Effects of pancreatic islet transplantation on the increased urinary albumin excretion rates in intact and uninephrectomized rats with diabetes mellitus.
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Biomedical subjects
Publications and source records attributed to M W Steffes.
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Thirteen patients with hypogonadotropic hypogonadism were treated with human menopausal gonadotropins (hMG) and human chorionic gonadotropin (hCG) to induce ovulation. Daily serum 17beta-estradiol (E2) assays were used to monitor the ovarian response to HMG. Apparent ovulation, documented by basal body temperatures, occurred in 41 of 53 hMG-hCG treatment cycles. Thirteen pregnancies occurred in 8 of the 13 patients. One twin pregnancy resulted. The hyperstimulation syndrome did not occur. Our data indicate that an optimal pregnancy rate with a minimum risk of hyperstimulation can be achieved when ovulation is induced 24 hours after the preovulatory serum E2 concentration has reached 500 to 900 pg/ml. Ovulation is induced by administering 10,000 IU and 5000 IU hCG on successive days. In addition, we now routinely give two or three injections of 2500 IU hCG at subsequent 3- to 4-day intervals to support the corpus luteum.
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Evaluation of pituitary gonadotropins, gonadal steroids, spermatogenesis, and menstrual function was undertaken in 32 patients (19 males and 13 females) treated with cyclophosphamide because of nephrotic syndrome. Patients were treated before, during, or after puberty. Evaluations took place after or in very late puberty. Spermatogenic dysfunction occurred in six of 15 boys who received the entire course before and during puberty and was probably dose related. Menstrual dysfunction did not occur following treatment of six prepubertal or pubertal girls, though only low total doses were used. Therapy after puberty was associated with spermatogenic dysfunction in all four boys, but did not cause menstrual dysfunction in any of seven women. Tentative guidelines are suggested that many minimize gonadal toxicity when cyclophosphamide is used in children with nephrotic syndrome. Factors of particular importance in the interpretation of gonadotropin determinations and of sperm counts in young cyclophosphamide-treated patients are discussed.
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It is not known whether the advantage of the portal vein as a transplant site for islet transplantation is caused by the immediate availability of a blood supply or by the localization of the islets in the portal circulation. We transplanted minimal quantities of islet tissue from neonatal rat donors to isogeneic adult rats with streptozotocin-induced diabetes. Transplants were performed to three sites, i.p., portal vein, and systemic vein (i.v.). When four neonatal donors were used for each recipient there were no i.p. cures but 90% i.v. and 100% portal vein cures, which suggests that access to a blood supply is important. As the amount of tissue transplanted was decreased, there were significantly more cures with the portal vein route, which suggests that localization of the islets in the portal circulation is also important to graft survival.
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A sustained decrease of plasma bilirubin concentrations occurred in homozygous recessive Gunn rats lacking the enzyme uridine diphosphate glucuronyltransferase following infusion into the portal vein of hepatocytes from heterozygous nonjaundiced Gunn rats possessing the enzyme. Transplantation of cells capable of continuous enzyme production could be an effective mode of therapy for congenital enzyme deficiency diseases.
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Twelve pancreases from human infants one year old or less were analyzed for tissue insulin and amylase content before and after dispersal of pancreatic fragments by mincing and collagenase digestion. Tissue insulin and amylase content provide an index of pancreatic islet mass and exocrine digestive enzyme content, respectively. The results were compared with similar anaylses performed on juvenile and adult human pancreases before and after islet isolation and on intact and dispersed neonatal rat and adult rat pancreas. Infant human pancreas has an average tissue insulin concentration of 1,128 mug./gm. of tissue and a total insulin content of 1,718 mug/pancreas, as against values of 140 mug./gm. of tissue and 7,209 mug./pancreas for adult human pancreas. Average tissue amylase concentration is 0.24 mg./gm. of tissue in infant human pancreas and 3.0 mg./gm. of tissue in adult human pancreas. The insulin/amylase ratio in infant pancreas is 4,800, as against 46 in the adult pancreas. Neonatal rat pancreas, which can be dissociated and transplanted without separation of islet and exocrine components, has a similarly high tissue insulin and low tissue amylase content when compared with adult rat pancreases. Infant human pancreas has a total islet mass 24 per cent that of an adult human pancreas, and neonatal rat pancreas has a total islet mass 11 per cent of that of an adult rat pancreas. One neonatal rat pancreas prepared by minimal collagenase digestion can cure diabetes when transplanted via the portal vein to a rat. Following dispersal of infant human pancreas by collagenase digestion, the islet content and the insulin/amylase ratio of the recovered tissue equals or exceeds that which usually can be isolated from adult cadaver pancreases. Infant human pancreas is a rich source of islet tissue that is relatively uncontaminated by exocrine digestive enzymes. After dispersal, infant human pancreas may be ideal for transplantation to selected diabetic patients.
Minced adult human, rat, and dog pancreatic fragments were cultured under various conditions in an attempt to selectively purify pancreatic islet tissue from exocrine digestive enzymes. Islet purification was assessed by measuring tissue insulin and amylase concentrations, proportional to islet beta cell mass and exocrine enzyme content, respectively. Tissue amylase content decreased rapidly over a 24 hour culture period under all conditions. By addition of pilocarpine, cobalt chloride, and aprotinin to the culture medium, pancreatic tissue insulin levels stabilized. Under these conditions the tissue insulin: amylase ratio increased rapidly and a high ratio was maintained, indicating that islet tissue decontaminated of exocrine digestive enzymes was preserved in short-term culture. Fifteen dogs rendered diabetic with streptozotocin immediately following a partial pancreatectomy received an autotransplant of pancreatic tissue fragments maintained in culture for 24 hours. Seven dogs were rendered normoglycemic. Six of these dogs have survived for longer than 30 days. Only one of 14 control pancreatectomized dogs injected with streptozotocin and not transplanted survived and was normoglycemic. Viable islet tissue free of exocrine enzymes can be obtained by short-term culture of pancreatic fragments, and separation of islet and exocrine components of adult pancreas is not essential for successful islet transplantation.