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  • Björck, Hanna, 1979- (författare)
  • Vessel wall integrity influence of genetics and flow
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Cardiovascular disease (CVD) is the major cause of death worldwide. Underlying causes, such as atherosclerosis and hypertension, are associated with remodeling of the vessel wall ultimately leading to loss of structural integrity. There are a number of factors that can influence vascular remodeling and hence structural integrity. The overall aim of this thesis was to investigate aortic wall integrity in relation to genetics and blood flow.</p><p>The influence of SNPs within the currently most robust susceptibility locus identified for CVD (chromosome 9p21.3) on abdominal aortic integrity was studied in elderly individuals. In men, risk-variants were associated with a decreased abdominal aortic stiffness, independent of other factors related to arterial stiffness. Impaired mechanical properties of the abdominal aortic wall may explain the association between chromosome 9p21.3 and vascular disease.</p><p>Plasminogen activator inhibitor 1 (PAI-1) is the key inhibitor of fibrinolysis, and involved in several processes associated with vascular remodeling. We investigated the impact of the PAI-1 4G/5G polymorphism on central aortic blood pressure as this pressure more strongly relates to cardiovascular morbidity and mortality than the peripheral pressure. Elderly women carrying the 4G/4G genotype had higher central aortic blood pressure than women carrying the 5G/5G genotype. The association was regardless of other risk factors related to hypertension, suggesting that an impaired fibrinolytic potential may play an important role in the development of hypertension in women.</p><p>Blood flow is a strong determinant of arterial growth and vascular function. We investigated flow-dependent gene expression and vessel wall morphology in the rat aorta under physiological conditions. Microarray analysis revealed a strong differential gene expression between disturbed and uniform flow pattern regions, particularly associated with transcriptional regulation. Moreover, several genes related to Ca<sup>2+</sup> signalling were among the most highly differentially expressed. Up-regulation of Ca<sup>2+</sup>-related genes may be due to endothelial response to disturbed flow and assembly of cilia, consequently leading to functional and structural modifications of the vessel wall.</p><p>Bicuspid aortic valve (BAV) is a congenital disorder associated with disturbed ascending aortic blood flow. Using a new strategy to dissect flow-mediated gene expression we identified several novel flow-associated genes, particularly related to angiogenesis, wound healing and mechanosensing, showing differential expression in the ascending aorta between BAV and tricuspid aortic valve patients. Fifty-five percent of the identified genes were confirmed to be flowresponsive in the rat aorta. A disturbed flow, and consequently an altered gene expression, may contribute to the increased aneurysm susceptibility associated with BAV morphology.</p>
  • Björk Wilhelms, Daniel (författare)
  • Fever : Role of brain endothelial prostaglandins
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Fever and loss of appetite are two of the most fundamental manifestations of disease. These disease symptoms, which lead to deviations from normal body temperature and food intake patterns, are seen in a vast array of infectious and inflammatory conditions. It is known that peripheral signals from the immune system are essential triggers for these responses, which are orchestrated by neuronal circuits in the brain. Due to the blood‐brain barrier, peripheral inflammatory signals require a specific mode of transmission into the brain. Such mechanisms have been proposed, but interventional studies of these mechanisms have never rendered conclusive results. In this thesis, we present the first functional evidence of cyclooxygenase 2 (COX‐2) and microsomal prostaglandin E synthase type 1 (mPGES‐1) mediated prostaglandin E2 synthesis in the blood‐brain barrier endothelial cells as a signaling mechanism in the initiation of inflammatory fever. We also show that one of the world’s most widely used antipyretics, paracetamol, acts by inhibition of COX‐2. Combined with the finding that COX‐2 and mPGES‐1 in brain endothelial cells play a key role in inflammatory fever, this finding suggests that paracetamol inhibits fever by specifically blocking prostaglandin E2 synthesis in blood‐brain barrier endothelium. In another symptom of inflammation, anorexia, the cellular origin of peripheral signals triggering acute anorexia are largely unknown. We show that the expression of myeloid differentiation primary response gene 88 (Myd88) in myeloid cells is important for the initiation of acute inflammatory anorexia and the maintenance of cancer anorexia‐cachexia.</p><p>Taken together, these findings provide a significant advancement of our understanding of the mechanisms triggering acute inflammatory fever and anorexia and also explain the antipyretic effect of paracetamol.</p>
  • Björnsson, Bergþór, 1975- (författare)
  • Methods to Reduce Liver Ischemia/Reperfusion Injury
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Introduction:</strong> During the last two decades, liver surgery has expanded enormously, partly due to improved surgical equipment and techniques as well as new and more powerful chemotherapy agents. As the liver is a very well-vascularized organ, there is an inherent risk of bleeding during liver resection. One of the most popular methods employed to reduce this risk is to close the vascular inflow to the liver using the Pringle’s maneuver (PM). However, this procedure has been recognized to cause ischemia/reperfusion injury (IRI) to the future liver remnant (FLR). In cases of extensive resection where the FLR is small and in cases when the liver suffers from chronic diseases, such as cirrhosis, IRI can greatly increase the risk of post-operative liver failure (POLF). Ischemic preconditioning (IPC) and, more recently, remote ischemic preconditioning (R-IPC) are methods that have been employed to reduce IRI.</p><p><strong>Aim:</strong> 1) To compare the effects of IPC and R-IPC in a rat model; 2) to investigate the clinical effect of IPC during modern liver surgery; 3) to investigate the role of the nitric oxide (NO) system in IRI, IPC and R-IPC; and 4) to explore the possible protective effects of nitrite administration before IRI.</p><p><strong>Methods:</strong> A rat model of segmental ischemia followed by 4 hours of reperfusion including microdialysis (μD) was developed from earlier models. The effects of IPC and R-IPC were compared using transaminases and histology as well as continuous μD sampling for glucose, pyruvate, lactate and glycerol. The role of the NO system was examined by serum and μD measurements of NOx as well as tissue measurements of iNOS mRNA and IL-1R mRNA. In study II, patients were randomized to IPC or no IPC prior to liver resection, where intermittent PM was used to decrease bleeding.</p><p><strong>Results:</strong> IPC was more effective in protecting the liver against IRI than R-IPC, as indicated by the levels of transaminases. Lower lactate levels were detected in patients treated with IPC before major liver resections than in controls. IPC reduced iNOS mRNA transcription during reperfusion; this result may be related to the early but not sustained increases in IL-1R transcription observed in the IPC group. Nitrite administered before ischemia reduced AST and ALT levels in the level after 4 hours of reperfusion; in addition, necrosis and glycerol release from the ischemic liver were reduced as well.</p><p><strong>Conclusion:</strong> IPC is more effective than R-IPC in animal models; however, this effect is unlikely to be of clinical importance. NOx decreases in the ischemic liver and the administration of nitrite before ischemia reduces IRI in rats. This may have clinical implications in the future.</p>
  • Björnsson Hallgren, Hanna Cecilia, 1976- (författare)
  • Treatment of subacromial pain and rotator cuff tears
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong><em>Shoulder pain</em></strong> is very common, affecting 14-21 % of the population at some time during their lifetime. The aims of this thesis were to improve the understanding of various aspects concerning the pathogenesis and treatment of subacromial pain and rotator cuff tears. Patients and healthy individuals were examined and compared in five studies:</p><p><strong><em>Study I</em>)</strong> Seventy patients were retrospectively examined, clinically and with ultrasound, 15 years after arthroscopic subacromial decompression. All patients had an intact rotator cuff at surgery. Ultrasound showed significantly fewer rotator cuff tears compared to the prevalence of asymptomatic tears reported in the literature for the same age group. This indicates that arthroscopic subacromial decompression might protect the rotator cuff.</p><p><strong><em>Study II)</em></strong> Forty-two patients were retrospectively examined, clinically and with ultrasound, 39 months (mean) after an acute rotator cuff repair. All patients had pseudoparalysis after trauma, a full thickness tear and no previous history of shoulder symptoms. A delay in surgical treatment of three months and the number of tendons injured did not affect the outcome. Age affected outcome negatively.</p><p><strong><em>Study III)</em></strong> Plasma samples from 17 patients with cuff tears and 16 plasma samples from healthy age- and gender-matched controls were collected and analysed regarding the levels of matrix metalloproteinases and their inhibitors, TIMP1-4. Elevated levels of TIMP-1 were found in the patients with cuff tears compared to controls. Higher levels of TIMP-1, TIMP-3 and MMP-9 were found in patients with full-thickness tears compared to patients with partial-thickness tears.</p><p><strong><em>Study IV)</em></strong> Ninety-seven patients with longstanding subacromial pain, on the waiting-list for arthroscopic subacromial decompression, were prospectively randomised to specific shoulder exercises or control exercises for three months. Thereafter they were clinically examined and asked if they still wanted surgery. The specific shoulder exercises focusing on eccentric exercise for the rotator cuff and scapula stabilisers were found to be effective in reducing subacromial pain and improving shoulder function, thereby reducing the need for surgery.</p><p><strong><em>Study V)</em> </strong>All patients including those operated, in <em>Study IV</em> were re-examined after one year using clinical assessment scores. The option of surgery was continuously available up to the one-year follow-up. Ultrasound and radiological examinations performed at inclusion were analysed in relation to the choice of surgery. The positive effects of the specific exercise programme were maintained after one year and significantly fewer patients in this group chose surgery. Surgery was significantly more often chosen by patients who had a low baseline shoulder score, and/or a full thickness rotator cuff tear.  All patients showed significant improvement in the clinical scores one year after inclusion or one year after surgery.</p><p>These results support the concept that subacromial pain has a multifactorial aetiology and that the first line of treatment should be specific shoulder exercises. When conservative treatment fails, an acceptable result can be achieved with arthroscopic subacromial decompression. The rotator cuff status is important to consider when treating and studying these patients.</p>
  • Borendal Wodlin, Ninnie (författare)
  • Fast track abdominal hysterectomy On the mode of anesthesia, postoperative recovery and health economics
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Introduction:</strong> Hysterectomy is the most common major gynecological operation in the Western World and approximately 5000 benign hysterectomies are performed in Sweden every year. Consequently it is a surgical procedure that affects many women. The procedure comprises challenges concerning perioperative health care, perceived postoperative symptoms, quality of life aspects and health economics. The concept of fast track is a multimodal strategy to reduce hormonal surgical stress response and achieve an enhanced postoperative recovery and is today considered to be evidence based in relation to colorectal surgery. Spinal anesthesia, as an important part of fast track, provides benefits of extended effect on analgesia and reduced postoperative morbidity. It is reasonable to believe that employing the strategies of fast track including spinal anesthesia could also provide substantial benefits for women requiring surgical removal of the uterus.</p><p><strong>Aims:</strong> To determine whether duration of hospital stay, presence and intensity of postoperative symptoms, duration of sick leave and cost-effectiveness differ between women undergoing benign fast track abdominal hysterectomy in spinal anesthesia with intrathecal morphine (SA) and in standard general anesthesia (GA).</p><p><strong>Material &amp; Methods:</strong> 180 women participated in this open randomized multicenter study with five participating hospitals in the southeast region of Sweden. One hundred and sixty two completed the study; 82 women were randomized to SA and 80 to GA. A fast track model comprising premedication without sedatives, intravenous fluid regulation, analgesics based on non-opioids, pre-emptive antiemetic therapy, early enteral nutrition and mobilization and standard criteria for discharge were used. End points were duration of hospital stay, use of analgesics, perceived postoperative symptoms, occurrence of postoperative complications, duration of sick leave and health economic evaluations.</p><p><strong>Results:</strong> Duration of hospital stay did not differ between the two modes of anesthesia. Vomiting and pruritus occurred significantly more often after SA. Complication rates did not differ between groups. Women with SA experienced less overall discomfort and had a reduced need for opioids postoperatively. Abdominal pain, drowsiness and fatigue occurred less often and with lower intensity among the women in the SA group. Health related quality of life improved faster and the duration of sick leave was shorter in women after SA. Total costs (hospital costs plus costs for productivity loss) were lower for the SA group. Within the first 29 days after hysterectomy the women in the SA group gained more QALYs than women in the GA group.</p><p><strong>Conclusions:</strong> The duration of hospitalisation after fast track abdominal hysterectomy was less than 50 hours and mode of anesthesia did not influence this. SA displayed considerable advantages regarding postoperative symptoms and recovery. SA was considered cost-effective in comparison with GA due to lower total costs and more QALYs gained. Our study indicates that SA should be recommended as the first choice of anesthesia in benign abdominal hysterectomy.</p>
  • Bostner, Josefine, 1981- (författare)
  • The Akt/mTOR Pathway and Estrogen Receptor Phosphorylations a crosstalk with potential to predict tamoxifen resistance in breast cancer
  • 2013
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Estrogen receptor α content is the primary breast cancer biomarker distinguishing the patients responsive from the non-responsive to endocrine treatments. Tamoxifen is an estrogen competitor with large potential to treat breast cancer patients and prolongs time to recurrence. Despite the estrogen receptor positivity and tamoxifen treatment, many women face recurrence of the disease. An important mechanism of resistance to endocrine treatments is upregulated growth factor signaling, and the subsequent effect on the estrogen receptor, rendering an active receptor that stimulates cell proliferation or reduced estrogen-receptor dependence.</p><p>This thesis concerns the investigation of biomarkers, as a complement to the existing markers, for determining optimal treatment for patients with primary invasive breast cancer. Randomized patient tumor materials were used in order to measure variations in gene copies, proteins, and protein phosphorylations and to further relate these variations to time-to-recurrence. Endocrine untreated groups within the patient tumor sets gave us the opportunity to study the prognostic potential of selected markers and to compare tamoxifen-treated patients with endocrine untreated, thus obtaining a treatment-predictive value of each marker or marker combination.</p><p>In endocrine-dependent cancer the 11q13 chromosomal region is frequently amplified, harboring the genes encoding the cell cycle stimulator cyclin D1 and the estrogen receptor phosphorylating kinase Pak1, respectively. Amplification of the genes was associated with reduced time-torecurrence, indicating a prognostic value, whereas PAK1 gene amplification predicted reduced response to tamoxifen treatment. Moreover, the protein expression of Pak1 tended to predict treatment response, which led to the investigation of this protein in a larger cohort. Together with one of its targets, the estrogen receptor phosphorylation at serine 305, Pak1 predicted reduced response to tamoxifen treatment when detected in the nucleus of tumor cells, suggesting activation of this pathway as a mechanism for tamoxifen-treatment resistance. The estrogen receptor is phosphorylated by several growth factor stimulated kinases. The role of serine-167 phosphorylation has been debated, with inconsistent results. To study the biomarker value of this site the upstream activity of Akt, mTOR, and the S6 kinases were analyzed individually and in combinations. As a prognostic factor, serine 167 indicated an improved breast cancer survival, and as a treatment predictive factor we could not detect a significant value of serine 167 as a single marker. However, in combination with serine 305, and Akt/mTOR-pathway activation, the response to tamoxifen treatment was reduced. The mTOR effector protein S6K1 was found to be associated with HER2 positivity and a worse prognosis. In the group of patients with S6K1 accumulation in the tumor cell nuclei, treatment did not prolong time-to-recurrence, similarly as observed with expression of active S6 kinases. In vitro, a simultaneous knockdown of the S6 kinases in estrogen receptor-positive breast cancer cells resulted in G1 arrest, and tamoxifen-induced G1 arrest was in part S6 kinase dependent.</p><p>The results presented herein suggest biomarkers that would improve treatment decisions in the clinic, specifically for estrogen receptor-positive breast cancer and tamoxifen treatment but in a broader perspective, also for other endocrine treatments and targeted treatments.</p>
  • Boström, Inger, 1946- (författare)
  • Epidemiological Studies of Multiple Sclerosis in Sweden with focus on the County of Värmland
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The aim of this thesis was to study the frequency of MS in the suggested high-risk area of Värmland county by investigating the current prevalence and analyzing the development over time; secondly to investigate some aetiological factors – the pattern of industry, both in relation to MS in Värmland and in the whole country, and also to examine the possible relation between the distribution of MS and ALS, as it has previously shown a positive correlation in two studies; finally to analyze the women-to-men ratio of MS in Sweden because of international reports of an increasing ratio.</p><p>Clinical data was collected from hospitals and other health care units in the county of Värmland, to calculate the prevalence ratio. The prevalence was 170.07 per 100,000 population on the prevalence day, 31 December 2002. The incidence rates analysed during ten years was 6.46 per 100,000 personyears (1991-1995) and 6.39 (1996-2000).</p><p>The ecological study used data from the beginning of the 20th century on industries in Värmland and in all Sweden, which were correlated with the two MS prevalence studies (1925-1934 and 2002), and the mortality study on the time period 1952-1990. There was a statistical significant association between large sawmills and the prevalence 1925-1934 (p = 0.022). For all Sweden, wood-pulp factories and papermills correlated significantly with MS mortality 1952-1990 (p = &lt;0.05).</p><p>Collected data from Causes of death Register and from the Total Population Register were used when analysing mortality from ALS and MS. The previously shown correlation between ALS and MS mortality distribution in the Swedish counties was not confirmed in this study. However, the mean MS mortality rate was still highest in the county in Värmland. The mean MS mortality rates for whole Sweden was increased from 1.65 per 100,000 person-years (1952-1992) to 2.04 (1990-2010).</p><p>For analysing sex ratio in MS, data from the Swedish Multiple Sclerosis Register and data from Total Population Register of the Swedish Statistics Office were used. These data was analysed by birth day cohort and by year of onset. The sex ratios in Sweden showed a stable women-to-men ratio.</p><p>These investigations give indication that Värmland is a high-risk region of multiple sclerosis, and particularly the municipality of Säffle.</p><p>We conclude that Värmland is a suitable area for continued epidemiological studies with both an environment and genetic focus.</p>
  • Bourghardt Peebo, Beatrice, 1968- (författare)
  • Angiogenesis from a new perspective
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Angiogenesis is the emergence of new blood and lymph vessels from existing ones. In the pathologic form it contributes to the onset and progression of numerous different human disorders such as cancer, inflammation, atherosclerosis and blinding eye diseases. There exist a number of models to study angiogenesis, both in vitro and in vivo, but there is no single perfect model so far. Consequently there is a need to develop new angiogenesis assays for evaluating blood and lymph vessel behaviour in different physiologic settings.</p><p>The aim of this thesis was to gain insight into in vivo angiogenesis introducing a new technique in an inflammatory corneal model. The method involved in vivo examination of the cornea and subsequent comparison of in vivo findings with ex vivo immunohistochemical analysis of the same tissue samples. An existing suture model for inflammatory angiogenesis in the cornea was modified for in vivo observations with a clinically-approved corneal confocal microscope.</p><p>In this thesis, corneal lymph vessels were characterized for the first time in vivo and findings from the experimental bench could be applied in a clinical setting, where presumed lymphatics were observed in a corneal transplant patient with rejection. Furthermore, the technique was extended to investigate time-lapse processes in sprouting and regressing capillaries, and led to a number of new observations. CD11b+ myeloid cells constitute the first bulk of infiltrating inflammatory cells and contribute to inflammatory sprouting and regression in numerous ways including pre-patterning of the corneal stroma and guiding of capillary sprouts. Newly formed hemangiogenic sprouts are perfused with a slow-moving fluid and have a lumen. In blood vessel regression, capillary remodeling occurred by abandonment of sprout tips in close association with macrophages and vascular loops formed by presumed intussusceptive angiogenesis. In addition, a network of pericyte- and endothelium-free basement membrane tubes was formed after desertion or degradation of vascular endothelium in former corneal capillaries.</p><p>In conclusion, we introduce a new in vivo technique for investigating angiogenesis in a corneal model were in vivo findings can be interpreted with ex vivo definitions of specific cell types by immunohistochemistry. Findings from pre-clinical experiments have been possible to apply in a clinical setting when examining patients with corneal pathology.</p>
  • Brüggemann, A. Jelmer (författare)
  • Toward an Understanding of Abuse in Health Care A Female Patient Perspective
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Background.</strong> High numbers of incidents of abuse in health care (AHC) have been reported by patients in Sweden. In questionnaire studies (n=9600), every fifth Swedish woman and every tenth Swedish man reported any lifetime experience of AHC, and a majority reported suffering from their experiences. Female patients with experiences of AHC described them as experiences of being nullified, and male patients as experiences of being mentally pinioned. Little is known about why AHC occurs and how it can prevail in a health care system that aims to relieve patients’ suffering.</p><p><strong>Aim.</strong> The overall aim of the thesis was to bring understanding to what AHC is and to start exploring what contributes to its occurrence, focusing on a female patient perspective.</p><p><strong>Methods.</strong> In study I, a concept analysis of AHC was conducted based on the concept’s appearance in scientific literature and through case studies. Also, AHC was demarcated against the related concepts patient dissatisfaction, medical error, and personal identity threat, in order to analyze differences and similarities with these concepts. For studies II and III the Transgressions of Ethical Principles in Health Care Questionnaire (TEP) was developed to measure to what extent female patients remain silent toward the health care system after having experienced abusive or wrongful ethical transgressions in the Swedish health care system. It was hypothesized that to a high degree female patients remain silent toward the health care system after such experiences, and this lack of feedback may in turn contribute to the hampering of structural change toward better encounters. The questionnaire was answered by female patients recruited at a women’s clinic in the south of Sweden (n=530). Study IV built on a constructed grounded theory design and included informants who reported experiences of AHC in TEP (n=12). The interviews focused on the informants’ stories of what contributed to their experiences of AHC.Results.</p><p><strong>Results.</strong> Based on the concept analysis, AHC was described as patients’ subjective experiences in health care of encounters devoid of care, in which they experienced suffering and loss of their human value. Study II showed that a majority of the female patients who perceived one or more transgressions as abusive or wrongful remained silent about at least one of them (70.3%). In 60% of all cases, patients remained silent about abusive or wrongful events. In study III it was examined whether patients remaining silent could be associated with any patient characteristics. Remaining silent was only found to be associated with younger age and a lower self-rated knowledge of patient rights. In study IV, female patients’ stories of what contributed to their experiences of AHC were analyzed. This was best characterized as a process where the patient loses power struggles. According to these patients, not only their vulnerability, but also their level of competence contributed to staff’s unintended use of domination techniques by which they felt abused.</p><p><strong>Conclusions.</strong> As AHC is defined from patients’ subjective experiences it is necessary for the prevention of AHC to listen to patients’ stories and complaints. The prevalence of female patients’ silence after abusive events could be worrying, as it constitutes a loss of essential feedback for the health care system. Patients do not bear responsibility for the quality of health care processes, but their knowledge may be very valuable for structural improvement of these processes and could be valued as such. Clinical interventions that stimulate these patients to speak up, accompanied by health care staff’s reflections on how to respond to patients speaking up, must therefore be explored.</p>
  • Brännmark, Cecilia, 1983- (författare)
  • Insulin Signaling in Human Adipocytes a Systems Biology Approach
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Obesity and a sedentary life style are associated with type 2 diabetes, a disease starting with insulin resistance in the adipose tissue, which spreads to the whole body. Despite large research efforts to understand the insulin signaling system, there is little knowledge of the mechanisms behind insulin resistance and type 2 diabetes developments. We have herein focused on the insulin signaling in adipocytes, elucidating mechanisms for early signaling. We have also modeled isolated adipocytes and data from the in vivo, whole bodysituation, concurrently. We also mapped and quantitatively described differences in the insulin signaling of adipocytes from type 2 diabetics and non-diabetics.</p><p>In paper I we show that neither insulin degradation, receptor internalization, nor feedback signals can as separate explanations cause the overshoot in tyrosine phosphorylation of IRS1, while an endocytosis-dependent feedback mechanism explains all available data.</p><p>In paper II we show that it is not possible to scale up the experimentally determined glucose uptake by isolated human adipocytes to match the glucose uptake profile of the whole adipose tissue in vivo. Other insulin effects need to be accounted for.</p><p>In paper III we show that attenuation of the positive feedback to serine 307 phosphorylation of IRS1 can explain the insulin resistance in the insulin signaling in adipocytes seen in type 2 diabetes. However, to fully explain both the signaling and the glucose uptake, a reduction in the amount of Glut4 is also needed.</p>
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