E. La Rocca

Lack of Feedback Inhibition of Insulin Secretion in Denervated Human Pancreas

In this study, pancreas transplantation is used as a clinical model of pancreas denervation in humans. To assess the role of innervation on the feedback autoinhibition of insulin secretion, we studied four groups of subjects--group 1: 16 patients with combined pancreas and kidney transplantation (plasma glucose = 5.1 mM, HbA1c = 6.4%, creatinine = 86 mM); group 2: 8 patients with chronic uveitis on the same immunosuppressive therapy as transplanted patients (12 mg/day prednisone, 5 mg.kg-1.day-1 CsA); group 3: 4 uremic, nondiabetic patients in chronic hemodialysis; group 4: 7 normal, nondiabetic control subjects. The following means were used to study the groups: 1) a two-step hyperinsulinemic euglycemic clamp (insulin infusion rate = 1 mU and 5 mU.kg-1.min-1); and 2) a 0.3 mU.kg-1.min-1 hypoglycemic clamp (steady-state plasma glucose = 3.1 mM). Basal plasma-free IRI (84 +/- 6, 42 +/- 12, 72 +/- 12, and 30 +/- 6 pM in groups 1, 2, 3, and 4, respectively), basal C-peptide (0.79 +/- 0.05, 0.66 +/- 0.05, 3.04 +/- 0.20, and 0.59 +/- 0.06 nM in groups 1, 2, 3, and 4, respectively), and glucagon (105 +/- 13, 69 +/- 4, 171 +/- 10, and 71 +/- 5 pg/ml in groups 1, 2, 3, and 4, respectively) were increased in groups 1 and 3 with respect to groups 2 and 4 (P < 0.01). During euglycemic hyperinsulinemia, plasma C-peptide decreased by 45, 20, and 44% in groups 2, 3, and 4, respectively, but showed no significant change from the basal in patients with transplanted pancreases.(ABSTRACT TRUNCATED AT 250 WORDS)

Patient survival and cardiovascular events after kidney-pancreas transplantation: comparison with kidney transplantation alone in uremic IDDM patients.

In diabetic patients cardiovascular morbidity and mortality is still a major problem. Our aim was to study the effect of kidney–pancreas transplantation on survival, cardiovascular events, and causes of death in diabetic type I uremic patients. Three hundred and thirty-three uremic IDDM patients were enrolled in our waiting list for kidney–pancreas transplantation: 107 underwent kidney–pancreas transplantation (KP), 34 underwent kidney transplantation alone (KA), whereas 192 patients remained on dialysis (WL). Actuarial survival and causes of death were recorded over a period of 7 years. Seven-year survival rate was 75% for the KP group, 63% for the KA group, and 37% for the WL group (p = 0.001). Cardiovascular death rate was 9.8% in the KP group, 17.6% in the KA group, and 18.1% in the WL group (KP vs. WL, p = 0.05). Rate of acute myocardial infarction in the KP group was lower than in the KA group (2.4% vs. 17.6%, p = 0.005) as well as rate of acute pulmonary edema (0.8% vs. 23.5%, p = 0.0001) and rate of hypertensive patients at 1 (40.9% vs. 85.0%, p = 0.0001) and at 2 years (57.6% vs. 80%, p = 0.03). Kidney–pancreas transplant helped to obtain euglycemia with positive effects on survival and cardiovascular events.

Combined pancreas and kidney transplantation normalizes protein metabolism in insulin-dependent diabetic-uremic patients

In order to assess the combined and separate effects of pancreas and kidney transplant on whole-body protein metabolism, 9 insulin-dependent diabetic-uremic patients (IDDUP), 14 patients after combined kidney-pancreas transplantation (KP-Tx), and 6 insulin-dependent diabetic patients with isolated kidney transplant (K-Tx), were studied in the basal postabsorptive state and during euglycemic hyperinsulinemia (study 1). [1-14C]Leucine infusion and indirect calorimetry were utilized to assess leucine metabolism. The subjects were studied again with a combined infusion of insulin and amino acids, given to mimic postprandial amino acid levels (study 2). In the basal state, IDDUP demonstrated with respect to normal subjects (CON): (a) higher free-insulin concentration (17.8 +/- 2.8 vs. 6.8 +/- 1.1 microU/ml, P < 0.01) (107 +/- 17 vs. 41 +/- 7 pM); (b) reduced plasma leucine (92 +/- 9 vs. 124 +/- 2 microM, P < 0.05), branched chain amino acids (BCAA) (297 +/- 34 vs. 416 +/- 10 microM, P < 0.05), endogenous leucine flux (ELF) (28.7 +/- 0.8 vs. 39.5 +/- 0.7 mumol.m-2.min-1, P < 0.01) and nonoxidative leucine disposal (NOLD) (20.7 +/- 0.2 vs. 32.0 +/- 0.7 mumol.m-2. min-1, P < 0.01); (c) similar leucine oxidation (LO) (8.0 +/- 0.1 vs. 7.5 +/- 0.1 mumol.m-2.min-1; P = NS). Both KP-Tx and K-Tx patients showed a complete normalization of plasma leucine (116 +/- 5 and 107 +/- 9 microM), ELF (38.1 +/- 0.1 and 38.5 +/- 0.9 mumol.m-2.min-1), and NOLD (28.3 +/- 0.6 and 31.0 +/- 1.3 mumol.m-2.min-1) (P = NS vs, CON). During hyperinsulinemia (study 1), IDDUP showed a defective decrease of leucine (42% vs. 53%; P < 0.05), BCAA (38% vs. 47%, P < 0.05), ELF (28% vs. 33%, P < 0.05), and LO (0% vs. 32%, P < 0.05) with respect to CON. Isolated kidney transplant reverted the defective inhibition of ELF (34%, P = NS vs. CON) of IDDUP, but not the inhibition of LO (18%, P < 0.05 vs. CON) by insulin. Combined kidney and pancreas transplanation normalized all kinetic parameters of insulin-mediated protein turnover. During combined hyperinsulinemia and hyperaminoacidemia (study 2), IDDUP showed a defective stimulation of NOLD (27.9 +/- 0.7 vs. 36.1 +/- 0.8 mumol.m-2.min-1, P < 0.01 compared to CON), which was normalized by transplantation (44.3 +/- 0.8 mumol.m-2.min-1).

Effect of pancreas transplantation on life expectancy, kidney function and quality of life in uraemic Type 1 (insulin-dependent) diabetic patients

SummaryThe aim of our study was to evaluate the effects of haemodialysis, kidney transplantation and simultaneous kidney and pancreas transplantation on survival of diabetic subjects and on kidney function. 40 Type 1 (insulin-dependent) diabetic patients received a kidney transplantation: in 31 cases the kidney was transplanted simultaneously to a pancreas graft from the same donor (KP group), while in 9 cases the pancreas was not available (K group). 44 uraemic Type 1(insulin-dependent) diabetic patients on dialysis and in waiting list for kidney transplantation, constituted the control group (HD group). Patient survival rate 1, 3 and 5 years following transplantation was better in KP group (93%, 89%, 89%, respectively) than in K group (88%, 88%, 73%, respectively) and in HD group (88%, 62%, 51%, respectively). Kidney graft survival at 1, 3 and 5 years post-transplant was better in KP group (93%, 72%, 72%, respectively) than in K group (76%, 61%, 31%, respectively). 1 year after transplantation, patients of the KP group who had lost the pancreas for technical reasons (thrombosis) were included in the K group so as to evaluate the effect of the transplanted pancreas on long-term patient and kidney survival. Patient survival rate in the KP group (17 patients) at 2 and 4 years was 100%, while at the same intervals it was 78% in the K group (13 patients). Kidney graft function rate at 2 and 4 years was 93% in the KP group (17 grafts) and 54% and 27% respectively in the K group (14 grafts). Evaluation of quality of life in patients receiving a kidney and pancreas transplantation showed an improvement in psychological well-being, when compared to patients receiving a kidney transplantation alone. Physical well-being was similar in patients transplanted with kidney and pancreas or with kidney alone.

First peak insulin release after intravenous glucose and arginine is maintained for up to 3 years after segmental pancreas transplantation

SummaryIn this study we have investigated blood glucose and serum free insulin response to glucose and to arginine orally or intravenously, 3 months and 3 years after a successful segmental, neoprene-injected, pancreas transplantation.Serum insulin responses to different secretagogues were normal 3 months after transplantation; they remained normal up to 3 years after transplantation.

Pancreas and kidney transplantation : the San Raffaele hospital (Milan, Italy) experience

SummaryResults of 33 simultaneous pancreas and kidney transplantations performed at the San Raffaele Hospital, Milan, Italy are presented. In 26 cases segmental neoprene duct-injected grafts were transplanted and in seven cases, duodenopancreatic bladder-drained grafts. Five-year patient, kidney and pancreas survival were respectively, 89%,72% and 58%. Five-year survival in patients with technically successful pancreas transplants was 73%. Thrombosis occured in 20% of cases. Mortality was 6% and overall morbidity 76%. Surgical complications were present in 51% of cases.

Intermediary Metabolism and Glycemic Control in Insulin-Dependent Diabetic Uremic Patients Treated by Continuous Peritoneal Dialysis

The effect on metabolic control and on intermediate metabolism of continuous ambulatory peritoneal dialysis (CAPD) was evaluated in 6 insulin-dependent diabetic uremic patients treated by CAPD, in 6 nondiabetic uremic patients in CAPD and in 6 normal subjects. During the study, 4 dialysis exchanges with 1.36 g/dl dextrose concentration were performed daily; regular insulin was added to the bags in diabetic patients. Our data show a well-controlled mean blood glucose in CAPD diabetic patients by intraperitoneal insulin administration as well as higher insulinemic levels in comparison with those of normal subjects. Plasma lactate and serum glycerol levels were higher and butyrate levels were lower reflecting a continuous ketogenesis inhibition.