Biomedical subjects
Publications and source records attributed to F C Goetz.
The results of pancreas transplantation at the University of Minnesota according to technique, donor source, and immunosuppressive therapy are discussed. Preliminary evidence suggests that not only prevention but reversal of lesions resulting from diabetes may be possible with pancreas transplantation.
Peptic digestion of gluten results in the production of substances having opiatelike activity in bio- and receptor assays. These substances have been termed exorphins. In this study, we determined the effect of gluten, hydrolyzed gluten, and hydrolyzed gluten plus the opiate blocker naloxone on a variety of hormonal parameters, gastrointestinal transit time, small bowel mucosal integrity, and satiety. Hydrolyzed gluten prolonged intestinal transit time, and this effect was reversed by concomitant administration of naloxone. Hydrolyzed gluten also produced a naloxone-reversible increase in plasma somatostatinlike activity, which may have been responsible for the delayed transit time. No effects of the "exorphins" could be demonstrated on serum gastrin, cortisol, carbohydrate metabolism, or small bowel mucosal integrity. Although a number of studies have suggested a role for endogenous opiates in appetite regulation, we could not demonstrate any effect of "exorphins" on the amount of calories ingested nor on the perception of satiety. This study defines a potential role for small opiatelike peptides in foodstuffs in the regulation of intestinal function.
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Between December, 1966 and October, 1981, 183 pancreas transplants were performed in attempts to correct the metabolic defect in 171 insulin-dependent diabetic patients. Nearly half of the transplants have been performed in the last two years. Currently, 20 patients have functioning grafts and are insulin independent. Twelve grafts (including six current ones) functioned for more than a year (the longest for four years). A variety of techniques have been used to drain or suppress the secretions of the exocrine pancreas; the most frequent method is injection of the pancreatic duct with a synthetic polymer. In most patients carbohydrate metabolism has been normal or nearly normal while the graft was functioning. Although the technical problems are not entirely solved, the major cause of graft failure has been rejection. The need for antirejection therapy has limited the application of pancreas transplantation to diabetic renal allograft recipients or to non-uraemic patients whose complications of diabetes are, or predictably will be, worse than the side- effects of chronic immunosuppression. If consistently effective methods to suppress the immune response of the recipient to donor histocompatibility antigens are developed, pancreas transplantation could be applied to a wider variety of diabetic patients.
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Forty-nine pancreas transplants were performed in 45 patients between July 23, 1978 and May 14, 1982, 18 from related donors. Currently (June 1982), 13 patients have functioning grafts and are insulin independent between 1 and 46 months after transplantation, 5 for more than 1 year. Nineteen patients lost graft function between 1 and 7 months. Sixteen grafts failed for technical reasons. Eight patients died between 1 and 21 months from infections or preexisting complications or for unknown reasons, three with functioning grafts. Actuarial 1-year graft survival is 24% and patient survival is 84%. A variety of techniques were used to handle exocrine secretions of 41 hemipancreas segmental grafts, 4 extended segmental grafts, and 4 whole pancreas grafts. Currently, 3 of 14 duct-open, 0 of 2 duct-ligated, 0 of 4 prolamine-injected, 6 of 19 silicone rubber-injected, and 4 of 10 jejunal anastomosed pancreatic grafts are functioning. Of 33 technically successful allografts, 5 in 12 conventionally immunosuppressed and 8 in 21 cyclosporin A (Cy A)-immunosuppressed recipients are functioning. Most technically successful grafts that failed were not biopsied or removed. In those that were biopsied, fibrosis was a dominant feature in all but one patient. In this patient endocrine and exocrine tissue was normal except for the absence of insulin-positive (beta) cells in the islets and an increase in glucagon-positive (alpha) cells, in contrast to the normal appearance of alpha and beta cells in islets at the time of the pancreas transplant. Currently, we perform pancreas transplants in diabetic patients who have previously received kidney transplants and therefore already require immunosuppression. For nonuremic patients, we perform pancreas transplant only if it is judged that their complications of diabetes exceed, or predictably will exceed, the potential side effects of chronic immunosuppression.
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Cyclosporin A (CsA) is a unique immunosuppressive cyclic polypeptide that is currently being used, either alone or in combination with low-dose prednisone, to treat recipients of renal or pancreas allografts in clinical trials. CsA is very effective in preventing rejection of heart and renal allografts in rodents, but in nontoxic doses does not consistently prevent rejection of pancreas and islet allografts. Therefore, we tested low-dose CsA in various combinations with low-dose prednisone, azathioprine, or total lymphoid irradiation in rat heart, pancreas, and islet allograft models. Several combinations are synergistic and when administered continuously can indefinitely prevent rejection of heart allografts, but only delay rejection of pancreatic allografts, transplanted across a major histocompatibility barrier, CsA by itself prolonged the survival of islet allografts transplanted across a minor, but not a major, histocompatibility barrier. CsA and azathioprine had a synergistic effect in the minor histocompatibility barrier islet transplant model, but, in the nontoxic combinations tested, could not prevent rejection indefinitely. A randomized prospective trial comparing standard immunosuppressive therapy (ALG, prednisone, and azathioprine), with CsA and low-dose prednisone for clinical renal allotransplantation is ongoing at the University of Minnesota. Current actuarial 1-yr graft survival is 93% for CsA-treated patients (N = 48) and 81% for conventionally treated patients (N = 52). Patient survival is 98% for CsA and 100% for conventionally treated patients. A pilot trial of CsA in the clinical pancreas transplant program at the University of Minnesota is also underway. Since 1978, 46 pancreas transplants have been performed in 43 patients. Of 30 technically successful pancreatic allografts, 5 of 12 recipients treated with conventional immunosuppression and 6 of 18 recipients treated with CsA currently have functioning grafts and are insulin independent between 1 and 44 months after transplantation. The results of metabolic studies are similar in conventional and CsA-treated patients with functioning pancreas grafts. Since pancreas grafts may fail for reasons other than rejection, further observations are needed to ascertain the role of CsA in clinical pancreas transplantation.
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A new modification of pancreas transplant technique, the vascularized segmental intraperitoneal graft without duct ligation, has provided reversal of insulin-dependent (type I) diabetes mellitus for as long as 2 years of comfortable life. Although the risks associated with immunosuppression remain high (two of the 12 patients have died of early postoperative infection), selected data are presented from six cases to show the following striking hormonal and metabolic results after transplantation and withdrawal of insulin: restoration of normal beta cell function as shown by 24-hour urine C-peptide excretion and acutely responsive serum insulin, restoration of normal suppressibility of plasma glucagon, elimination of ketosis and negative nitrogen balance, normal fasting plasma glucose and glycosylated hemoglobin, and normal or near-normal glucose tolerance. These results provide a standard for current explorations of new ways of treating insulin-dependent diabetes.
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Between July 25, 1978, and January 25, 1981, 20 segmental pancreas transplants from 14 cadaver (cad) and six related (rel) donors were performed. All but two recipients had previously received renal allografts for treatment of end-sage diabetic nephropathy. The grafts were placed intraperitoneally-13 with open ducts, 4 with prolamine-injected ducts, and 3 with silicone rubber-injected ducts. At this writing six patients have functioning grafts (3 silicone, 3 open duct) at less than 1 (cad), 2 (cad), 3 (rel), 15 (cad), 20 (rel), and 31 (cad) months. Five open-duct grafts failed for technical reasons. Two prolamine-injected grafts lost function between 1 and 3 months; biopsy specimens showed severe fibrosis. The others lost function between 2 and 4 months. Three patients died 1 to 3 months after transplantation. Metabolic test results were normal or nearly normal in most recipients with functioning grafts. Splenectomy was required in one related donor; there were no other complications of donation. Technical problems and rejection are impediments to application of pancreas transplantation, but a sustained correction of the metabolic defect has been achieved in a few patients, and the effect on secondary complications are studied.
Killing of Staphylococus aureus by neutrophils from untreated patients with acute bacterial infection was increased compared with neutrophils from uninfected controls or the same patients after antibiotic treatment. In contrast, neutrophils from diabetics failed to increase their bactericidal activity in response to infection to the same degree as neutrophils from nondiabetic subjects. The latter abnormality was pronounced in poorly controlled (plasma glucose level, greater than 130 mg/100 ml), but was also present in well-controlled (plasma glucose levels, less than 130 mg/100 ml), diabetics. In parallel studies neutrophils from poorly controlled, uninfected diabetics did not kill S. aureus to the same degree as neutrophils from normal subjects or controlled diabetics. Finally, neutrophils from two diabetics who underwent controlled insulin withdrawal developed a bactericidal defect that was corrected by treating the patients with insulin or by preincubating their neutrophils with insulin in vitro. These results support the possibility that defective neutrophil bactericidal activity may contribute to the proposed increased susceptibility to bacterial infection of diabetics.
Total or near total pancreatectomy is the surest way to relieve the pain of chronic pancreatitis but is rarely applied because the metabolic consequences are so severe. For most patients drainage procedures are applicable, but pancreatectomy may be the only alternative for small duct disease or where procedures to improve duct drainage have failed. Preservation of endocrine function is a major problem in patients who require pancreatectomy. Experiments in pancreatectomized dogs have shown that intrasplenic or intraportal transplantation of unpurified pancreatic islet tissue dispersed by collagenase digestion can prevent diabetes. We have applied this technique to ten patients with chronic pancreatitis, small ducts, and intractable pain. The entire pancreas of > 95% of the pancrease was excised, minced, dispersed by collagenase digestion and infused into the portal vein < 2 1/2 hours after removal. Mean (+/- SD) rise in portal pressure was 17 +/- 8 cm of water. Liver function tests were altered minimally. All patients were relieved of pain. One patient died of a complication not related to the islet autotransplant; viable islets were identified in the liver at autopsy. Of the remaining nine patients, three have been insulin independent for 1, 9, and 38 months. One patient was insulin indpendent for 15 months and now takes 12 units of insulin daily. Three have nonketosis prone diabetes (tested by insulin withdrawal) and take 15--30 units of insulin per day. C-peptide studies in these patients show that functioning islets are present. Two patients are diabetic and require 35 and 60 units of insulin per day. In eight of nine patients tested serum insulin concentrations fell to undetectable levels during the interval between pancreatectomy and islet transplantation. Serum insulin levels during the first few hours after islet transplantation predicted success. In the insulin independent or in the patients with mild diabetes, insulin levels were persistently greater than or equal to 6 microU/ml. In the other two patients, the increase in insulin concentration was not sustained. Islet tissue preparation from a diseased pancreas is difficult. The surgeon and the patient must still be willing to accept diabetes for relief of pain when performing this operation. In some patients, however, islet autotransplantation can prevent or partially ameliorate diabetes after pancreatectomy, and preservation of endocrine function is worthwhile.
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Segmental pancreatic allografts with unligated ducts were transplanted intraperitoneally to five diabetic patients who had received renal allografts more than 2 yr earlier. One patient is alive with a functioning graft 10.5 mo later. Two patients rejected their grafts at approximately 2 and 3 mo but are alive 8--9 mo later after resumption of exogenous insulin therapy. In both patients, carbohydrate metabolism was nearly normal during the period of graft function. Two patients died of infectious complications between 1 and 2 mo after transplantation. The main hazard of pancreas transplantation relates to the immunosuppression necessary to prevent rejection, setting the stage for infectious complications. Technically, pancreas transplantation is a feasible and efficient procedure, and, if better methods are developed for preventing rejection, it should be applicable to patients prone to develop secondary complications of diabetes.