LONG-TERM METABOLIC AND HORMONAL EFFECTS OF EXENATIDE ON ISLET TRANSPLANT RECIPIENTS WITH ALLOGRAFT DYSFUNCTION: 1318

The initial success of islet transplantation (ITx) is followed by graft dysfunction (GDF) and insulin reintroduction. Exenatide, a GLP-1 agonist, increases insulin and decreases glucagon secretion and has potential for β-cell regeneration. To improve functional islet mass, exenatide treatment was given to ITx recipients with GDF. The objective of this study was to assess metabolic and hormonal effects of exenatide in GDF. In this prospective, single-arm, nonrandomized study, 11 type 1 diabetes recipients of ITx with GDF had HbA1c, weight, insulin requirements, and 5-h mixed meal tolerance test (MMTT; with/without exenatide given before test) at baseline, 3, 6, and 12 months after initiating exenatide treatment. Baseline MMTT showed postprandial hyperglycemia and hyperglucagonemia. Daily exenatide treatment resulted in improved glucose, increased amylin/insulin ratio, and decreased proinsulin/insulin ratio as assessed by MMTT. Glucagon responses remained unchanged. Exenatide administration 1 h before MMTT showed decreased glucagon and glucose at 0 min and attenuation in their postprandial rise. Time-to-peak glucose was delayed, followed by insulin, proinsulin, amylin, and C-peptide, indicating glucose-driven insulin secretion. Five subjects completed 12-month follow-up. Glucose and glucagon suppression responses after MMTT with exenatide were no longer observed. Retrospective 3-month analysis of these subjects revealed higher and sustained glucagon levels that did not suppress as profoundly with exenatide administration, associated with higher glucose levels and increased C-peptide responses. In conclusion, Exenatide suppresses the abnormal postprandial hyperglucagonemia and hyperglycemia observed in GDF. Changes in amylin and proinsulin secretion may reflect more efficient insulin processing. Different degrees of responsiveness to exenatide were identified. These may help guide the clinical management of ITx recipients

Metabolic Indicators of Islet Graft Dysfunction

Assessing p-cell mass and function is of great importance in the islet transplant setting but it has been challenging. Although achieving insulin independence has been one of the most important end points of islet transplantation (IT), it is critical that it is associated with good glycemic control. Numerous tests have been suggested for the assessment of graft dysfunction. Unfortunately, there are no effective indicators for the early detection of graft dysfunction in IT patients.1 In this chapter we discuss the different metabolic approaches for the assessment of graft dysfunction, nevertheless it is important to recognize that there is no consensus on which test is best to study |3-cell mass and function in patients after IT. The early detec­ tion of graft dysfunction could facilitate the identification of underlying causes and guide in the management of transplanted patients, especially if appropriate anti-rejection therapies become available

Obesity in people living with type 1 diabetes

Although type 1 diabetes is traditionally considered a disease of lean people, overweight and obesity are becoming increasingly more common in individuals with type 1 diabetes. Non-physiological insulin replacement that causes peripheral hyperinsulinaemia, insulin profiles that do not match basal and mealtime insulin needs, defensive snacking to avoid hypoglycaemia, or a combination of these, are believed to affect body composition and drive excessive accumulation of body fat in people with type 1 diabetes. The consequences of overweight or obesity in people with type 1 diabetes are of particular concern, as they increase the risk of both diabetes-related and obesity- related complications, including cardiovascular disease, stroke, and various types of cancer. In this Review, we summarise the current understanding of the aetiology and consequences of excessive bodyweight in people with type 1 diabetes and highlight the need to optimise future prevention and treatment strategies in this population

Early metabolic markers of islet allograft dysfunction

Islet transplantation can restore normoglycemia to patients with unstable type 1 diabetes mellitus, but long-term insulin independence is usually not sustained. Identification of predictor(s) of islet allograft dysfunction (IGD) might allow for early intervention(s) to preserve functional islet mass. Fourteen islet transplantation recipients with long-term history of type 1 diabetes mellitus underwent metabolic testing by mixed meal tolerance test, intravenous glucose tolerance test, and arginine stimulation test every 3 months postislet transplant completion. Metabolic responses were compared between subjects who maintained insulin independence at 18 months (group 1; n=5) and those who restarted insulin within 18 months (group 2; n=9). Data were analyzed before development of islet graft dysfunction and while insulin independent. The 90-min glucose, time-to-peak C-peptide, and area under the curve for glucose were consistently higher in group 2 and increased as a function of time. At 12 months, acute insulin release to glucose in group 2 was markedly reduced as compared with baseline (5.62+/-1.21 microIU/mL, n=4 vs. 16.14+/-3.69 microIU/mL, n=8), whereas it remained stable in group 1 (22.36+/-4.98 microIU/mL, n=5 vs. 27.70+/-2.83 microIU/mL, n=5). Acute insulin release to glucose, acute C-peptide release to glucose (ACpRg), and mixed meal stimulation index were significantly decreased and time-to-peak C-peptide, 90-min glucose, and area under the curve for glucose were significantly increased when measured at time points preceding intervals where IGD occurred compared with intervals where there was no IGD. The intravenous glucose tolerance test and mixed meal tolerance test may be useful in the prediction of IGD and should be essential components of the metabolic testing of islet transplant recipients

Stable Renal Function After Islet Transplantation : Importance of Patient Selection and Aggressive Clinical Management

BACKGROUND: Proteinuria development and decrease in glomerular filtration rate (GFR) has been observed after successful islet transplantation. The aim of this study was to determine clinical, laboratory and immunosuppressant-related factors associated with kidney dysfunction in islet transplant recipients. METHODS: A retrospective cohort study was conducted in 35 subjects submitted to pancreatic islet transplantation as treatment for unstable type 1 diabetes mellitus. Demographic, anthropometrical and laboratory data, as well as immunosuppressive and anti-hypertensive therapy were recorded. Kidney function was assessed by albuminuria and estimated GFR (eGFR), calculated by Modification of Diet in Renal Disease formula. RESULTS: Age was the only independent risk factor for low eGFR (<60 ml/min/1.73 m(2)) [OR=1.78 (1.22–2.61)]. LDL-cholesterol [OR=2.90 (1.37–6.12)] and previous microalbuminuria [OR=6.42 (1.42–29.11)] were risk factors for transient macroalbuminuria. Interestingly, tacrolimus was a protective factor for macroalbuminuria [OR=0.12 (0.06–0.26)]. Six-out-of-thirty (20%) normoalbuminuric subjects at baseline progressed to microalbuminuria. No subject developed sustained macroalbuminuria. Surprisingly, overall eGFR remained stable during follow-up (before transplant: 74.0±2.0, during immunosuppressive therapy: 75.4±2.8, after withdrawal: 76.3±5.3 ml/min/1.73 m(2); P>0.05). Even subjects with low eGFR and/or microalbuminuria at baseline (n=10) maintained stable values post-transplantation (61.13±3.25 vs. 63.32±4.36 ml/min/1.73 m(2), P=0.500). CONCLUSIONS: Kidney function remained stable after islet transplantation alone. The unchanged kidney function found in this sample may be attributed to healthier kidney status at baseline and possibly to prompt treatment of modifiable risk factors. Aggressive treatment of risk factors for nephropathy, such as blood pressure, LDL-cholesterol and careful tacrolimus levels monitorization, should be part of islet transplant recipient care