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1.	Törn, Carina, et al. (författare) Glutamic acid decarboxylase antibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as Type 1 diabetes on clinical grounds 2000 Ingår i: Diabetes/Metabolism Research and Reviews. - 1520-7552 .- 1520-7560. ; 16:6, s. 442-447 Tidskriftsartikel (refereegranskat)abstract Background Differentiation between Type 1 and Type 2 diabetes in adults is difficult at diagnosis. In this study we tested the hypothesis that autoantibodies at diagnosis are predictive for insulin treatment within 3 years in patients initially not classified as Type 1 diabetes. Methods In a nationwide population-based study, blood samples were obtained from 764 patients, all diagnosed with diabetes during a 2-year period. At diagnosis, 583 (76%) were classified as Type 1, 110 (14%) as Type 2 and 71 (9.3%) could not be classified. Results Among patients not classified as Type 1 diabetes, 52 (47%) of Type 2 and 42 (59%) of unclassified patients were positive for islet cell antibodies CICA), glutamic acid decarboxylase antibodies (GADA) or tyrosine phosphatase antibodies (IA-2A). These patients (n=94) had lower body mass index (BMI) (p<0.001) and lower C-peptide (p<0.001) compared to the autoantibody negative patients (n=87). Compared to clinically classified Type 1 diabetes patients positive for autoantibodies (n=477), they have higher BMI (p<0.001), higher C-peptide (p<0.001) and the same levels of ICA, GADA and IA-2A. After 3 years, 93% of autoantibody positive patients initially not classified as Type 1 were on insulin. When ICA, GADA, IA-2A, BMI and C-peptide were tested in a multiple logistic regression, only GADA was signiificant for insulin treatment within 3 years (OR = 18.8; 95% CI 1.8-191) in patients treated with diet or oral drugs at diagnosis. Conclusions A correct classification is difficult in adult diabetic patients. The presence of pancreatic autoantibodies, especially GADA, at diagnosis of diabetes are highly predictive for insulin therapy within 3 years from diagnosis.
2.	Abdul-Ghani, Muhammad A., et al. (författare) The shape of plasma glucose concentration curve during OGTT predicts future risk of type 2 diabetes 2010 Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 26:4, s. 280-286 Tidskriftsartikel (refereegranskat)abstract Background The aim of the study is to assess the relationship between the shape of plasma glucose concentration during the OGTT and future risk for T2DM. Methods 2445 non-diabetic subjects from the Botnia study received an OGTT at baseline and after 7-8 years of follow-up. Results NGT and IFG subjects who returned their plasma glucose concentration following an ingested glucose load below FPG within 60 min had increased insulin sensitivity, greater insulin secretion and lower risk for future T2DM compared to NGT and IFG subjects whose post-load plasma glucose concentration required 120 min or longer to return their plasma glucose level to FPG level. IGT subjects who had a lower plasma glucose concentration at 1-h compared to 2-h during oGrr had greater insulin sensitivity, better beta cell function and lower risk for future T2DM. Conclusions These data suggest that the shape of glucose curve can be utilized to assess future risk for T2DM. Copyright (C) 2010 John Wiley & Sons, Ltd.
3.	Andersson, Christian X, 1973, et al. (författare) Inflamed adipose tissue, insulin resistance and vascular injury 2008 Ingår i: Diabetes/Metabolism Research and Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:8, s. 595-603 Tidskriftsartikel (refereegranskat)abstract Type 2 diabetes is the most common metabolic disorder today and has reached epidemic proportions in many countries. Insulin resistance and inflammation play a central role in the pathogenesis of type 2 diabetes and are present long before the onset of the disease. During this time, many of the complications associated with type 2 diabetes are initiated. Of major concern is the two- to fourfold increase in cardiovascular morbidity and mortality in this group compared to a nondiabetic population. Obesity, characterized by enlarged fat cells, and insulin resistance are, like type 2 diabetes, associated with impaired adipogenesis and a low-grade chronic inflammation that to a large extent emanates from the adipose tissue. Both these processes contribute to unfavourable alterations of the circulating levels of several bioactive molecules (adipokines) that are secreted from the adipose tissue, many of which have documented inhibitory effects on insulin sensitivity in the liver and peripheral tissues and, in addition, have negative effects on the cardiovascular system.Here we review current knowledge of the adipose tissue as an endocrine organ, the local and systemic effects of a chronic state of low-grade inflammation residing in the adipose tissue, and, in particular, the effects of inflammation and circulating adipokines on the vascular wall.
4.	Apelqvist, Jan, et al. (författare) Practical guidelines on the management and prevention of the diabetic foot - Based upon the International Consensus on the Diabetic Foot (2007) prepared by the International Working Group on the Diabetic Foot 2008 Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:S1, s. 181-187 Tidskriftsartikel (refereegranskat)
5.	Apelqvist, Jan, et al. (författare) The development of global consensus guidelines on the management of the diabetic foot 2008 Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:S1, s. 116-118 Tidskriftsartikel (refereegranskat)abstract The future for diabetes is grave. Now described as the global epidemic of the 21st century, the increasing incidence of diabetes (in 2007 over 246 million people affected by diabetes) will place considerable strain on resources and will bring suffering to many if the preventative measures promoted by the International Diabetes Federation (IDF), the International Working Group on the Diabetic Foot (IWGDF) and other diabetes representative organizations are not put into effect. Ulcers of the foot in diabetes are a source of major suffering and cost. Investing in a diabetic foot care guideline can be one of the most cost-effective forms of healthcare expenditure, provided the guideline is goal-focused and properly implemented. The objective of the IWGDF, founded in 1996, is to develop guidelines that will reduce the impact of diabetic foot disease through cost-effective and quality healthcare, based on the principles of evidence-based medicine. Three IWGDF working groups were invited to write specific consensus guidelines on different subjects, according to the current standards of evidence based medicine. Therefore, for the first time, new 2007 texts were produced according to a systematic review of the literature, in order to inform protocols for routine care and to highlight areas which should be considered for further study. After reaching worldwide consensus, the review reports and specific guidelines were launched in May 2007.
6.	Apelqvist, Jan (författare) The foot in perspective. 2008 Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:1, s. 110-115 Tidskriftsartikel (refereegranskat)abstract The diabetic foot constitutes a tremendous challenge for patients, caregivers and the health care system. The International Consensus Document of 1999 was a milestone in the recognition of the importance and consequences of the diabetic foot. Since then, many original papers have been published in this area.Large cohort studies have given us a deeper understanding regarding factors related to the outcome of diabetic foot ulcers: according to these studies, the severity of diabetic foot ulcers is greater than previously reported. More than 50% of individuals' foot ulcers have signs of infection at admission, and one-third have signs of both peripheral artery disease (PAD) and infection. The co-morbidities increase significantly with increasing severity of the foot disease. However, the trend in all these studies is a successive improvement in healing rate (50-60% at 20 weeks follow-up, > 75% at 1 year). It is important to differentiate between neuropathic and neuro-ischaemic ulcers with regard to factors related to outcome and co-morbidities.Recent research has emphasized the importance of psychological factors in the development and outcome of diabetic foot ulcers. Studies have shown that perceptions of the individual's own risks based on symptoms, and their own beliefs in the efficacy of self-care, can affect foot-care practice.The importance and influence of the health care organization and reimbursement should not be underestimated, both in the prevention and management of diabetic foot lesions. The diabetic foot should be considered a lifelong condition, as having had one ulcer dramatically increases the risk of developing a new ulcer.In an individual with diabetes and a foot ulcer, the ulcer should be considered as a sign of multi-organ disease, and a holistic approach to both management and prevention is recommended. Copyright (c) 2008 John Wiley & Sons, Ltd.
7.	Arner, P (författare) Insulin resistance in type 2 diabetes: role of fatty acids 2002 Ingår i: Diabetes/metabolism research and reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 1818 Suppl 2, s. S5-S9 Tidskriftsartikel (refereegranskat)
8.	Axelsson, Stina, et al. (författare) Early induction of GAD(65)-reactive Th2 response in type 1 diabetic children treated with alum-formulated GAD(65) 2010 Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley and Sons. - 1520-7552 .- 1520-7560. ; 26:7, s. 559-568 Tidskriftsartikel (refereegranskat)abstract Background We have previously shown that two injections of 20 mu g alum-formulated glutamic acid decarboxylase 65 (GAD(65)) (GAD-alum; Diamyd (R)) in children with recent-onset type 1 diabetes lead to preservation of residual insulin secretion. In vitro cytokine production at the 15 months follow-up indicated immunomodulation. In the present study, we took advantage of peripheral blood mononuclear cells, cryopreserved during early follow-ups, to investigate whether the immunomodulatory effect of GAD-alum was apparent earlier after treatment, preceding the changes previously reported at 15 months.Methods Peripheral blood mononuclear cells from 70 type 1 diabetic children, randomly assigned GAD-alum (n = 35) or placebo (n = 35), that had been frozen at baseline (n = 27) and after 1 (n = 58), 3 (n = 67) and 9 (n = 66) months, were stimulated in vitro with GAD(65), tyrosine phosphatase-like protein IA-2 peptide, insulin peptide, GAD-alum, alum formulation or phytohaemagglutinin. Interleukin (IL)-5, -6, -10, -12, -13, -17, tumour necrosis factor and interferon-gamma were measured in cell supernatants and serum samples using Luminex. Expression of FOXP3 and transforming growth factor-beta was determined by real-time reverse transcription polymerase chain reaction.Results Already 1 month after the first injection, GAD(65)-induced IL-5 and IL-13 together with FOXP3 were enhanced in GAD-alum-treated patients compared to those with placebo. The in vitro response at 3 and 9 months was characterized by a broader range of cytokines in the treated group. Notably, only the T-helper 2-associated cytokines IL-5 and IL-13 together with FOXP3 increased continuously over time.Conclusions Treatment with GAD-alum in type 1 diabetic children induced an early T-helper 2 immune enhanced response to GAD(65), followed by a wider spectrum of cytokines at 3 and 9 months. Copyright (C) 2010 John Wiley & Sons, Ltd.
9.	Baldimtsi, Evangelia, et al. (författare) HbA1c and the risk of developing peripheral neuropathy in childhood-onset type 1 diabetes : A follow-up study over 3 decades 2024 Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 40:5 Tidskriftsartikel (refereegranskat)abstract AIMS: We have evaluated long-term weighted mean HbA1c (wHbA1c), HbA1c variability, diabetes duration, and lipid profiles in relation to the development of diabetic peripheral neuropathy (DPN), nephropathy, and retinopathy in childhood-onset type 1 diabetes.MATERIALS AND METHODS: In a longitudinal cohort study, 49 patients (21 women) with childhood-onset type 1 diabetes were investigated with neurophysiological measurements, blood tests, and clinical examinations after a diabetes duration of 7.7 (±3.3) years (baseline) and followed with repeated examinations for 30.6 (±5.2) years. We calculated wHbA1c by integrating the area under all HbA1c values since the diabetes diagnosis. Lipid profiles were analysed in relation to the presence of DPN. Long-term fluctuations of HbA1c variability were computed as the standard deviation of all HbA1c measurements. Data regarding the presence of other diabetes complications were retrieved from medical records.RESULTS: In this follow-up study, 51% (25/49) of the patients fulfilled electrophysiological criteria for DPN. In nerve conduction studies, there was a deterioration in the amplitudes and conduction velocities for the median, peroneal, and sural nerves over time. Patients with DPN had a longer duration of diabetes, higher wHbA1c, and increased HbA1c variability. The lowest wHbA1c value associated with the development of DPN was 62 mmol/mol (7.8%). The presence of albuminuria and retinopathy was positively correlated with the presence of neuropathy.CONCLUSIONS: More than half of the patients had developed DPN after 30 years. None of the patients who developed DPN had a wHbA1c of less than 62 mmol/mol (7.8%).
10.	Benevento, D, et al. (författare) Birth weight influences the clinical phenotype and the metabolic control of patients with type 1 diabetes (T1D) 2013 Ingår i: Diabetes/metabolism research and reviews. - : Wiley. - 1520-7560 .- 1520-7552. ; 29:1, s. 60-65 Tidskriftsartikel (refereegranskat)
11.	Bennet, Louise, et al. (författare) Adult-onset diabetes in Middle Eastern immigrants to Sweden : Novel subgroups and diabetic complications—The All New Diabetes in Scania cohort diabetic complications and ethnicity 2021 Ingår i: Diabetes/Metabolism Research and Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 37:6 Tidskriftsartikel (refereegranskat)abstract Background: Middle Eastern immigrants to Europe represent a high risk population for type 2 diabetes. We compared prevalence of novel subgroups and assessed risk of diabetic macro- and microvascular complications between diabetes patients of Middle Eastern and European origin. Methods: This study included newly diagnosed diabetes patients born in Sweden (N = 10641) or Iraq (N = 286), previously included in the All New Diabetes in Scania cohort. The study was conducted between January 2008 and August 2016. Patients were followed to April 2017. Incidence rates in diabetic macro- and microvascular complications were assessed using cox-regression adjusting for the confounding effect of age at onset, sex, anthropometrics, glomerular filtration rate (eGFR) and HbA1c. Findings: In Iraqi immigrants versus native Swedes, severe insulin-deficient diabetes was almost twice as common (27.9 vs. 16.2% p < 0.001) but severe insulin-resistant diabetes was less prevalent. Patients born in Iraq had higher risk of coronary events (hazard ratio [HR] 1.84, 95% CI 1.06–3.12) but considerably lower risk of chronic kidney disease (CKD) than Swedes (HR 0.19; 0.05–0.76). The lower risk in Iraqi immigrants was partially attributed to better eGFR. Genetic risk scores (GRS) showed more genetic variants associated with poor insulin secretion but lower risk of insulin resistance in the Iraqi than native Swedish group. Interpretation: People with diabetes, born in the Middle East present with a more insulin-deficient phenotype and genotype than native Swedes. They have a higher risk of coronary events but lower risk of CKD. Ethnic differences should be considered in the preventive work towards diabetes and its complications.
12.	Berendt, A R, et al. (författare) Diabetic foot osteomyetitis: a progress report on diagnosis and a systematic review of treatment 2008 Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:S1, s. 145-161 Forskningsöversikt (refereegranskat)abstract The International Working Group on the Diabetic Foot appointed an expert panel to provide evidence-based guidance on the management of osteomyelitis in the diabetic foot. Initially, the panel formulated a consensus scheme for the diagnosis of diabetic foot osteomyelitis (DFO) for research purposes, and undertook a systematic review of the evidence relating to treatment. The consensus diagnostic scheme was based on expert opinion; the systematic review was based on a search for reports of the effectiveness of treatment for DFO published prior to December 2006. The panel reached consensus on a proposed scheme that assesses the probability of DFO, based on clinical findings and the results of imaging and laboratory investigations. The literature review identified 1168 papers, 19 of which fulfilled criteria for detailed data extraction. No significant differences in outcome were associated with any particular treatment strategy. There was no evidence that surgical debridement of the infected bone is routinely necessary. Culture and sensitivity of isolates from bone biopsy may assist in selecting properly targeted antibiotic regimens, but empirical regimens should include agents active against staphylococci, administered either intravenously or orally (with a highly bioavailable agent). There are no data to support the superiority of any particular route of delivery of systemic antibiotics or to inform the optimal duration of antibiotic therapy. No available evidence supports the use of any adjunctive therapies, such as hyperbaric oxygen, granulocyte-colony stimulating factor or larvae. We have proposed a scheme for diagnosing DFO for research purposes. Data to inform treatment choices in DFO are limited and further research is, urgently needed.
13.	Berendt, A R, et al. (författare) Specific guidelines for treatment of diabetic foot osteomyelitis 2008 Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:S1, s. 190-191 Tidskriftsartikel (refereegranskat)abstract This article is based upon "The management of diabetic foot osteomyelitis - a progress report on diagnosing and a consensus on treating osteomyelitis". The principle of treatment is to administer antibiotics while providing a local environment in which the medication can work. This typically involves the removal of dead, soft tissue and accessible dead bone during the wound care process. These interventions may be undertaken by any appropriately trained health care provider.
14.	Bertolaso, M, et al. (författare) Gene therapy and enhancement for diabetes (and other diseases): the multiplicity of considerations 2010 Ingår i: Diabetes/metabolism research and reviews. - : Wiley. - 1520-7560 .- 1520-7552. ; 26:7, s. 520-524 Tidskriftsartikel (refereegranskat)
15.	Burén, Jonas, et al. (författare) Is insulin resistance caused by defects in insulin's target cells or by a stressed mind? 2005 Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 21:6, s. 487-494 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract The importance of understanding insulin action is emphasized by the increasing prevalence of insulin resistance in various populations and by the fact that it plays an important pathophysiological role in many common disorders, for example, diabetes, obesity, hypertension and dyslipidemia. The primary factors responsible for the development of insulin resistance are so far unknown, although both genetic and environmental factors are involved. The genetic defects responsible for the common forms of insulin resistance, for example, in type 2 diabetes, are largely unidentified. Some studies from our group as well as by other investigators suggest that cellular insulin resistance is reversible and that it may be secondary to factors in the in vivo environment. These may include insulin-antagonistic action of hormones like catecholamines, glucocorticoids, sex steroids and adipokines as well as dysregulation of autonomic nervous activity and they could contribute to the early development of insulin resistance. Some of these factors can directly impair glucose uptake capacity and this might be due to alterations in key proteins involved in insulin's intracellular signaling pathways. This article briefly summarizes proposed mechanisms behind cellular and whole-body insulin resistance. In particular, we question the role of intrinsic defects in insulin's target cells as primary mechanisms in the development of insulin resistance in type 2 diabetes and we suggest that metabolic and neurohormonal factors instead are the main culprits.
16.	Bus, Sicco A., et al. (författare) Guidelines on offloading foot ulcers in persons with diabetes (IWGDF 2019 update) 2020 Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 36:Suppl 1 Tidskriftsartikel (refereegranskat)abstract The International Working Group on the Diabetic Foot (IWGDF) has published evidence-based guidelines on the prevention and management of diabetic foot disease since 1999. This guideline is on the use of offloading interventions to promote the healing of foot ulcers in people with diabetes and updates the previous IWGDF guideline. We followed the GRADE methodology to devise clinical questions and critically important outcomes in the PICO format, to conduct a systematic review of the medical-scientific literature, and to write recommendations and their rationale. The recommendations are based on the quality of evidence found in the systematic review, expert opinion where evidence was not available, and a weighing of the benefits and harms, patient preferences, feasibility and applicability, and costs related to the intervention. For healing a neuropathic plantar forefoot or midfoot ulcer in a person with diabetes, we recommend that a nonremovable knee-high offloading device is the first choice of offloading treatment. A removable knee-high and removable ankle-high offloading device are to be considered as the second- and third-choice offloading treatment, respectively, if contraindications or patient intolerance to nonremovable offloading exist. Appropriately, fitting footwear combined with felted foam can be considered as the fourth-choice offloading treatment. If non-surgical offloading fails, we recommend to consider surgical offloading interventions for healing metatarsal head and digital ulcers. We have added new recommendations for the use of offloading treatment for healing ulcers that are complicated with infection or ischaemia and for healing plantar heel ulcers. Offloading is arguably the most important of multiple interventions needed to heal a neuropathic plantar foot ulcer in a person with diabetes. Following these recommendations will help health care professionals and teams provide better care for diabetic patients who have a foot ulcer and are at risk for infection, hospitalization, and amputation.
17.	Bus, Sicco A., et al. (författare) Guidelines on offloading foot ulcers in persons with diabetes (IWGDF 2023 update) 2024 Ingår i: Diabetes/Metabolism Research Reviews. - : American Physical Society. - 1520-7552 .- 1520-7560. ; 40:3 Tidskriftsartikel (refereegranskat)abstract AIMS: Offloading mechanical tissue stress is arguably the most important of multiple interventions needed to heal diabetes-related foot ulcers. This is the 2023 International Working Group on the Diabetic Foot (IWGDF) evidence-based guideline on offloading interventions to promote healing of foot ulcers in persons with diabetes. It serves as an update of the 2019 IWGDF guideline.MATERIALS AND METHODS: We followed the GRADE approach by devising clinical questions and important outcomes in the PICO (Patient-Intervention-Control-Outcome) format, undertaking a systematic review and meta-analyses, developing summary of judgement tables and writing recommendations and rationales for each question. Each recommendation is based on the evidence found in the systematic review, expert opinion where evidence was not available, and a careful weighing of GRADE summary of judgement items including desirable and undesirable effects, certainty of evidence, patient values, resources required, cost effectiveness, equity, feasibility, and acceptability.RESULTS: For healing a neuropathic plantar forefoot or midfoot ulcer in a person with diabetes, use a non-removable knee-high offloading device as the first-choice offloading intervention. If contraindications or patient intolerance to non-removable offloading exist, consider using a removable knee-high or ankle-high offloading device as the second-choice offloading intervention. If no offloading devices are available, consider using appropriately fitting footwear combined with felted foam as the third-choice offloading intervention. If such a non-surgical offloading treatment fails to heal a plantar forefoot ulcer, consider an Achilles tendon lengthening, metatarsal head resection, joint arthroplasty, or metatarsal osteotomy. For healing a neuropathic plantar or apex lesser digit ulcer secondary to flexibile toe deformity, use digital flexor tendon tenotomy. For healing rearfoot, non-plantar or ulcers complicated with infection or ischaemia, further recommendations have been outlined. All recommendations have been summarised in an offloading clinical pathway to help facilitate the implementation of this guideline into clinical practice.CONCLUSION: These offloading guideline recommendations should help healthcare professionals provide the best care and outcomes for persons with diabetes-related foot ulcers and reduce the person's risk of infection, hospitalisation and amputation.
18.	Catrina, SB, et al. (författare) Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers 2016 Ingår i: Diabetes/metabolism research and reviews. - : Wiley. - 1520-7560 .- 1520-7552. ; 3232 Suppl 1, s. 179-185 Tidskriftsartikel (refereegranskat)
19.	Christensen, Michael, et al. (författare) Metformin attenuates renal medullary hypoxia in diabetic nephropathy through inhibition uncoupling protein-2 2019 Ingår i: Diabetes/Metabolism Research Reviews. - : WILEY. - 1520-7552 .- 1520-7560. ; 35:2 Tidskriftsartikel (refereegranskat)abstract Background: The purpose of the study is to examine the effect of metformin on oxygen metabolism and mitochondrial function in the kidney of an animal model of insulinopenic diabetes in order to isolate any renoprotective effect from any concomitant effect on blood glucose homeostasis.Methods: Sprague-Dawley rats were injected with streptozotocin (STZ) (50 mg kg(-1)) and when stable started on metformin treatment (250 mg kg(-1)) in the drinking water. Rats were prepared for in vivo measurements 25 to 30 days after STZ injection, where renal function, including glomerular filtration rate and sodium transport, was estimated in anesthetized rats. Intrarenal oxygen tension was measured using oxygen sensors. Furthermore, mitochondrial function was assessed in mitochondria isolated from kidney cortex and medulla analysed by high-resolution respirometry, and superoxide production was evaluated using electron paramagnetic resonance.Results: Insulinopenic rats chronically treated with metformin for 4 weeks displayed improved medullary tissue oxygen tension despite of no effect of metformin on blood glucose homeostasis. Metformin reduced UCP2-dependent LEAK and differentially affected medullary mitochondrial superoxide radical production in control and diabetic rats.Conclusions: Metformin attenuates diabetes-induced renal medullary tissue hypoxia in an animal model of insulinopenic type 1 diabetes. The results suggest that the mechanistic pathway to attenuate the diabetes-induced medullary hypoxia is independent of blood glucose homeostasis and includes reduced UCP2-mediated mitochondrial proton LEAK.
20.	Coppieters, Ken T., et al. (författare) Persistent glucose transporter expression on pancreatic beta cells from longstanding type 1 diabetic individuals 2011 Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 27:8, s. 746-754 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Recent reports have established the notion that many patients with longstanding type 1 diabetes (T1D) possess a remnant population of insulin-producing beta cells. It remains questionable, however, whether these surviving cells can physiologically sense and respond to glucose stimuli.METHODS: Frozen pancreatic sections from non-diabetic donors (n=8), type 2 diabetic patients (n=4), islet autoantibody-positive non-diabetic patients (n=3), type 1 diabetic patients (n=10) and one case of gestational diabetes were obtained via the network for Pancreatic Organ Donors. All longstanding T1D samples were selected based on the detection of insulin-producing beta cells in the pancreas by immunohistochemistry. RNA was isolated from all sections followed by cDNA preparation and quantitative real-time polymerase chain reaction for insulin, glucose transporter 1 (GLUT1), GLUT2 and GLUT3. Finally, immunofluorescent staining was performed on consecutive sections for all four of these markers and a comparison was made between the expression of GLUT2 in humans versus NOD mice.RESULTS: In contrast to islets from the most widely used T1D model, the NOD mouse, human islets predominantly express GLUT1 and, to a much lesser extent, GLUT3 on their surface instead of GLUT2. Relative expression levels of these receptors do not significantly change in the context of the various (pre-)diabetic conditions studied. Moreover, in both species preservation of GLUT expression was observed even under conditions of substantial leucocyte infiltration or decades of T1D duration.CONCLUSIONS: These data suggest that despite being subjected to multiple years of physiological stress, the remaining beta-cell population in longstanding T1D patients retains a capacity to sense glucose via its GLUTs.
21.	Dietrich, Fabricia, et al. (författare) Immune response differs between intralymphatic or subcutaneous administration of GAD-alum in individuals with recent onset Type 1 diabetes 2022 Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 38:3 Tidskriftsartikel (refereegranskat)abstract Aims: Immunomodulation with autoantigens potentially constitutes a specific and safe treatment for Type 1 diabetes (T1D). Studies with GAD-alum administrated subcutaneously have shown to be safe, but its efficacy has been inconclusive. Administration of GAD-alum into the lymph nodes, aimed to optimize antigen presentation, has shown promising results in an open-label clinical trial. Here we compared the immune response of the individuals included in the trial with a group who received GAD-alum subcutaneously in a previous study.Materials and methods: Samples from T1D individuals collected 15 months after administration of either three doses 1 month apart of 4 μg GAD-alum into lymph nodes (LN, n=12) or two doses one month apart of 20 μg subcutaneously (SC, n=12) were studied. GADA, GADA subclasses, GAD65 -induced cytokines, PBMCs proliferation and T cells markers were analyzed.Results: Low doses of GAD-alum into the lymph nodes induced higher GADA levels than higher doses administrated subcutaneously. Immune response in the LN group was characterized by changes in GADA subclasses, with a relative reduction of IgG1 and enhanced IgG2, IgG3 and IgG4 proportion, higher GAD65 -induced secretion of IL-5, IL-10 and TNF-α and reduction of cell proliferation and CD8+ T cells. These changes were not observed after subcutaneous injections of GAD-alum.Conclusions: GAD-specific immune responses 15 months after lymph node injections of GAD-alum differed from the ones induced by subcutaneous administration of the same autoantigen.
22.	Edlund, Jenny, et al. (författare) The roles of NADPH-oxidase and nNOS for the increased oxidative stress and the oxygen consumption in the diabetic kidney 2010 Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 26:5, s. 349-356 Tidskriftsartikel (refereegranskat)abstract Background Sustained hyperglycaemia induces increased renal oxygen consumption resulting in reduced oxygen availability in the diabetic kidney. We investigated the roles of the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase and the neuronal nitric oxide synthase (nNOS) for the increased oxygen consumption in streptozotocin-diabetic rats.MethodsOxygen consumption was measured in isolated proximal tubular cells (PTC) from streptozotocin-induced diabetic rats (n = 7-9 per group) with and without chronic treatment with apocynin, a NADPH-oxidase inhibitor, or S-methyl-L-thiocitrulline (SMTC), a selective nNOS inhibitor, or a combination of the two and the results were compared to normoglycaemic controls (n = 10). Oxidative stress was estimated from thiobarbituric acid reactive substances and protein expression measured by Western blot.ResultsProximal tubular cells from untreated diabetic rats had increased oxygen consumption compared to controls (40.6 +/- 7.9 versus 10.9 +/- 2.0 nmol/mg protein/min). All treatments reduced the diabetes-induced increase in oxygen consumption (apocynin 10.5 +/- 1.7, SMTC 19.7 +/- 3.0 and apocynin +/- SMTC 21.6 +/- 3.6 nmol/mg protein/min). Neither apocynin nor SMTC had any effect on the oxygen consumption in cells pre-incubated with ouabain, an inhibitor of active electrolyte transport. Oxidative stress was elevated in the diabetic kidney and inhibited by all treatments. The increased oxygen consumption by diabetic proximal tubular cells correlated with increased protein expressions of p47phox and nNOS and the treatments prevented these increases.ConclusionsDiabetes induces oxidative stress, which increases oxygen consumption in proximal tubular cells. Inhibition of either NADPH-oxidase or nNOS prevented the increased oxygen consumption. The effect of blocking both these enzymes was less than additive suggesting overlapping pathways which warrant further studies.
23.	Edstorp, Jessica, et al. (författare) Does a prior diagnosis of infectious disease confer an increased risk of latent autoimmune diabetes in adults? 2024 Ingår i: Diabetes/Metabolism Research and Reviews. - 1520-7552. ; 40:3, s. e3758- Tidskriftsartikel (refereegranskat)abstract Aims: Infections are proposed risk factors for type 1 diabetes in children. We examined whether a diagnosis of infectious disease also confers an increased risk of latent autoimmune diabetes in adults (LADA). Materials and methods: We used data from a population-based Swedish case-control study with incident cases of LADA (n = 597) and matched controls (n = 2386). The history of infectious disease was ascertained through national and regional patient registers. We estimated adjusted odds ratios (OR) with 95% confidence intervals for ≥1 respiratory (any/upper/lower), gastrointestinal, herpetic, other or any infectious disease episode, or separately, for 1 and ≥2 infectious disease episodes, within 0–1, 1–3, 3–5 and 5–10 years before LADA diagnosis/matching. Stratified analyses were performed on the basis of HLA risk genotypes and Glutamic acid decarboxylase antibodies (GADA) levels. Results: Individuals who developed LADA did not have a higher prevalence of infectious disease 1–10 years before diabetes diagnosis. For example, OR was estimated at 0.87 (0.66, 1.14) for any versus no respiratory infectious disease within 1–3 years. Similar results were seen for LADA with high-risk HLA genotypes (OR 0.95 [0.64, 1.42]) or high GADA levels (OR 1.10 [0.79, 1.55]), ≥2 episodes (OR 0.89 [0.56, 1.40]), and in infections treated using antibiotics (OR 1.03 [0.73, 1.45]). The only significant association was observed with lower respiratory disease the year preceding LADA diagnosis (OR 1.67 [1.06, 2.64]). Conclusions: Our findings do not support the idea that exposure to infections increases the risk of LADA. A higher prevalence of respiratory infection in the year before LADA diagnosis could reflect increased susceptibility to infections due to hyperglycemia.
24.	Eltayeb-Elsheikh, Nezar, et al. (författare) Association of HLA-DR-DQ alleles, haplotypes, and diplotypes with type 1 diabetes in Saudis 2020 Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 36:8 Tidskriftsartikel (refereegranskat)abstract Aims: Type 1 diabetes (T1D) is an autoimmune disease that affects many children worldwide. Genetic factors and environmental triggers play crucial interacting roles in the aetiology. This study aimed to assess the contribution of HLA-DRB1-DQA1-DQB1 alleles, haplotypes, and genotypes to the risk of T1D among Saudis.Methods: A total of 222 children with T1D and 342 controls were genotyped for HLA-DRB1, -DQA1, and -DQB1 using reverse sequence-specific oligonucleotide (rSSO) Lab Type high definition (HD) kits. Alleles, haplotypes, and diplotypes were compared between cases and controls using the SAS statistical package.Results: DRB103:01-DQA105:01-DQB102:01 (32.4%; OR = 3.68; P-c < .0001), DRB104:05-DQA103:02-DQB103:02 (6.6%; OR = 6.76; P-c < .0001), DRB104:02-DQA103:01-DQB103:02 (6.0%; OR = 3.10; P-c = .0194), DRB104:01-DQA103:01-DQB103:02 (3.7%; OR = 4.22; P-c = .0335), and DRB104:05-DQA103:02-DQB102:02 (2.7%; OR = 6.31; P-c = .0326) haplotypes were significantly increased in cases compared to controls, whereas DRB107:01-DQA102:01-DQB102:02 (OR = 0.41; P-c = .0001), DRB113:01-DQA101:03-DQB106:03 (OR = 0.05; P-c < .0001), DRB115:01-DQA101:02-DQB106:02 (OR = 0.03; P-c < .0001), and DRB111:01-DQA105:05-DQB103:01 (OR = 0.07; P-c = .0291) were significantly decreased. Homozygous DRB103:01-DQA105:01-DQB102:01 genotypes and combinations of DRB103:01-DQA105:01-DQB102:01 with DRB104:05-DQA103:02-DQB103:02, DRB104:02-DQA103:01-DQB103:02, and DRB104:01-DQA103:01-DQB103:02 were significantly increased in cases than controls. Combinations of DRB103:01-DQA105:01-DQB102:01 with DRB107:01-DQA102:01-DQB102:02 and DRB113:02-DQA101:02-DQB1*06:04 showed low OR values but did not remain significantly decreased after Bonferroni correction.Conclusions: HLA-DRB1-DQA1-DQB1 alleles, haplotypes, and diplotypes in Saudis with T1D are not markedly different from those observed in Western and Middle-Eastern populations but are quite different than those of East Asians.
25.	Eneroth, Magnus, et al. (författare) The value of debridement and Vacuum-Assisted Closure (V.A.C.) Therapy in diabetic foot ulcers. 2008 Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:S1, s. 76-80 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Treatment of diabetic foot ulcers includes a number of different regimes such as glycaemic control, re-vascularization, surgical, local wound treatment, offloading and other non-surgical treatments. Although considered the standard of care, the scientific evidence behind the various debridements used is scarce. This presentation will focus on debridement and V.A.C. Therapy, two treatments widely used in patients with diabetes and foot ulcers. METHODS: A review of existing literature on these treatments in diabetic foot ulcers, with focus on description of the various types of debridements used, the principles behind negative pressure wound therapy (NPWT) using the V.A.C. Therapy system and level of evidence. RESULTS: Five randomized controlled trials (RCT) of debridement were identified; three assessed the effectiveness of a hydrogel as a debridement method, one evaluated surgical debridement and one evaluated larval therapy. Pooling the three hydrogel RCTs suggested that hydrogels are significantly more effective than gauze or standard care in healing diabetic foot ulcers. Surgical debridement and larval therapy showed no significant benefit. Other debridement methods such as enzyme preparations or polysaccharide beads have not been evaluated in RCTs of people with diabetes. More than 300 articles have been published on negative pressure wound therapy, including several small RCTs and a larger multi-centre RCT of diabetic foot ulcers. Negative pressure wound therapy seems to be a safe and effective treatment for complex diabetic foot wounds, and could lead to a higher proportion of healed wounds, faster healing rates, and potentially fewer re-amputations than standard care. CONCLUSIONS: Although debridement of the ulcer is considered a prerequisite for healing of diabetic foot ulcers, the grade of evidence is quite low. This may be due to a lack of studies rather than lack of effect. Negative pressure wound therapy seems to be safe and effective in the treatment of some diabetic foot ulcers, although there is still only one well-performed trial that evaluates the effect. Copyright (c) 2008 John Wiley & Sons, Ltd.
26.	Fritz, T., et al. (författare) Effects of Nordic walking on cardiovascular risk factors in overweight individuals with type 2 diabetes, impaired or normal glucose tolerance 2013 Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 29:1, s. 25-32 Tidskriftsartikel (refereegranskat)abstract Background Physical activity remains a valuable prevention for metabolic disease. The effects of Nordic walking on cardiovascular risk factors were determined in overweight individuals with normal or disturbed glucose regulation. Methods We included 213 individuals, aged 60 +/- 5.3 years and with body mass index (BMI) of 30.2 +/- 3.8 kg/m(2); of these, 128 had normal glucose tolerance (NGT), 35 had impaired glucose tolerance (IGT) and 50 had type 2 diabetes mellitus (T2DM). Participants were randomized to unaltered physical activity or to 5 h per week of Nordic walking with poles, for a 4-month period. Dietary habits were unaltered. BMI, waist circumference, blood pressure, glucose tolerance, clinical chemistry, maximal oxygen uptake (peak VO2) and self-reported physical activity (questionnaire) were assessed at the time of inclusion and after 4 months. The participants in the exercise-intervention group kept a walking diary. Results In the NGT exercise group, self-reported physical activity increased markedly, and body weight (-2.0 +/- 3.8 kg), BMI (-0.8 +/- 1.4 kg/m(2)) and waist circumference (- 4.9 +/- 4.4 cm) (mean +/- SD) decreased. Exercise power output (12.9 +/- 9.9 W) and peak VO2 (2.7 +/- 2.8 mL/kg/min) increased in the IGT exercise group. More cardiovascular risk factors were improved after exercise intervention in people with NGT compared with those with IGT or T2DM. Exercise capacity improved significantly in all three groups of participants who reported at least 80% compliance with the scheduled exercise. Conclusions Nordic walking improved anthropometric measurements and exercise capacity. However, unsupervised Nordic walking may not provide a sufficient increase in exercise intensity to achieve ultimate health-promoting benefits on the cardiovascular parameters assessed in this study, particularly for those with disturbed glucose regulation. Copyright (C) 2012 John Wiley & Sons, Ltd.
27.	Fritz, Tomas, et al. (författare) Low-intensity exercise increases skeletal muscle protein expression of PPARdelta and UCP3 in type 2 diabetic patients 2006 Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 22:6, s. 492-498 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Physical exercise provides health benefits for people with type 2 diabetes mellitus, partly by enhancing skeletal muscle insulin action. We tested the hypothesis that changes in expression of key genes in skeletal muscles relate to exercise-induced improvements in type 2 diabetic patients. METHODS: We determined mRNA expression of 20 selected genes following a self-supervised program of walking (> 150 min per week) over a 4-month period. RESULTS: This level of physical activity improved clinical parameters in approximately half the participants, as determined by reduced hypertension and enhanced insulin sensitivity (defined by reduced plasma-insulin levels and improved homeostasis model assessment (HOMA)). Skeletal muscle mRNA expression of Cbl-associated protein (CAP), diacylglycerol kinase (DGK)delta, uncoupling protein (UCP) 3, nuclear respiratory factor (NRF)-1, and peroxisome proliferator-activated receptor (PPAR)delta tended to increase in type 2 diabetic patients with an improved clinical profile. Skeletal muscle protein expression of PPARdelta and UCP3 was increased significantly after physical exercise in patients with an improved clinical profile, but were unchanged in patients who did not show exercise-mediated improvements in clinical parameters. CONCLUSIONS: This study provides clinical evidence that improvements in insulin sensitivity can be achieved in type 2 diabetic patients after individually executed low-intensity exercise training. Moreover, the positive clinical response to exercise is correlated with changes in skeletal muscle proteins involved in the regulation of mitochondrial biogenesis and metabolism. These changes in skeletal muscle gene expression offer a possible molecular explanation for the improvements in clinical outcomes.
28.	Ghanaat-Pour, H, et al. (författare) Gene expression regulated by pioglitazone and exenatide in normal and diabetic rat islets exposed to lipotoxicity 2009 Ingår i: Diabetes/metabolism research and reviews. - : Wiley. - 1520-7560 .- 1520-7552. ; 25:2, s. 163-184 Tidskriftsartikel (refereegranskat)
29.	Gigante, Isabella, et al. (författare) Offloading of diabetes-related neuropathic foot ulcers at Swedish prosthetic and orthotic clinics 2023 Ingår i: Diabetes-Metabolism Research and Reviews. - : Wiley. - 1520-7552 .- 1520-7560. Tidskriftsartikel (refereegranskat)abstract Aims: This study aimed to assess (1) the use of different offloading interventions in Sweden for the healing of diabetes-related plantar neuropathic forefoot ulcers, (2) factors influencing the offloading intervention choice, and (3) the awareness of current gold standard offloading devices.Methods: An online questionnaire was distributed via SurveyMonkey to 51 prosthetic and orthotic clinics in Sweden.Results: Thirty-five (69%) practitioners responded to the questionnaire. Eighty-six percent of the practitioners provided modified off-the-shelf footwear combined with insoles to treat diabetes-related plantar neuropathic forefoot ulcers. A total contact cast (TCC) was provided by 20% of the practitioners, and a nonremovable knee-high walker was provided by 0%. Multiple practitioner-, patient-, intervention-, and wound-related factors were considered when practitioners provided offloading interventions to patients with this type of ulcer. The majority of the practitioners did not or were unsure whether they considered TCC or a non-removable knee-high walker to be the gold standard treatment.Conclusions: Practitioners mainly provided the offloading intervention that the International Working Group on the Diabetic Foot strongly recommends not be provided, namely, modified off-the-shelf footwear with insoles. In contrast, TCC and nonremovable knee-high walkers, as the gold standards, were vastly underutilised. Therefore, the pattern of providing offloading interventions was almost exactly opposite to the recommendations of evidence-based guidelines. Different factors were considered when providing offloading interventions to patients with diabetes-related plantar neuropathic forefoot ulcers. The practitioners' lack of awareness regarding gold standard devices may have contributed to the underutilisation of TCC and nonremovable knee-high walkers.
30.	Hellebö Johanson, Else, 1969, et al. (författare) No acute effect of nateglinide on postprandial lipid and lipoprotein responses in subjects at risk for type 2 diabetes 2005 Ingår i: Diabetes Metab Res Rev. - : Wiley. - 1520-7552. ; 21:4, s. 376-81 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: To study the acute effect of nateglinide, an insulinotropic agent, on the postprandial triglyceride and lipoprotein responses in subjects at risk for type 2 diabetes. METHODS: Six women and 10 men, with at least one first-degree relative with type 2 diabetes were included (Age: 48 +/- 7 years, BMI: 27.5 +/- 2.8 kg m(-2), P-triglycerides: 1.3 +/- 0.4 mmol L(-1), P-cholesterol: 5.4 +/- 0.6 mmol L(-1), B-glucose: 4.6 +/- 0.3 mmol L(-1)). They each had two 8-h meal tolerance tests with either nateglinide or placebo given 10 min prior to the meals in randomized order. Lipoprotein fractions were separated by density gradient ultracentrifugation. First-phase insulin secretion was assessed by an intravenous glucose tolerance test (300 mg kg(-1) body weight) and insulin sensitivity by a hyperinsulinaemic euglycaemic clamp (40 mU m(-2) min(-1)). RESULTS: The 1-h insulin levels during the meal tolerance test were significantly higher with nateglinide (577 +/- 81 vs 376 +/- 58 pmol L(-1), p < 0.001), as well as the response during the first two hours (IAUC: 41 243 +/- 5844 vs 29 956 +/- 4662 pmol L(-1) min, p < 0.01). Accordingly, nateglinide lowered the 8-h postprandial glucose response by around 60% compared to placebo (p < 0.001). In contrast, no significant lowering was seen in the excursion of postprandial triglycerides in total plasma or lipoprotein fractions. Consistently, the concentration of exogenous (apoB-48) and endogenous (apoB-100) lipoproteins was not reduced by nateglinide. CONCLUSIONS: Acute administration of nateglinide reduces, as expected, the postprandial glucose concentration, but no reduction in triglyceride or lipoprotein responses are seen in subjects at risk for type 2 diabetes.
31.	Hinchliffe, R J, et al. (författare) A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes 2008 Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:S1, s. 119-144 Forskningsöversikt (refereegranskat)abstract The outcome of management of diabetic foot ulcers is poor and there is uncertainty concerning optimal approaches to management. We have undertaken a systematic review to identify interventions for which there is evidence of effectiveness. A search was made for reports of the effectiveness of interventions assessed in terms of healing, ulcer area or amputation in controlled clinical studies published prior to December 2006. Methodological quality of selected studies was independently assessed by two reviewers using Scottish Intercollegiate Guidelines Network (SIGN) criteria. Selected studies fell into the following categories: sharp debridement and larvae; antiseptics and dressings; chronic wound resection hyperbaric oxygen (HBO); reduction of tissue oedema; skin grafts; electrical and magnetic stimulation and ultrasound. Heterogeneity of studies prevented pooled analysis of results. Of the 2251 papers identified, 60 were selected for grading following full text review. Some evidence was found to support hydrogels as desloughing agents and to suggest that a systemic (HBO) therapy may be effective. Topical negative pressure (TNP) may promote healing of post-operative wounds, and resection of neuropathic plantar ulcers may be beneficial. More information was needed to confirm the effectiveness and cost-effectiveness of these and other interventions. No data were found to justify the use of any other topically applied product or dressing, including those with antiseptic properties. Further evidence to substantiate the effect of interventions designed to enhance the healing of chronic ulcers is urgently needed. Until such evidence is available from robust trials, there is limited justification for the use of more expensive treatments and dressings.
32.	Hinchliffe, R J, et al. (författare) Specific guidelines on wound and wound-bed management 2008 Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:S1, s. 188-189 Tidskriftsartikel (refereegranskat)
33.	Hoffmann-Petersen, IT, et al. (författare) Effect of dipeptidyl peptidase-4 inhibitors on complement activation 2021 Ingår i: Diabetes/metabolism research and reviews. - : Wiley. - 1520-7560 .- 1520-7552. ; 37:3, s. e3385- Tidskriftsartikel (refereegranskat)
34.	Honkanen, Jarno, et al. (författare) Poor in vitro induction of FOXP3 and ICOS in type 1 cytokine environment activated T-cells from children with type 1 diabetes 2008 Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:8, s. 635-641 Tidskriftsartikel (refereegranskat)abstract BackgroundType 1 diabetes (T1D) is characterised by loss of tolerance to beta-cell antigens, and the insulin-producing beta-cells in the pancreatic islets are destroyed by the host's own immune system. Immunological risk factors associated with T1D are related to the defects in the polarization of T-cells and in the function of regulatory T (Treg)-cells. We set out to study whether an impaired induction of regulatory mechanisms during the generation of T-cell responses upon stimulation is associated with T1D.MethodsNaive T-cells were isolated from 18 children with recent T1D (0–14days from diagnosis; mean age 9.3 years), 11 children who had had T1D for at least 1 year (mean age 10.6) and 14 non-diabetic children (mean age 8.1). CD45RA+ T-cells were stimulated with PHA for 72 h in type 1 cytokine [interleukin (IL)-12 and anti-IL-4] or type 2 cytokine (IL-4 and anti-IL-12) environment. T-cell polarization and regulation related markers were analysed by quantitative reverse transcription polymerase chain reaction (QRT-PCR) (Th1 promoting T-bet, Th2 promoting GATA-3 and regulation related FOXP3, ICOS and NFATc2).ResultsChildren with recently diagnosed T1D showed decreased induction of FOXP3, ICOS and NFATc2 in T-cells activated in type 1 cytokine milieu (p = 0.007, p = 0.001, and p = 0.02), whereas no differences between the diabetic and healthy children were seen in the up-regulation of activation markers, T-bet and GATA-3.ConclusionsThe poor induction of factors that mediate down-modulation of T-cell responses upon stimulation in type 1 cytokine environment may contribute to the development of autoreactive type 1 responses in T1D.
35.	Jendle, Johan, 1963-, et al. (författare) Efficacy and Safety of Dulaglutide in the Treatment of Type 2 Diabetes : A Comprehensive Review of the Dulaglutide Clinical Data Focusing on the AWARD Phase 3 Clinical Trial Program 2016 Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley-Blackwell. - 1520-7552 .- 1520-7560. ; 32:8, s. 776-790 Forskningsöversikt (refereegranskat)abstract Dulaglutide (DU) is a once weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved for the treatment of type 2 diabetes mellitus (T2DM). Glycaemic efficacy and safety characteristics of DU have been assessed in six Phase 3 studies in the AWARD program. The objective of this review article is to summarise these results from the 6 completed AWARD studies. At the primary endpoint, in 5 of the 6 studies, once weekly dulaglutide 1.5 mg was superior to the active comparator (exenatide, insulin glargine [two studies], metformin, and sitagliptin), with a greater proportion of patients reaching glycated haemoglobin A1c (HbA1c) targets of <7.0% (53.0 mmol/mol) and ≤6.5% (47.5 mmol/mol). Dulaglutide 1.5 mg was non-inferior to liraglutide in AWARD-6. Once weekly dulaglutide 0.75 mg was evaluated in 5 of these trials and demonstrated superiority to the active comparator in 4 of 5 AWARD studies (exenatide, glargine, metformin, and sitagliptin), and non-inferiority to glargine in the AWARD-2 study. Similar to other GLP-1 RAs, treatment with dulaglutide was associated with weight loss or attenuation of weight gain and low rates of hypoglycaemia when used alone or with non-insulin-secretagogue therapy. The most frequently reported adverse events were gastrointestinal, including nausea, diarrhoea, and vomiting. The incidence of dulaglutide antidrug antibody formation was 1%-2.8% with rare injection site reactions. In conclusion, dulaglutide is an effective treatment for T2DM and has an acceptable tolerability and safety profile.
36.	Julin, Bettina, et al. (författare) Association between sociodemographic determinants and health outcomes in individuals with type 2 diabetes in Sweden 2018 Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 34:4, s. -9 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Concurrent multifactorial treatment is needed to reduce consequent risks of diabetes, yet most studies investigating the relationship between sociodemographic factors and health outcomes have focused on only one risk factor at a time. Swedish health care is mainly tax-funded, thus providing an environment that should facilitate equal health outcomes in patients, independent of background, socioeconomic status or health profile. This study aimed at investigating the association between several sociodemographic factors and diabetes-related health outcomes represented by HbA1c , systolic blood pressure, LDL cholesterol, predicted 5-year risk of cardiovascular disease as well as statin use.METHODS: This large retrospective registry-study was based on patient-level data from individuals diagnosed with type 2 diabetes mellitus during 2010-2011 (n = 416,228) in any of seven Swedish regions (~65% of the Swedish population). Health equity in diabetes care was analyzed through multivariate regression analyses on intermediary outcomes (HbA1c , systolic blood pressure, LDL), predicted 5-year risk of cardiovascular disease and process (i.e. statin use) after one-year follow-up, adjusting for several sociodemographic factors.RESULTS: We observed differences in intermediary risk measures, predicted 5-year risk of cardiovascular disease as well as process dependent on place of birth, sex, age, education and social setting, despite Sweden's articulated vision of equal health care.CONCLUSIONS: Diabetes patients' health was associated with sociodemographic prerequisites. In addition to demographics (age, sex) and disease history; educational level, marital status and region of birth are important factors to consider when benchmarking health outcomes, e.g. average HbA1c level, between organizational units or between different administrative regions.
37.	Karlsson Faresjö, Maria, 1971-, et al. (författare) Diminished IFN-γ response to diabetes-associated autoantigens in children at diagnosis and during follow up of type 1 diabetes 2006 Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 22:6, s. 462-470 Tidskriftsartikel (refereegranskat)abstract BackgroundImbalance of T-helper (Th)1- and Th2-like cytokines has been associated with type 1 diabetes. We therefore studied the immune deviation in antigen-specific T cells from diagnosis onwards in type 1 diabetic children.MethodsPeripheral blood mononuclear cells (PBMC) were collected from 15 children after 4 days, 3 months and 18 months of being diagnosed with type 1 diabetes, from 15 healthy children matched by age and gender to the type 1 diabetic children and from 14 children with and 35 children without HLA-risk genes. Secretion of interferon-γ (IFN-γ) and interleukin-4 (IL-4) was detected by ELISPOT after stimulation with glutamic acid decarboxylase (GAD65, protein and aa 247–279), recombinant tyrosinphosphatase (IA-2), insulin, ovalbumin and phytohaemagglutinin (PHA).ResultsSecretion of IFN-γ in PBMC stimulated with GAD65 (p < 0.05), the GAD65-peptide (p < 0.01), IA-2 (p < 0.01), and insulin (p < 0.01) was lower in diabetic children at diagnosis than in healthy children. Stimulation of PBMC with GAD65 and IA-2 decreased the secretion of IFN-γ in children with HLA-risk genotype. Spontaneous and antigen-induced IFN-γ secretion increased significantly after diagnosis of the disease, but did not exceed the levels observed in healthy children. Fasting C-peptide levels at diagnosis correlated with insulin-induced IFN-γ (R = 0.52; p = 0.05) and negatively with spontaneous IL-4 secretion (R = −0.62; p < 0.05).ConclusionA diminished IFN-γ secretion and the association of fasting C-peptide levels with cytokine response in children with type 1 diabetes suggest that factors related to β-cell function in type 1 diabetes may modify T-cell function. Thus, the T-cell responses detected at or after diagnosis may not reflect the pathogenic process leading to type 1 diabetes.
38.	Kubota, M, et al. (författare) Enhanced insulin action following subcutaneous co-administration of insulin and C-peptide in rats 2014 Ingår i: Diabetes/metabolism research and reviews. - : Wiley. - 1520-7560 .- 1520-7552. ; 30:2, s. 124-131 Tidskriftsartikel (refereegranskat)
39.	Kuoppamaa, H, et al. (författare) Globular adiponectin stimulates glucose transport in type 2 diabetic muscle 2008 Ingår i: Diabetes/metabolism research and reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 24:7, s. 554-562 Tidskriftsartikel (refereegranskat)
40.	Lazzarini, P A, et al. (författare) Effectiveness of offloading interventions for people with diabetes-related foot ulcers : A systematic review and meta-analysis 2023 Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 40:3 Forskningsöversikt (refereegranskat)abstract BACKGROUND: Offloading treatment is crucial to heal diabetes-related foot ulcers (DFU). This systematic review aimed to assess the effectiveness of offloading interventions for people with DFU.METHODS: We searched PubMed, EMBASE, Cochrane databases, and trials registries for all studies relating to offloading interventions in people with DFU to address 14 clinical question comparisons. Outcomes included ulcers healed, plantar pressure, weight-bearing activity, adherence, new lesions, falls, infections, amputations, quality of life, costs, cost-effectiveness, balance, and sustained healing. Included controlled studies were independently assessed for risk of bias and had key data extracted. Meta-analyses were performed when outcome data from studies could be pooled. Evidence statements were developed using the GRADE approach when outcome data existed.RESULTS: From 19,923 studies screened, 194 eligible studies were identified (47 controlled, 147 non-controlled), 35 meta-analyses performed, and 128 evidence statements developed. We found non-removable offloading devices likely increase ulcers healed compared to removable offloading devices (risk ratio [RR] 1.24, 95% CI 1.09-1.41; N = 14, n = 1083), and may increase adherence, cost-effectiveness and decrease infections, but may increase new lesions. Removable knee-high offloading devices may make little difference to ulcers healed compared to removable ankle-high offloading devices (RR 1.00, 0.86-1.16; N = 6, n = 439), but may decrease plantar pressure and adherence. Any offloading device may increase ulcers healed (RR 1.39, 0.89-2.18; N = 5, n = 235) and cost-effectiveness compared to therapeutic footwear and may decrease plantar pressure and infections. Digital flexor tenotomies with offloading devices likely increase ulcers healed (RR 2.43, 1.05-5.59; N = 1, n = 16) and sustained healing compared to devices alone, and may decrease plantar pressure and infections, but may increase new transfer lesions. Achilles tendon lengthening with offloading devices likely increase ulcers healed (RR 1.10, 0.97-1.27; N = 1, n = 64) and sustained healing compared to devices alone, but likely increase new heel ulcers.CONCLUSIONS: Non-removable offloading devices are likely superior to all other offloading interventions to heal most plantar DFU. Digital flexor tenotomies and Achilles tendon lengthening in combination with offloading devices are likely superior for some specific plantar DFU locations. Otherwise, any offloading device is probably superior to therapeutic footwear and other non-surgical offloading interventions to heal most plantar DFU. However, all these interventions have low-to-moderate certainty of evidence supporting their outcomes and more high-quality trials are needed to improve our certainty for the effectiveness of most offloading interventions.
41.	Lazzarini, Peter A., et al. (författare) Effectiveness of offloading interventions to heal foot ulcers in persons with diabetes : a systematic review 2020 Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 36:Suppl. 1 Forskningsöversikt (refereegranskat)abstract BACKGROUND: Offloading interventions are commonly used in clinical practice to heal foot ulcers. The aim of this updated systematic review is to investigate the effectiveness of offloading interventions to heal diabetic foot ulcers.METHODS: We updated our previous systematic review search of PubMed, EMBASE, and Cochrane databases to also include original studies published between July 29, 2014 and August 13, 2018 relating to four offloading intervention categories in populations with diabetic foot ulcers: (a) offloading devices, (b) footwear, (c) other offloading techniques, and (d) surgical offloading techniques. Outcomes included ulcer healing, plantar pressure, ambulatory activity, adherence, adverse events, patient-reported measures, and cost-effectiveness. Included controlled studies were assessed for methodological quality and had key data extracted into evidence and risk of bias tables. Included non-controlled studies were summarised on a narrative basis.RESULTS: We identified 41 studies from our updated search for a total of 165 included studies. Six included studies were meta-analyses, 26 randomised controlled trials (RCTs), 13 other controlled studies, and 120 non-controlled studies. Five meta-analyses and 12 RCTs provided high-quality evidence for non-removable knee-high offloading devices being more effective than removable offloading devices and therapeutic footwear for healing plantar forefoot and midfoot ulcers. Total contact casts (TCCs) and non-removable knee-high walkers were shown to be equally effective. Moderate-quality evidence exists for removable knee-high and ankle-high offloading devices being equally effective in healing, but knee-high devices have a larger effect on reducing plantar pressure and ambulatory activity. Low-quality evidence exists for the use of felted foam and surgical offloading to promote healing of plantar forefoot and midfoot ulcers. Very limited evidence exists for the efficacy of any offloading intervention for healing plantar heel ulcers, non-plantar ulcers, and neuropathic ulcers with infection or ischemia.CONCLUSION: Strong evidence supports the use of non-removable knee-high offloading devices (either TCC or non-removable walker) as the first-choice offloading intervention for healing plantar neuropathic forefoot and midfoot ulcers. Removable offloading devices, either knee-high or ankle-high, are preferred as second choice over other offloading interventions. The evidence bases to support any other offloading intervention is still weak and more high-quality controlled studies are needed in these areas.
42.	Lehtisalo, Jenni, et al. (författare) Diabetes, glycaemia, and cognitiona secondary analysis of the Finnish Diabetes Prevention Study 2016 Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 32:1, s. 102-110 Tidskriftsartikel (refereegranskat)abstract Background: Type 2 diabetes is linked with cognitive dysfunction and dementia in epidemiological studies, but these observations are limited by lack of data on the exact timing of diabetes onset. We investigated diabetes, dysglycaemia, and cognition in the Finnish Diabetes Prevention Study, in which the timing and duration of diabetes are well documented.Methods: The Finnish Diabetes Prevention Study comprised middle-aged, overweight participants with impaired glucose tolerance but no diabetes at baseline (n=522), randomized to lifestyle intervention or a control group. After an intervention period (mean duration 4years) and follow-up (additional 9years), cognitive assessment with the CERAD test battery and Trail Making Test A (TMT) was executed twice within a 2-year interval. Of the 364 (70%) participants with cognitive assessments, 171 (47%) had developed diabetes.Results: Cognitive function did not differ between those who developed diabetes and those who did not. Lower mean 2-h glucose at an oral glucose tolerance test (OGTT) and HbA(1C) during the intervention period predicted better performance in the TMT (p=0.012 and 0.024, respectively). Those without diabetes or with short duration of diabetes improved in CERAD total score between the two assessments (p=0.001) whereas those with long duration of diabetes did not (p=0.844).Conclusions: Better glycemic control among persons with baseline impaired glucose tolerance predicted better cognitive performance 9years later in this secondary analysis of the Finnish Diabetes Prevention Study population. In addition, learning effects in cognitive testing were not evident in people with long diabetes duration.
43.	Lindahl, Emma, et al. (författare) Early transcriptional regulation by C-peptide in freshly isolated rat proximal tubular cells 2011 Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 27:7, s. 697-704 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Clinical studies have shown that proinsulin C-peptide exerts renoprotective effects in type 1 diabetes, although the underlying mechanisms are poorly understood. As C-peptide has been shown to induce several intracellular events and to localize to nuclei, we aimed to determine whether gene transcription is affected in proximal tubular kidney cells, and if so, whether genes with altered transcription include those related to protective mechanisms. METHODS: The effect of C-peptide incubation (2h) on gene expression was investigated in freshly isolated proximal tubular cells from streptozotocin-diabetic Sprague-Dawley rats using global gene expression profiling and RT-qPCR. Protein expression was assayed using western blotting. Different bioinformatic strategies were employed. RESULTS: Gene transcription profiling demonstrated differential transcription of 492 genes (p<0.01) after 2h of C-peptide exposure, with the majority of these genes repressed (83%). RT-qPCR validation supported a trend of several GPCR's being activated, and certain transcription factors to be repressed. Also, C-peptide repressed the transcription of genes associated with pathways of circulatory and inflammatory diseases. CONCLUSIONS: This study shows that C-peptide exerts early effects on gene transcription in proximal tubular cells. The findings also bring further knowledge to the renoprotective mechanisms of C-peptide in type I diabetes, and supports a transcriptional activity for C-peptide. It is suggested that C-peptide may play a regulatory role in the gene expression of proximal tubular cells.
44.	Lindholm, Eero, et al. (författare) Gender differences in GAD antibody - positive diabetes mellitus in relation to age at onset, C-peptide and other endocrine autoimmune diseases. 2004 Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 20:2, s. 158-164 Tidskriftsartikel (refereegranskat)
45.	Loseth, Sissel, et al. (författare) Polyneuropathy in type 1 and type 2 diabetes : comparison of nerve conduction studies, thermal perception thresholds and intraepidermal nerve fibre densities 2010 Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 26:2, s. 100-106 Tidskriftsartikel (refereegranskat)abstract Background To evaluate possible differences in distal polyneuropathy (PN) characteristics and degree of abnormalities for various small and large fibre parameters in diabetes type 1 (DM1) and type 2 (DM2). Methods Sixty-six DM1 and 57 DM2 patients with or without PN symptoms were included. Nerve conduction studies (NCS), quantitative sensory testing (QST) and quantification of intraepidermal nerve fibres (IENFs) were performed. Z-scores were calculated from reference materials. Results In both groups, 42% had abnormal NCS classification, 42% (DM1) and 39% (DM2) abnormal QST, as well as 40% (DM1) and 32% (DM2) abnormal IENF density. Seventy percent (DM1) and 65% (DM2) had one of the three tests abnormal (differences not significant). Correlations were found between most Z-score parameters and disease duration and HbAlc in DM1, but fewer in DM2. In multivariate analysis, some NCS and QST Z-scores were more abnormal in DM2. Symptom scoring correlated better with NCS and QST parameters in DM1. Conclusions The differences could be referred to disease duration, glycaemic control and possibly patient age. The various parameters from NCS, QST and IENF analysis contribute differently in the assessment of polyneuropathy. Copyright (C) 2009 John Wiley & Sons, Ltd.
46.	Ludvigsson, Johnny (författare) C-peptide an adequate endpoint in type 1 diabetes 2009 Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 25:8, s. 691-693 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract n/a
47.	Ludvigsson, Johnny, et al. (författare) Combined Etanercept, GAD-alum and vitamin D treatment: an open pilot trial to preserve beta cell function in recent onset type 1 diabetes 2021 Ingår i: Diabetes-Metabolism Research and Reviews. - : Wiley. - 1520-7552 .- 1520-7560. Tidskriftsartikel (refereegranskat)abstract Aim We aimed to study the feasibility and tolerability of a combination therapy consisting of glutamic acid decarboxylase (GAD-alum), Etanercept and vitamin D in children and adolescents with newly diagnosed with type 1 diabetes (T1D), and evaluate preservation of beta cell function. Material and Methods Etanercept Diamyd Combination Regimen is an open-labelled multi-centre study pilot trial which enrolled 20 GAD antibodies positive T1D patients (7 girls and 13 boys), aged (mean +/- SD): 12.4 +/- 2.3 (8.3-16.1) years, with a diabetes duration of 81.4 +/- 22.1 days. Baseline fasting C-peptide was 0.24 +/- 0.1 (0.10-0.35) nmol/l. The patients received Day 1-450 Vitamin D (Calciferol) 2000 U/d per os, Etanercept sc Day 1-90 0.8 mg/kg once a week and GAD-alum sc injections (20 mu g, Diamyd (TM)) Day 30 and 60. They were followed for 30 months. Results No treatment related serious adverse events were observed. After 6 months 90-min stimulated C-peptide had improved in 8/20 patients and C-peptide area under the curve (AUC) after Mixed Meal Tolerance Test in 5 patients, but declined thereafter, while HbA1c and insulin requirement remained close to baseline. Administration of Etanercept did not reduce tumour necrosis factor (TNF) spontaneous secretion from peripheral blood mononuclear cells, but rather GAD65-induced TNF-alpha increased. Spontaneous interleukin-17a secretion increased after the administration of Etanercept, and GAD65-induced cytokines and chemokines were also enhanced following 1 month of Etanercept administration. Conclusions Combination therapy with parallel treatment with GAD-alum, Etanercept and vitamin D in children and adolescents with type 1 diabetes was feasible and tolerable but had no beneficial effects on the autoimmune process or beta cell function.
48.	Ludvigsson, Johnny, et al. (författare) Does modern high standard life style cause type 1 diabetes in children? 2013 Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley and Sons. - 1520-7552 .- 1520-7560. ; 29:2, s. 161-165 Tidskriftsartikel (refereegranskat)abstract Background Type 1 diabetes is a serious disease which, in spite of intensive treatment, causes serious complications and increased mortality. The incidence is increasing, but the aetiology is unknown. As part of modern lifestyle, increased hygiene has been suspected as one contributing cause but so far there is no evidence. Several large epidemiological studies, mainly restricted to children with increased genetic risk for type 1 diabetes, have so far given no clue. Methods All Babies in Southeast Sweden is unique in its design as it has followed an unselected group of children from birth 19971999 and onwards with regular follow-ups. This report is based on questionnaires from initially 16051 children of whom 80 have later on developed type 1 diabetes. The parents answered questionnaires at the birth of their child and then after 1, 23, 56 and 8years. A number of parameters possibly related to hygiene were analysed with several statistical methods, both with univariate and in regression models. Results Our study cannot identify any crucial environmental factor. This indicates that hygiene-related parameters traditionally regarded as part of modern life style do not play any important role for the aetiology of type 1 diabetes. Conclusions There is no reason to recommend a change of that part of our lifestyle. We find weak associations to previous gastrointestinal infections, which gives a hint that development of type 1 diabetes may be related to problems in the gut and maybe one should look closer into the microbes living in the gut.
49.	Ludvigsson, Johnny, et al. (författare) GAD-treatment of children and adolescents with recent-onset Type 1 diabetes preserves residual insulin secretion after 30 months 2014 Ingår i: Diabetes/Metabolism Research Reviews. - : Wiley-Blackwell. - 1520-7552 .- 1520-7560. ; 30:5, s. 405-414 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: This study aimed to analyse data from two different studies (Phase II and Phase III) regarding the safety and efficacy of treatment with alum formulated glutamic acid decarboxylase GAD65 (GAD-alum), 30 months after administration to children and adolescents with Type 1 diabetes (T1D).METHODS: The Phase II trial was a double-blind, randomized placebo-controlled study, including 70 children and adolescents which were followed for 30 months. Participants received a subcutaneous injection of either 20 µg of GAD-alum or placebo at baseline and one month later. During a subsequent larger European Phase III trial including three treatment arms, participants received two or four subcutaneous injections of either 20 µg of GAD-alum and/or placebo at baseline, 1, 3 and 9 months. The Phase III trial was prematurely interrupted at 15 months, but of the 148 Swedish patients, a majority completed the 21 months follow-up and 45 patients completed the trial at 30 months. Both studies included GADA-positive patients with fasting C-peptide ≥0.10 nmol/l. We have now combined the results of these two trials.RESULTS: There were no treatment related adverse events. In patients treated with 2 GAD-alum doses, stimulated C-peptide AUC had decreased significantly less (9 m: p < 0.037; 15 m p < 0.032; 21 m p < 0.003 and 30 m p < 0.004) and a larger proportion of these patients were also able to achieve a peak stimulated C-peptide >0.2 nmol/l (p < 0.05), as compared to placebo.CONCLUSION: Treatment with two doses of GAD-alum in children and adolescents with recent-onset T1D shows no adverse events and preserves residual insulin secretion. This article is protected by copyright. All rights reserved.
50.	Ludvigsson, Johnny (författare) Therapy with GAD in diabetes 2009 Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 25:4, s. 307-315 Forskningsöversikt (refereegranskat)abstract The enzyme glutamic acid decarboxylase (GAD) is of great importance for the neurotransmission in the central nervous system, and therefore of interest for treatment of pain and neurological disease. However, it is also released in pancreas although its role is not quite clear. GAD is a major auto-antigen in the process leading to type 1 diabetes with both a clear cell-mediated immune response to GAD and auto-antibodies to GAD (GADA), which call be used as a predictor of diabetes. Administration of the isoform GAD65 can prevent autoimmune destruction of pancreatic beta cells in non-obese diabetic (NOD) mice and the subsequent need for exogenous insulin replacement. In Phase I and II studies an alum-formulated vaccine (Diamyd) has shown to be safe, and in a dose-finding study in Latent Autoimmune Diabetes in Adults (LADA) patients 20-mu g was given subcutaneously one month apart indicating preservation of residual insulin secretion. A double-blind randomized Phase II trial in 70 patients (10-18 years old) with recent-onset type 1 diabetes showed significant preservation of residual insulin secretion and a GAD-specific immune response, both humoral and cell-mediated, but no treatment-related adverse events. With this promising background further studies are on their way, both intervention in newly diagnosed type 1 diabetic patients, and trials to prevent the disease.

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