Regulation of alpha cell function and fatty acid levels by hyperinsulinaemia after islet cell transplantation in Type 1 diabetes     — ASN Events
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Regulation of alpha cell function and fatty acid levels by hyperinsulinaemia after islet cell transplantation in Type 1 diabetes     (#166)

Glenn M Ward 1 2 3 4 , Jacqueline M Walters 1 3 , Judith L Gooley 1 3 , Margaret Krishnapillai 1 , Raymond C Boston 3 5 , Shireene R Vethakkan 6 , Alicia J Jenkins 1 7 , Richard J MacIsaac 1 3 , Kathy Howe 1 , David J Goodman 8 , Jane DJ Holmes-Walker 9 , Philip J O'Connell 9 , Thomas WH Kay 10
  1. Endocrinology and Diabetes, St. Vincent's Hospital, Melbourne, Australia
  2. Clinical Biochemistry, St. Vincent's Hospital, Melbourne, Australia
  3. University of Melbourne Department of Medicine, St. Vincent's Hospital, Melbourne, Australia
  4. Pathology, University of Melbourne, Melbourne, Australia
  5. University of Pennsylvania, Philadelphia, USA
  6. Department of Medicine (Endocrinology), University of Malaysia, Kuala Lumpur, Malaysia
  7. NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
  8. Nephrology, St. Vincent's Hospital, Melbourne, Australia
  9. Westmead Hospital, Sydney, Australia
  10. St. Vincent's Institute of Medical Research, Melbourne, Australia

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.

  1. O'Connell PJ et al. Am J Transplantation 2013 doi: 10.1002/ajt.12250
  2. Rickels M et al. Diabetes 2015;64:1713–1718
  3. Kamel, J et al. Diabetes Metab Rev 2015 DOI: 10.1002/dmrr.2652
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