| 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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| 6. |
- Abels, Mia, et al.
(författare)
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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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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 59:9, s. 1928-1937
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Adiels, Martin, 1976, et al.
(författare)
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Acute suppression of VLDL(1) secretion rate by insulin is associated with hepatic fat content and insulin resistance
- 2007
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 50:11, s. 2356-2365
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Overproduction of VLDL(1) seems to be the central pathophysiological feature of the dyslipidaemia associated with type 2 diabetes. We explored the relationship between liver fat and suppression of VLDL(1) production by insulin in participants with a broad range of liver fat content. METHODS: A multicompartmental model was used to determine the kinetic parameters of apolipoprotein B and TG in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol during a hyperinsulinaemic-euglycaemic clamp in 20 male participants: eight with type 2 diabetes and 12 control volunteers. The participants were divided into two groups with low or high liver fat. All participants with diabetes were in the high liver-fat group. RESULTS: The results showed a rapid drop in VLDL(1)-apolipoprotein B and -triacylglycerol secretion in participants with low liver fat during the insulin infusion. In contrast, participants with high liver fat showed no significant change in VLDL(1) secretion. The VLDL(1) suppression following insulin infusion correlated with the suppression of NEFA, and the ability of insulin to suppress the plasma NEFA was impaired in participants with high liver fat. A novel finding was an inverse response between VLDL(1) and VLDL(2) secretion in participants with low liver fat: VLDL(1) secretion decreased acutely after insulin infusion whereas VLDL(2) secretion increased. CONCLUSIONS/INTERPRETATION: Insulin downregulates VLDL(1) secretion and increases VLDL(2) secretion in participants with low liver fat but fails to suppress VLDL(1) secretion in participants with high liver fat, resulting in overproduction of VLDL(1). Thus, liver fat is associated with lack of VLDL(1) suppression in response to insulin.
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| 9. |
- Adiels, Martin, 1976, et al.
(författare)
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Overproduction of large VLDL particles is driven by increased liver fat content in man
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 49:4, s. 755-65
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: We determined whether hepatic fat content and plasma adiponectin concentration regulate VLDL(1) production. METHODS: A multicompartment model was used to simultaneously determine the kinetic parameters of triglycerides (TGs) and apolipoprotein B (ApoB) in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol in ten men with type 2 diabetes and in 18 non-diabetic men. Liver fat content was determined by proton spectroscopy and intra-abdominal fat content by MRI. RESULTS: Univariate regression analysis showed that liver fat content, intra-abdominal fat volume, plasma glucose, insulin and HOMA-IR (homeostasis model assessment of insulin resistance) correlated with VLDL(1) TG and ApoB production. However, only liver fat and plasma glucose were significant in multiple regression models, emphasising the critical role of substrate fluxes and lipid availability in the liver as the driving force for overproduction of VLDL(1) in subjects with type 2 diabetes. Despite negative correlations with fasting TG levels, liver fat content, and VLDL(1) TG and ApoB pool sizes, adiponectin was not linked to VLDL(1) TG or ApoB production and thus was not a predictor of VLDL(1) production. However, adiponectin correlated negatively with the removal rates of VLDL(1) TG and ApoB. CONCLUSIONS/INTERPRETATION: We propose that the metabolic effect of insulin resistance, partly mediated by depressed plasma adiponectin levels, increases fatty acid flux from adipose tissue to the liver and induces the accumulation of fat in the liver. Elevated plasma glucose can further increase hepatic fat content through multiple pathways, resulting in overproduction of VLDL(1) particles and leading to the characteristic dyslipidaemia associated with type 2 diabetes.
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| 12. |
- Agardh, Carl-David, et al.
(författare)
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GAD65 vaccination: 5 years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes.
- 2009
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 52, s. 1363-1368
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: The aim of this study was to ascertain whether treatment of GAD65 autoantibody (GADA)-positive diabetic patients with alum-formulated recombinant GAD65 (GAD-alum) is safe and does not compromise beta cell function. METHODS: This Phase 2, placebo-controlled, dose-escalation clinical trial, which was randomized through a central office, was performed in 47 GADA-positive type 2 diabetic patients, who received subcutaneous injections of GAD-alum (4 [n = 9], 20 [n = 8], 100 [n = 9] or 500 [n = 8] mug) or placebo (n = 13) at weeks 1 and 4 of the trial. Participants and caregivers were blinded to group assignments. The primary outcome was safety as assessed by neurological tests, medications and beta cell function evaluated over 5 years, representing the end of the trial. RESULTS: No severe study-related adverse events occurred during the 5 year follow-up. None of the dose groups was associated with an increased risk of starting insulin treatment compared with the placebo group. The use of oral hypoglycaemic agents did not differ between the dose groups. After 5 years, fasting C-peptide levels declined in the placebo group (-0.24; 95% CI -0.41 to -0.07 log(10) nmol/l; p = 0.01) and the 500 microg dose group (-0.37; 95% CI -0.57 to -0.17 log(10) nmol/l; p = 0.003), but not in the 4 microg (-0.10; 95% CI -0.28 to 0.07 log(10) nmol/l; p = 0.20), 20 microg (0.04; 95% CI -0.12 to 0.19 log(10) nmol/l; p = 0.58) and 100 microg (0.00; 95% CI -0.20 to -0.20 log(10) nmol/l; p = 0.98) dose groups. CONCLUSIONS/INTERPRETATION: The primary outcome of safety was achieved, since no severe study-related adverse events occurred. TRIAL REGISTRATION: Because the study was initiated before 1 July 2005, the protocol was not registered in a registry. FUNDING: This trial was funded by the National Institutes of Health (grant numbers DK26190 and DK53004), the Swedish Research Council (grant number 72X-14064) and Diamyd Therapeutics (Stockholm, Sweden).
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| 14. |
- Agardh, Daniel, et al.
(författare)
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HLA-DQB1*0201/0302 is associated with severe retinopathy in patients with IDDM
- 1996
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 39:11, s. 1313-1317
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Tidskriftsartikel (refereegranskat)abstract
- Some insulin-dependent diabetic (IDDM) patients develop severe forms of retinopathy. Putative risk factors such as hypertension, poor metabolic control, nephropathy and growth hormone levels do not fully explain the progress of retinopathy in these patients. It has been discussed whether there is a genetic marker, since some diabetic patients without any known predisposing risk factors develop severe retinopathy and others do not. In the present study, HLA-DR and DQ were compared in two patient groups with IDDM. One group consisted of patients with early-onset diabetes, with severe non-proliferative or proliferative retinopathy; the other group had no or only mild signs of retinopathy. High resolution HLA typing was carried out by polymerase chain reaction (PCR) and hybridization with allele specific probes. Alleles on the DR3-DQ2 haplotype, DRB1*0301, DQA1*0501 and DQB1*0201, were more frequent in patients with severe retinopathy. A difference was seen when combining certain alleles in the genotypes of DQA1*03/0501 (p > 0.05) and DQB1*0201/0302 (p < 0.01). The findings of the present study suggest that DQB1*0201/0302 is the strongest genetic marker for severe retinopathy and DRB1*0301/0401 only has a secondary influence when combined with this genotype. It seems as if IDDM patients who are positive for the genotype DR3-DQ2/DR4-DQ8 (DRB1*0301-DQA1*0501-DQB1*0201/DRB1*0401 -DQA1*03-DQB1*0302) are at greater risk of developing severe retinopathy.
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| 15. |
- Agardh, Elisabet, et al.
(författare)
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Visual acuity and perimetry as measures of visual function in diabetic macular oedema
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:1, s. 200-206
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: We examined to what extent visual acuity and perimetric sensitivity as measures of central and paracentral visual function would be useful for evaluating the presence and severity of diabetic macular oedema.MATERIALS AND METHODS: We evaluated 59 eyes of 59 diabetic patients by identifying the presence (n=20) or absence (n=39) of macular oedema on stereo fundus photographs. The area of oedema and its distance to the centre of the macula were measured. Ischaemic macular damage was quantified by measuring the foveal avascular zone and adjacent perifoveolar intercapillary areas on fluorescein angiograms. Visual function was assessed by visual acuity charts and by short-wavelength perimetry and standard white-on-white perimetry of the central 10 degrees field.RESULTS: Visual acuity did not differ between eyes with and without macular oedema. In eyes with oedema, visual acuity was correlated to the distance of the oedema from the centre of the macula (log of minimum angle of resolution {LogMar} score decreased by 0.15/mm; p=0.006) and to the thickness of the retina when the centre was affected (LogMar score decreased by 0.003/mum of thickness; p=0.0002). Multivariate analyses confirmed the results (R (2)=0.46 and 0.77, respectively). Short-wavelength perimetry sensitivity was more depressed in eyes with oedema (p=0.033) but was not significantly associated with the presence of oedema after correction for macular ischaemic damage. There was no correlation between these field defects and the severity of oedema.CONCLUSIONS/INTERPRETATION: Visual acuity was a useful measure of visual function in diabetic macular oedema involving the centre. Visual field defects were more common in eyes with macular oedema but reflected ischaemic damage of the macula rather than macular oedema itself.
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| 16. |
- 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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| 18. |
- Ahlqvist, Emma, et al.
(författare)
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A common variant upstream of the PAX6 gene influences islet function in man.
- 2012
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 55, s. 94-104
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Impaired glucose tolerance and impaired insulin secretion have been reported in families with PAX6 mutations and it is suggested that they result from defective proinsulin processing due to lack of prohormone convertase 1/3, encoded by PCSK1. We investigated whether a common PAX6 variant would mimic these findings and explored in detail its effect on islet function in man. METHODS: A PAX6 candidate single nucleotide polymorphism (rs685428) was associated with fasting insulin levels in the Diabetes Genetics Initiative genome-wide association study. We explored its potential association with glucose tolerance and insulin processing and secretion in three Scandinavian cohorts (N = 8,897 individuals). In addition, insulin secretion and the expression of PAX6 and transcriptional target genes were studied in human pancreatic islets. RESULTS: rs685428 G allele carriers had lower islet mRNA expression of PAX6 (p = 0.01) and PCSK1 (p = 0.001) than AA homozygotes. The G allele was associated with increased fasting insulin (p (replication) = 0.02, p (all) = 0.0008) and HOMA-insulin resistance (p (replication) = 0.02, p (all) = 0.001) as well as a lower fasting proinsulin/insulin ratio (p (all) = 0.008) and lower fasting glucagon (p = 0.04) and gastric inhibitory peptide (GIP) (p = 0.05) concentrations. Arginine-stimulated (p = 0.02) insulin secretion was reduced in vivo, which was further reflected by a reduction of glucose- and potassium-stimulated insulin secretion (p = 0.002 and p = 0.04, respectively) in human islets in vitro. CONCLUSIONS/INTERPRETATION: A common variant in PAX6 is associated with reduced PAX6 and PCSK1 expression in human islets and reduced insulin response, as well as decreased glucagon and GIP concentrations and decreased insulin sensitivity. These findings emphasise the central role of PAX6 in the regulation of islet function and glucose metabolism in man.
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- Ahluwalia, Tarun, et al.
(författare)
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Common variants in CNDP1 and CNDP2, and risk of nephropathy in type 2 diabetes.
- 2011
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 54, s. 2295-2302
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Several genome-wide linkage studies have shown an association between diabetic nephropathy and a locus on chromosome 18q harbouring two carnosinase genes, CNDP1 and CNDP2. Carnosinase degrades carnosine (β-alanyl-L-: histidine), which has been ascribed a renal protective effect as a scavenger of reactive oxygen species. We investigated the putative associations of genetic variants in CNDP1 and CNDP2 with diabetic nephropathy (defined either as micro- or macroalbuminuria) and estimated GFR in type 2 diabetic patients from Sweden. METHODS: We genotyped nine single nucleotide polymorphisms (SNPs) and one trinucleotide repeat polymorphism (D18S880, five to seven leucine repeats) in CNDP1 and CNDP2 in a case-control set-up including 4,888 unrelated type 2 diabetic patients (with and without nephropathy) from Sweden (Scania Diabetes Registry). RESULTS: Two SNPs, rs2346061 in CNDP1 and rs7577 in CNDP2, were associated with an increased risk of diabetic nephropathy (rs2346061 p = 5.07 × 10(-4); rs7577 p = 0.021). The latter was also associated with estimated GFR (β = -0.037, p = 0.014), particularly in women. A haplotype including these SNPs (C-C-G) was associated with a threefold increased risk of diabetic nephropathy (OR 2.98, 95% CI 2.43-3.67, p < 0.0001). CONCLUSIONS/INTERPRETATION: These data suggest that common variants in CNDP1 and CNDP2 play a role in susceptibility to kidney disease in patients with type 2 diabetes.
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| 22. |
- Ahluwalia, Tarunveer S., et al.
(författare)
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A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria
- 2019
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 62:2, s. 292-305
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants. Methods: We performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included. Results: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10−11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction = 7.0 × 10−4, β with diabetes = 0.69, β without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni < 2.7 × 10−6). Conclusions/interpretation: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.
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| 25. |
- Ahrén, Bo
(författare)
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Creative use of novel glucose-lowering drugs for type 2 diabetes: where will we head in the next 50 years?
- 2015
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 58:8, s. 1740-1744
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Tidskriftsartikel (refereegranskat)abstract
- Research conducted over the last 50 years has produced discoveries on the importance of glucose control for reducing the risk of diabetic complications, the pathophysiology of type 2 diabetes, the development and validation of mechanistic glucose-lowering targets, and the preclinical and clinical development of individual drugs. This science established the different drug classes that are clinically used today in association with lifestyle changes for lowering glucose in type 2 diabetes. For the next 50 years, we can anticipate that science will explore (1) the use of current drugs and, as they become available, newly developed drugs in early (initial) oral combinations followed by intensification with injectable combinations when glycaemia deteriorates, (2) the validation of novel mechanistic biochemical and physiological targets, including indirect effects of future antiobesity drugs, and (3) the development of true disease-modifying strategies based on knowledge of islet cell biology and replacement. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015).
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