Islet cell transplantation in diabetic dogs: Studies of graft function and storage

Alderson, Derek; Walsh, T. N.; Farndon, John

doi:10.1002/bjs.1800711007

Cited by 22 publications

(16 citation statements)

References 17 publications

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“…With the assumption that the islets are spherical, the calculated volume of islet tissue needed to induce normoglycemia was 0.0027-0.0045 ml/kg in the former group and >0.0045 ml/kg in the latter. Although the islet mass was different in the two groups, K values did not differ, confirming previous observations that K is not a sensitive index of functioning islet mass (15).…”

Section: Discussionsupporting

confidence: 90%

Critical Mass of Purified Islets That Induce Normoglycemia After Implantation Into Dogs

Warnock

Rajotte²

1988

Diabetes

108

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Twenty grafts of highly purified islets of Langerhans (mean +/- SE vol 0.98 +/- 0.3 ml, islet diam 122 +/- 5 micron) were autoimplanted into the spleen or liver of totally pancreatectomized dogs. Portal venous pressure did not change significantly. Incremental doses of islets of 1000-3000 (n = 3), 3000-4000 (n = 6), 4000-5000 (n = 5), 5000-6000 (n = 3), and 6000-8000 (n = 3) per kilogram body weight resulted in corresponding fasting plasma glucose (PG) of 258 +/- 18, 163 +/- 13, 158 +/- 17, 138 +/- 15, and 108 +/- 6 mg/dl. In 3 apancreatic control dogs, PG was 338 +/- 9 mg/dl. One (normoglycemic) dog died of wound complications, and follow-up PG at 1 mo was 89 +/- 5 mg/dl in 6 of 10 dogs that received 3000-5000 islets/kg and 91 +/- 6 mg/dl in all 6 that received greater than 5000 islets/kg. K values 1 mo after surgery during glucose tolerance tests were 1.8 +/- 0.3 for 6 spleen dogs and 1.6 +/- 0.3 for 6 liver dogs. Six months after splenic implantation, PG was 75 +/- 4 mg/dl and rose to greater than 350 mg/dl after splenectomy. These data define the critical number of purified dog islets of known size that is necessary to induce prolonged normoglycemia. Sufficient pure islets can be collected from 1 dog pancreas to correct diabetes after autoimplantation into the liver or spleen.

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Section: Discussionsupporting

confidence: 90%

Critical Mass of Purified Islets That Induce Normoglycemia After Implantation Into Dogs

Warnock

Rajotte²

1988

Diabetes

108

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“…Transplantation of a less than optimal mass of islet tissue might be expected to result in reduced secretion of insulin and other hormones in response to glucose or other stimuli. There is abundant evidence that this is the case in models of islet autotransplantation in pancreatectomized large animals, despite the fact that fasting normoglycaemia can be reproduced [4][5][6]. Furthermore, recent studies in the dog [6] and monkey [4] have shown that many autografts will fail between 4 and 18months after transplantation, and that the rapidity of failure is predicted by the insulin secretory capacity at 6 weeks [4].…”

Section: Discussionmentioning

confidence: 99%

The effect of hyperglycaemia on pancreatic islets transplanted into rats beneath the kidney capsule

et al. 1989

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Summary. The effect of hyperglycaemia on islet transplantation in the rat has been examined in two ways, using syngeneic transplantation of 400 islets to the kidney capsule and subsequent measurement of kidney insulin content as a measurement of B-cell survival. Firstly, islets were transplanted into either diabetic or normal rats, then 6 months later the composite kidney/islet graft was transplanted into a normal rat. The insulin content was measured after a further 6 months and was found to be significantly reduced in islets exposed to hyperglycaemia in the primary recipient. These findings are interpreted as showing that long-term exposure of islets to hyperglycaemia results in B-cell loss. In the second experiment 400 islets were transplanted into either a long-term (6 months) diabetic or a normal rat. Two weeks later the composite kidney/islet graft was transplanted into a normal rat. The insulin content was measured after a further 6 months and no significant difference was found, whether the primary recipient was diabetic or not. These results are interpreted as showing that islet graft implantation is not impaired in longterm diabetic rats.Key words: Hyperglycaemia, islet transplantation, diabetes, rat.Persistent hyperglycaemia has long been suspected of having a detrimental effect on pancreatic islet function [11. The influence of persistent hyperglycaemia on pancreatic islet transplantation has not been investigated in detail, although it could be deleterious in at least two ways. The first is a direct effect on the transplanted islets themselves which could be important after transplantation. The second is the effect of long-term hyperglycaemia on the recipient which might impair successful implantation of the transplanted islets.We have developed a quantitative model of islet transplantation in the rat [2] and have used an adaptation of this model to investigate both of the above possibilities in the rodent. By transplantation of a mass of islets insufficient to reverse diabetes we have previously shown that short-term exposure of islets to hyperglycaemia did not result in impaired implantation or loss of tissue mass [21. However, the possibility remains that long-term exposure to hyperglycaemia results in exhaustion with eventual loss of the transplanted insulin secreting tissue and this possibility was in no way excluded by our previous study [2]. We have also adapted this model to determine whether the implantation of islets was impaired in animals exposed to hyperglycaemia for prolonged periods prior to transplantation. Materials and methods Animals and induction of diabetesDark Agouti (DA) rats (bred in the Biomedical Services Unit, John Radcliffe Hospital) were used as both donors and recipients. One sibling of paired littermate DA rats was made diabetic by i.v. injection of streptozotocin 65 mg/kg, diabetes being confirmed by a repeated serum glucose of > 22 mmol/1 2 weeks later, Isolation of pancreatic isletsPancreatic islets were isolated from 3 donors by an intraductal collagenase technique...

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“…In addition, the number of islets needed to reverse surgical diabetes in dogs was similar when transplanted into the liver or spleen [22]. Intrasplenic pancreatic islet grafts demonstrated functional improvement with time [26]. There was a case report of one patient with juvenile diabetes and subsequent renal failure who was successfully treated with simultaneous kidney and intrasplenic pancreatic islet allotransplants.…”

Section: The Spleenmentioning

confidence: 98%

Islet Transplantation: Alternative Sites

Rajab

2010

Curr Diab Rep

102

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The portal vein is currently the site of choice for clinical islet transplantation, even though it is far from being an ideal site. Low oxygen tension and the induction of an inflammatory response impair islet implantation and lead to significant early loss. Even if enough islets survive the early implantation period to render insulin independence, few patients maintain it. Therefore, the search for an ideal site for islet transplantation continues. Experimentally, islets have been transplanted into the portal vein, kidney subcapsule, spleen, pancreas, peritoneum, omentum, gastrointestinal wall, testis, thymus, bone marrow, anterior chamber of the eye, cerebral ventricles, and subcutaneous and intramuscular spaces. Some of these sites are suitable for gathering scientific data, whereas others have potential clinical application. Varying degrees of success have been reported with the use of all these transplant sites in an experimental setting. However, the optimal transplant site remains to be finally established.

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Islet cell transplantation in diabetic dogs: Studies of graft function and storage

Cited by 22 publications

References 17 publications

Critical Mass of Purified Islets That Induce Normoglycemia After Implantation Into Dogs

Critical Mass of Purified Islets That Induce Normoglycemia After Implantation Into Dogs

The effect of hyperglycaemia on pancreatic islets transplanted into rats beneath the kidney capsule

Islet Transplantation: Alternative Sites

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