Metabolic effect of pancreaticoduodenal transplantation in diabetic rats.

Outbred Wistar rats were randomly assigned to three experimental groups: GI, 10 nondiabetic control rats; GII, 10 alloxan-diabetic control rats; GIII, 25 alloxan-diabetic rats that received pancreaticoduodenal transplantation (PDT) from normal donor Wistar rats and were immunosuppressed with cyclosporin A. For 7 prior and 4, 7, 14, 21, and 30 days posttransplantation (during which the animals were housed in metabolic cages for periods of 24 hours) body weight, water and food intake, urine output, blood and urinary glucose, plasma insulin, and glucagon were recorded. These parameters were also concurrently recorded for diabetic and nondiabetic control rats. Animals were sacrificed after 30 days and histological and immunohistochemical studies of the pancreas were performed. Pancreatic transplants consistently and significantly improved the metabolic abnormalities of the diabetic rat (P less than 0.01) by restoring body weight gain, and by immediate relief of hyperglycemia, glucosuria, polyuria, polydipsia, and also the low levels of plasma insulin. The plasma glucagon, elevated in diabetic control rats, did not change after transplant.     

The effect of pancreas transplantation on diabetic polyneuropathy

Neuromuscular function was evaluated in long-term type I diabetic patients who retained a functioning pancreas graft. A group of 34 patients was examined at 1 year and another group of 11 patients at 2 years after pancreas transplantation. In this report the clinical and electrophysiological course of motor features of polyneuropathy are described. Before pancreas transplantation, clinical evidence of polyneuropathy was present in all patients. The mean motor nerve conduction velocities (NCV) were below normal and the mean amplitude of the evoked muscle action potentials (MAP) were in the low normal range. The observed abnormalities of muscle strength and tendon reflexes had not progressed in these intervals. Motor NCV improved slightly and MAP amplitude was essentially unchanged. These preliminary results indicate that the progression of diabetic polyneuropathy may be halted by successful pancreas transplantation.     

Long-term effect of pancreas transplantation on diabetic hyperglucagonemia

Pancreas isotransplantation was performed on streptozotocin-diabetic Wistar rats. To study the influence of the graft on diabetic hyperglucagonemia, immunoreactive glucagon (IRG) and its response to alanine (peak IRG) were determined in peripheral blood at intervals for up to 8 months after the transplantation. Concentrations of IRG and immunoreactive insulin (IRI) in effluent blood from host pancreas (portal vein) and graft (caval vein) were measured 4 months after the transplantation to estimate the hormone release from both organs. Following transplantation, caval IRI increased sixfold. Portal IRI increased 180% and reached 65% of the concentration observed in control rats. Peripheral basal and peak IRG were initially restored to normal, but were later increased to levels equal to those of diabetic rats. Also portal and caval IRG concentrations were similar in recipients and diabetic rats. The results show that relatively small amounts of glucagon are released from the graft, and that the exaggerated glucagon release from the host pancreas is only transiently normalized following pancreas transplantation.     

Beneficial effect of pancreas and kidney transplantation on advanced diabetic retinopathy

In pancreas recipients with advanced diabetic eye disease, conflicting ophthalmologic results over different follow-up periods have been reported. In the present prospective study we performed ophthalmologic evaluation groups of type I diabetic patients: 1) normoglycemic recipients of pancreas and kidney grafts (group SPK, n = 43, follow-up 44.9 +/- 35.1 months), 2) pancreas and kidney graft recipients with nonfunctioning pancreatic graft, and recipients of isolated kidney graft (group K, n = 45, follow-up 60.3 +/- 34.2 months). The examinations were performed before transplantation, at the end of follow-up (at least 1 year), and in 63 recipients also at 3 years posttransplant. Visual acuity results at baseline and at the end of follow-up were 0.48 +/- 0.39 vs. 0.50 +/- 0.39 in the SPK group, and 0.46 +/- 0.38 vs. 0.40 +/- 0.39 in the K group. While intragroup changes were not significant, the changes were significantly different between the groups (p < 0.05). Fundoscopic findings at the end of follow-up were improved, stabilized, or deteriorated in the SPK group in 21.3%, 61.7%, and 17.0%, respectively. The respective figures for the K group were 6.1%, 48.8%, and 45.1% (p < 0.001). Similar results were obtained when evaluating findings at 3 years posttransplant. Before transplantation, 78% of the SPK group and 81% of the K group had been treated by laser. The need for additional posttransplant laser therapy was significantly lower in the SPK (31%) than in the K group (58%; p < 0.001). In conclusion, pancreas transplant exerts a beneficial effect on the course of diabetic retinopathy even in its late stage.     

胰腺移植对大鼠糖尿病早期肾病的治疗

通过对大鼠肌注链脲霉素制成稳定的糖尿病模型后，尿中２４小时β２－微球蛋白、白蛋白排泄总量的检测，发现其均明显地高于正常水平，最高可达正常倍左右；并对胰腺移植后尿中增高的β２－微球蛋白、白蛋白，能重／１００克体重恢复情况进行观察，认为成功的胰腺移植可以使糖水病早期肾病的微量蛋白尿和增大的肾脏体积恢复正常。     

The long-term management of pancreas transplantation

Diabetes mellitus (DM) is a major health problem worldwide, which affects 18.2 million individuals (6.3% of the population) in the United States. Currently, the prevalence of Type 1 DM in the United States is estimated to be 1,000,000 individuals, and 30,000 new cases are diagnosed each year. In addition to end-stage renal disease (ESRD), DM is associated with blindness, accelerated atherosclerosis, dyslipidemia, cardio- and cerebrovascular disease, amputation, poor quality of life, and overall lifespan reduction. It accounts for more than 160,000 deaths per year in the United States alone. In 2002, the annual national direct and indirect costs of Types 1 and 2 DM exceeded $130 billion, which included hospital and physician care, laboratory tests, pharmaceutical products, and patient workdays lost because of disability or premature death. Hyperglycemia alone or in concert with hypertension is the primary factor influencing the development of major diabetic complications. From 1990 to 2001, the number of existing ESRD cases to DM increased by more than 300%, while the rate per million populations increased from 167% to 491%. The number is expected to grow 10-fold by 2030 to 1.3 million accounting for 60% of ESRD population. To date, DM is the leading indication for transplantation and is the cause of ESRD in more than 40% of all transplant recipients each year.     

Effect of pancreas transplantation on diabetic somatic neuropathy

To determine whether pancreas transplantation is capable of preventing diabetic somatic neuropathy, metabolic studies and electron microscopic morphometry of the sciatic nerve were performed monthly for 2 years in four groups of highly inbred rats: (1) NC-28 nondiabetic controls; (2) DC-82 untreated alloxan-diabetic controls; (3) WPT-122 diabetic rats that received a syngeneic whole-pancreas transplant; and (4) IT-90 diabetic rats that received intraportal injections of 1500 to 2000 syngeneic pancreatic islets. Five diabetic nerve lesions were quantitated by a "blind" protocol: intra-axonal glycogen deposits, axons with glycogen deposits, demyelinated axons, intact axoglial junctions in paranodal terminal myelin loops, and basal lamina thickness of vasa nervorum. Untreated diabetic control animals had significant and progressive increases in all five nerve lesions compared to nondiabetic controls (p less than 0.01). Whole pancreas transplants produced precise metabolic control of diabetes and prevented development and progression of all five diabetic nerve lesions throughout the 2-year study period. Pancreatic islet transplantation produced strict metabolic control and prevented diabetic neuropathy for the first 6 months, but then diabetes recurred and nerve lesions that were similar in severity to those in untreated diabetic rats developed. The finding that whole pancreas transplantation prevents diabetic somatic neuropathy adds to and extends our previous studies showing that whole-pancreas transplants prevent diabetic nephropathy.     

低氧预处理对大鼠自体肝移植后胰腺的保护作用

目的探讨低氧预处理对大鼠自体肝移植后胰腺的保护作用及其机制。方法 90只大鼠随机分成假手术组(sham组,术后6h、24h、48h,每组10只)、自体肝移植组(术后6h、24h、48h,每组10只)和低氧预适应组(术前通过低氧装置给予低氧预适应90min,氧浓度为8%O2∶92%N2;12 h后行自体肝脏移植,6 h、24h、48 h,每组10只)。测定血淀粉酶、脂肪酶,了解胰腺外分泌功能;测定胰腺组织MDA的含量;光镜、电镜观察胰腺形态学改变。SP法检测HIF-1a在胰腺中的表达。结果低氧预适应组大鼠血淀粉酶、脂肪酶、胰腺组织MDA的含量与自体肝移植组比较显著降低(P0.05),光镜、电镜观察低氧预适应组大鼠组织学结构损害轻于自体肝移植组,相应时间点低氧预处理组HIF-1a表达增加(P0.05)。结论低氧预处理对大鼠自体肝移植后胰腺具有保护作用,其机制与胰腺组织HIF-1a表达增加有关。     

Consequences on beta-cell function and reserve after long-term pancreas transplantation

beta-Cell replacement in diabetes using pancreatic islets or beta-cell surrogates is a research area undergoing intense scrutiny. Once this approach is demonstrated to be reproducibly successful, the next major issue will be the length of time that success will be sustained. Whole and segmental pancreas transplants are now successful for up to two decades. Study of these grafts can provide insight into and predictions about beta-cell function and reserve when islet transplantation becomes a routine. The studies described herein investigated 102 human whole and segmental transplant recipients and control subjects to address the following five questions. 1) Is the usual reciprocal relationship between the acute insulin response to intravenous glucose (AIR(gluc)) and the level of fasting plasma glucose (FPG) maintained in pancreas transplant recipients? 2) Do recipients who have no AIR(gluc) have an acute insulin response to intravenous arginine (AIR(arg))? 3) Do recipients of whole pancreata from cadaveric donors have twice the amount of insulin secretory reserve as that found in recipients of 50% segmental grafts from living, related donors? 4) What clinically accessible measure of insulin secretion best correlates with glucose potentiation of arginine-induced insulin secretion (GPAIS)? 5) Do successful pancreas transplant recipients evince time-dependent declines in beta-cell function and glycemic regulation when studied long term and longitudinally? The results demonstrate that 1) the normal relationship between AIR(gluc) and fasting glucose levels is maintained despite systemic venous drainage of allografts and consequent hyperinsulinemia; 2) AIR(gluc) and AIR(arg) decrease in parallel as fasting glucose levels rise, although AIR(arg) is still present after AIR(gluc) disappears; 3) AIR(arg) and AIR(gluc) are strongly predictive of beta-cell mass; 4) AIR(arg) and AIR(gluc) are strongly predictive of insulin secretory reserve; and 5) transplant recipients who have successfully maintained normoglycemia for an average of 10 years and up to 22 years nonetheless experience time-related declines in beta-cell function.     

Effect of the surgical technique on long-term outcome of pancreas transplantation

To date there is no general consensus as to the best surgical technique for pancreas transplantation. Patients with a pancreas transplant functioning for 3 years or more were retrospectively investigated to compare three surgical techniques: segmental graft with duct obstruction (DO), whole graft with bladder drainage (BD), and whole graft with enteric drainage (ED). Several parameters were studied: patient and graft survival, rejection, long-term surgical and medical complications, and endocrine function. The best results in terms of graft survival and quality of metabolic control were obtained in the group that underwent whole graft transplantation with ED. At 3 years, overall pancreas graft survival was 65 % for ED, 60 % for BD, and 47 % for DO. This surgical method has become the preferred technique in our unit. Received: 9 October 1997 Received after revision: 29 January 1998 Accepted: 30 March 1998     

Temporal relationship between successful pancreas transplantation and control of ocular complications in alloxan-induced diabetic rats

PURPOSE: The impact of pancreas transplantation (PT) on the progression of eye disease is still controversial. This study evaluated the course of retinopathy in transplanted rats in two different diabetic stages. METHODS: Sixty inbred male Lewis rats were assigned to four experimental groups: NC-15 nondiabetic control rats; DC-15 untreated diabetic control rats; PT1-15 diabetic rats that received syngeneic pancreas transplants 2 weeks after alloxan diabetes induction; PT2-15 diabetic rats that received pancreas transplants 12 weeks after diabetes onset. Clinical and laboratory parameters and lens opacity were examined in all rats prior to treatment and at 1-, 6-, and 12-months follow-up. Nucleated eyes from five rats in each group processed for ultrastructural study of the retinal at 6 and 12 months after PT or at follow-up. RESULTS: Cataracts were observed in 20%, 60%, and 100% of DC rats at 1-, 6-, and 12-months follow-up, respectively. Early PT (2 weeks) significantly reduced the prevalence of this complication but not late (12 weeks) PT. PT1 rats also showed improved ultrastructure of the superficial and deep capillary plexuses of the retina, and of Müller cells, compared with DC and PT2. In the last group, retinopathy continued to evolve despite successful PT. CONCLUSION: Our results suggested that prevention of diabetic ocular lesions by PT was closely dependent on earlier performance of the procedure.     

Metabolic effects of IGF-I in diabetic rats

Insulinlike growth factor I (IGF-I) stimulates glucose utilization (GU) in nondiabetic rats. We compared the effects of IGF-I and insulin on glucose metabolism in control (fed plasma glucose 7.7 +/- 0.1 mM, n = 30) and partially (90%) pancreatectomized diabetic (plasma glucose 18.4 +/- 0.8 mM, n = 30) awake unstressed rats. IGF-I was infused at 0.65 or 1.96 nmol.kg-1.min-1 and insulin at 22 or 29 pmol.kg-1.min-1 in combination with [3-3H]glucose while euglycemia was maintained by a variable glucose infusion. In controls, GU during the 0.65- and 1.96-nmol.kg-1.min-1 IGF-I infusions (127 +/- 7 and 168 +/- 4 mumol.kg-1.min-1, respectively) was similar to rates observed during the 22- and 29-pmol.kg-1.min-1 insulin infusions (121 +/- 2 and 156 +/- 5 mumol.kg-1.min-1). Whole-body glycolytic rate (3H2O generation) and muscle glycogen synthetic rate were identical during insulin and IGF-I infusions. In diabetic rats, GU was reduced by 30% versus control rats (P less than 0.01) during both the low-dose (88 +/- 7 vs. 121 +/- 7 mumol.kg-1.min-1) and higher-dose (109 +/- 4 vs. 156 +/- 5 mumol.kg-1.min-1) insulin clamps. The defect in insulin action involved both muscle glycogen synthesis and glycolysis. In diabetic rats, IGF-I elicited rates of GU similar to controls (115 +/- 10 and 164 +/- 12 mumol.kg-1.min-1 during the 0.65- and 1.96-nmol.kg-1.min-1 infusions, respectively) and corrected the intracellular defects in glycogen synthesis and glycolysis.(ABSTRACT TRUNCATED AT 250 WORDS)