Implantation Site–Dependent Dysfunction of Transplanted Pancreatic Islets

Lau, Joey; Mattsson, Göran; Carlsson, Carina; Nyqvist, Daniel; Köhler, Martin; Berggren, Per Olof; Jansson, Leif; Carlsson, Per

doi:10.2337/db06-1258

Cited by 72 publications

(64 citation statements)

References 33 publications

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“…This argues for the importance of finding an alternate nonhepatic site that will not interfere with full glucagon responses to hypoglycemia. Recently, additional metabolic defects in intrahepatically transplanted islets involving insulin synthesis, insulin secretion, and glucose oxidation have been reported (15). One study reported that ␣-cell responses to mild non-insulin-induced hypoglycemia (80 Ϯ 3 mg/dl) in dogs were subnormal (16).…”

Section: Discussionmentioning

confidence: 99%

Intrahepatic Glucose Flux as a Mechanism for Defective Intrahepatic Islet α-Cell Response to Hypoglycemia

et al. 2008

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OBJECTIVE— Glucagon responses to hypoglycemia from islets transplanted in the liver are defective. To determine whether this defect is related to intrahepatic glycogen, islets from inbred Lewis rats were transplanted into the hepatic sinus (H group), peritoneal cavity (P group), omentum (O group), and kidney capsule (K group) of recipient Lewis rats previously rendered diabetic with streptozotocin (STZ). RESEARCH DESIGN AND METHODS— Glucagon responses to hypoglycemia were obtained before and after transplantation under fed conditions and after fasting for 16 h and 48 h to deplete liver glycogen. RESULTS— Glucagon (area under the curve) responses to hypoglycemia in the H group (8,839 ± 1,988 pg/ml per 90 min) were significantly less than in normal rats (40,777 ± 8,192; P < 0.01). Fasting significantly decreased hepatic glycogen levels. Glucagon responses in the H group were significantly larger after fasting (fed 8,839 ± 1,988 vs. 16-h fasting 24,715 ± 5,210 and 48-h fasting 29,639 ± 4,550; P < 0.01). Glucagon response in the H group decreased after refeeding (48-h fasting 29,639 ± 4,550 vs. refed 10,276 ± 2,750; P < 0.01). There was no difference in glucagon response to hypoglycemia between the H and the normal control group after fasting for 48 h (H 29,639 ± 4,550 vs. control 37,632 ± 5,335; P = NS). No intragroup differences were observed in the P, O, and K groups, or normal control and STZ groups, when comparing fed or fasting states. CONCLUSIONS— These data suggest that defective glucagon responses to hypoglycemia by intrahepatic islet α-cells is due to dominance of a suppressive signal caused by increased glucose flux and glucose levels within the liver secondary to increased glycogenolysis caused by systemic hypoglycemia.

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Section: Discussionmentioning

confidence: 99%

Intrahepatic Glucose Flux as a Mechanism for Defective Intrahepatic Islet α-Cell Response to Hypoglycemia

et al. 2008

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“…The main non-endocrine component consists of duct cells [2,10] that might be considered as potential inducers and active participants in local inflammatory and immune reactions, given their expression of tissue factor [11], CD40 [12] and MHC-II antigens [13], and their production of cytokines and nitric oxide [14,15]. The duct cell contamination of human islet cell grafts could make them particularly vulnerable after injection into the portal vein, as this exposes the graft directly to blood-and liver-mediated reactions [3,11,[16][17][18].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Human islet cell implants in a nude rat model of diabetes survive better in omentum than in liver with a positive influence of beta cell number and purity

Jacobs‐Tulleneers‐Thevissen

Bartholomeus

Suenens

et al. 2010

Diabetologia

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Aims/hypothesis Intraportal human islet cell grafts do not consistently and sustainably induce insulin-independency in type 1 diabetic patients. The reasons for losses in donor cells are difficult to assess in patients. This study in streptozotocin-diabetic nude rats examines whether outcome is better in an extra-hepatic site such as omentum. Methods Intraportal and omental implants of human islet cell grafts with the same beta cell number were followed for function and cellular composition over 5 weeks. Their outcome was also compared with that of rat islet cell grafts with similar beta cell numbers but higher purity. Results While all intraportal recipients of rat islet cell grafts were normoglycaemic until post-transplant (PT) week 5, none was with human islet cell grafts; loss of human implants was associated with early infiltration of natural killer and CD45R-positive cells. Human islet cell implants in omentum achieved plasma human C-peptide positivity and normoglycaemia in, respectively, nine of 13 and five of 13 recipients until PT week 5; failures were not associated with inflammatory infiltrates but with lower beta cell numbers and purity of the grafts. Observations in human and rat islet cell implants in the omentum suggest that a delayed revascularisation can interfere with their metabolic outcome. Irrespective of normalisation, human omental implants presented beta cell aggregates adjacent to alpha cells and duct cells. Conclusions/interpretation In nude rats, human islet cell implants survive better in omentum than in liver, with positive influences of the number and purity of implanted beta cells. These observations can guide studies in patients.

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“…Currently, extensive islet cell significant after correction. death occurs in the immediate posttransplantation period (2,3,10,11), as well as a functional impairment in the RESULTS surviving endocrine cells (16,21).Our previous studies have shown that heterotopically implanted islets become The YC-3.0 islets retained their EYFP expression and remained at least 6 months after intrapancreatic transpoorly revascularized. Similar results were obtained irrespective of whether the islets were implanted beneath plantation (two out of two animals).…”

Section: Introductionmentioning

confidence: 99%

“…Remaining native pancreatic islets do not seem to interfere with the ulated expansion of the remnant endothelial cell pool or strategies to overcome the barrier for ingrowth of host formation of new blood vessels in islet graft; the vascular density in the grafts is similar to that obtained in vessels into the endocrine tissue are clearly warranted. islets implanted to cure diabetic recipients (22 pression for key enzymes in β-cell metabolism (16).…”

Section: Introductionmentioning

confidence: 99%

Beneficial Role of Pancreatic Microenvironment for Angiogenesis in Transplanted Pancreatic Islets

et al. 2009

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Pancreatic islets implanted heterotopically (i.e., into the kidney, spleen, or liver) become poorly revascularized following transplantation. We hypothesized that islets implanted into the pancreas would become better revascularized. Islets isolated from transgenic mice expressing enhanced yellow fluorescent protein (EYFP) in all somatic cells were cultured before they were implanted into the pancreas or beneath the renal capsule of athymic mice. Vascular density was evaluated in histological sections 1 month posttransplantation. EYFP was used as reporter for the transgene to identify the transplanted islets. Islet endothelial cells were visualized by staining with the lectin Bandeiraea simplicifolia (BS-1). Capillary numbers in intrapancreatically implanted islets were only slightly lower than those counted in endogenous islets, whereas islets implanted beneath the renal capsule had a markedly lower vascular density. In order to determine if this high graft vascular density at the intrapancreatic site reflected expansion of remnant donor endothelial cells or increased ingrowth of blood vessels from the host, also islets from Tie2-green fluorescent protein (GFP) mice (i.e., islets with fluorescent endothelial cells) were transplanted into the pancreas or beneath the renal capsule of athymic mice. These islet grafts revealed that the new vascular structures formed in the islet grafts contained very few GFP-positive cells, and thus mainly were of recipient origin. The reason(s) for the much better ingrowth of blood vessels at the intrapancreatic site merits further studies, because this may help us form strategies to overcome the barrier for ingrowth of host vessels also into islets in heterotopic implantation sites.

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Implantation Site–Dependent Dysfunction of Transplanted Pancreatic Islets

Cited by 72 publications

References 33 publications

Intrahepatic Glucose Flux as a Mechanism for Defective Intrahepatic Islet α-Cell Response to Hypoglycemia

Intrahepatic Glucose Flux as a Mechanism for Defective Intrahepatic Islet α-Cell Response to Hypoglycemia

Human islet cell implants in a nude rat model of diabetes survive better in omentum than in liver with a positive influence of beta cell number and purity

Beneficial Role of Pancreatic Microenvironment for Angiogenesis in Transplanted Pancreatic Islets

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