Energy Balance Following Islet Transplantation

Background and rationale for the study: Type 1 Diabetes, Hypoglycaemia, IAH and Islet Transplantation

Type 1 diabetes is caused by autoimmune destruction of beta cells within the islets of the pancreas. Those with Type 1 diabetes are dependent on daily insulin replacement for survival and despite major advances in treatment (3), life-expectancy is reduced significantly due to metabolic crises and increased risk of major atherosclerotic vascular events (4). All complications of chronic high glucose can be prevented by tight glycaemic control (5) but this is, however, counter-balanced by a high risk of severe hypoglycaemia leading to a reduced ability to perceive the onset of hypoglycaemia, with disabling confusion and collapse without warning, termed Impaired A Awareness of Hypoglycaemia (AIH). IAH affects up to 25% of people with established Type 1 diabetes every year (10-15 million people world-wide) (6, 7). Approximately 30,000 people in Scotland have Type 1 diabetes and the prevalence is increasing (8). Those with recurrent hypoglycaemia with severe IAH, often experience fluctuations in blood glucose and may be eligible for islet transplantation (5). Islets are transplanted in high numbers via the portal vein under radiological guidance into the liver with glucocorticoid free immunosuppression ("Edmonton protocol"). Two or more transplants are usually necessary to regain insulin secretion to allow adequate control of glucose concentrations and restore awareness of hypoglycaemia.

UK Islet Transplant Consortium (UKITC), Scottish National Islet Programme and anthropometric changes post islet transplantation

Our transplant programme is one of seven in the UKITC; other sites include Newcastle, Oxford, London (Kings, Royal Free), Manchester and Bristol. The primary goal in the UK is to reduce the frequency and restore awareness of hypoglycaemia. Referred patients are assessed in depth by a multidisciplinary team pre-transplant, at the time of transplant and then serially post-transplant. In the UK from April 2008-September 2013 there have been 96 transplants in 76 recipients. Graft survival is >88%, as defined by a stimulated c-peptide of >100pmol/L (90 min following a Fortisip meal), and there have been significant decreases in the frequency of hypoglycaemia: pre- vs. post-transplant, median (interquartile range): 21(7-79) vs. 0(0-1) episodes of hypoglycaemia per annum with significant reductions in HbA1c and insulin dose (all p<0.01)(9). Body weight at 1 year in the UKITC cohort is significantly diminished; pre-transplant: mean (±SEM) 66.3(±1.2) vs. 62.3(±1.1) kg (p=0.001). In common with many programmes (10) peak function is seen at 3 months following the first transplant often with insulin independence but a variable degree of attrition in function may be seen following this with many patients on insulin 1 year following their transplant, although at a much reduced dose versus pre-transplant. In Scotland we have performed 47 transplants in 29 recipients. Those patients with Type 1 diabetes and normal renal function have been assessed previously (≥3<30 months) post-transplant (n=14; 6 males, 8 females; age (range: 30-57 years); all have functioning grafts. Following islet transplantation we have observed significant reductions in body weight, pre versus post-transplant: median(interquartile range) 70.9(64.9-82.5) vs. 66.0(59.8-79.9)kg, p=0.01; BMI: 26.2(24.4-28.6) vs. 24.5(22.2-26.1) kg/m2, p=0.01; %fat mass: 30.0(21.2-35.2) vs. 24.1(18.4-31.2)%, p=0.004; and waist circumference: 85.5(77-89.7) vs. 77.5(73.5-88.3)cm, p=0.01. Total calorific intake assessed via 7 day dietary histories were not different pre- versus post-transplant 1700(1581-1842) vs. 1528(1319-1708) kcal, (p=0.09), although frequency of hypoglycaemia (10(6-18) vs 1(0-3)) episodes per week and calorific intake for hypoglycaemia were reduced. Concurrently HbA1c has improved p<0.001 (11).

Consistent with our observations, significant reductions in body weight of >4kg (10, 12), waist circumference and body fat mass, the latter measured using bioelectrical impedence, within a year of islet transplantation, have been previously reported, despite no significant changes in caloric intake post-transplant (12). In the latter study 30 subjects had all assessments completed and 12 subjects were not on insulin at the time of their last data collection. Insulin use reduced 10 fold and glycaemic control improved. Regression analyses adjusting for confounding variables including exogenous insulin dose and glucagon-like peptide-1 agonist use, confirmed the association of weight loss with islet transplantation. Of note in this cohort of islet transplant recipients, no measurements of energy expenditure were made and the patients including those with islet transplants following kidney transplants were on a variety of immunosuppressant agents which may affect energy balance. More recently the same group published a retrospective study in islet transplant recipients and found a decrease in BMI in their cohort of 33 recipients at 3 years post-transplant versus pre-transplant (13). Dietetic habits and caloric intake and activity, both assessed by open ended questionnaires, were not significantly altered pre- versus post-transplant.