| 1. |
- Abadpour, S., et al.
(författare)
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Inhibition of the prostaglandin D-2-GPR44/DP2 axis improves human islet survival and function
- 2020
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 63, s. 1355-1367
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Agyemang, Charles, et al.
(författare)
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Type 2 diabetes burden among migrants in Europe : unravelling the causal pathways
- 2021
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 64, s. 2665-2675
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Forskningsöversikt (refereegranskat)abstract
- European populations are ethnically and culturally diverse due to international migration. Evidence indicates large ethnic inequalities in the prevalence of type 2 diabetes. This review discusses the burden of type 2 diabetes and its related complications, and the potential explanatory mechanisms among migrants in Europe. The current available data suggest that the rate of type 2 diabetes is higher in all migrant groups and that they develop this disease at an earlier age than the host European populations. The level of diabetes awareness among migrant populations is high, but glycaemic control remains suboptimal compared with Europeans. The culturally adapted lifestyle modification intervention trials to prevent type 2 diabetes mainly focus on South Asian adults in Europe. Diabetes-related microvascular and macrovascular complications remain a major burden among migrant populations in Europe. Earlier studies found higher mortality rates among migrants, but recent studies seem to suggest a shifting trend in favour of first-generation migrants. However, the extent of the burden of type 2 diabetes varies across migrant groups and European countries. Despite the higher burden of type 2 diabetes among migrants, the key underlying factors are not well understood mainly due to limited investment in basic science research and development of prospective cohort studies. We hypothesise that the underlying risk factors for the high burden of type 2 diabetes and its related complications in migrants are multifaceted and include pre-migration factors, post-migration factors and genetic predispositions. Given the multi-ethnic nature of the current European population, there is a clear need for investment in research among migrant populations to gain insight into factors driving the high burden of type 2 diabetes and related complications to facilitate prevention and treatment efforts in Europe. Graphical abstract: [Figure not available: see fulltext.]
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| 3. |
- Almby, K. E., et al.
(författare)
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Two-year follow-up after gastric bypass surgery : sustained beneficial effect on metabolic health and hormonal dynamics in subjects with type 2 diabetes
- 2020
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 63:SUPPL 1, s. S263-S263
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Gastric bypass surgery (GBP) not only reduces weight but improves glycaemic control in type 2 diabetes (T2DM) patients as well. To explore the mechanisms behind this, we studied the metabolic effects of GBP over time using an integrative approach.Materials and methods: We conducted a prospective study of 13 subjects with T2DM since 4 ±3 years, treated with oral glucose lowering drugs (GLD), recruited before their GBP surgery (3M/ 10F, age 51 ± 9 years). Subjects were assessed at preoperative baseline (BL) and four weeks (4W), six months (6M) and two years (2Y) post-operatively. During visits, fasting hormone and metabolite levels were measured, as well as resting heart rate variability (HRV) followed by subcutaneous adipose tissue (AT) biopsies, a 30 min 5 gram IV-arginine challenge (ARG) and a 180 min oral glucose tolerance test (OGTT).Results: All but one subject discontinued their GLD after surgery and remained without antidiabetic drugs at 2Y follow-up. HbA1c was reduced after surgery and remained at non-diabetic levels at 2Y (see Table. SD=standard deviation. SEM=standard error of the mean. P-value from Student’s T-test). Fasting insulin was reduced significantly 4W after surgery (28.0 ±10.8 mE/L vs 14.4 ±10.8 mE/L) and even lower at 6M (8.9 ±5.6 mE/L) and 2Y (8.0 ±6.2 mE/L). Fasting cortisol was significantly lower than BL at 4W, but significantly increased relative to BL levels at 6M. ACTH was lower than BL at 4W and 6M (borderline significant), but returned to BL levels at 2Y. Insulin excursions after arginine stimulation were markedly reduced 4W after surgery and remained so at 6M and 2Y (data not shown). At all time points after surgery, peak p-glucose during OGTT occurred earlier, as did the consequent drop in glucose levels. The secretion of insulin during OGTT mirrored this pattern. Total GLP-1 levels during OGTT (area under the curve=AUC) increased significantly 4W after surgery and remained increased at 6M and 2Y. AUC for GIP during OGTT had decreased significantly 4W after surgery and continued to do so for 6M and 2Y. Both GLP-1 and GIP however showed an earlier peak in secretion. HOMA-IR improved after surgery (see Table) and remained so at 2Y. Total body fat decreased with GBP (Table), as did adipocyte cell size vs BL (diameter 110.7±11.2 μm) at 4W (94.9±13.1 μm, p=0.013), 6M (101.6±13.1 μm, p=0.0035) and 2Y (93.1±12.7 μm, p<0.001).Conclusion: GBP improves glucose control in T2DM and reduces the need for GLD. Beneficially effects on metabolic parameters and adipocyte morphology are still seen after 2Y of follow-up. A marked increase in AUC for GLP-1 whereas AUC for GIP decreases after surgery, although both have an earlier peak in secretion during OGTT. A decrease in morning cortisol is seen at 4W after GBP, but no concomitant rise in ACTH, suggesting a central mechanism might affect cortisol and in turn contribute to early improvements in glucose homeostasis.
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| 4. |
- Andersson, Emelie, et al.
(författare)
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Costs of diabetes complications : hospital-based care and absence from work for 392,200 people with type 2 diabetes and matched control participants in Sweden
- 2020
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 63:12, s. 2582-2594
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: The risk of complications and medical consequences of type 2 diabetes are well known. Hospital costs have been identified as a key driver of total costs in studies of the economic burden of type 2 diabetes. Less evidence has been generated on the impact of individual diabetic complications on the overall societal burden. The objective of this study was to analyse costs of hospital-based healthcare (inpatient and outpatient care) and work absence related to individual macrovascular and microvascular complications of type 2 diabetes in Sweden in 2016.METHODS: Data for 2016 were retrieved from a Swedish national retrospective observational database cross-linking individual-level data for 1997-2016. The database contained information from population-based health, social insurance and socioeconomic registers for 392,200 people with type 2 diabetes and matched control participants (5:1). Presence of type 2 diabetes and of diabetes complications were derived using all years, 1997-2016. Costs of hospital-based care and of absence from work due to diabetes complications were estimated for the year 2016. Regression analysis was used for comparison with control participants to attribute absence from work to individual complications, and to account for joint presence of complications.RESULTS: Use of hospital care for complications was higher in type 2 diabetes compared with control participants in 2016: 26% vs 12% had ≥1 hospital contact; there were 86,104 vs 24,608 outpatient visits per 100,000 people; and there were 9894 vs 2546 inpatient admissions per 100,000 people (all p < 0.001). The corresponding total costs of hospital-based care for complications were €919 vs €232 per person (p < 0.001), and 74.7% of costs were then directly attributed to diabetes (€687 per person). Regression analyses distributed the costs of days absent from work across diabetes complications per se, basic type 2 diabetes effect and unattributed causes. Diabetes complications amounted to €1317 per person in 2016, accounting for possible complex interactions (25% of total costs of days absent). Key drivers of costs were the macrovascular complications angina pectoris, heart failure and stroke; and the microvascular complications eye diseases, including retinopathy, kidney disease and neuropathy. Early mortality in working ages cost an additional €579 per person and medications used in risk-factor treatment amounted to €418 per person.CONCLUSIONS/INTERPRETATION: The economic burden of complications in type 2 diabetes is substantial. Costs of absence from work in this study were found to be greater than of hospital-based care, highlighting the need for considering treatment consequences in a societal perspective in research and policy. Graphical abstract.
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| 5. |
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| 6. |
- Bao, Xue, et al.
(författare)
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Plasma prostasin : a novel risk marker for incidence of diabetes and cancer mortality
- 2022
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 65:10, s. 1642-1651
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Diabetes is associated with an increased risk of cancer. Prostasin is an epithelial sodium channel stimulator that has been associated with suppression of tumours, glucose metabolism and hyperglycaemia-associated tumour pathology. However, the association between prostasin, diabetes and cancer mortality has not been well investigated in humans. We aim to investigate the associations between plasma prostasin and diabetes, and to explore whether prostasin has an effect on cancer mortality risk in individuals with hyperglycaemia. Methods: Plasma prostasin was measured using samples from the Malmö Diet and Cancer Study Cardiovascular Cohort, and statistical analysis was performed from both sex-specific quartiles and per 1 SD. The cross-sectional association between plasma prostasin and diabetes was first studied in 4658 participants (age 57.5 ± 5.9 years, 39.9% men). After excluding 361 with prevalent diabetes, the associations of prostasin with incident diabetes and cancer mortality risk were assessed using Cox regression analysis. The interactions between prostasin and blood glucose levels as well as other covariates were tested. Results: The adjusted OR for prevalent diabetes in the 4th vs 1st quartile of prostasin concentrations was 1.95 (95% CI 1.39, 2.76) (p for trend <0.0001). During mean follow-up periods of 21.9 ± 7.0 and 23.5 ± 6.1 years, respectively, 702 participants developed diabetes and 651 died from cancer. Prostasin was significantly associated with the incidence of diabetes. The adjusted HR for diabetes in the 4th vs 1st quartile of prostasin concentrations was 1.76 (95% CI 1.41, 2.19) (p for trend <0.0001). Prostasin was also associated with cancer mortality There was a significant interaction between prostasin and fasting blood glucose for cancer mortality risk (p for interaction =0.022), with a stronger association observed in individuals with impaired fasting blood glucose levels at baseline (HR per 1 SD change 1.52; 95% CI 1.07, 2.16; p=0.019). Conclusions/interpretation: Plasma prostasin levels are positively associated with diabetes risk and with cancer mortality risk, especially in individuals with high blood glucose levels, which may shed new light on the relationship between diabetes and cancer. Graphical abstract: [Figure not available: see fulltext.]
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| 7. |
- Bediaga, Naiara G, et al.
(författare)
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Simplifying prediction of disease progression in pre-symptomatic type 1 diabetes using a single blood sample
- 2021
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 64:11, s. 2432-2444
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw.METHODS: Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial-Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da.RESULTS: Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M60, M90 and M120, based on sampling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood samples. In TEDDY, where only 120 min blood sampling had been performed, the M120 AUC was 0.865. In Fr1da, the M120 AUC of 0.742 was significantly greater than the M60 AUC of 0.615.CONCLUSIONS/INTERPRETATION: Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M120, its validity across different at-risk populations and the requirement for 120 min sampling to stage type 1 diabetes suggest M120 could be readily applied to decrease the cost and complexity of risk stratification.
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| 8. |
- Bélteky, Malin, et al.
(författare)
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Infant gut microbiome composition correlated with type 1 diabetes acquisition in the general population: the ABIS study
- 2023
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Ingår i: Diabetologia. - : SPRINGER. - 0012-186X .- 1432-0428. ; 66:6, s. 1116-1128
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis While autoantibodies are traditional markers for type 1 diabetes development, we identified gut microbial biomarkers in 1-year-old infants associated with future type 1 diabetes up to 20 years before diagnosis. Methods Infants enrolled in the longitudinal general population cohort All Babies In Southeast Sweden (ABIS) provided a stool sample at a mean age of 12.5 months. Samples (future type 1 diabetes, n=16; healthy controls, n=268) were subjected to 16S ribosomal RNA (rRNA) sequencing and quantitative PCR. Microbial differences at the taxonomic and core microbiome levels were assessed. PICRUSt was used to predict functional content from the 16S rRNA amplicons. Sixteen infants, with a future diagnosis of type 1 diabetes at a mean age of 13.3 +/- 5.4 years, and one hundred iterations of 32 matched control infants, who remained healthy up to 20 years of age, were analysed. Results Parasutterella and Eubacterium were more abundant in healthy control infants, while Porphyromonas was differentially more abundant in infants with future type 1 diabetes diagnosis. Ruminococcus was a strong determinant in differentiating both control infants and those with future type 1 diabetes using random forest analysis and had differing trends of abundance when comparing control infants and those with future type 1 diabetes. Flavonifractor and UBA1819 were the strongest factors for differentiating control infants, showing higher abundance in control infants compared with those with future type 1 diabetes. Alternatively, Alistipes (more abundant in control infants) and Fusicatenibacter (mixed abundance patterns when comparing case and control infants) were the strongest factors for differentiating future type 1 diabetes. Predicted gene content regarding butyrate production and pyruvate fermentation was differentially observed to be higher in healthy control infants. Conclusions/interpretation This investigation suggests that microbial biomarkers for type 1 diabetes may be present as early as 1 year of age, as reflected in the taxonomic and functional differences of the microbial communities. The possibility of preventing disease onset by altering or promoting a healthy gut microbiome is appealing. Data availability The forward and reverse 16S raw sequencing data generated in this study are available through the NCBI Sequence Read Archive under BioProject PRJNA875929. Associated sample metadata used for statistical comparison are available in the source data file. R codes used for statistical comparisons and figure generation are available at: https://github.com/PMilletich/T1D_Pipeline.
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| 9. |
- Bennet, L., et al.
(författare)
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Mortality in first- and second- generation immigrants to Sweden diagnosed with type 2 diabetes
- 2020
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 63:Suppl. 1, s. S43-S43
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Non-western immigrants to Europe are at high risk for type 2 diabetes (T2D). In this nationwide study including incident cases of T2D, the aim was to compare mortality in first- and second generation immigrants with native Swedes.Materials and methods: Patients living in Sweden diagnosed with a new-onset pharmacologically treated T2D between 2006 to 2012 were identified through the Swedish Prescription Drug Register. Patients were followed until December 31, 2016 for all-cause mortality (ACM) and until December 31, 2012 for cause-specific mortality (CSM). Analyses were adjusted for age at diagnosis, sex, year of diagnosis, socioeconomy, education, treatment and region. Comparisons were assessed using coxregression analysis.Results: In total, 169 300 individuals (129 533 (76.3%) native Swedes; 31 988 (18.9%) first-generation immigrants, and 7 799 (4.8%) second-generation immigrants with either one or both parents born outside Sweden) were diagnosed with T2D between 2006 and 2012 and fulfilled inclusion criteria. First-generation immigrants had lower ACM rate [hazard ratio (HR): 0.85, 95% CI 0.82 to 0.89] compared with native Swedes. The mortality was particularly low in persons born in the Middle East [0.45,0.40 to 0.51], Asia [0.56, 0.46 to 0.68], and Africa [0.88. 0.82 to 0.95]. Mortality rates decreased with older age at migration and shorter stay in Sweden, with the lowest rate in those originating from the Middle East living in Sweden <25 years [0.40, 0.34 to 0.46]. First-generation immigrants born in the Middle East (0.43; 0.30-0.62), and Asia (0.38; 0.19- 0.77) had lower cardiovascular disease related mortality rates compared with native Swedes. Middle Eastern immigrants further displayed lower cancer related mortality rate (0.59, 0.42 to 0.84) compared with native Swedes. Second generation immigrants displayed similar survival rates as native Swedes.Conclusion: Our data indicate that in T2D patients, exposure to the Swedish environment seems to have a larger impact on mortality risk than region of origin. This study indicates protecting mechanisms on mortality related to the non-western environment.
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| 10. |
- Bennet, Louise, et al.
(författare)
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Mortality in first- and second-generation immigrants to Sweden diagnosed with type 2 diabetes : a 10 year nationwide cohort study
- 2020
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 64:1, s. 95-108
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Non-Western immigrants to Europe are at high risk for type 2 diabetes. In this nationwide study including incident cases of type 2 diabetes, the aim was to compare all-cause mortality (ACM) and cause-specific mortality (CSM) rates in first- and second-generation immigrants with native Swedes.Methods: People living in Sweden diagnosed with new-onset pharmacologically treated type 2 diabetes between 2006 and 2012 were identified through the Swedish Prescribed Drug Register. They were followed until 31 December 2016 for ACM and until 31 December 2012 for CSM. Analyses were adjusted for age at diagnosis, sex, socioeconomic status, education, treatment and region. Associations were assessed using Cox regression analysis.Results: In total, 138,085 individuals were diagnosed with type 2 diabetes between 2006 and 2012 and fulfilled inclusion criteria. Of these, 102,163 (74.0%) were native Swedes, 28,819 (20.9%) were first-generation immigrants and 7103 (5.1%) were second-generation immigrants with either one or both parents born outside Sweden. First-generation immigrants had lower ACM rate (HR 0.80 [95% CI 0.76, 0.84]) compared with native Swedes. The mortality rates were particularly low in people born in non-Western regions (0.46 [0.42, 0.50]; the Middle East, 0.41 [0.36, 0.47]; Asia, 0.53 [0.43, 0.66]; Africa, 0.47 [0.38, 0.59]; and Latin America, 0.53 [0.42, 0.68]). ACM rates decreased with older age at migration and shorter stay in Sweden. Compared with native Swedes, first-generation immigrants with <= 24 years in Sweden (0.55 [0.51, 0.60]) displayed lower ACM rates than those spending >24 years in Sweden (0.92 [0.87, 0.97]). Second-generation immigrants did not have better survival rates than native Swedes but rather displayed higher ACM rates for people with both parents born abroad (1.28 [1.05, 1.56]).Conclusions/interpretation: In people with type 2 diabetes, the lower mortality rate in first-generation non-Western immigrants compared with native Swedes was reduced over time and was equalised in second-generation immigrants. These findings suggest that acculturation to Western culture may impact ACM and CSM in immigrants with type 2 diabetes but further investigation is needed.
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