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Per-Ola Carlsson

Publications and source records attributed to Per-Ola Carlsson.

16 recordsLinked to original sources
PubMed2003

[Severe vascular dysfunction shown in transplanted islets].

Despite recent advances in clinical islet transplantation, a surprisingly large number of islets (approximately 1 million) are still required to obtain insulin independence in type 1 diabetes. The reasons for this are obscure and likely multifactorial. One explanation may be disturbances in engraftment of the transplanted islets, i.e. the adaptation of the islet transplant to its new surroundings with regard to e.g. revascularization and blood perfusion. Endogenous islets have a dense glomerular-like angioarchitecture. Transplantation of isolated islets causes a disruption of their vascular connections, making the islets dependent on the formation of new blood vessels for optimal function. Evidence from experimental islet transplantation indicates an insufficient revascularization of transplanted islets with subsequent chronically decreased blood perfusion and oxygen tension, which has metabolic consequences within the tissue.

Animals↗
PubMed2003

Impaired revascularization of transplanted mouse pancreatic islets is chronic and glucose-independent.

BACKGROUND: Pancreatic islets are avascular immediately after transplantation and depend on revascularization. Recently, the authors found decreased vascular density in mouse islets 1 month after implantation into nondiabetic recipients. This study investigated possible differences in revascularization between islets implanted into nondiabetic and diabetic recipients, and also evaluated changes in vascular density up to 6 months posttransplantation. METHODS: Islets were syngenically transplanted beneath the renal capsule of normoglycemic or alloxan-diabetic C57BL/6 mice. One to 6 months later, the animals were killed and the grafts removed. Histologic slides were prepared and stained with Bandeiraea simplicifolia. RESULTS: The vascular density in all transplanted islets was decreased compared with native islets. There were no differences in the islet graft vascular density between nondiabetic and diabetic animals. No improvement over time occurred. CONCLUSIONS: The vascular density is decreased in islets implanted to cure diabetic recipients. No improvement occurs in transplanted islets after 1 month posttransplantation.

Animals↗
PubMed2003

Changes in intracellular sodium, potassium, and calcium concentrations in transplanted mouse pancreatic islets.

BACKGROUND: Our previous studies have suggested a chronically low oxygen tension in transplanted pancreatic islets. The present study tested the hypothesis that this may be coupled to changes in intracellular concentrations of crucial ions within the transplanted islet cells and, thus, their function. METHODS: X-ray microanalysis was used for studies of native islet cells and islet grafts residing for 1 day or 1 month in nondiabetic or diabetic recipients. RESULTS: Markedly increased sodium concentrations and decreased potassium concentrations were recorded in all transplanted islet cells, irrespective of whether the grafts had been implanted into nondiabetic or diabetic recipients or whether they were investigated 1 day or 1 month after transplantation. The calcium concentration in 1-day-old islet grafts was similar to that in native islet cells, but it decreased markedly between 1 day and 1 month after transplantation. Again this was seen in both nondiabetic and diabetic recipients. CONCLUSIONS: Most probably, the disturbances in graft sodium and potassium concentrations reflect ATP depletion and inhibition of the Na/K-ATPase in the plasma membrane as a result of impeded oxygen supply. The decreased calcium concentrations developing over time in the transplanted islet cells might be potentially detrimental, because calcium plays a fundamental role in the control of a variety of cellular functions, including insulin secretion, in beta cells.

Animals↗
PubMed2003

Caerulein-induced pancreatitis and islet blood flow in anesthetized rats.

BACKGROUND: Microcirculatory mechanisms have been suggested to be involved in the development of acute pancreatitis. Islet blood flow has not previously been studied in this disease. The present study aimed to investigate the effects of caerulein-induced pancreatitis on pancreatic blood perfusion, especially islet blood flow. MATERIALS AND METHODS: Continuous 4 h caerulein-infusion was used to induce mild, edemateous pancreatitis in anesthetized Sprague-Dawley rats. Some animals were then given an additional 2 h infusion of saline. Thus, at 4 or 6 h after initiating caerulein infusion the blood flow to the pancreas, pancreatic islets, and intestines was measured with a microsphere technique. RESULTS: All infused animals demonstrated an edemateous pancreatitis, without hemorrhages. Both total pancreatic and islet blood flow was increased after the 4-h infusion. However, the increase was less pronounced in the islets. After an additional 2 h with only saline infused, the blood flow values in rats initially infused with caerulein were lower than at 4 h, but total pancreatic blood was still higher than in control rats. No effects on intestinal blood flow values were seen. CONCLUSIONS: Pancreatic islet blood flow in rats with mild edematous pancreatitis is increased, but not to the same extent as that in the whole pancreas.

Amylases↗
PubMed2002

pH is decreased in transplanted rat pancreatic islets.

Recent studies of transplanted pancreatic islets have indicated incomplete revascularization. We investigated the pH, in relation to oxygen tension (Po(2)), in endogenous islets and islets syngeneically transplanted to the renal subcapsular site of nondiabetic and streptozotocin-diabetic recipients. Tissue pH and Po(2) were measured using microelectrodes. In the endogenous islets, tissue pH was similar to that in arterial blood. In the transplanted islets, tissue pH was 0.11-0.15 pH units lower. No differences in islet graft pH were seen between nondiabetic and diabetic animals, and none if the islet grafts were investigated 1 day or 1 mo posttransplantation. The Po(2) in the endogenous islets was approximately 35 mmHg. Transplanted islets had a markedly lower tissue Po(2) both 1 day and 1 mo after transplantation. A negative correlation between the tissue Po(2) and the hydrogen ion concentration was seen in the 1-mo-old islet transplants in diabetic animals. In conclusion, decreased Po(2) in transplanted islets is associated with a decreased tissue pH, suggesting a shift toward more anaerobic glucose metabolism after transplantation.

Animals↗
PubMed2002

Oxygen tension in isolated transplanted rat islets and in islets of rat whole-pancreas transplants.

Despite similar immunosuppressive protocols having been applied, the success rate of pancreatic islet transplantation has been much lower than that of whole-pancreas transplantation. We compared the oxygen tension in syngeneically transplanted isolated rat islets and islets of syngeneic rat whole-pancreatic grafts, with native islets, using Clark-type microelectrodes. An oxygen tension of approximately 40 mmHg was recorded in both native islets and in islets of the whole-pancreas graft. Isolated islets transplanted under the renal capsule had a markedly lower oxygen tension ( approximately 6 mmHg). The exocrine parenchyma of the native and of the transplanted pancreatic gland had an oxygen tension of approximately 30 mmHg. The lower oxygen tension in transplanted isolated islets may be one explanation for the more frequent failures of transplanted islets compared with the outcome when the whole pancreatic gland is transplanted.

Animals↗
PubMed2002

Microdialysis measurements demonstrate a shift to nonoxidative glucose metabolism in rat pancreatic islets transplanted beneath the renal capsule.

BACKGROUND: We aimed to use microdialysis to assess, for the first time, the internal milieu of pancreatic islet grafts. METHODS: One month after transplantation, microdialysis probes were inserted into syngeneic rat islet transplants (500-700 islets) placed beneath the renal capsule of nondiabetic or diabetic recipients. The number of grafted islets was purposely chosen not to cure the diabetic recipients. RESULTS: During an intravenous glucose challenge, insulin concentrations increased in parallel in serum and in the graft interstitium of nondiabetic animals suggesting the existence of a functionally well-established vascularization. Diabetic recipients had both a lower serum and dialysate insulin concentration than normoglycemic animals. The lactate/pyruvate ratios were determined in the dialysates as a measure of the degree of anaerobic metabolism in the islet grafts. Lactate/pyruvate ratios were between 50 and 100 in grafts of both nondiabetic and diabetic recipients, and they almost doubled in response to the intravenous glucose challenge in the grafts of nondiabetic recipients. In comparison, lactate/pyruvate ratios were approximately 12 in the medium of cultured islets incubated at low glucose (5.6 mmol/L) or high glucose (16.7 mmol/L) concentrations. CONCLUSIONS: The microdialysis technique has proven to be a valuable tool for evaluating the internal environment of islet transplants. Moreover, the high lactate/pyruvate ratio suggests that islet grafts have an increased anaerobic glucose metabolism.

Animals↗
PubMed2002

Glucose-induced islet blood flow increase in rats: interaction between nervous and metabolic mediators.

This study investigated the mechanisms for glucose-induced islet blood flow increase in rats. The effects of adenosine, adenosine receptor antagonists, and vagotomy on islet blood flow were evaluated with a microsphere technique. Vagotomy prevented the islet blood flow increase expected 3, 10, and 20 min after injection of glucose, whereas theophylline (a nonspecific adenosine receptor antagonist) prevented the islet blood flow increase from occurring 10 and 20 min after glucose administration. Administration of selective adenosine receptor antagonists suggested that the response to theophylline was mediated by A1 receptors. Exogenous administration of adenosine did not affect islet blood flow, but local accumulation of adenosine, induced by the adenosine uptake inhibitor dipyridamole, caused a doubling of islet blood flow. In conclusion, the increased islet blood flow seen 3 min after induction of hyperglycemia is caused by the vagal nerve, whereas the increase in islet blood perfusion seen at 10 and 20 min after glucose administration is caused by both the vagal nerve and adenosine.

Adenosine↗
PubMed2002

Histological markers for endothelial cells in endogenous and transplanted rodent pancreatic islets.

BACKGROUND/AIMS: To obtain a selective marker to identify endothelial cells is difficult, due to the heterogeneity of these cells. Most described markers perform well in some applications, but fail in others. The aim of this study was to identify a selective and specific marker for rodent microvascular endothelial cells, especially for use in studies on the vascular system of pancreatic islets. METHODS: A biotin-labelled form of the lectin Bandeiraea or Griffonia simplicifolia in combination with a streptAB-Complex with alkaline phosphatase was used to stain endothelium in paraffin-embedded tissue sections from C57BL/6 mice, Sprague-Dawley or Wistar-Furth rats. RESULTS: We were consistently able to selectively stain microvascular endothelial cells in lungs, small intestines, white and brown adipose tissue, pancreas and islets of Langerhans with the lectin Bandeiraea simplicifolia. Furthermore, we were able to visualise the vasculature in syngenically transplanted islets of Langerhans in Wistar-Furth rats and C57BL/6 mice. Attempts to stain rodent endothelial cells with antibodies against CD34, CD31, CD200, Ox43, von Willebrand factor and the lectin Ulex europaeus were not uniformly successful. CONCLUSION: The lectin Bandeiraea simplicifolia is a versatile marker for rodent endothelial cells, and may be used to study revascularisation after transplantation of pancreatic islet in rodents.

Animals↗
PubMed2002

Low revascularization of experimentally transplanted human pancreatic islets.

Pancreatic islets are avascular immediately after transplantation. Although the islets are rapidly revascularized, it is uncertain whether the revascularization produces an adequate oxygenation of the transplanted islet tissue. We measured pO(2), blood flow and vascular density in mouse or human islets 1 month after transplantation to nude mice. Tissue pO(2) was measured with Clark microelectrodes. Blood perfusion was measured with laser-Doppler flow cytometry, whereas vascular density was determined in histological specimens stained for the lectin Bandeiraea simplicifolia (BS-1). Both the transplanted mouse and human islets had a pO(2) 15-20% of that in endogenous mouse islets. Moreover, the vascular density of the transplanted islets was decreased compared with that of endogenous mouse and human islets. Graft blood perfusion was approximately 50% of renal cortex blood flow. A negative correlation was found between donor age and blood perfusion of the human islet grafts. A similar correlation was seen between donor age and the total vascular density of these grafts. In conclusion, transplanted human islets had a markedly decreased vascular density and pO(2) compared with endogenous islets. This has potential implications for clinical islet transplantations, because poor vascular engraftment may significantly increase the number of islets needed to obtain insulin independence.

Adult↗
PubMed2002

Unaltered pancreatic islet blood perfusion in islet amyloid polypeptide-deficient mice.

OBJECTIVE: Several biological activities have been ascribed to islet amyloid polypeptide (IAPP). However, their physiological relevance remains unclear. Previous studies in rats with exogenous administration of IAPP suggest that the peptide may increase splanchnic vascular resistance and redistribute the blood flow within the pancreas to the islets. In this study, the use of IAPP-deficient mice allowed us to evaluate possible effects of the lack of IAPP on splanchnic blood perfusion and we could thereby circumvent the potentially pharmacological actions of exogenously administered IAPP. DESIGN: Regional splanchnic blood flow was measured after exogenous administration of IAPP and in IAPP-deficient mice. METHODS: Blood flow values were determined using a non-radioactive microsphere technique in anesthetized animals. RESULTS: No differences in whole pancreatic blood flow or islet blood flow could be detected in IAPP-deficient mice when compared with control mice; neither did IAPP deficiency affect the glucose-induced increase in islet blood flow. Duodenal, ileal and colonic blood flows were similar in IAPP-deficient and control mice. Exogenous administration of IAPP selectively increased islet blood flow in wild-type control mice. CONCLUSIONS: The present findings in the IAPP-deficient mice suggest that the vascular effects seen in the islets after exogenous administration of IAPP to normal mice reflect pharmacological, rather than physiological effects of the peptide. We conclude that the lack of endogenous IAPP within the splanchnic vascular system does not alter the blood perfusion of pancreatic islets or other splanchnic organs.

Amyloid↗
PubMed2002

Primary in vivo oscillations of metabolism in the pancreas.

The role of metabolism in the generation of plasma insulin oscillations was investigated by simultaneous in vivo recordings of oxygen tension (pO(2)) in the endocrine and exocrine pancreas and portal blood insulin concentrations in the anesthetized rat. At the start of the experiment, the blood glucose concentration of seven rats was 6.2 +/- 0.1 mmol/l and the arterial blood pressure was 116 +/- 5 mmHg. These values did not differ from those obtained at the end of the experiment. Islet pO(2) was measured by impaling superficially located islets with a miniaturized Clark electrode. The pO(2) measurements revealed slow (0.21 +/- 0.03 min(-1)) with superimposed rapid (3.1 +/- 0.3 min(-1)) oscillations. The average pO(2) was 39 +/- 5 mmHg. Simultaneous recordings of pO(2) in the exocrine pancreas were significantly lower (16 +/- 6 mmHg), but showed a slow and a rapid oscillatory activity with similar frequencies as seen in the endocrine pancreas. Corresponding measurements of portal insulin concentrations revealed insulin oscillations at a frequency of 0.22 +/- 0.02 min(-1). The results are the first in vivo recordings of an oscillatory islet parameter with a frequency corresponding to that of plasma insulin oscillations; they support a primary role of metabolic oscillations in the induction of plasma insulin oscillations.

Animals↗
PubMed2002

Decreased vascular density in mouse pancreatic islets after transplantation.

An adequate revascularization is crucial for islet survival and function after transplantation. Previous studies have suggested that islet revascularization is concluded within 14 days after transplantation. We investigated if the vascular density of transplanted islets and endogenous pancreatic islets differs. Cultured islets were syngeneically transplanted into the kidney, liver, or spleen of C57BL/6 mice. One month later, the graft-bearing organ was removed, and histological specimens were prepared and stained for endothelium with the lectin Bandeiraea simplicifolia. Pancreata from nontransplanted control animals were prepared similarly. Uniform staining of endothelium within the grafts and endogenous islets was obtained. The vascular density was markedly decreased in transplanted islets at all implantation sites, but preferentially in islets implanted into the spleen. The vascular density in the connective tissue surrounding the transplanted islets was very high compared with that of graft intra-islet capillaries. A much lower vascular density was detected in connective tissue surrounding implanted microspheres of a size similar to the islets, which suggests that the islets per se induced blood vessel formation in their vicinity. We conclude that the vascular density in revascularized transplanted islets is markedly decreased compared with endogenous islets. This has potential implications for islet graft metabolism and function.

Animals↗
PubMed2002

Multiple injections of coloured microspheres for islet blood flow measurements in anaesthetised rats: influence of microsphere size.

We investigated if coloured microspheres could be used for repeated measurements of pancreatic islet blood flow in rats. An initial injection of 1.0-1.5 x 10(5) microspheres (black colour), with a size of 10 or 15 microm, was made into the ascending aorta, while an arterial reference sample was collected from the femoral artery. Twelve min later, 1 ml of saline or 30% D-glucose was injected intravenously. Three min after this injection a second injection of 10- or 15-microm microspheres (green colour) was given. The animals were then killed, and the pancreas and adrenals were removed and samples (150-200 mg) were secured from the duodenum, ileum, colon, right kidney and liver. The microsphere contents were determined with the aid of a freeze-thawing technique and blood flow values were calculated. Our results suggest that 10-microm microspheres, but not 15-microm microspheres, provide reproducible islet and total pancreatic blood flow measurements when repeatedly injected. Values for the blood flow to the intestines, kidney and liver were less sensitive to the size of the microspheres. We conclude that repeated administration of 15-microm microspheres induces a high risk for erroneous islet and total pancreatic blood flow measurements, whereas two such measurements can be performed if 10-microm microspheres are used.

Animals↗
PubMed2002

Oxygen tension and blood flow in relation to revascularization in transplanted adult and fetal rat pancreatic islets.

We have previously recorded a decreased oxygen tension and blood flow in syngeneically transplanted rat pancreatic islets. The present study related measurements of oxygen tension and blood flow to the vascular density in such grafts implanted beneath the renal capsule. We also evaluated whether transplanted fetal islets are better revascularized than adult islets, and if the degree of revascularization is directly related to the islet vascular endothelial growth factor (VEGF) production. Tissue pO2 was measured using Clark microelectrodes, whereas islet graft blood flow was measured with laser-Doppler flowmetry. The vascular density of endogenous and transplanted islets was quantified in histological specimens stained with the lectin Bandeiraea simplicifolia (BS-1). Tissue pO2 in the transplanted adult and fetal islet grafts was similar and markedly lower than in the endogenous islets. The blood perfusion of both the adult and fetal islet grafts was 60-65% of that in the renal cortex. Administration of D-glucose did not affect tissue pO2 in either the endogenous or transplanted islets, nor graft blood perfusion. The number of capillaries found in the transplanted adult and fetal islets was similar and markedly lower than in endogenous islets. However, in the connective tissue stroma, which constituted approximately 20% of all islet grafts, the vascular density was higher than in the corresponding endocrine parts of these grafts. Incubated adult islets released higher amounts of VEGF than fetal islets. In conclusion, the previously described low oxygen tension of syngeneically transplanted adult rat islets is related to a low vascular density. Similar low oxygen tension and vascular density are seen in grafted fetal islets. The amount of VEGF production does not correlate to the degree of revascularization of the grafts.

Age Factors↗