| 1. |
- Boman, Kurt, et al.
(författare)
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Healthcare resource utilisation and costs associated with a heart failure diagnosis : A retrospective, population-based cohort study in Sweden
- 2021
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To examine healthcare resource use (HRU) and costs among heart failure (HF) patients using population data from Sweden.Design: Retrospective, non-interventional cohort study.Setting: Two cohorts were identified from linked national health registers (cohort 1, 2005-2014) and electronic medical records (cohort 2, 2010-2012; primary/secondary care patients from Uppsala and Västerbotten).Participants: Patients (aged ≥18 years) with primary or secondary diagnoses of HF (≥2 International Classification of Diseases and Related Health Problems, 10th revision classification) during the identification period of January 2005 to March 2015 were included.Outcome measures: HRU across the HF phenotypes was assessed with logistic regression. Costs were estimated based on diagnosis-related group codes and general price lists.Results: Total annual costs of secondary care of prevalent HF increased from SEK 6.23 (€0.60) to 8.86 (€0.85) billion between 2005 and 2014. Of 4648 incident patients, HF phenotype was known for 1715: reduced ejection fraction (HFrEF): 64.5%, preserved ejection fraction (HFpEF): 35.5%. Within 1 year of HF diagnosis, the proportion of patients hospitalised was only marginally higher for HFrEF versus HFpEF (all-cause (95% CI): 64.7% (60.8 to 68.4) vs 63.7% (60.8 to 66.5), HR 0.91, p=0.14; cardiovascular disease related (95% CI): 61.1% (57.1 to 64.8) vs 60.9% (58.0 to 63.7), HR 0.93, p=0.28). Frequency of hospitalisations and outpatient visits per patient declined after the first year. All-cause secondary care costs in the first year were SEK 122 758 (€12 890)/patient/year, with HF-specific care accounting for 69% of the costs. Overall, 10% of the most expensive population (younger; predominantly male; more likely to have comorbidities) incurred ~40% of total secondary care costs.Conclusions: HF-associated costs and HRU are high, especially during the first year of diagnosis. This is driven by high hospitalisations rates. Understanding the profile of resource-intensive patients being at younger age, male sex and high Charlson comorbidity index scores at the time of the HF diagnosis is most likely a sign of more severe disease.
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| 2. |
- Burén, Jonas, et al.
(författare)
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In vitro reversal of hyperglycemia normalizes insulin action in fat cells from type 2 diabetes patients : is cellular insulin resistance caused by glucotoxicity in vivo?
- 2003
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Ingår i: Metabolism. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 52:2, s. 239-45
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Tidskriftsartikel (refereegranskat)abstract
- Chronic hyperglycemia promotes the development of insulin resistance. The aim of this study was to investigate whether cellular insulin resistance is secondary to the diabetic state in human type 2 diabetes. Subcutaneous fat biopsies were taken from 3 age-, sex-, and body mass index (BMI)-matched groups with 10 subjects in each group: type 2 diabetes patients with either good (hemoglobin A(1c) [HbA(1c)] < 7%, G) or poor (HbA(1c) > 7.5%, P) metabolic control and healthy control subjects (C). Insulin action in vitro was studied by measurements of glucose uptake both directly after cell isolation and following a 24-hour incubation at a physiological glucose level (6 mmol/L). The relationship with insulin action in vivo was addressed by employing the euglycemic clamp technique. Freshly isolated fat cells from type 2 diabetes patients with poor metabolic control had approximately 55% lower maximal insulin response (1,000 microU/mL) on glucose uptake (P <.05) compared to C. Cells from P were more insulin-resistant (P <.05) than cells from G at a low (5 microU/mL) but not at a high (1,000 microU/mL) insulin concentration, suggesting insulin insensitivity. However, following 24 hours of incubation at physiological glucose levels, insulin resistance was completely reversed in the diabetes cells and no differences in insulin-stimulated glucose uptake were found among the 3 groups. Insulin sensitivity in vivo assessed with hyperinsulinemic, euglycemic clamp (M-value) was significantly associated with insulin action on glucose uptake in fresh adipocytes in vitro (r = 0.50, P <.01). Fasting blood glucose at the time of biopsy and HbA(1c), but not serum insulin, were negatively correlated to insulin's effect to stimulate glucose uptake in vitro (r = -0.36, P =.064 and r = - 0.41, P <.05, respectively) in all groups taken together. In the in vivo situation, fasting blood glucose, HbA(1c), and serum insulin were all negatively correlated to insulin sensitivity (M-value; r = -0.62, P<.001, r= -0.61, P<.001, and r = -0.56, p <.01, respectively). Cell size, waist-to-hip ration (WHR), and BMI correlated negatively with insulin's effect to stimulate glucose uptake both in vitro (r = -0.55, P <.01, r = -0.54, P <.01, and r = -0.43, P <.05, respectively) and in vivo (r = -0.43, P <.05, r = -0.50, P <.01, and r = -0.36, P <.05, respectively). Multiple regression analyses revealed that adipocyte cell size and WHR independently predicted insulin resistance in vitro. Furthermore, insulin sensitivity in vivo could be predicted by fasting blood glucose and serum insulin levels. We conclude that insulin resistance in fat cells from type 2 diabetes patients is fully reversible following incubation at physiological glucose concentrations. Thus, cellular insulin resistance may be mainly secondary to the hyperglycemic state in vivo.
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| 3. |
- Freiburghaus, Catja, et al.
(författare)
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Lactoferricin treatment decreases the rate of cell proliferation of a human colon cancer cell line.
- 2009
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Ingår i: Journal of Dairy Science. - : American Dairy Science Association. - 1525-3198 .- 0022-0302. ; 92:6, s. 2477-2484
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Tidskriftsartikel (refereegranskat)abstract
- Food components modify the risk of cancer at a large number of sites but the mechanism of action is unknown. In the present investigation, we studied the effect of the peptide lactoferricin derived from bovine milk lactoferrin on human colon cancer CaCo-2 cells. The cells were either untreated or treated with 2.0, 0.2, or 0.02 microM lactoferricin. Cell cycle kinetics were investigated with a bromodeoxyuridine DNA flow cytometric method. The results show that lactoferricin treatment slightly but significantly prolonged the S phase of the cell cycle. Lactoferricin treatment lowered the level of cyclin E1, a protein involved in the regulation of genes required for G(1)/S transition and consequently for efficient S phase progression. The slight prolongation of the S phase resulted in a reduction of cell proliferation, which became more apparent after a long treatment time.
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| 4. |
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| 5. |
- Freiburghaus, Catja, et al.
(författare)
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Reduction of ultraviolet light-induced DNA damage in human colon cancer cells treated with a lactoferrin-derived peptide
- 2012
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Ingår i: Journal of Dairy Science. - : American Dairy Science Association. - 1525-3198 .- 0022-0302. ; 95:10, s. 5552-5560
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of Caco-2 cells with the peptide lactoferricin(4-14), results in reduction of the growth rate by prolongation of the S phase of the cell cycle. Lactoferricin(1-25) is formed in the gut by cleavage from lactoferrin and the bioactive amino acids are found within lactoferricin(4-14). Our hypothesis is that the reduction of the rate of S phase progression may result in increased DNA repair. To test this hypothesis, Caco-2 cells were subjected to UV light that caused DNA lesions and then the cells were grown in the absence or presence of 2.0 mu M lactoferricin(4-14). Evaluation of DNA strand breaks using the comet assay showed that lactoferricin(4-14) treatment indeed resulted in a reduction of comets showing damaged DNA. In the search for a mechanism, we have investigated the levels of several proteins involved in cell cycle regulation, DNA replication, and apoptosis using Western blot. Lactoferricin(4-14) treatment resulted in an increased expression of flap endonuclease-1 pointing to increased DNA synthesis activity. Lactoferricin(4-14) treatment decreased the expression of the proapoptotic protein B-cell lymphoma 2-associated X protein (or Bax), indicating decreased cell death. As we have found previously, lactoferricin(4-14) treatment reduced the expression of cyclin E involved in the G(1)/S transition. Immunofluorescence microscopy showed that a lower gamma-H2AX expression in lactoferricin(4-14)-treated cells, pointing to more efficient DNA repair. Thus, altogether our data show that lactoferricin(4-14) treatment has beneficial effects.
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| 6. |
- Jansson, Per-Anders, 1961, et al.
(författare)
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Endocrine abnormalities in healthy first-degree relatives of type 2 diabetes patients--potential role of steroid hormones and leptin in the development of insulin resistance.
- 2002
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Ingår i: European journal of clinical investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 32:3, s. 172-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: First-degree relatives of type 2 diabetes patients are at risk of developing diabetes and they display several metabolic and hormonal perturbations. The interplay between insulin resistance, steroid hormones and circulating leptin is, however, still not fully explored in this group. DESIGN: Thirty-three healthy first-degree relatives of type 2 diabetic patients (relatives; M/F 19/14) were compared to 33 healthy subjects without a family history of diabetes (controls) and the groups were matched for gender, age and body mass index (BMI). We performed euglycaemic hyperinsulinaemic clamps and blood was sampled for hormone analyses. RESULTS: Relatives exhibited decreased insulin sensitivity (index of metabolic clearance rate of glucose; MCRI) but when genders were analysed separately, this difference was significant only in males (11.3 +/- 1.3 vs. 15.0 +/- 1.5 units, means +/- SEM, P = 0.030). In male relatives morning cortisol and testosterone levels were lower, whereas leptin was higher than in male controls (P = 0.018, 0.008 and 0.063, respectively). In male relatives plasma testosterone levels were significantly associated with insulin sensitivity (r = 0.48, P = 0.040). Circulating leptin levels were inversely correlated with insulin sensitivity in all subject groups (r-values -0.49 to -0.66; P < 0.05, except in female control subjects P = 0.063). These associations were present also when age and BMI or waist:hip ratio were included in stepwise multiple regression analyses. CONCLUSION: Male subjects genetically predisposed for type 2 diabetes display several endocrine abnormalities including leptin, cortisol and testosterone levels. Dysregulation of these hormones may be important in the development of insulin resistance and type 2 diabetes.
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| 7. |
- Lindmark, Stina, et al.
(författare)
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Does the autonomic nervous system play a role in the development of insulin resistance? : a study on heart rate variability in first-degree relatives of type 2 diabetes patients and control subjects
- 2003
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 20:5, s. 399-405
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Tidskriftsartikel (refereegranskat)abstract
- Aims To investigate dysregulation of the autonomic nervous system as a potential mechanism for early insulin resistance in the development of Type 2 diabetes. Methods Thirteen healthy individuals with first-degree relatives with Type 2 diabetes (R) were compared with 14 control subjects without family history of diabetes (C), matched for age, body mass index and sex. An oral glucose tolerance test and a hyperinsulinaemic euglycaemic clamp were performed. Analysis of heart rate variability during rest, controlled breathing, an orthostatic manoeuvre and a standardized physical stress (cold pressor test (CPT)), were used to evaluate the activity of the autonomic nervous system. Results Fasting blood glucose, HbA1c and serum insulin were similar in the R and C groups. The M-value, reflecting insulin sensitivity, did not differ significantly between the groups. Total spectral power and high-frequency power were lower in R during controlled breathing (P = 0.05 and P = 0.07, respectively), otherwise there were no significant differences between R and C in heart rate variability. However, low-frequency (LF)/high-frequency (HF) spectral power ratio during CPT, reflecting sympathetic/parasympathetic balance, was negatively associated with insulin sensitivity (r = −0.53, P = 0.006). When all subjects were divided into two groups by the mean M-value, the low M-value group displayed an overall higher LF/HF ratio (P = 0.04). HF power was lower in the low M-value group during controlled breathing and CPT (P = 0.01 and P = 0.03, respectively). Conclusion An altered balance of the parasympathetic and sympathetic nervous activity, mainly explained by an attenuated parasympathetic activity, might contribute to the development of insulin resistance and Type 2 diabetes.
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| 8. |
- Lindmark, Stina, et al.
(författare)
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Dysregulation of the autonomic nervous system can be a link between visceral adiposity and insulin resistance
- 2005
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Ingår i: Obesity Research. - : Wiley. - 1071-7323 .- 1550-8528. ; 13:4, s. 717-728
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To evaluate the interplay among abdominal adipose tissue distribution, the cortisol axis, the autonomic nervous system, and insulin resistance. RESEARCH METHODS AND PROCEDURES: Two age-, sex-, and BMI-matched groups were studied. Fifteen subjects were first-degree relatives of patients with type 2 diabetes (R), and 15 had no family history of diabetes (controls, C). A hyperinsulinemic euglycemic clamp, cortisol measurements, and analysis of heart rate variability (HRV) were performed. Computed tomography was performed in a subgroup (n = 9 + 9) to determine abdominal adipose tissue distribution. RESULTS: R tended to be less insulin-sensitive than C (M value 9.2 +/- 1.0 vs 10.3 +/- 0.7 mg/kg per minute, not significant). Stimulation with tetracosactin or corticotropin releasing hormone yielded lower peak serum cortisol levels in R (p = 0.03 and p = 0.06, respectively). The amount of visceral abdominal fat (VAT) tended to be greater in R. In all subjects, VAT was negatively correlated to insulin sensitivity (r = -0.93, p < 0.001). There was a positive association between VAT and resting heart rate (r = 0.70, p = 0.003) and sympathetic/parasympathetic ratio in HRV assessment after tilt (r = 0.53, p = 0.03). Subcutaneous abdominal tissue was not associated with insulin sensitivity or any of the hormonal or HRV assessments. DISCUSSION: Subjects genetically predisposed for type 2 diabetes had a tendency toward a larger amount of VAT and to lower insulin sensitivity compared with control subjects. The amount of visceral fat was strongly associated with insulin resistance and signs of a high ratio of sympathetic vs. parasympathetic reactivity. A large amount of visceral fat may act in concert with sympathetic/parasympathetic imbalance to promote the development of insulin resistance, and this may be partly independent of genetic background.
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| 9. |
- Lindmark, Stina, et al.
(författare)
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Insulin resistance, endocrine function and adipokines in type 2 diabetes patients at different glycaemic levels : potential impact for glucotoxicity in vivo
- 2006
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Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664 .- 1365-2265. ; 65:3, s. 301-309
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate the interplay between hyperglycaemia, insulin resistance, hormones and adipokines in patients with type 2 diabetes mellitus (T2DM). Design and methods Ten patients with T2DM with good glycaemic control (G), 10 with poor control (P) and 10 nondiabetic control subjects (C) were matched for sex (M/F 6/4), age and body mass index. A hyperinsulinaemic, euglycaemic clamp was performed and cytokines and endocrine functions, including cortisol axis activity were assessed. Results Patients with diabetes were more insulin resistant than group C, and group P exhibited the highest degree of insulin resistance ( P = 0·01, P vs C). Tumour necrosis factor (TNF)-alpha levels were elevated in patients with diabetes ( P = 0·05) and group P had the highest levels of fasting serum cortisol ( P = 0·05), nonesterified fatty acids (NEFA; P = 0·06) and C-reactive protein (CRP; P = 0·01). Adiponectin levels were lower in the P group. In partial correlation analyses, significant associations were found: glycaemic level (HbA1c) with insulin resistance, TNF-alpha, CRP and basal and ACTH-stimulated cortisol levels, insulin resistance with plasma NEFA, TNF-alpha and stimulated cortisol levels. Conclusion Poor glycaemic control in patients with T2DM was associated with insulin resistance and with elevated TNF-alpha, CRP and basal as well as stimulated cortisol levels. Inflammatory mediators, e.g. TNF-alpha, may contribute to insulin resistance in hyperglycaemic patients with T2DM and this might be a partial explanation for glucotoxicity.
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| 10. |
- Lindmark, Stina, 1965-
(författare)
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Neurohormonal mechanisms in insulin resistance and type 2 diabetes
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Insulin resistance usually occurs early in the development of type 2 diabetes. An altered balance in the autonomic nervous system and in certain endocrine and inflammatory pathways, might contribute to the development of insulin resistance. In diabetes, hyperglycemia further aggravates insulin resistance as well as beta cell dysfunction but the mechanisms causing this phenomenon, i.e. glucotoxicity, are not fully understood. Insulin resistance can be demonstrated in healthy first-degree relatives of type 2 diabetes patients who also have a high risk of developing type 2 diabetes. Relatives and control subjects without family history of diabetes were studied with respect to insulin sensitivity and the activity in the autonomic nervous system (ANS) and in the cortisol axis. Levels of sex hormones, leptin and cytokines were analysed. Abdominal adipose tissue distribution was determined with computed tomography. Male relatives had decreased testosterone levels and increased leptin levels. There was an inverse relationship between insulin sensitivity and leptin levels, and in males a positive association between insulin sensitivity and testosterone levels. A tendency to lower parasympathetic reactivity was found in the relatives using heart rate variability assessment. The sympathetic/parasympathetic ratio during stress provocation was inversely correlated to insulin sensitivity, measured with glucose clamp. The insulin-resistant subjects also exhibited an overall blunted reactivity in the ANS. Cortisol reactivity after stimulation with ACTH and CRH was lower in the relatives. The amount of visceral adipose tissue (VAT) was associated with insulin resistance and with heart rate at rest and during controlled breathing and it also correlated with heart rate and sympathetic/parasympathetic ratio after an orthostatic manoeuvre. Type 2 diabetic subjects with good and poor glycemic control, respectively, and matched healthy control subjects were examined with respect to insulin sensitivity, cortisol axis activity and blood levels of leptin, sex hormones and the adipocyte-secreted inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Biopsies were taken from subcutaneous adipose tissue for determination of adipocyte size. Diabetes subjects were more insulin-resistant than controls and diabetics with poor control exhibited the highest degree of insulin resistance. This group also had the highest levels of TNF-α, morning serum cortisol and non-esterified fatty acids (NEFA). In correlation analyses, significant associations were seen between glycemic level and insulin resistance, TNF-α, IL- 6 and serum cortisol levels. Insulin resistance was positively correlated to NEFA levels, TNF-α and ACTH-stimulated cortisol levels. Adipocyte size was associated with insulin resistance and levels of IL-6 and leptin. The findings support a connection between insulin resistance and VAT amount, activity in the ANS and blood levels of hormones and adipocyte-derived molecules. Dysregulation in the complex interplay between such factors may contribute to the early pathogenesis of insulin resistance and type 2 diabetes. Adipokines and the cortisol system can also potentially aggravate hyperglycemia in patients with manifest type 2 diabetes.
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