Patient-reported outcomes following islet cell or pancreas transplantation (alone or after kidney) in type 1 diabetes: a systematic review

Aims For selected individuals with complex Type 1 diabetes, pancreatic islet transplantation (IT) offers the potential of excellent glycaemic controlwithout significant hypoglycaemia, balanced by the need for ongoing systemic immunosuppression. Increasingly, patient-reported outcomes (PROs) are considered alongside biomedical outcomes as a measure of transplant success. PROs in IT have not previously been compared directlywith the closest alternate treatment option, pancreas transplant alone (PTA) or pancreas after kidney (PAK).

Methods We used a Population, Intervention, Comparisons, Outcomes (PICO) strategy to search Scopus and screened 314 references for inclusion.

Results Twelve studies [including PRO assessment of PAK, PTA, islet-after kidney (IAK) and islet transplant alone (ITA); n = 7–205] used a total of nine specified and two unspecified PRO measures. Results were mixed but identified some benefits which remained apparent up to 36 months post-transplant, including improvements in fear of hypoglycaemia, as well as some aspects of diabetes-specific quality of life (QoL) and general health status. Negative outcomes included short-term pain associated with the procedure, immunosuppressant side effects and depressed mood associated with loss of graft function.

Conclusions The mixed resultsmay be attributable to limited sample sizes. Also, some PROmeasures may lack sensitivity to detect actual changes, as they exclude issues and domains of life likely to be important forQoL post-transplantation and when patients may no longer perceive themselves to have diabetes. Thus, the full impact of islet ⁄ pancreas transplantation (alone or after kidney) on QoL is unknown. Furthermore, no studies have assessed patient satisfaction, which may highlight further advantages and disadvantages of transplantation.

Amyloid formation in human IAPP transgenic mouse islets and pancreas, and human pancreas, is not associated with endoplasmic reticulum stress

Aims/hypothesis Supraphysiological levels of the amyloidogenic peptide human islet amyloid polypeptide have been associated with beta cell endoplasmic reticulum (ER) stress. However, in human type 2 diabetes, levels of human IAPP are equivalent or decreased relative to matched controls. Thus, we sought to investigate whether ER stress is induced during amyloidogenesis at physiological levels of human IAPP.

Methods Islets from human IAPP transgenic mice that develop amyloid, and non-transgenic mice that do not, were cultured for up to 7 days in 11.1, 16.7 and 33.3 mmol/l glucose. Pancreases from human IAPP transgenic and non-transgenic mice and humans with or without type 2 diabetes were also evaluated. Amyloid formation was determined histologically. ER stress was determined in islets by quantifying mRNA levels of Bip, Atf4 and Chop (also known as Ddit3) and alternate splicing of Xbp1 mRNA, or in pancreases by immunostaining for immunoglobulin heavy chain-binding protein (BIP), C/EBP homologous protein (CHOP) and X-box binding protein 1 (XBP1).

Results Amyloid formation in human IAPP transgenic islets was associated with reduced beta cell area in a glucose- and time-dependent manner. However, amyloid formation was not associated with significant increases in expression of ER stress markers under any culture condition. Thapsigargin treatment, a positive control, did result in significant ER stress. Amyloid formation in vivo in pancreas samples from human IAPP transgenic mice or humans was not associated with upregulation of ER stress markers.

Conclusions/interpretation Our data suggest that ER stress is not an obligatory pathway mediating the toxic effects of amyloid formation at physiological levels of human IAPP.

Intestinal and pancreas enzyme activity of broilers exposed to thermal stress

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

The adaptive compensations in endocrine pancreas from glucocorticoid-treated rats are reversible after the interruption of treatment

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Insulin and glucose sensitivity, insulin secretion and beta-cell distribution in endocrine pancreas of the fruit bat Artibeus lituratus

The fruit bat Artibeus lituratus absorbs large amounts of glucose in short periods of time and maintains normoglycemia even after a prolonged starvation period. Based on these data, we aimed to investigate various aspects related with glucose homeostasis analyzing: blood glucose and insulin levels, intraperitoneal glucose and insulin tolerance tests (ipGTT and ipITT), glucose-stimulated insulin secretion (2.8, 5.6 or 8.3 mmol/L glucose) in pancreas fragments, cellular distribution of beta cells, and the amount of pAkt/Akt in the pectoral muscle and liver. Blood glucose levels were higher in fed bats (6.88 +/- 0.5 mmol/L) than fasted bats (4.0 +/- 0.8 mmol/L), whereas insulin levels were similar in both conditions. The values of the area-under-the curve obtained from ipGTT were significantly higher when bats received 2 (5.5-fold) or 3 g/kg glucose (7.5-fold) b.w compared to control (saline). These bats also exhibited a significant decrease of blood glucose values after insulin administration during the iplTT. Insulin secretion from fragments of pancreas under physiological concentrations of glucose (5.6 or 8.3 mmol/L) was similar but higher than in 2.8 mmol/L glucose 1.8- and 2.0-fold, respectively. These bats showed a marked beta-cell distribution along the pancreas, and the pancreatic beta cells are not exclusively located at the central part of the islet. The insulin-induced Akt phosphorylation was more pronounced in the pectoral muscle, compared to liver. The high sensitivity to glucose and insulin, the proper insulin response to glucose, and the presence of an apparent large beta-cell population could represent benefits for the management of high influx of glucose from a carbohydrate-rich meal, which permits appropriate glucose utilization. (C) 2010 Elsevier B.V. All rights reserved.

Functional alterations in endocrine pancreas of rats with different degrees of dexamethasone-induced insulin resistance

Objectives: We have analyzed the peripheral insulin and glucose sensitivity in vivo, and islet function ex vivo in rats with different degrees of insulin resistance induced by dexamethasone (DEX).Methods: Dexamethasone, in the concentrations of 0.1 (DEX 0.1), 0.5 (DEX 0.5), and 1.0 mg/kg body weight (DEX 1.0) was administered daily, intraperitoneally, to adult Wistar rats for 5 days, whereas controls received saline.Results: Dexamethasone treatment induced peripheral insulin resistance in a dose-dependent manner. At the end of the treatment, only DEX 1.0 rats showed significant increase of postabsorptive blood glucose and serum triglycerides, and nonesterified fatty acids levels. Incubation of pancreatic islets in increasing glucose concentrations (2.8-22 mM) led to an augmented insulin secretion in all DEX-treated rats. Leucine, carbachol, and high KCl concentrations induced the insulin release in DEX 0.5 and DEX 1.0, whereas arginine augmented secretion in all DEX-treated groups.Conclusions: We demonstrate that in DEX 0.5 and, especially in DEX 0.1 groups, but not in DEX 1.0, the adaptations that occurred in the endocrine pancreas are able to counteract metabolic disorders (glucose intolerance and dyslipidemia). These animal models seem to be interesting approaches for the study of degrees of subjacent effects that may mediate type 2 diabetes (DEX 1.0) and islet function alterations, without collateral effects (DEX 0.1 and DEX 0.5).

Effects of pancreas transplantation on oxidative stress in pulmonary tissue from alloxan-induced diabetic rats

Purpose. There is considerable evidence that cellular oxidative stress caused by hyperglycemia plays an important role in the genesis and evolution of chronic diabetic lesions. In this study, we determined the effectiveness of pancreas transplantation (PT) in preventing the imbalance caused by excessive production of reactive oxygen species over antioxidant defenses in lungs of rats rendered diabetic by alloxan injection.Methods. Sixty inbred male Lewis rats, weighing 250-280 g, were randomly assigned to 3 experimental groups: NC, 20 nondiabetic control rats; DC, 20 untreated diabetic control rats; and PT, 20 diabetic rats that received syngeneic PT from normal donor Lewis rats. Each group was further divided into 2 subgroups of 10 rats each which were killed after 4 and 12 weeks of follow-up. Plasma glucose, glycosylated hemoglobin, and insulin levels were determined in all rats. Lipid hydroperoxide (LPO) concentrations and enzyme activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) were measured in the pulmonary tissue of all rats.Results. The DC rats showed elevated blood glucose and glycosylated hemoglobin levels, with insulin blood levels significantly lower than the NC rats (P < .001). They also showed significantly increased LPO concentrations in the lungs (P < .01) after 4 and 12 weeks of follow-up. In contrast, SOD, CAT, and GSH-Px antioxidant activities were significantly reduced in these periods (P < .01) 12 weeks after diabetes induction. Successful PT corrected all clinical and metabolic changes in the diabetic rats, with sustained normoglycemia throughout the study. Excessive lung LPO production and low SOD, CAT, and GSH-Px antioxidant activities were already back to normal 4 weeks after PT.Conclusion. PT can control oxidative stress in pulmonary tissue of diabetic rats. It may be the basis for preventing chronic diabetic lesions in lungs.

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 tens 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 Muller 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.

Pancreas transplantation prevents cellular oxidative stress in kidneys of alloxan-induced diabetic rats

Purpose. Oxidative stress is one of the most important mechanisms to explain genesis of the complications in the chronic progression of diabetes. In this investigation we studied the effects of pancreas transplantation (PT) on the imbalance caused by excessive production of free oxygen radicals by antioxidant defenses of rats with serious chronic hyperglycemia induced by alloxan.Methods. Ninety inbred male Lewis rats were randomly distributed into three groups: NC-30 nondiabetic controls; DC-30 diabetic controls without any treatment; PT-30 diabetic rats undergoing syngeneic PT from normal donor Lewis rats. Each experimental group was then split into three subgroups of 10 animals for sacrifice after 1, 3, or 6 months. Clinical and laboratory parameters from all rats as well as lipid hydroperoxide (LPO) concentrations and renal tissue enzyme activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) were recorded for all rats.Results. Successful PT corrected clinical and laboratory alterations in diabetic rats with sustained normoglycemia throughout the study. A significant increase in LPO concentration and a marked reduction in SOD and CAT enzyme activity were observed in DC rats; there was no significant variation in renal tissue GSH-Px in this group. However, alterations in DC rats were completely restored from 1st month after PT; all evaluated enzyme levels did not significantly differ (P < .01) from those in NC controls.Conclusion. Successful PT controlled cellular oxidative stress in diabetic kidneys, which may prevent chronic lesions.

Pancreas Transplantation Prevents Morphologic and Ultrastructural Changes in Pulmonary Parenchyma of Alloxan-Induced Diabetic Rats

Purpose. The aim of this study was to evaluate whether pancreas transplantation (PT) is a suitable method for controlling histopathologic changes in lungs of alloxan-induced diabetic rats.Methods. Sixty inbred male Lewis rats were randomly assigned to 3 experimental groups: NC, 20 nondiabetic control rats; DC, 20 untreated diabetic control rats; and PT, 20 diabetic rats that received syngeneic PT from normal donor Lewis rats. Each group was further divided into 2 subgroups of 10 rats each, which were killed after 4 and 12 weeks of follow-up. Clinical and laboratory parameters, fresh and fixed lung weights, and fixed lung volumes were recorded for all rats. Total number of alveoli, alveolar perimeter, alveolar surface area, and alveolar epithelial (AE) and endothelial capillary (EC) basal laminae thickening were randomly measured in 5 rats from each subgroup by using an image analyzer. For light microscopy, 250 alveoli were analyzed in each subgroup. For electron microscopy, 50 electron micrographs were examined for each subgroup.Results. The DC rats showed elevated blood glucose and glycosylated hemoglobin levels, with insulin blood levels significantly lower than the NC rats (P < .001). Fresh and fixed lung weights and fixed volumes were significantly reduced in these rats, although their proportions to body weight were increased at 12 weeks (P < .01). The total number of alveoli in diabetic rats was higher than in control rats, whereas alveolar perimeter and surface area were significantly diminished (P < .01). AE and EC basal laminae were significantly thicker in DC than in NC (P < .01). Successful PT corrected all clinical and metabolic changes in diabetic rats, with sustained normoglycemia throughout the study. Morphologic and morphometric changes observed in diabetic lungs were completely prevented in PT rats from 4 weeks after transplant.Conclusion. We conclude that PT can control morphologic and ultrastructural changes in pulmonary parenchyma, suggesting a promising perspective for preventing other chronic diabetic lesions.

Study of the evolution of the placenta and fetal pancreas in the pathophysiology of growth retardation intrauterine due to restricted maternal diet

CONTEXTO: O retardo do crescimento intra-uterino (RCIU) continua sendo importante problema em perinatologia neste final de século. A natureza do agente etiológico, o período da gestação em que ocorreu o insulto e a sua duração influenciam o tipo de RCIU. OBJETIVO: Estudar a fisiopatologia do retardo de crescimento intrauterino (RCIU) em ratas, decorrente da restrição protéico-calórica materna, em relação à evolução do pâncreas fetal e placenta entre o 18o e 21o dias de prenhez. TIPO DE ESTUDO: Ensaio clínico randomizado em animal de laboratório. PARTICIPANTES: 41 ratas prenhes, normoglicêmicas, da raça Wistar. INTERVENÇÃO: Constituíram-se seis grupos experimentais: controle, com dieta ad libitum e cesárea, respectivamente, no 18º e 21º dias; grupos dieta restritiva a 25% introduzida no 1o dia da prenhez e cesárea no 18o e 21o dias; grupos com a mesma restrição, porém iniciada no 3o dia, com cesárea no 18o e 21o dias. VARIÁVEIS ESTUDADAS: Os recém-nascidos foram classificados, em relação à média mais ou menos um desvio padrão do grupo controle, em peso pequeno (PIP), adequado (AIP) e grande (GIP) para a idade de prenhez; as placentas foram pesadas e processadas para estudo histopatológico, incluindo morfologia e histoquímica, e os pâncreas fetais, para estudo morfológico. RESULTADOS: A desnutrição protéico-calórica materna causou RCIU após o 18o dia da prenhez. Antes desse período não ocorreu RCIU, porque a desnutrição materna diminuiu o número da prole e a placenta tornou-se vicariante. A restrição alimentar não interferiu com a morfologia do pâncreas fetal, e o estudo imunohistoquímico da placenta mostrou que, quando a restrição é introduzida no 1o dia de prenhez, os estoques de glicogênio também não sofrem alterações, diminuindo entre o 18o e 21o dias, como na prenhez normal. A restrição no 3o dia cursou com baixas concentrações de glicogênio placentário no 18o dia e desaparecimento no 21o dia. CONCLUSÃO: A fisiopatologia do RCIU, decorrente da restrição protéico-calórica materna em ratas, está relacionada com menor peso placentário e baixos estoques de glicogênio placentário.