| 1. |
- Berglund, Lisa, et al.
(författare)
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Glucose-Dependent Insulinotropic Polypeptide (GIP) Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB.
- 2016
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 65:1, s. 239-254
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Tidskriftsartikel (refereegranskat)abstract
- Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the pro-atherogenic cytokine osteopontin (OPN) in mouse arteries, via local release of endothelin-1 (ET-1) and activation of cAMP response element binding protein (CREB). Infusion of GIP increases plasma OPN levels in healthy individuals. Plasma ET-1 and OPN levels are positively correlated in patients with critical limb ischemia. Fasting GIP levels are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared to controls. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients; and expression associates to parameters characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from human, mouse, rat and pig; remarkable up-regulation is observed in endothelial and smooth muscle cells upon culture conditions yielding a "vascular disease-like" phenotype. Moreover, a common variant rs10423928 in the GIPR gene associated with increased risk of stroke in type 2 diabetes patients.
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| 2. |
- Engelen, Lian, et al.
(författare)
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Improved glycemic control induced by both metformin and repaglinide is associated with a reduction in blood levels of 3-deoxyglucosone in nonobese patients with type 2 diabetes
- 2011
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Ingår i: European Journal of Endocrinology. - 1479-683X. ; 164:3, s. 371-379
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Metformin has been reported to reduce alpha-dicarbonyls, which are known to contribute to diabetic complications. It is unclear whether this is due to direct quenching of alpha-dicarbonyls or to an improvement in glycemic control. We therefore compared the effects of metformin versus repaglinide, an antihyperglycemic agent with an insulin-secreting mechanism, on the levels of the alpha-dicarbonyl 3-deoxyglucosone (3DG). Methods: We conducted a single-center, double-masked, double-dummy, crossover study involving 96 nonobese patients with type 2 diabetes. After a 1-month run-in on diet-only treatment, patients were randomized to either repaglinide (6 mg daily) followed by metformin (2 g daily) or vice versa each during 4 months with a 1-month washout between interventions. Results: 3DG levels decreased after both metformin (-19.3% (95% confidence interval (CI): -23.5, -14.8)) and repaglinide (-20.8% (95% CI: -24.9, -16.3)) treatments, but no difference was found between treatments (1.8% (95% CI: -3.8, 7.8)). Regardless of the treatment, changes in glycemic variables were associated with changes in 3DG. Specifically, 3DG decreased by 22.7% (95% CI: 19.0, 26.5) per S. D. decrease in fasting plasma glucose (PG), by 20.0% (95% CI: 16.2, 23.9) per S. D. decrease in seven-point mean plasma glucose, by 22.5% (95% CI: 18.6, 26.6) per S. D. decrease in area under the curve for PG, by 17.2% (95% CI: 13.8, 20.6) per S. D. decrease in HbAlc, and by 10.9% (95% CI: 6.4, 15.5) per S. D. decrease in Amadori albumin. In addition, decreases in 3DG were associated with decreases in advanced glycation endproducts and endothelial markers. Conclusion: Improved glycemic control induced by both metformin and repaglinide is associated with a reduction in 3DG levels in nonobese individuals with type 2 diabetes. This may constitute a shared metabolic pathway through which both treatments have a beneficial impact on the cardiovascular risk.
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| 3. |
- Game, Frances, et al.
(författare)
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LeucoPatch system for the management of hard-to-heal diabetic foot ulcers in the UK, Denmark, and Sweden : an observer-masked, randomised controlled trial
- 2018
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Ingår i: The Lancet Diabetes and Endocrinology. - 2213-8595. ; 6:11, s. 870-878
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Tidskriftsartikel (refereegranskat)abstract
- METHODS: This was a multicentre, international, observer-masked, randomised controlled trial of people with diabetes and a hard-to-heal foot ulcer done in 32 specialist diabetic foot clinics in three countries (UK, Denmark, and Sweden). After a 4-week run-in period, those with a reduction in ulcer area of less than 50% were randomly allocated (1:1) by computer-generated, web-based randomisation (block sizes of two, four, and six) to either prespecified good standard care alone or care plus weekly application of LeucoPatch. The primary outcome was the proportion of ulcers that healed within 20 weeks assessed in the intention-to-treat population (all participants with post-randomisation data collected), defined as complete epithelialisation (confirmed by an observer who was masked to randomisation group), and remained healed for 4 weeks. This trial is registered with the ISRCTN registry, number 27665670, and ClinicalTrials.gov, number NCT02224742.FINDINGS: Between Aug 30, 2013, and May 3, 2017, 269 participants were randomly allocated to receive treatment (137 to receive standard care and 132 to receive LeucoPatch). The mean age was 61·9 years (SD 11·6), 217 (82%) were men, and 222 (83%) had type 2 diabetes. In the LeucoPatch group, 45 (34%) of 132 ulcers healed within 20 weeks versus 29 (22%) of 134 ulcers in the standard care group (odds ratio 1·58, 96% CI 1·04-2·40; p=0·0235) by intention-to-treat analysis. Time to healing was shorter in the LeucoPatch group (p=0·0246) than in the standard care group. No difference in adverse events was seen between the groups. The most common serious adverse event (SAE) was diabetic foot infection (24 events in the LeucoPatch group [24% of all SAEs] and 20 in the standard care group [27% of all SAEs]. There were no device-related adverse events.INTERPRETATION: The use of LeucoPatch is associated with significant enhancement of healing of hard-to-heal foot ulcers in people with diabetes.FUNDING: Reapplix ApS.BACKGROUND: The LeucoPatch device uses bedside centrifugation without additional reagents to generate a disc comprising autologous leucocytes, platelets, and fibrin, which is applied to the surface of the wound. We aimed to test the effectiveness of LeucoPatch on the healing of hard-to-heal foot ulcers in people with diabetes.
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| 4. |
- Lund, Soren S., et al.
(författare)
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Combining insulin with metformin or an insulin secretagogue in non-obese patients with type 2 diabetes: 12 month, randomised, double blind trial
- 2009
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Ingår i: BMJ (International Edition). - : BMJ. - 0959-8146 .- 0959-8138 .- 1468-5833. ; 339
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To study the effect of insulin treatment in combination with metformin or an insulin secretagogue, repaglinide, on glycaemic regulation in non-obese patients with type 2 diabetes. Design Randomised, double blind, double dummy, parallel trial. Setting Secondary care in Denmark between 2003 and 2006. Participants Non-obese patients (BMI <= 27) with preserved beta cell function. Interventions After a four month run-in period with repaglinide plus metformin combination therapy, patients with a glycated haemoglobin (HbA(1c)) concentration of 6.5% or more were randomised to repaglinide 6 mg or metformin 2000 mg. All patients also received biphasic insulin aspart 70/30 (30% soluble insulin aspart and 70% intermediate acting insulin aspart) 6 units once a day before dinner for 12 months. Insulin dose was adjusted aiming for a fasting plasma glucose concentration of 4.0-6.0 mmol/l. The target of HbA(1c) concentration was less than 6.5%. Treatment was intensified to two or three insulin injections a day if glycaemic targets were not reached. Main outcome measure HbA(1c) concentration. Results Of the 459 patients who were eligible, 102 were randomised, and 97 completed the trial. Patients had had type 2 diabetes for approximately 10 years. At the end of treatment, HbA(1c) concentration was reduced by a similar amount in the two treatment groups (insulin plus metformin: mean (standard deviation) HbA(1c) 8.15% (1.32) v 6.72% (0.66); insulin plus repaglinide: 8.07% (1.49) v 6.90% (0.68); P=0.177). Total daily insulin dose and risk of hypoglycaemia were also similar in the two treatment groups. Weight gain was less with metformin plus biphasic insulin aspart 70/30 than with repaglinide plus biphasic insulin aspart 70/30 (difference in mean body weight between treatments -2.51 kg, 95% confidence interval -4.07 to -0.95). Conclusions In non-obese patients with type 2 diabetes and poor glycaemic regulation on oral hypoglycaemic agents, overall glycaemic regulation with insulin in combination with metformin was equivalent to that with insulin plus repaglinide. Weight gain seemed less with insulin plus metformin than with insulin plus repaglinide.
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| 5. |
- Lund, Soren S, et al.
(författare)
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Impact of metformin versus the prandial insulin secretagogue, repaglinide, on fasting and postprandial glucose and lipid responses in non-obese patients with type 2 diabetes
- 2008
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Ingår i: European Journal of Endocrinology. - 1479-683X. ; 158:1, s. 35-46
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Non-obese patients with type 2 diabetes (T2DM) are characterized by predominant defective insulin secretion. However, in non-obese T2DM patients, metformin, targeting insulin resistance. is non-inferior to the prandial insulin secretagogue, repaglinide, controlling overall glycaemia (HbA(1c)). Whether the same apply for postprandial glucose and lipid metabolism is unknown. Here. we compared the effect of metformin versus repaglinide on postprandial metabolism in non-obese T2DM patients. Design: Single-centre. double-masked, double-dummy. crossover study during 2 X 4 months involving 96 non-obese (body mass index:! 2 7 kg/m(2)) insulin-naive T2DM patients. At enrolment, patients stopped prior oral hypoglycaemic agents therapies and after a 1-month run-in period on diet-only treatment, patients were randomized to repaglinide (2 mg) thrice daily followed by metformin (1 g) twice daily or vice versa each during 4 months with 1-month washout between interventions. Methods: Postprandial metabolism was evaluated by a standard test meal (3 515 kJ: 54%, fat, 13% protein and 33%, carbohydrate) with blood sampling 0-6 h postprandially. Results: Fasting levels and total area under the curve (AUC) for plasma glucose, triglycerides and free fatty acids (FFA) changed equally between treatments. In contrast, fasting levels and AUC of total cholesterol. low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (non-HDL) cholesterol and serum insulin were lower during metformin than repaglinide (mean (95% confidence intervals), LDL cholesterol difference metformin versus repaglinide: AUC: -0.17mmol/l (-0.26; -0.08)). AUC differences remained significant after adjusting for fasting levels. Conclusions: In non-obese T2DM patients, metformin reduced postprandial levels of glycaemia, triglycerides and FFA similarly compared to the prandial insulin secretagogue, repaglinide. Furthermore, metformin reduced fasting and postprandial chotesterolaemia and insulinaemia compared with repaglinide. These data support prescription of metformin as the preferred drug in non-obese patients with T2DM targeting fasting and postprandial glucose and lipid metabolism.
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| 6. |
- Möllsten, Anna, et al.
(författare)
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A polymorphism in the angiotensin II type 1 receptor gene has different effects on the risk of diabetic nephropathy in men and women.
- 2011
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Ingår i: Molecular Genetics and Metabolism. - : Elsevier. - 1096-7192 .- 1096-7206. ; 103:1, s. 66-70
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Tidskriftsartikel (refereegranskat)abstract
- Background The etiology of diabetic nephropathy depends partly on genetic factors. Elevated systemic and intraglomerular blood pressure and glomerular filtration rate, partly regulated by the renin–angiotensin system, increase the risk of diabetic nephropathy. Methods The present case–control study investigated the association of the rs5186 polymorphism, in the angiotensin II type 1 receptor gene (AGTR1), with diabetic nephropathy. The study included 3561 patients with type 1 diabetes from Denmark, Finland, France and Sweden. Microalbuminuria was defined as albumin excretion rate (AER) ≥ 20 to < 200 μg/min or albumin concentration ≥ 30 to < 300 mg/l (n = 707), macroalbuminuria was defined as AER ≥ 200 μg/min or ≥ 300 mg/l (n = 1546), and patients with renal replacement therapy were also included in this group. The controls had > 15 years diabetes duration, AER < 20 μg/min or < 30 mg/l, and no antihypertensive treatment (n = 1308). Results AA genotype of the rs5186 polymorphism significantly increased the risk of diabetic nephropathy in male patients, OR = 1.27 (95% CI = 1.02–1.58), P = 0.03, adjusted for age at diabetes onset, HbA1c, diabetes duration, smoking and country of origin. Among the women, there were no significant associations between rs5186 and diabetic nephropathy, OR = 0.89 (0.71–1.11), P = 0.30. Conclusion We conclude that the AGTR1 gene may be associated with increased risk of diabetic nephropathy in men with type 1 diabetes.
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| 7. |
- Möllsten, Anna, 1973-
(författare)
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Factors influencing the risk of diabetic nephropathy : analyses of genes, smoking and diet
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diabetic long-term complications, despite intensive treatment, cause serious handicaps at relatively young age in diabetic patients. Diabetic nephropathy (DN) develops in up to 30% of patients with type 1 diabetes (T1D). Besides the eventual loss of kidney function, with need for dialysis treatment and transplantation, this complication also increases the risk of early death from cardiovascular disease. In addition to hyperglycaemia, the risk of developing DN is influenced by a number of life-style related factors, such as smoking and diet, but the mechanisms of action of these factors are largely unknown. The incidence of DN is not linearly related to diabetes duration. There is a peak incidence of DN at 15-20 years and this, together with results from family studies, shows that genetic factors are important contributors. Possible candidate genes are those involved in regulation of intraglomerular pressure and blood pressure, oxidative stress and inflammation. The main aims of this thesis were: ● To investigate the risk of DN associated with polymorphisms in; A) the endothelial NO-synthase gene (NOS3) and genes in the renin-angiotensin-system (RAAS) (all involved in the regulation of intraglomerular pressure). B) the manganese superoxide dismutase gene (SOD2) (involved in the regulation of oxidative stress). C) the ICAM1 gene (involved in activation and migration of lymphocytes) ● To investigate gene-smoking interactions ● To investigate the influence of normal diet on risk of microalbuminuria. The aims were addressed in different case-control settings, including 347 T1D patients from Sweden and 1163 patients from Finland, with or without DN, defined as; overt DN – having albumin excretion rate (AER) ≥200 μg/min, incipient DN – AER between 20 and 200 μg/min, non-DN controls – having AER <20 μg/min and at least 20 years of diabetes duration. In one study also non-diabetic healthy individuals were included to asses the risk of T1D associated with the ICAM1 gene. Results: The RAAS genes were investigated in the Swedish sample set and there was an association between a polymorphism in the angiotensin II type 1 receptor (AGTR1) gene and overt DN, when adjusting for age, duration of diabetes, HbA1c, sex and smoking (adjusted OR=3.04, 99% CI=1.02-9.06). Also a synergistic interaction with smoking was indicated. The ICAM1 gene was investigated in the Swedish sample set, but no association with DN was found. There were, however, associations between T1D and two polymorphisms in this gene, rs281432 (OR=1.64, 95% CI=1.14-2.38) and rs5498 (OR=2.46, 95% CI=1.59-3.80). In the combined Swedish/Finnish sample set, the Glu/Glu genotype of the Glu298Asp polymorphism in the NOS3 gene was associated with DN when age at diabetes onset, duration of diabetes, HbA1c, blood pressure, sex and smoking were taken into account (adjusted OR=1.46, 95% CI=1.12-1.91). There was also association between a polymorphism in the MnSOD gene and DN in this sample set. Homozygosity for the valine-allele of the Val16Ala polymorphism was associated with increased risk of DN in a model including age at diabetes onset, duration of diabetes, HbA1c, sex and smoking (adjusted OR=1.32, 95% CI=1.00-1.74). Smoking was associated with DN (OR=2.00, 95% CI=1.60-2.50) and in the Swedish sample set there were indications of interactions between smoking and the NOS3 and SOD2 genes, but these results could not be confirmed in the Finnish sample set. A high protein intake can enhance glomerular filtration rate and accelerate progression to DN, also other dietary components such as fat, fibres, vitamins and the ratio red/white meat have been discussed as important for DN development. In a nested case-control study including young T1D patients, the normal dietary intakes of protein and other nutrients were assessed using a semiquantitative questionnaire. The results showed that T1D patients consuming more than 6.5 g fish protein (>75th percentile) per day were at slightly lower risk to have microalbuminuria in both crude (OR=0.49, 95% CI=0.25-0.97) and adjusted analyses (OR=0.26, 95% CI=0.09-0.76, adjusted for age, duration of diabetes, sex, HbA1c, mean arterial pressure, BMI, region, smoking, energy intake and fish fat intake). Conclusions: The risk of having diabetic nephropathy is influenced by at least two genes controlling blood pressure and one gene protecting against oxidative stress. Smoking also increases the risk of DN and our findings indicate that smoking may accentuate the effect of the AGTR1, NOS3 and SOD2 genes. Normal dietary intake of protein was not associated with risk of having microalbuminuria in young T1D patients, on the other hand, an intake of fish protein above the 75th percentile decreased the risk of microalbuminuria.
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| 8. |
- Möllsten, Anna, et al.
(författare)
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The endothelial nitric oxide synthase gene and risk of diabetic nephropathy and development of cardiovascular disease in type 1 diabetes
- 2009
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Ingår i: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192 .- 1096-7206. ; 97:1, s. 80-84
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Tidskriftsartikel (refereegranskat)abstract
- Nitric oxide (NO) is important in the maintenance of vascular tone and regulation of blood pressure. NO may also play a role in the development of both nephropathy and cardiovascular disease (CVD) in patients with diabetes. The susceptibility to nephropathy and CVD depends to some extent on genetic factors, therefore polymorphisms in the gene coding for endothelial NO-synthase, NOS3, can affect the risk of developing these diseases. Type 1 diabetes patients attending the Steno Diabetes Center, Denmark, between 1993 and 2001 were enrolled in this study. A total of 458 cases with diabetic nephropathy (albumin excretion >300 mg/24h) and 319 controls with persistent normoalbuminuria (<30 mg/24h), despite > or =20 years of diabetes duration at follow-up were identified. Patients were followed until death or end of the study. Associations between seven NOS3-gene polymorphisms and nephropathy, progression of nephropathy and CVD were studied. There was significant association between the rs743507 TT-genotype and diabetic nephropathy. When including age at diabetes onset, diabetes duration at follow-up, baseline Hb(A1c), sex and ever smoking in the analysis the OR was 1.43 (95% CI=1.03-2.00), P=0.035. In analyses of CVD development using Cox-regression the rs1799983 GG-genotype was a significant protective factor in normoalbuminuric patients, HR=0.32 (0.12-0.82), P=0.018, but not in patients with macroalbuminuria (covariates were; age at follow-up, baseline Hb(A1c), baseline systolic blood pressure, baseline cholesterol, sex and ever smoking). Our conclusion is that the NOS3-gene may be involved in the development of diabetic nephropathy in patients with type 1 diabetes and can be predictive of CVD during follow-up.
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| 9. |
- Sandholm, Niina, et al.
(författare)
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Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes
- 2014
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Ingår i: Diabetologia. - Berlin Heidelberg : Springer-Verlag. - 0012-186X .- 1432-0428. ; 57:6, s. 1143-1153
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes.METHODS: The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10(-4) were followed up in 3,750 additional patients withtype 1 diabetes from seven studies.RESULTS: The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10(-8)). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic associationobserved at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes.CONCLUSIONS/INTERPRETATION: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.
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| 10. |
- Sandholm, Niina, et al.
(författare)
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New susceptibility loci associated with kidney disease in type 1 diabetes
- 2012
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Ingår i: PLOS Genetics. - San Francisco, USA : Public Library of Science, PLOS. - 1553-7390 .- 1553-7404. ; 8:9, s. e1002921-
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genomewide association studies (GWAS) of T1D DN comprising similar to 2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 x 10(-7)), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
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