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- Abadpour, S., et al.
(author)
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Inhibition of the prostaglandin D-2-GPR44/DP2 axis improves human islet survival and function
- 2020
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 63, s. 1355-1367
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Journal article (peer-reviewed)abstract
- Aims/hypothesis Inflammatory signals and increased prostaglandin synthesis play a role during the development of diabetes. The prostaglandin D-2 (PGD(2)) receptor, GPR44/DP2, is highly expressed in human islets and activation of the pathway results in impaired insulin secretion. The role of GPR44 activation on islet function and survival rate during chronic hyperglycaemic conditions is not known. In this study, we investigate GPR44 inhibition by using a selective GPR44 antagonist (AZ8154) in human islets both in vitro and in vivo in diabetic mice transplanted with human islets. Methods Human islets were exposed to PGD(2) or proinflammatory cytokines in vitro to investigate the effect of GPR44 inhibition on islet survival rate. In addition, the molecular mechanisms of GPR44 inhibition were investigated in human islets exposed to high concentrations of glucose (HG) and to IL-1 beta. For the in vivo part of the study, human islets were transplanted under the kidney capsule of immunodeficient diabetic mice and treated with 6, 60 or 100 mg/kg per day of a GPR44 antagonist starting from the transplantation day until day 4 (short-term study) or day 17 (long-term study) post transplantation. IVGTT was performed on mice at day 10 and day 15 post transplantation. After termination of the study, metabolic variables, circulating human proinflammatory cytokines, and hepatocyte growth factor (HGF) were analysed in the grafted human islets. Results PGD(2) or proinflammatory cytokines induced apoptosis in human islets whereas GPR44 inhibition reversed this effect. GPR44 inhibition antagonised the reduction in glucose-stimulated insulin secretion induced by HG and IL-1 beta in human islets. This was accompanied by activation of the Akt-glycogen synthase kinase 3 beta signalling pathway together with phosphorylation and inactivation of forkhead box O-1and upregulation of pancreatic and duodenal homeobox-1 and HGF. Administration of the GPR44 antagonist for up to 17 days to diabetic mice transplanted with a marginal number of human islets resulted in reduced fasting blood glucose and lower glucose excursions during IVGTT. Improved glucose regulation was supported by increased human C-peptide levels compared with the vehicle group at day 4 and throughout the treatment period. GPR44 inhibition reduced plasma levels of TNF-alpha and growth-regulated oncogene-alpha/chemokine (C-X-C motif) ligand 1 and increased the levels of HGF in human islets. Conclusions/interpretation Inhibition of GPR44 in human islets has the potential to improve islet function and survival rate under inflammatory and hyperglycaemic stress. This may have implications for better survival rate of islets following transplantation.
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| 5. |
- Abels, Mia, et al.
(author)
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CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion
- 2016
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 59:9, s. 1928-1937
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Journal article (peer-reviewed)abstract
- Aims/hypothesis Insufficient insulin release and hyperglucagonaemia are culprits in type 2 diabetes. Cocaine- and amphetamine-regulated transcript (CART, encoded by Cartpt) affects islet hormone secretion and beta cell survival in vitro in rats, and Cart(-/-) mice have diminished insulin secretion. We aimed to test if CART is differentially regulated in human type 2 diabetic islets and if CART affects insulin and glucagon secretion in vitro in humans and in vivo in mice. Methods CART expression was assessed in human type 2 diabetic and non-diabetic control pancreases and rodent models of diabetes. Insulin and glucagon secretion was examined in isolated islets and in vivo in mice. Ca2+ oscillation patterns and exocytosis were studied in mouse islets. Results We report an important role of CART in human islet function and glucose homeostasis in mice. CART was found to be expressed in human alpha and beta cells and in a subpopulation of mouse beta cells. Notably, CART expression was several fold higher in islets of type 2 diabetic humans and rodents. CART increased insulin secretion in vivo in mice and in human and mouse islets. Furthermore, CART increased beta cell exocytosis, altered the glucose-induced Ca2+ signalling pattern in mouse islets from fast to slow oscillations and improved synchronisation of the oscillations between different islet regions. Finally, CART reduced glucagon secretion in human and mouse islets, as well as in vivo in mice via diminished alpha cell exocytosis. Conclusions/interpretation We conclude that CART is a regulator of glucose homeostasis and could play an important role in the pathophysiology of type 2 diabetes. Based on the ability of CART to increase insulin secretion and reduce glucagon secretion, CART-based agents could be a therapeutic modality in type 2 diabetes.
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| 6. |
- Abels, Mia, et al.
(author)
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Overexpressed beta cell CART increases insulin secretion in mouse models of insulin resistance and diabetes
- 2022
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In: Peptides. - : Elsevier BV. - 0196-9781. ; 151
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Journal article (peer-reviewed)abstract
- Impaired beta cell function and beta cell death are key features of type 2 diabetes (T2D). Cocaine- and amphetamine-regulated transcript (CART) is necessary for normal islet function in mice. CART increases glucose-stimulated insulin secretion in vivo in mice and in vitro in human islets and CART protects beta cells against glucotoxicity-induced cell death in vitro in rats. Furthermore, beta cell CART is upregulated in T2D patients and in diabetic rodent models as a consequence of hyperglycaemia. The aim of this study was to assess the impact of upregulated beta cell CART on islet hormone secretion and glucose homeostasis in a transgenic mouse model. To this end, mice with beta cell-specific overexpression of CART (CARTtg mice) were generated. CARTtg mice challenged by aging, high fat diet feeding or streptozotocin treatment were phenotyped with respect to in vivo and in vitro insulin and glucagon secretion, glucose homeostasis, and beta cell mass. In addition, the impact of adenoviral overexpression of CART on insulin secretion was studied in INS-1 832/13 cells. CARTtg mice had a normal metabolic phenotype under basal conditions. On the other hand, with age CARTtg mice displayed increased insulin secretion and improved glucose elimination, compared with age-matched WT mice. Furthermore, compared with WT controls, CARTtg mice had increased insulin secretion after feeding a high fat diet, as well as lower glucose levels and higher insulin secretion after streptozotocin treatment. Viral overexpression of CART in INS-1 832/13 cells resulted in increased glucose-stimulated insulin secretion. Together, these results imply that beta cell CART acts to increase insulin secretion when beta cell function is challenged. We propose that the increase in beta cell CART is part of a compensatory mechanisms trying to counteract the hyperglycaemia in T2D.
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| 7. |
- Acosta, Juan Ramón
(author)
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Inflammation and impaired adipogenesis in human white adipose tissue
- 2018
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Doctoral thesis (other academic/artistic)abstract
- This thesis aimed to study inflammation and adipogenesis capacity in human subcutaneous white adipose tissue with respect to the development of obesity and associated comorbidities, including insulin resistance. Study I showed that the transcription factor, MAFB, was associated with increased adiposity and involved in regulation of TNFα-mediated inflammatory response, yet did not seem to directly influence adipogenesis or metabolism in human adipocytes. MAFB expression was upregulated during adipogenesis, and knocking down MAFB mRNA led to reduced TNFα-mediated inflammation. However, MAFB was highly expressed in white adipose tissue (WAT) macrophages, which most likely explains its association with BMI and metabolic syndrome. Study II identified increased fat cell size as a hallmark of non-obese type 2 diabetic individuals. This hypertrophic status was associated with insulin resistance, inflammation and adipose tissue lipolysis indicating fat cell size to be a marker of pathogenesis. Relative amount of pro-inflammatory macrophages (M1/M2 ratio) correlated positively with fat cell size, lipolysis and TNFα secretion. In addition, early and late adipogenesis markers correlated negatively with fat cell size, suggesting impaired production of new fat cells in WAT hypertrophy. Study III revealed that human adipocyte progenitors from subcutaneous WAT of healthy individuals consist of a single homogenous cell population. Furthermore, multiple macrophage subtypes were identified. We could not exclude that adipose progenitor subtypes might exist. However, any subtypes were not detectable by the methods employed in this study. Both findings are significant and warrant further investigation. To conclude the finding in this thesis, we defined a role for MAFB in adipose tissue inflammation, which can possibly serve as a biomarker of insulin resistance and inflammation in WAT. Fat cell size seemed to be the best predictor for insulin resistance in non-obese individuals and this appeared likely connected to impaired adipogenic capacity of WAT. However, a search for different progenitor populations bearing varied abilities to become fat cells through the use of a single-cell RNA sequencing technique was not successful as only one major population of progenitors in healthy WAT was found. This demonstrated a need for further studies in larger cohorts of individuals characterized by different metabolic statuses.
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- Adiels, Martin, 1976, et al.
(author)
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Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome.
- 2008
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In: Arteriosclerosis, thrombosis, and vascular biology. - 1524-4636 .- 1079-5642. ; 28:7, s. 1225-36
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Research review (peer-reviewed)abstract
- Insulin resistance is a key feature of the metabolic syndrome and often progresses to type 2 diabetes. Both insulin resistance and type 2 diabetes are characterized by dyslipidemia, which is an important and common risk factor for cardiovascular disease. Diabetic dyslipidemia is a cluster of potentially atherogenic lipid and lipoprotein abnormalities that are metabolically interrelated. Recent evidence suggests that a fundamental defect is an overproduction of large very low-density lipoprotein (VLDL) particles, which initiates a sequence of lipoprotein changes, resulting in higher levels of remnant particles, smaller LDL, and lower levels of high-density liporotein (HDL) cholesterol. These atherogenic lipid abnormalities precede the diagnosis of type 2 diabetes by several years, and it is thus important to elucidate the mechanisms involved in the overproduction of large VLDL particles. Here, we review the pathophysiology of VLDL biosynthesis and metabolism in the metabolic syndrome. We also review recent research investigating the relation between hepatic accumulation of lipids and insulin resistance, and sources of fatty acids for liver fat and VLDL biosynthesis. Finally, we briefly discuss current treatments for lipid management of dyslipidemia and potential future therapeutic targets.
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| 10. |
- Afghahi, Henri, 1966
(author)
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Epidemiological Aspects of Renal Impairment in Patients with Type 2 Diabetes
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Diabetes is a leading cause of renal impairment (RI) and indication of the need for renal replacement therapy in many parts of the world. Albuminuria and RI are the two main forms of diabetic kidney disease. The overall aims of this thesis were to explore risk factors and consequences associated with albuminuria and RI in patients with type 2 diabetes (T2D), as well as to assess the relationship between blood pressure variables, cardiovascular events and all-cause mortality. The studies were based on data from the Swedish National Diabetes Register (NDR). Study I followed 3,367 patients with T2D who did not exhibit signs of albuminuria or RI from 2002 to 2007 in order to evaluate the risk of developing them. A total of 20% of patients developed albuminuria and 11% developed RI. Among those with one of the two conditions, 62% had normoalbuminuric RI. Development of albuminuria or RI was independently associated with advanced older age, high systolic blood pressure and elevated triglycerides. The independent risk factors were obesity, poor glycemic control, smoking, low HDL- cholesterol and male gender for developing albuminuria, as opposed to elevated plasma creatinine at baseline and female gender for developing RI. Different sets of risk factors were associated with development of the two conditionsRI and albuminuria. High body mass index (BMI) was an independent risk factor for RI when renal function was calculated with the MDRD equation, while low BMI was a risk factor with when the Cockcroft-Gault equation was used. In other words, the equation chosen to estimate renal function is important in when interpreting data. Thus, patients with T2D face have distinct risk factors for albuminuria and RI. Study II included 94,446 patients with T2D, including 19,330 with RI. The majority with T2D and RI were normoalbuminuric. Normoalbuminuric RI may be partly due to treatment with RAAS blockade. Given, however, that only 25% of the patients with normoalbuminuric renal impairment had received RAAS blockade, the possibility that other underlying pathophysiological mechanisms play a role should be further evaluated. Study III followed 33,356, and Study IV 27,732, patients with T2D and RI in 2005-2011 in order to evaluate correlations associations between systolic blood pressure (SBP) and all-cause mortality. We observed U-shaped relationships between various aspects of SBP and the risk of all-cause mortality. The greatest risks for Cardiovascular events (CVEs) and all-cause mortality were at the highest and lowest blood pressure intervals. SBP of 135-139 and diastolic blood pressure (DBP) of 72-74 mmHg showed the lowest risks of CVEs and all-cause mortality. Adjusting for presence of albuminuria or chronic heart failure did not significantly alter the results. A reduction in SBP during follow-up is was associated with a greater risk of all-cause mortality. In summary, this thesis shows that obesity and other traditional cardiovascular risk factors are associated with development of albuminuria and RI in patients with T2D. We also found that normoalbuminuric RI is common in patientsly associated with T2D. Finally, both the highest and lowest blood pressure intervals are associated with greater risks of cardiovascular events and all-cause mortality.
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