| 1. |
- Espes, Daniel, et al.
(author)
-
Betatrophin in Diabetes Mellitus : the Epidemiological Evidence in Humans
- 2015
-
In: Current Diabetes Reports. - : Springer Science and Business Media LLC. - 1534-4827 .- 1539-0829. ; 15:12
-
Research review (peer-reviewed)abstract
- The prevalence of type 2 diabetes is increasing worldwide, and while numerous treatments exist, none of the current pharmacologic therapies is curative. Pharmacologic approaches that increase beta cell mass may present an avenue for actual cure. There have been numerous reports on factors that can induce beta cell proliferation in rodents, whereas there are still very limited data on the occurrence of beta cell proliferation in humans. The recent discovery of the hormone betatrophin, which in mice counteracted glucose intolerance induced by insulin resistance by potently stimulating beta cell proliferation, has boosted the hope for a new target for drug development for the treatment of diabetes mellitus in humans. With the encouraging preclinical findings as a background, this review presents the available clinical data on betatrophin and discusses its possible role in humans.
|
|
| 2. |
- Espes, Daniel, 1985-, et al.
(author)
-
Function and Gene Expression of Islets Experimentally Transplanted to Muscle and Omentum
- 2020
-
In: Cell Transplantation. - THOUSAND OAKS, CA USA : SAGE Publications. - 0963-6897 .- 1555-3892. ; 29, s. 1-10
-
Journal article (peer-reviewed)abstract
- Islet transplantation to the liver is a potential curative treatment for patients with type 1 diabetes. Muscle and the greater omentum are two alternative implantation sites, which can provide excellent engraftment and hold potential as future sites for stem-cell-derived beta-cell replacement. We evaluated the functional outcome after islet transplantation to muscle and omentum and found that alloxan-diabetic animals were cured with a low number of islets (200) at both sites. The cured animals had a normal area under the curve blood glucose response to intravenous glucose, albeit animals with intramuscular islet grafts had increased 120-min blood glucose levels. They also demonstrated an exaggerated counter regulatory response to hypoglycemia. The expression of genes important for beta-cell function was, at both implantation sites, comparable to that in native pancreatic islets. The gene expression of insulin (INS1 and INS2) and glucose transporter-2 was even increased, and the expression of lactate dehydrogenase decreased, at both sites when compared to native islets. We conclude that muscle and omentum provide excellent conditions for engraftment of transplanted islets. When compared to control, 200 islets implanted to the omentum displayed a restored glucose tolerance, whereas animals with intramuscular islet grafts of similar size displayed mild glucose intolerance.
|
|
| 3. |
- Espes, Daniel, 1985-, et al.
(author)
-
GABA induces a hormonal counter-regulatory response in subjects with long-standing type 1 diabetes
- 2021
-
In: BMJ Open Diabetes Research & Care. - : BMJ Publishing Group Ltd. - 2052-4897. ; 9
-
Journal article (peer-reviewed)abstract
- Introduction: Experimentally, gamma-aminobutyric acid (GABA) has been found to exert immune-modulatory effects and induce beta-cell regeneration, which make it a highly interesting substance candidate for the treatment of type 1 diabetes (T1D). In many countries, including those in the European Union, GABA is considered a pharmaceutical drug. We have therefore conducted a safety and dose escalation trial with the first controlled-release formulation of GABA, Remygen (Diamyd Medical).Research design and methods: Six adult male subjects with long-standing T1D (age 24.8 +/- 1.5 years, disease duration 14.7 +/- 2.2 years) were enrolled in an 11-day dose escalation trial with a controlled-release formulation of GABA, Remygen. Pharmacokinetics, glucose control and hormonal counter-regulatory response during hypoglycemic clamps were evaluated at every dose increase (200 mg, 600 mg and 1200 mg).Results: During the trial there were no serious and only a few, transient, adverse events reported. Without treatment, the counter-regulatory hormone response to hypoglycemia was severely blunted. Intake of 600 mg GABA more than doubled the glucagon, epinephrine, growth hormone and cortisol responses to hypoglycemia.Conclusions: We find that the GABA treatment was well tolerated and established a counter-regulatory response to hypoglycemia in long-standing T1D. Further studies regarding not only the clinical potential of Remygen for beta-cell regeneration but also its potential use as hypoglycemic prophylaxis are warranted. Trail registration number and EudraCT2018-001115-73.
|
|
| 4. |
- Jansson, Leif, et al.
(author)
-
Pancreatic islet blood flow and its measurement
- 2016
-
In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 121:2, s. 81-95
-
Research review (peer-reviewed)abstract
- Pancreatic islets are richly vascularized, and islet blood vessels are uniquely adapted to maintain and support the internal milieu of the islets favoring normal endocrine function. Islet blood flow is normally very high compared with that to the exocrine pancreas and is autonomously regulated through complex interactions between the nervous system, metabolites from insulin secreting beta-cells, endothelium derived mediators, and hormones. The islet blood flow is normally coupled to the needs for insulin release and is usually disturbed during glucose intolerance and overt diabetes. The present review provides a brief background on islet vascular function and especially focuses on available techniques to measure islet blood perfusion. The gold standard for islet blood flow measurements in experimental animals is the microsphere technique, and its advantages and disadvantages will be discussed. In humans there are still no methods to measure islet blood flow selectively, but new developments in radiological techniques hold great hopes for the future.
|
|
| 5. |
- Liljebäck, Hanna, 1990-, et al.
(author)
-
Alterations of Decidual Stromal Cells in Culture and their Effect on Human Pancreatic Islets in Vitro
-
Other publication (other academic/artistic)abstract
- Several studies have shown improved outcome of islet transplantation after co-culture or co-transplantation with mesenchymal stromal cells (MSCs). Since there is no standardized MSC source or protocol, studies revealing the mechanism behind these promising results are fundamental for further advances and for the implementation of this treatment in clinical practice. In this study, we investigated the features of decidual stromal cells (DSCs), a type of MSCs isolated from the decidual layer of human placentas, their alterations in culture and their effect on human beta-cells in vitro.Human DSCs were isolated after planned caesarian sections and characterized during culture up to passage 10. Inflammatory biomarkers were analyzed in culture medium and in lysates of DSCs and human islets. After 48 hours of co-culture, assessment of islet function by high glucose and forskolin perifusion and gene expression analysis of DSCs and islets were performed. Additionally, islets were co-cultured with pro-inflammatory cytokines to evaluate the cytoprotective ability of DSCs in different co-culture systems.DSCs were easily isolated and of maternal origin. The cells retained the typical MSC surface marker expression up to 10 passages and were to some extent able to differentiate into three mesenchymal lineages. Gene expression analysis, after culture, showed the highest number of altered genes between passage 2 and 5. DSCs had variable effect on human islet function after co-culture, where the impact appeared dependent on islet quality of the donor. DSCs increased human islet cell death when combined with cytokine stress.DSCs are an eligible MSC source, easily isolated and expanded in culture. We report on changes in gene expression during culture and an ambiguous effect on human islet function.
|
|
| 6. |
- Liljebäck, Hanna
(author)
-
Challenges in Islet Transplantation and Strategies to Improve Beta-Cell Function
- 2020
-
Doctoral thesis (other academic/artistic)abstract
- The incidence of type 1 diabetes is increasing worldwide and therapies of islet transplantation and potential cell-based therapies are rapidly evolving. Choosing the optimal site for such therapies is crucial for safety and for obtaining the best possible outcome. The liver is currently the site of choice, but is unfortunately associated with disadvantages for graft survival.In paper I, intraportally transplanted human islets were evaluated for hypoxia, apoptosis, and beta-cell survival. This revealed a substantial graft loss of approximately 50 % of transplanted islet mass at one month posttransplantation. At the same time, revascularization was increased, yet still lower than that of native islets. The highest rate of apoptosis was associated with prolonged time in culture prior transplantation.Due to progressive loss of graft function, repeated islet transplantation is often performed. A mouse model, used in paper II, demonstrated an increased survival rate of islets transplanted one week after a first transplant. This finding may reflect an improved engraftment environment “primed” by the first islet injection. No difference in islet vascular density could be ascribed to it. As stem cell-based therapies improve, graft monitoring possibilities and retrieval are of importance for safely introducing these techniques into the clinic. Islet grafts to omentum and muscle cured diabetic mice in paper III. Gene expression was unaltered or increased for genes important for beta-cell function.Decidual stromal cells (DSCs) have immunomodulatory properties that could prove useful for treatments of autoimmune or inflammatory conditions. In paper IV, DSCs were found to be easily isolated from human placenta. The cells were characterized by surface markers, differentiation capacity and gene expression during culture. Co-culture with human pancreatic islets was also conducted. DSCs were observed to be very similar to other types of mesenchymal stromal cells. Greatest change in gene expression was seen between passage 2 and 5. The effect on human islet function may depend on islet viability prior to co-culture.
|
|
| 7. |
|
|
| 8. |
- Liljebäck, Hanna, et al.
(author)
-
Extensive Loss of Islet Mass Beyond the First Day After Intraportal Human Islet Transplantation in a Mouse Model
- 2016
-
In: Cell Transplantation. - 0963-6897 .- 1555-3892. ; 25:3, s. 481-489
-
Journal article (peer-reviewed)abstract
- Clinical islet transplantation is characterized by a progressive deterioration of islet graft function, which renders many patients once again dependent on exogenous insulin administration within a couple of years. In this study, we aimed to investigate possible engraftment factors limiting the survival and viability of experimentally transplanted human islets beyond the first day after their transplantation to the liver. Human islets were transplanted into the liver of nude mice and characterized 1 or 30 days after transplantation by immunohistochemistry. The factors assessed were endocrine mass, cellular death, hypoxia, vascular density and amyloid formation in the transplanted islets. One day posttransplantation, necrotic cells, as well as apoptotic cells, were commonly observed. In contrast to necrotic death, apoptosis rates remained high 1 month posttransplantation, and the total islet mass was reduced by more than 50% between 1 and 30 days posttransplantation. Islet mass at 30 days posttransplantation correlated negatively to apoptotic death. Vascular density within the transplanted islets remained less than 30% of that in native human islets up to 30 days posttransplantation and was associated with prevailing hypoxia. Amyloid formation was rarely observed in the 1-day-old transplants, but was commonly observed in the 30-day-old islet transplants. We conclude that substantial islet cell death occurs beyond the immediate posttransplantation phase, particularly through apoptotic events. Concomitant low vascularization with prevailing hypoxia and progressive amyloid development was observed in the human islet grafts. Strategies to improve engraftment at the intraportal site or change of implantation site in the clinical setting are needed.
|
|
| 9. |
- Liljebäck, Hanna, et al.
(author)
-
Fewer Islets Survive from a First Transplant than a Second Transplant : Evaluation of Repeated Intraportal Islet Transplantation in Mice
- 2019
-
In: Cell Transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 28:11, s. 1455-1460
-
Journal article (peer-reviewed)abstract
- Beta cell replacement is an exciting field where new beta cell sources and alternative sites are widely explored. The liver has been the implantation site of choice in the clinic since the advent of islet transplantation. However, in most cases, repeated islet transplantation is needed to achieve normoglycemia in diabetic recipients. This study aimed to investigate whether there are differences in islet survival and engraftment between a first and a second transplantation, performed 1 week apart, to the liver. C57BL/6 mice were accordingly transplanted twice with an initial infusion of syngeneic islets expressing green fluorescent protein (GFP). The second islet transplant was performed 1 week later and consisted of islets isolated from non-GFP C57BL/6-mice. Animals were sacrificed either 1 day or 1 month after the second transplantation. A control group received a saline infusion instead of GFP-expressing islets, 1 week later obtained a standard non-GFP islet transplant, and was subsequently sacrificed 1 month later. Islet engraftment in the liver was assessed by immunohistochemistry and serum was analyzed for angiogenic factors induced by the first islet transplantation. Almost 70% of islets found in the liver following repeated islet transplantation originated from the second transplantation. The vascular density in the transplanted non-GFP-expressing islets did not differ depending on whether their transplantation was preceded by a primary islet transplantation or saline administration only nor did angiogenic factors in serum prior to the transplantation of non-GFP islets differ between animals that had received a previous islet transplantation or a saline infusion. We conclude that first islet transplantation creates, by unknown mechanisms, favorable conditions for the survival of a second transplant to the liver.
|
|
| 10. |
- Liljebäck, Hanna, et al.
(author)
-
Unsurpassed Intrahepatic Islet Engraftment : the Quest for New Sites for Beta Cell Replacement
- 2019
-
In: Cell Medicine. - : Sage Publications. - 2155-1790. ; 11
-
Journal article (other academic/artistic)abstract
- The liver is currently the site of choice for clinical islet transplantation, even though many alternative implantation sites have lately been proposed as more ideal for graft survival. The suggested sites, for example intramuscular space, omentum, bone marrow, and spleen, are sometimes difficult to compare due to differences in animal model, islet isolation procedure, and islet quality. In addition, the variation in transplanted islet mass is vast. The aim of this commentary is to review alternative implantation sites tested experimentally as well as in clinical islet transplantation. Although many sites have been investigated, none have convincingly proved better suited for clinical islet transplantation than intraportal injection to the liver, regardless of whether it is autologous or allogeneic transplantation. However, in order to fully evaluate upcoming bioengineering techniques, such as scaffolds containing insulin-producing cells derived from stem cells, the need of an alternative site has arisen to enable cellular monitoring, which currently cannot be achieved within the liver.
|
|
