A comparison between islet transplantation and parenteral insulin in the control of diabetes and prevention of renal complications in mice

Mandel, T. E.; Carter, Wendy M.; Koulmanda, Maria; Martin, F. I. R.; Campbell, D. Grant; McMillan, N. J.

doi:10.1016/0026-0495(83)90006-9

Cited by 11 publications

(4 citation statements)

References 15 publications

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“…It is tempting to speculate, therefore, that resistance of GSK-3 phosphorylation by insulin in cardiomyocytes may contribute not only to impaired glycogen synthesis but also to increased rates of apoptosis and reduced protein synthesis, leading to the development of diabetic cardiomyopathy. Islet transplantation has been shown to improve metabolic abnormalities and slow the progression of chronic complications in experimental diabetes (17)(18)(19)(20)(21)(22)57,58). Metabolic alterations and contractile dysfunction are also reportedly reversed in the myocardium of islet-transplanted diabetic animals (21).…”

Section: Discussionmentioning

confidence: 89%

“…Moreover, excessive or inappropriate insulin administration has been suggested to favor the risk of cardiovascular disease, probably through an accelerated progression of coronarosclerosis (14 -16). By contrast, diabetes therapy with islet transplantation may have beneficial effects on the progression of diabetic vascular complications (17)(18)(19)(20) and is associated with improved contractile performance of the cardiac muscle (21). It is possible that the reported beneficial effects of islet transplantation on cardiac function involve correction of altered signaling mechanisms in the cardiac tissue.…”

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confidence: 82%

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Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart

et al. 2001

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The insulin signaling cascade was investigated in rat myocardium in vivo in the presence of streptozocin (STZ)-induced diabetes and after diabetes treatment by islet transplantation under the kidney capsule. The levels of insulin-stimulated tyrosine phosphorylation of the insulin receptor ␤-subunit, insulin receptor substrate (IRS)-2, and p52Shc were increased in diabetic compared with control heart, whereas tyrosine phosphorylation of IRS-1 was unchanged. The amount of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and the level of PI 3-kinase activity associated with IRS-2 were also elevated in diabetes, whereas no changes in IRS-1-associated PI 3-kinase were observed. Insulin-induced phosphorylation of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. In contrast with Akt phosphorylation, insulin-induced phosphorylation of glycogen synthase kinase (GSK)-3, a major cellular substrate of Akt, was markedly reduced in diabetes. In islet-transplanted rats, the majority of the alterations in insulin-signaling proteins found in diabetic rats were normalized, but insulin stimulation of IRS-2 tyrosine phosphorylation and association with PI 3-kinase was blunted. In conclusion, in the diabetic heart, 1) IRS-1, IRS-2, and p52Shc are differently altered, 2) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated, and 3) the increased activity of proximal-signaling proteins (i.e., IRS-2 and PI 3-kinase) is not propagated distally to GSK-3. Islet transplantation under the kidney capsule is a potentially effective therapy to correct several diabetes-induced abnormalities of insulin signaling in cardiac muscle but does not restore the responsiveness of all signaling reactions to insulin. Diabetes 50:2709 -2720, 2001

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Section: Discussionmentioning

confidence: 89%

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confidence: 82%

Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart

et al. 2001

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“…In animal models of experimentally-induced diabetes, islet transplantation has been able to restore good metabolic control (Keymeulen et al, 1992), although most studies have been undertaken only for short periods after transplantation and have used only fasting blood glucose to monitor metabolic control. At variance with pancreas transplantation (Ramsay et al, 1988;Bilous et al, 1989;Navamo et al, 1990), there are few data available on the effects of islet transplantation on chronic diabetic complications (Steffes et al, 1980;Hoffman et al, 1983;Orloff et aZ., 1987) and in particular on diabetic CNS abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Peripheral, but not Central, Nervous System Abnormalities are Reversed by Pancreatic Islet Transplantation in Diabetic Lewis Rats

Sensi

Gregorio²,

Pozzessere

et al. 1996

Eur J of Neuroscience

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Neuroelectrophysiological recordings represent a non-invasive and reproducible method of detecting central and peripheral nervous system alterations in diabetes mellitus. In order to evaluate whether the normalization of metabolic control obtained by pancreatic islet transplantation could reverse diabetic neuroelectrophysiological alterations, or prevent further deterioration, we used an experimental model in which pancreatic islets (n = 1200) were injected into the portal vein of inbred Lewis rats (used as islet donors as well as recipients). Islets were injected 4 months after diabetes induction, since previous work had shown functional but not morphological damage at the nervous tissue level at this stage of the disease. Visual (V), brainstem auditory (BA) and somatosensory (S) evoked potentials (EPs) were measured in streptozotocin-induced, islet-recipient diabetic rats (n = 7), streptozotocin-induced diabetic rats (n = 16) and non-diabetic control rats (n = 12). Metabolic parameters and electrophysiological recordings were evaluated before diabetes induction, before transplantation and 4 months later. After transplantation, glycaemic levels returned to normal values within 1 week and remained so until the end of the study, as confirmed by a normal oral glucose tolerance test and by an increase in body weight. Electrophysiological recordings were altered in diabetic animals before transplantation. Four months after transplantation EP recordings improved, with a detectable gradient from the peripheral to the central structures. SEPs were significantly improved in the peripheral tarsus-L6 tract and the L6-cortex tract (P < 0.005 and P < 0.01 versus diabetic rats) and were ameliorated without achieving statistical significance in the central L6-cortex tract. BAEP latency values tended to improve in transplanted rats, but the differences versus non-transplanted diabetic animals failed to reach significance. VEP values remained clearly pathological and even deteriorated after transplantation. These results show that normalization of metabolic control by pancreatic islet transplantation can reverse some of the already established neuroelectrophysiological alterations at the peripheral nervous system level, but does not affect other alterations at the central nervous system level.

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“…Each diabetic mouse was grafted with islets derived from one-half of a fetal pancreas (except in a study in which 2 half pancreases of tissue were transplanted to the spleen [21,22]), since one of the key points of our studies was to determine whether tissue from one donor was sufficient to produce euglycemia in each recipient. Animals were anesthetized with methoxyflurane (Penthrane, Abbott Labs.…”

Section: Transplantationmentioning

confidence: 99%

Transplantation of organ‐cultured fetal pancreas: Experimental studies and potential clinical application in diabetes mellitus

Mandel

1984

World j. surg.

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Transplantation of organ-cultured fetal islets of Langerhans may be one way of overcoming the dual difficulties of finding a suitable source of tissue and controlling graft rejection. Experiments in mice have clearly shown that fetal pancreas is an excellent source of islets. Tissue from one donor can be used to treat one or more recipients and provides excellent control of drug-induced diabetes, including prevention of diabetic renal microangiopathy. The fetal islets display selective survival in vitro and organ culture can be used to obtain large amounts of tissue for transplantation. In addition, growth in "normoglycemic" media results in functional maturation of the fetal tissue.Culture conditions can be modified to eliminate from the putative graft immunogenic "passenger leukocytes," the cells responsible for initiating graft rejection. Such immunogenic cell-depleted grafts can be transplanted across histocompatibility barriers without the need for recipient immunosuppression.Fetal human pancreas shares n~any properties in common with fetal mouse pancreas. Continuing growth and differentiation occur in vitro and following xenotransplantation into athymic mice. However, fetal human pancreas is frequently damaged by ischemia before it can be used, and also appears to be more susceptible to oxygen toxicity than is fetal mouse pancreas. Nevertheless, when fresh human tissue is available, it may be a suitable source of islets for transplantation in type I diabetics.

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A comparison between islet transplantation and parenteral insulin in the control of diabetes and prevention of renal complications in mice

Cited by 11 publications

References 15 publications

Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart

Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart

Peripheral, but not Central, Nervous System Abnormalities are Reversed by Pancreatic Islet Transplantation in Diabetic Lewis Rats

Transplantation of organ‐cultured fetal pancreas: Experimental studies and potential clinical application in diabetes mellitus

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