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Biomedical subjects

D E Sutherland

Publications and source records attributed to D E Sutherland.

At least 811 records · Page 45Linked to original sources
PubMed1975

Glucagon biosynthesis in human pancreatic islets: preliminary evidence for a biosynthetic intermediate.

Viable pancreatic islets were isolated from the pancreas of humans using modifications of the collagenase digestion and Ficoll gradient techniques. Gel filtration of tissue extracts following islet incubation in the presence of 3H- tryptophan indicated that radioactivity becomes incorporated into at least two islet proteins. The larger of the two (LGI) has the approximate molecular size of proinsuiln and the smaller coelutes with glucagon as determined by column standardization. Radioimmunoassay of the gel filtration eluate for glucagon revealed that both molecules have glucagon immunoreactivity. Gel filtration in the presence of 8M urea did not alter the elution pattern of the LGI molecule. Polyacrylamide gel electrophoresis was performed on these glucagon immunoreactive molecules. The 3H radioactivity and the glucagon immunoreactivity of the smaller molecule were found to co-migrate electrophoretically with crystalline porcine glucagon and monodesamidoglucagon. With electrophoresis at high pH the electrophoretic mobility of the LGI molecule proved to be lower than that of glucagon. Partial tryptic degradation of the human LGI molecule yields 3H-tryptophan labeled products having charge and immunologic characteristics indistinguishable from porcine glucagon and monodesamidoglucagon. Although further investigation is indicatend may thus serve as a precursor or an intermediate in human glucagon biosynthesis.

Antigens↗
PubMed1975

Islet transplantation in diabetic rats receiving corticosteroids.

Pancreatic tissue fragments from neonatal inbred Lewis rats were distributed throughout the peritoneal cavities of isologous diabetic recipients receiving prednisolone on a schedule similar to that used in clinical transplantation beginning 9-44 days before transplantation. Plasma glucose levels in six of seven diabetic rats receiving prednislone returned to normal levels 3 weeks after transplantation. Plasma insulin levels in the animals with successful transplants reached, at 1 week after transplantation, levels measured in normal control rats, but never attained the high insulin levels observed in the normal control animals receiving steroids. As with glucose the insulin levels remained in the normal range, and the animals steadily gained weight. During i.v. glucose tolerance tests (IVGTTs) in the rats with successful transplants at 4, 11-14, and 26-29 weeks after transplantation, the glucose levels were similar to those observed during IVGTTs in the control animals before and during corticosteroid therapy. In contrast, insulin levels during the IVGTTs were lower in the rats with successful transplants than in the control rats with or without steroids; however, insulin release during the IVGTTs was rapid in all animals, both with successful transplants and controls. These observations demonstrate that islet tissue implanted in the peritoneal cavities of diabetic rats receiving immunosuppressive chronic corticosteroid therapy can respond with a rapid and sufficient release of insulin to reverse diabetes as documented by normal glucose levels under stimulated and nonstimulated conditions.

Animals↗
PubMed1975

Studies of the rate of regression of the glomerular lesions in diabetic rats treated with pancreatic islet transplantation.

Diabetes was induced in Lewis rats with streptozotocin. Six to eight months later glomeruli showed mesangial thickening: IgG, IgM and C3 were seen in large quantities in the mesangium by immunofluorescent microscopy. Ten animals then had successful pancreatic transplantation resulting in normal glucose and insulin levels within one to three weeks. Biopsies obtained within the first two weeks following transplantation demonstrated a significant reduction in mesangial thickening and in mesangial staining for IgG, IgM and C3. Three to four weeks after transplantation C3 staining was no longer detected. A gradual reduction in mesangial IgG and IgM localization continued so that by nine weeks following islet transplantation only minimal staining for immunoglobulins was present. Although mesangial thickening was reduced, this abnormality could still be detected in most animals six to nine weeks after transplantation. Three rats showed improvement in glomerular morphology within two weeks despite persistent hyperglycemia. These rats had normal insulin levels at this time. Islet transplantation in inbred diabetic rats effectively returns glucose and insulin levels to normal and results in rapid regression of the light microscopic and immunopathologic glomerular lesions. These studies support the concept of reversible mesangial dysfunction in diabetic rats.

Animals↗
PubMed1975

Plasma insulin and glucose levels in diabetic rats prior to and following islet transplantation.

Transplantation of islets of Langerhans into the peritoneal cavity of diabetic rats returns the recipients to a normal metabolic state and provides the capability to respond to a glucose stimulation with a rapid release of insulin. Of the two groups of transplanted diabetic rats studied, each had normal nonfasting glucose levels and normal glucose profiles following intravenous glucose tolerance tests. However, one group had significantly lower insulin levels than normal controls both under nonfasting conditions and 4 minutes following glucose stimulation. The other group demonstrated insulin levels greater than those of the normal controls when drawn under nonfasting conditions and essentially identical to the levels of the normal controls following a glucose load. Each transplanted group responded similarly to normal rats with a rapid release of insulin following glucose administration.

Animals↗
PubMed1974

Renal transplantation in diabetes mellitus in rats.

Immunoglobulins and complement are deposited in the glomerular mesangium of rats with progressive glomerulosclerosis secondary to chemically induced diabetes mellitus. Isotransplantation of a kidney from a rat diabetic for 6 mo into a normal recipient results within 2 mo in the disappearance of IgG, IgM, and beta(1)C from the mesangium and arrest or reversal of the light microscopic glomerular lesions. Kidneys isotransplanted from normal donors into diabetic rats developed mesangial matrix thickening and deposition of IgG, IgM) and beta(1)C in the mesangium. No glomerular changes occur upon transplantation of a normal kidney into a normal rat. These findings indicate that diabetic glomerular changes in the rat are reversible and are secondary to the diabetic state rather than to the inducing agent.

Animals↗
PubMed1974

Prolonged survival of renal allografts in outbred rabbits treated with donor specific F(ab')2 alloantibody.

Renal allograft survival was prolonged in rabbits, a species in which antibody mediated hyperacute rejection can occur, by administering large quantities of donor specific F(ab')(2) alloantibody. In 13 control animals, onset of uremia with histological evidence of rejection occurred at a mean of 6.0 days. Eight of eight rabbits actively immunized and seven of nine rabbits passively immunized with unmodified donor specific IgG alloantibody hyperacutely rejected an allografted kidney. Four rabbits treated with non-specific F(ab')(2) for one week acutely rejected an allografted kidney at a mean of 6.2 days. In 12 recipient rabbits receiving 100-500 mg of donor specific F(ab')(2) alloantibody for a mean of 8.5 days, onset of uremia was delayed to a mean of 14.5 days following transplantation. Recipients were selected so that the donor specific F(ab')(2) alloantibody employed had no activity against recipient antigens. This selection maximized the antigenic difference between the donor and recipient, and also assured us that the donor specific F(ab')(2) was directed against antigens present in the donor but absent in the recipient. Passive administration of donor specific F(ab')(2) allowed antibody mediated suppression of a specific immune response to occur without risk of hyperacute rejection. However, the onset of rejection could not be delayed indefinitely by this treatment. The experimental conditions employed and the difficulties encountered closely resemble those which will occur for clinical utilization of passive immunological enhancement.

Animals↗
PubMed1973

The glomerular mesangium. 3. Acute immune mesangial injury: a new model of glomerulonephritis.

A mechanism of immune glomerular injury is described based on the fixation of antibody (Ab) to an antigen (Ag) that has localized in the glomerular mesangium. Rabbits were given, intravenously (i.v.), aggregated human IgG (AHIgG) or albumin (AHSA) and 10 h later, when the Ag by immunofluorescent microscopy was present in the mesangium, a kidney was removed and transplanted into a normal rabbit. The recipient then received, i.v., rabbit anti-HIgG or anti-HSA. Within minutes of Ab infusion, glomeruli of the donor kidney had polymorphonuclear (PMN) infiltration that over the next few hours became marked and was associated with glomerular cell swelling. At 24 h a decrease in PMN's and early mesangial proliferation was seen. By 3 days there was marked mesangial hypercellularity and increased mesangial matrix. Within minutes after Ab administration rabbit IgG, C3, and fibrin were seen in the glomerular mesangium. There was a fall in complement titer by 1 min after Ab infusion that was due to complement consumption by the donor kidney. Complement then returned to normal levels by 48 h. Significant glomerular injury did not occur (a) in the recipient's own kidney, (b) from Ag administration and transplantation without recipient Ab administration, or (c) from transplantation and Ab administration without prior Ag administration. These studies demonstrated that Ag localized in the glomerular mesangium can react with circulating Ab and complement resulting in severe glomerular injury.

Animals↗