Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

Delay in insulin secretion following an oral glucose load after islet transplantation in human type 1 diabetes (#29)

Glenn M Ward 1 2 3 , Jacqueline M Walters 1 4 , Judith L Gooley 1 4 , Shireene R Vethakkan 5 , Margaret Krishnapillai 1 4 , Raymond C Boston 1 4 6 , Alicia J Jenkins 7 , Richard J MacIsaac 1 4 , Kathy Howe 1 8 , David Goodman 8 , D. Jane Holmes-Walker 9 , Philip 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. Pathology, University of Melbourne, Melbourne, Australia
  4. University of Melbourne Department of Medicine, St. Vincent's Hospital, Melbourne, Australia
  5. Department of Medicine (Endocrinology), University of Malaysia, Kuala Lumpur, Malaysia
  6. University of Pennsylvania, Philadelphia, USA
  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

Introduction: Islet cell transplantation (ICT) is a highly effective therapy for Type 1 diabetes (T1D) with impaired awareness of hypoglycaemia (IAH) (1). We detected after ICT a deficiency of early insulin secretion by intravenous glucose tolerance tests (IVGTT)(2), despite transplantation of healthy islets.

Aims: The study aim was to further investigate this deficiency of early insulin secretion in ICT using oral glucose tolerance tests (OGTT). OGTTs have incretin effects(IE) boosting insulin secretion, though we found IE reduced by 40% of normal following ICT(3).

Methods: Seven insulin-independent T1D ICT recipients (Mean±SE Age=56±4yr, BMI=19.8±1.0kg/m2, T1D-duration=46±10yr) had frequently-sampled 75-gram OGTTs, compared to nine similar non-diabetic controls (ND) (53±4yr, BMI=24.8±1.0).

Results: Total insulin secretion in ICT-recipients was 21% of ND (Median[IQR] glucose-corrected incremental-AUC-insulin, ICTvsND=6.4[3.9-7.5] vs 29.5[17.2-37.1], mU/mmol, p<0.01 Wilcoxon). However, the 30-minute Insulinogenic Index (ΔInsulin[0-30]/Δglucose[0-30]), in ICT was 15% of the ND (ICTvsND =2.3[0.7-6.7] vs15.1[8.0-28.0]. Despite the reduced secretion, average ICT glucose levels were near-normal (HBA1c%, ICTvsND =5.7±0.3 vs5.5±0.1, NS), and 2-hour OGTT glucose was non-diabetic in 2 ICT-recipients. Although the mean ICT-recipients’ 2-hour glucose was elevated (13.8±1.7 mmol/L) it returned to baseline by 4-hours (5.8±1.2). The good glycaemic control may be related not only to a trend to higher mean insulin sensitivity (HOMA2-%S) in ICTvsND (117±28% vs83±8%, NS); but also, to the portal route of ICT causing suppression of hepatic glucose production via high intrahepatic insulin concentrations.

Conclusions: Selective measurement of early insulin release by OGTT in ICT could underestimate later secretion by ~30%, confirming our previous IVGTT report (2). The defect of early insulin secretion may reflect beta-cell overdrive causing depletion of readily-releasable insulin stores, but with good control of glycaemia due to the portal route of transplantation. Our results indicate OGTT evaluation of beta-cell function or incretin effects in ICT should measure both early and later insulin secretion.

  1. 1. P J O 'Connell, D J Holmes-Walker, D Goodman, W J Hawthorne, T Loudovaris, J E Gunton, H E Thomas, S T Grey, C J Drogemuller, G M Ward, D J Torpy, P T Coates, T W Kay, On Behalf of the Australian Islet Transplant Consortium. Multicenter Australian Trial of Islet Transplantation: Improving Accessibility and Outcomes of the Australian Islet Transplant Consortium. American Journal of Transplantation 07/2013; 13(7) DOI:10.1002/ajt.12250
  2. 2. SR Vethakkan, AJ Jenkins, TWH Kay, DJ Goodman, JM Walters, JL Gooley, RC Boston, DJ Holmes-Walker, GM Ward: Improved Second Phase Insulin Secretion and Preserved Insulin Sensitivity After Islet Transplantation. Transplantation 05/2010; 89(10):1291
  3. 3. SR Vethakkan, JM Walters, JL Gooley, RC Boston, TWH Kay, DJ Goodman, AJ Jenkins, GM Ward: The Incretin Response After Successful Islet Transplantation. Transplantation 01/2014; 97(2):e9-e11.