Islet cell transplants (ICT) (1) include alpha-cells: restoring glucagon counter-regulation (2) and hypoglycaemic awareness (3) in Type 1 Diabetes (T1D). However hyperglucagonaemia pre-exists in T1D. In normal islets alpha-cells are regulated by "paracrine" suppression by insulin secreted by the intra-islet beta-cells. Are the excess alpha-cells after ICT able to be regulated normally by insulin suppression? If not then increased hyperglucagonaemia would lead to insulin resistance and increased non-esterified fatty acids (NEFA) leading to impaired survival of transplanted beta-cells.
The suppression by insulin of alpha- and beta-cell function and NEFA levels was assessed in ICT recipients (n=10 before, n=5 after) at baseline (Plasma insulin=16±4SEM mU/L) and during euglycaemic-hyperinsulinaemic clamps at plasma insulin 98±6mU/L.
Baseline plasma glucagon concentrations did not show a significant increase (pre-ICT=75±8 vs post-ICT=69±5pg/ml) and showed similar percent supression by hyperinsulinaemia before and after ICT (pre-ICT=47±6% vs post-ICT=36±10%). Post-ICT beta-cell function (plasma C-peptide) showed downregulation by hyperinsulinaemia (baseline=0.35±0.03 vs hyperinsulinaemic=0.21±0.05 pmol/ml, p<0.05) . Baseline NEFA was not increased by ICT (pre-ICT=0.74±0.13 vs post-ICT=0.57±0.09 mmol/L) and pre- and post-ICT NEFA was similarly suppressed by hyperinsulinaemia (suppression: pre-ICT=97±1% versus post-ICT=98±1%). Insulin sensitivity during the clamps was significantly increased post-ICT (pre-ICT=3.4±0.5 vs post-ICT=5.2±0.8x10-2 min-1.mU-1.L, p<0.05).
Our findings indicate that transplanted alpha- and beta-cells are able to be regulated normally by insulin suppression. Therefore ICT, despite increasing alpha-cell mass, does not result in increases in glucagon or NEFA that could contribute to insulin resistance, consistent with our finding of increased insulin sensitivity post-ICT. This indicates that glucagon and NEFA levels after ICT are not likely to impair transplanted beta-cell survival.