ng kg-1 min-1, or normal saline was commenced at 2 hours and continued. Blood and breath samples were taken at 0, 90, 100, 110, 120 minutes and at 210, 220, 230 and 240 minutes (2 steady-states). The 1st steady-state data was averaged.
Insulin sensitivity was similar in PGDM and controls (median and interquartile ranges): 172(150-181) versus 155(130-208) umol l-1 min-1 respectively (p=0.80). Plasma glucose concentrations at the 1st steady state were higher in PGDM versus controls: 5.30(4.99-5.60) mmol l-1 versus 4.92(4.67-5.14) mmol l-1 (p=0.05). No difference in EGP was observed, but EGP was maintained in the PGDM, but decreased in the controls at the 2 ndsteady state (p=0.004) during the saline infusion. Glycerol turnover was lower in the PGDM at the 1st steady state in relation to fat-mass (FM): 0.69(0.57-1.3) versus 1.30(0.81-1.55) mg kgFM-1 min-1, weight and FFM (all p<0.01). Similarly, palmitate turnover and oxidation were diminished in PGDM versus controls 0.84(0.48-0.98) versus 0.96(0.83-1.15) mg kg-1 min-1 (p=0.03); and 17.66(14.22-24.57) versus 27.04(21.72-30.74) umol min-1 (p=0.01) respectively. During adrenaline, turnover of glucose, glycerol and palmitate increased but no difference in the increment, between PGDM and controls, was observed.
Failure to suppress EGP during starvation, diminished lipolysis and fatty acid oxidation are early abnormalities. This may imply a tendency to store fat. Adrenaline sensitivity is not implicated.