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- Chittezhath, M, et al.
(author)
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Islet macrophages are associated with islet vascular remodeling and compensatory hyperinsulinemia during diabetes
- 2019
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In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 317:6, s. E1108-E1120
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Journal article (peer-reviewed)abstract
- β-Cells respond to peripheral insulin resistance by first increasing circulating insulin during diabetes. Islet remodeling supports this compensation, but its drivers remain poorly understood. Infiltrating macrophages have been implicated in late-stage type 2 diabetes, but relatively little is known on islet resident macrophages, especially during compensatory hyperinsulinemia. We hypothesized that islet resident macrophages would contribute to islet vascular remodeling and hyperinsulinemia during diabetes, the failure of which results in a rapid progression to frank diabetes. We used chemical (clodronate), genetics (CD169-diphtheria toxin receptor mice), or antibody-mediated (colony-stimulating factor 1 receptor α) macrophage ablation methods in diabetic (db/db) and diet-induced models of compensatory hyperinsulinemia to investigate the role of macrophages in islet remodeling. We transplanted islets devoid of macrophages into naïve diabetic mice and assessed the impact on islet vascularization. With the use of the above methods, we showed that macrophage depletion significantly and consistently compromised islet remodeling in terms of size, vascular density, and insulin secretion capacity. Depletion of islet macrophages reduced VEGF-A secretion in both human and mouse islets ex vivo, and this functionally translated to delayed revascularization upon transplantation in vivo. We revealed that islet resident macrophages were associated with islet remodeling and increased insulin secretion during diabetes. This suggests utility in harnessing islet macrophages during this phase to promote islet vascularization, remodeling, and insulin secretion.
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- Drigo, RAE, et al.
(author)
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Structural basis for delta cell paracrine regulation in pancreatic islets
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3700-
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Journal article (peer-reviewed)abstract
- Little is known about the role of islet delta cells in regulating blood glucose homeostasis in vivo. Delta cells are important paracrine regulators of beta cell and alpha cell secretory activity, however the structural basis underlying this regulation has yet to be determined. Most delta cells are elongated and have a well-defined cell soma and a filopodia-like structure. Using in vivo optogenetics and high-speed Ca2+ imaging, we show that these filopodia are dynamic structures that contain a secretory machinery, enabling the delta cell to reach a large number of beta cells within the islet. This provides for efficient regulation of beta cell activity and is modulated by endogenous IGF-1/VEGF-A signaling. In pre-diabetes, delta cells undergo morphological changes that may be a compensation to maintain paracrine regulation of the beta cell. Our data provides an integrated picture of how delta cells can modulate beta cell activity under physiological conditions.
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- Fan, YL, et al.
(author)
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Local release of rapamycin by microparticles delays islet rejection within the anterior chamber of the eye
- 2019
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 3918-
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Journal article (peer-reviewed)abstract
- The anterior chamber of the eye (ACE) has emerged as a promising clinical islet transplantation site because of its multiple advantages over the conventional intra-hepatic portal site. This includes reduced surgical invasiveness and increased islet graft survival rate. It also allows for enhanced accessibility and monitoring of the islets. Although the ACE is initially an immuno-privileged site, this privilege is disrupted once the islet grafts are re-vascularized. Given that the ACE is a confined space, achieving graft immune tolerance through local immunosuppressive drug delivery is therefore feasible. Here, we show that islet rejection in the ACE of mice can be significantly suppressed through local delivery of rapamycin by carefully designed sustained-release microparticles. In this 30-day study, allogeneic islet grafts with blank microparticles were completely rejected 18 days post-transplantation into mice. Importantly, allogeneic islet grafts co-injected with rapamycin releasing microparticles into a different eye of the same recipient were preserved much longer, with some grafts surviving for more than 30 days. Hence, islet allograft survival was enhanced by a localized and prolonged delivery of an immunosuppressive drug. We envisage that this procedure will relieve diabetic transplant recipients from harsh systemic immune suppression, while achieving improved glycemic control and reduced insulin dependence.
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- Kilpelainen, TO, et al.
(author)
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Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity
- 2019
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In: Nature communications. - London : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 376-
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Journal article (peer-reviewed)abstract
- Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
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- Peng, Y, et al.
(author)
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The effect of low volume high-intensity interval training on metabolic and cardiorespiratory outcomes in patients with type 2 diabetes mellitus: A systematic review and meta-analysis
- 2023
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In: Frontiers in endocrinology. - : Frontiers Media SA. - 1664-2392. ; 13, s. 1098325-
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Journal article (peer-reviewed)abstract
- The present systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to investigate the effect of low volume high-intensity interval training (LVHIIT) on the metabolic and cardiorespiratory outcomes in patients with type 2 diabetes mellitus (T2DM).MethodsRelevant articles were sourced from PubMed, EBSCO, Web of Science, Embase, and the Cochrane Library from inception to October 2022. The study search strategy and all other processes were implemented in accordance with the PRISMA statement.ResultsFive randomized controlled trials that satisfied the inclusion criteria were included in this meta-analysis. The LVHIIT group had significantly lower fasting blood glucose levels (RR= -1.21; 95% CI= -2.02— -0.40, p = 0.0032) and HbA1c levels (RR= -0.65; 95% CI= -1.06— -0.23, p = 0.002) and higher levels of insulin resistance indicator HOMA-IR (RR= -1.34; 95% CI = -2.59— -0.10, p = 0.03) than the control group. Moreover, our results show that LVHIIT can reduce body mass (RR = -0.94, 95% CI = -1.37— -0.51, p<0.0001) and body mass index (RR = -0.31, 95% CI = -0.47— -0.16, p<0.0001). LVHIIT had a better therapeutic effect on blood lipid metabolism, such as total cholesterol, high-density lipoprotein, low-density lipoprotein and triglycerides. However, the change in fasting insulin levels was not statistically significant (RR= -1.43; 95% CI = -3.46— 0.60, p =0.17). Furthermore, LVHIIT reduced the systolic blood pressure (RR =-4.01, 95% CI = -4.82 – -3.21, p<0.0001) and improved peak oxygen uptake (VO2peak) compared to the control group (RR= 5.45; 95% CI = 1.38 – 9.52, p =0.009).ConclusionAfter a certain period of LVHIIT, glycaemic control, insulin resistance, body weight, lipid profile and cardiorespiratory outcomes were significantly improved in T2DM patients.
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| 41. |
- Pluta, J, et al.
(author)
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Identification of 22 susceptibility loci associated with testicular germ cell tumors
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 4487-
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Journal article (peer-reviewed)abstract
- Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.
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- Tun, SBB, et al.
(author)
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Islet Transplantation to the Anterior Chamber of the Eye-A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate
- 2020
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In: Cell transplantation. - : SAGE Publications. - 1555-3892 .- 0963-6897. ; 29, s. 963689720913256-
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Journal article (peer-reviewed)abstract
- Replacement of the insulin-secreting beta cells through transplantation of pancreatic islets to the liver is a promising treatment for type-1 diabetes. However, low oxygen tension, shear stress, and the induction of inflammation lead to significant islet dysfunction and loss. The anterior chamber of the eye (ACE) has gained considerable interest and represents an alternative therapeutic islet transplantation site because of its accessibility, high oxygen tension, and immune-privileged milieu. We have previously demonstrated the feasibility of intraocular islet transplant in mouse and nonhuman primate models of type-1 diabetes and are now assessing its efficacy on glucose homeostasis in a nonhuman primate model of type-2 diabetes. We transplanted allogeneic donor islets (1,500 islet equivalents/kg) into the anterior chamber of one eye in a cynomolgus monkey with high-fat-diet-induced type-2 diabetes. Repeated examinations of the anterior and posterior segments of both eyes were done to monitor the engrafted islets and assess the overall ocular health. Fasting blood glucose level, blood biochemistry, and other metabolic parameters were routinely evaluated to determine the function of the islet graft and diabetes status. The transplanted islets were rapidly engrafted onto the iris and became vascularized 1 month after transplantation. We did not detect changes in intraocular pressure, cataract formation, ophthalmitis, or retinal vessel deformation. A significant lower fasting blood glucose level was observed while the graft was in place, and the transplantation reverts the progression of diabetes. The metabolic markers, hemoglobin A1C and fructosamine, demonstrated improvement following islet transplantation. As a conclusion, intraocular islet transplantation in one eye of a cynomolgus monkey with type-2 diabetes improved its overall plasma glucose homeostasis, as evidenced by short-term measures and long-term metabolic markers. These results further support the future application of the ACE as an alternative site for clinical islet transplants in the context of type-2 diabetes.
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| 47. |
- Wang, HD, et al.
(author)
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Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015
- 2016
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In: Lancet (London, England). - : Elsevier. - 1474-547X .- 0140-6736. ; 388:10053, s. 1725-1774
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Journal article (peer-reviewed)
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