The liver plays a major role in regulating glucose metabolism, and since its function is influenced by sympathetic/ parasympathetic innervation, we used liver graft as a model of denervation to study the role of CNS in modulating hepatic glucose metabolism in humans. 22 liver transplant subjects were randomly studied by means of the hyperglycemic/ hyperinsulinemic (study 1), hyperglycemic/isoinsulinemic (study 2), euglycemic/hyperinsulinemic (study 3) as well as insulin-induced hypoglycemic (study 4) clamp, combined with bolus-continuous infusion of [3-3 H]glucose and indirect calorimetry to determine the effect of different glycemic/insulinemic levels on endogenous glucose production and on peripheral glucose uptake. In addition, postabsorptive glucose homeostasis was cross-sectionally related to the transplant age (range ϭ 40 d-35 mo) in 4 subgroups of patients 2, 6, 15, and 28 mo after transplantation. 22 subjects with chronic uveitis (CU) undergoing a similar immunosuppressive therapy and 35 normal healthy subjects served as controls. The results showed that successful transplantation was associated with fasting glucose concentration and endogenous glucose production in the lower physiological range within a few weeks after transplantation, and this pattern was maintained throughout the 28-mo follow-up period. Fasting glucose (4.55 Ϯ 0.06 vs. 4.75 Ϯ 0.06 mM; P ϭ 0.038) and endogenous glucose production (11.3 Ϯ 0.4 vs. 12.9 Ϯ 0.5 mol/[kg·min]; P ϭ 0.029) were lower when compared to CU and normal patients. At different combinations of glycemic/insulinemic levels, liver transplant (LTx) patients showed a comparable inhibition of endogenous glucose production. In contrast, in hypoglycemia, after a temporary fall endogenous glucose production rose to values comparable to those of the basal condition in CU and normal subjects (83 Ϯ 5 and 92 Ϯ 5% of basal), but it did not in LTx subjects (66 Ϯ 7%; P Ͻ 0.05 vs. CU and normal subjects). Fasting insulin and C-peptide levels were increased up to 6 mo after transplantation, indicating insulin resistance partially induced by prednisone. In addition, greater C-peptide but similar insulin levels during the hyperglycemic clamp (study 1)suggested an increased hepatic insulin clearance in LTx as compared to normal subjects. Fasting glucagon concentration was higher 6 mo after transplantation and thereafter. During euglycemia/hyperinsulinemia (study 3), the insulininduced glucagon suppression detectable in CU and normal subjects was lacking in LTx subjects; furthermore, the counterregulatory response during hypoglycemia was blunted. In summary, liver transplant subjects have normal postabsorptive glucose metabolism, and glucose and insulin challenge elicit normal response at both hepatic and peripheral sites. Nevertheless, ( a) minimal alteration of endogenous glucose production, ( b ) increased concentration of insulin and glucagon, and ( c ) defective counterregulation during hypoglycemia may reflect an alteration of the liver-CNS-islet circuit which is due to denerv...

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)

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 (KPTx), 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). 11-14ClLeucine infusion and indirect calorimetry were utilized to assess leucine metabolism. The subjects were studied again with a combined infusion ofinsulin and amino acids, given to mimic postprandial amino acid levels (study 2). Amol* m-2. min-') (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 transplantation normalized all kinetic parameters of insulin-mediated protein turnover. During combined hyperinsulinemia and hyperaminoacidemia (study 2), IDDUP showed a defective stimulation of NOLD

Abstract. Conventional insulin therapy does not correct the counter-regulatory abnormalities of insulindependent diabetes mellitus. Pancreas transplantation is an alternative therapy that restores the endogenous insulin secretion in diabetes. In this study, the effects of segmental pancreas transplantation on counterregulation to mild hypoglycaemia were evaluated. Glucose kinetics and the counter-regulatory hormonal responses were assessed in eight insulin-dependent diabetics with end-stage renal failure who had received pancreas and kidney transplantation 1 year previously, seven diabetic uraemic subjects (candidates for combined transplantation), five patients with chronic uveitis on immunosuppressive therapy comparable to pancreas recipients and 10 normal subjects. Insulin (0-3 mU kg-' min-I) was infused for 2 h to induce mild hypoglycaemia (plasma glucose 3.2-3.5 mmoll-I) and exogenous glucose was infused as required to prevent any glucose decrease below 3.1 mmol 1-* . After transplantation, two of eight recipients had hypoglycaemic episodes reported in their medical records. During the study, hepatic glucose production was rapidly suppressed in the controls and in the patients on immunsuppression (-80 f 7 and -54 41 7%, P < 0.001 vs. basal), and rebounded to the baseline values within 1 h (-3 f 1 and -6 i 2%, P = NS vs. basal). The transplant recipients had similar suppression in the first hour (-88 f 8%, P < 0.001 vs. basal), but the suppression persisted in the second hour (-69 f 11%, P < 0.001 vs. basal) indicating a lack of glucose counter-regulatory response. The uraemic-diabetics had reduced suppression of hepatic glucose production (-45 f 14%, P < 0.001 vs. basal) with respect to the recipients (P < 0.001), but had the same lack of response in the second hour (suppression: -39 f 12%, P < 0