Specific SNPs in intronic regions of the human TCF7L2 gene are associated with an elevated risk of T2D development and progression. Several investigations have suggested a role of TCF7L2 in pancreatic β-cells. Whether this transcription factor is indeed expressed in the pancreatic islets of rodent species, however, has been a controversial issue. Here, we found that TCF7L2 mRNA level was significantly lower in the pancreas compared to the gut or Ins-1 cell line. In addition, TCF7L2 mRNA abundance in the pancreas was decreased by insulin. Finally, both TCF7 and TCF7L1 but not LEF-1 could be detected in the mouse pancreas. mRNA abundance for these two transcription factors was also decreased by insulin, and the level of TCF7, TCF7L1, and TCF7L2 mRNAs could be down-regulated by HFD. We speculate that reduced expression of these TCF genes during hyperinsulinemia may alter the Wnt signalling pathway and therefore impair the function of β-cells.

The unfolded protein response, which is activated during ER stress, counteracts stress conditions by increasing folding capacity and by increasing the degradation of misfolded ER proteins by the ER-Associated Degradation (ERAD) system. Studies using an engineered insulinoma cell line with inducible expression of the Akita folding-deficient insulin have shown a large induction of Herp, a protein that has been implicated in the ERAD pathway. We hypothesized that Herp is an essential protein that regulates the degradation of misfolded insulin during the ER stress response. Indeed, we found that the degradation of mutant insulin is Herp-dependent and that maintaining Herp expression is vital for maintaining cell survival. We have also observed that the expression of Herp mRNA and protein is induced in various cell culture and animal models of diabetes. These results suggest that Herp is an important ER stress response protein that is induced under diabetic conditions in pancreatic β-cells.

PI3K signaling in pancreatic β cells has been shown to be important in modulating β cell mass and function under basal condition. Evidence suggests that a specific group of insulin promoter-expressing neurons also modulates glucose metabolism and energy homeostasis through their PI3K signaling. Thus we hypothesize that PI3K activation via PTEN deletion under the control of rat insulin promoter (RIP) in pancreatic β cells and RIP-expressing neurons will protect against hyperglycemia and diabetes in experimentally induced mouse models of type 2 diabetes. In Chapter IV, we showed that RIP-mediated PTEN deletion in pancreatic β cells led to PI3K activation and subsequent increased β cell mass and function, thus protected the mice from high fat diet (HFD)-induced diabetes. Furthermore in the absence of global leptin signaling, β cell-specific PTEN deletion maintained β cell function in the setting of severe insulin resistance, therefore prevented diabetes development. Interestingly, RIP-mediated PTEN deletion also resulted in increased peripheral insulin sensitivity due to PI3K activation in central nervous system. In Chapter V, we showed this increased insulin sensitivity was maintained after HFD feeding, which also contributed to the protection against diabetes. These mice also showed increased visceral adipogenesis and subcutaneous adiposity on HFD, which were dramatically attenuated in the absence of leptin signaling, indicated the essential role of peripheral leptin action in mediating the insulin sensitive phenotype from neuronal RIP PTEN deletion. Finally, we demonstrated that the insulin sensitizing phenotype in these mice was not mediated through ventromedial hypothalamic nuclei (VMH), such that VMH-specific PTEN deletion did not alter energy homeostasis or glucose metabolism. Together, the data from this thesis points to an inhibitory role of PTEN in both central nervous system and pancreatic β cells in glycemic control. Therefore, PTEN may represent a potential target for diabetes prevention and treatment.

An important mechanism involved in the pathogenesis of type 2 diabetes is elevation of plasma free fatty acids which induce insulin resistance and may impair both β-cell function and mass (β-cell lipotoxicity). The objective of my thesis was to investigate the role of oxidative stress in β-cell lipotoxicity, using in vivo, ex vivo, and in vitro models. I used in vivo models of 48h i.v. oleate or olive oil infusion in Wistar rats followed by hyperglycemic clamps, or islet secretion studies ex vivo, and in vitro models of 48h exposure to oleate in isolated islets. My first study showed that 48h oleate infusion decreased the insulin response to a hyperglycemic clamp, an effect prevented by coinfusion of the antioxidants N-acetylcysteine and taurine. Similar to the findings in vivo, 48h infusion of oleate decreased glucose stimulated insulin secretion (GSIS) ex vivo, and induced oxidative stress in isolated islets, effects prevented by coinfusion of the antioxidants N-acetylcysteine, taurine, or tempol. Islets exposed to oleate or palmitate showed a decreased insulin response to high glucose and increased levels of oxidative stress, effects prevented by taurine. Therefore, my data are the first demonstration that oxidative stress plays a role in the decrease in β-cell secretory function induced by prolonged exposure to FFA, in vitro and in vivo. My second study addressed downstream effects of oxidative stress involving inflammation. A 48h infusion of oleate or olive oil decreased β-cell function during a hyperglycemic clamp, an effect prevented by coinfusion of the IKKβ inhibitor salicylate. GSIS in isolated islets was impaired by olive oil or oleate and restored by salicylate. These results suggest a potential role for both oxidative stress and inflammation in lipid-induced β-cell dysfunction. My third study addressed downstream effects of oxidative stress involving β-cell insulin signalling. A 48h infusion of oleate or olive oil decreased β-cell function during a hyperglycemic clamp, an effect prevented by coinfusion of the tyrosine phosphatase inhibitor bisperoxovanadate. GSIS in isolated islets was impaired by olive oil or oleate and restored by bisperoxovanadate, suggesting a role of FFA in decreasing β-cell function by induction of β-cell insulin resistance.

Chronic hyperglycemia, a hallmark of type 2 diabetes, can decrease β-cell function and mass (β-cell glucotoxicity); however, the mechanisms are incompletely understood. The objective was to examine the mechanisms of β-cell glucotoxicity using in vivo and ex vivo models. The hypothesis is that oxidative stress plays a causal role in high glucose-induced β-cell dysfunction in vivo via pathways that involve endoplasmic reticulum (ER) stress and JNK. The model of β-cell glucotoxicity was achieved by prolonged i.v. glucose infusion (to achieve hyperglycemia). In Study 1, 48h glucose infusion increased total and mitochondrial superoxide levels in islets, and impaired β-cell function in vivo and ex vivo. Co-infusion of the superoxide dismutase mimetic Tempol decreased total and mitochondrial superoxide, and prevented high glucose-induced β-cell dysfunction in vivo and ex vivo. These results suggest that increased superoxide generation plays a role in β-cell glucotoxicity. In Study 2, 48h glucose infusion increased activation of the unfolded protein response (XBP-1 mRNA splicing and phospho-eIF2α levels). This was partially prevented by Tempol. Co-infusion of the chemical chaperone 4-phenylbutyrate with glucose decreased spliced XBP-1 levels, and prevented high glucose-induced β-cell dysfunction in vivo and ex vivo. Co-infusion of 4-phenylbutyrate also decreased total and mitochondrial superoxide induced by high glucose. These results suggest that 1) ER stress plays a causal role in high glucose-induced β-cell dysfunction, and 2) there is a link between oxidative stress and ER stress in high glucose-induced β-cell dysfunction in vivo. In Study 3, JNK inhibition using the inhibitor SP600125 in rats or JNK-1 null mice prevented high glucose-induced β-cell dysfunction ex vivo and in vivo. SP600125 prevented high-glucose-induced β-cell dysfunction without decreasing total and mitochondrial superoxide levels. Both Tempol and 4-phenylbutyrate prevented JNK activation induced by high glucose. These results suggest a role of JNK activation in high glucose-induced β-cell dysfunction downstream of increased superoxide generation and ER stress in vivo. Together, the results suggest that 1) oxidative stress, ER stress and JNK activation are causally involved in β-cell glucotoxicity, and 2) High glucose-induced oxidative stress and ER stress are linked, and both impair β-cell dysfunction via JNK activation in vivo.

No description available.

Bakgrund: I Sverige är det idag 3-4 procent av befolkningen som har diagnosen diabetes mellitus typ 2 och antalet insjuknade ökar kontinuerligt. Diabetes kan leda till allvarliga komplikationer som kärl- och nervförändringar, ögon och njurpåverkan. Sjuksköterskans roll i omvårdnaden är att ge stöd och utföra kontroller för att förhindra komplikationer. Syfte: Beskriva vilket stöd från sjuksköterskan som vuxna med diabetes typ 2 upplever att de är i behov av. Metod: En allmän litteraturstudie med nio vetenskapliga artiklar sammanställdes. Efter genomläsning lyftes ord och meningar ut ur texten, orden skapade slutligen övergripande teman under vilka resultatet presenterats. Resultat: Litteratursammanställningen visade att patienterna vill ha mer kunskap och information, patienterna ansåg även att det var viktigt att de själva fick bestämma över sin vård. Stödet kan delas in under kategorierna, trygghet, förtroende och bekräftelse. Slutsats: De nationella riktlinjerna för diabetesvård säger att patienten ska få kontinuerlig information angående sitt sjukdomstillstånd, det är även enligt Hälso-och Sjukvårdslagen ett krav att patienten har rätt till självbestämmande under rådande sjukdomsbehandling.För att uppnå dessa krav bör sjusköterskan arbeta för att etablera trygghet och förtroende samt att ge bekräftelse. / Background: In Sweden it is currently 3-4 percent of the population who has a diagnosed type 2 diabetes mellitus and the number of patients is increasing steadily. Diabetes can lead to serious complications such as vascular and nervous changes, eye and kidney problems. The Nurse role in the health care is to support and carry out check up´s to prevent complications. Aim: To describe the support that adult with type 2 diabetes feel that they are in need of and what they actually get from the nurse. Method: A literature review of nine scientific papers were compiled. After reading words were highlighted and sentences taken out of the text, these words finally created the broad themes under which the result is presented. Results: The literature summary showed that patients want more knowledge and information, the patients also felt that it was important that they themselves had to decide about their care. The support can be divided into subcategories, confidence, trust and affirmation. Conclusion: The national guidelines for diabetes care, says that patients should receive continuous information about their illness, it is also under the Health Care Act requires that the patient has the right to self-determination in the current therapies.In order to satisfy these demands nurses need to work for establishing confidence, trust and affirmation in patient suffering from diabetes type 2.

Inledning: Det här är en litteraturstudie om sjuksköterskan bemötande av patienter med diabetes typ 2 genom information och motivering till egenvård och livsstilsförändringar. Bakgrund: Diabetes typ 2 är en sjukdom som ständigt ökar världen över liksom fetma. Genom att göra förändringar i livsstilen kan biverkningar av sjukdomen minskas. Syfte: Syftet med litteraturöversikten är att sammanställa och belysa forskning som beskriver sjuksköterskans olika omvårdnadsstrategier i att bemöta och motivera patienter med diabetes typ 2 till att ändra livsstil. Metod: En litteraturöversikt baserad på tio vetenskapliga artiklar. Resultat: Tre områden identifierades: Att motivera till livsstilsförändring, Vikten av bra bemötande och utbildning i egenvård. Genom att sjuksköterskan använder sig av motiverande samtal och utbildning i egenvård ökar chansen att patienten lyckas med en livsstilsförändring. För detta krävs att en god relation mellan sjuksköterska och patient. Detta kan uppnås genom en patient-centrerad vård där sjuksköterskan ser varje patient som en unik individ. Slutsats: Det fordras ytterligare utbildning för sjuksköterskorna för att de ska kunna tillämpa patientutbildning och egenvård med goda resultat. Sjuksköterskorna måste ha förmåga att stödja patienter till egenvård. / Introduction: This is a literature review of nurses nursing strategies in caring for patient with type 2 diabetes Background: Type 2 diabetes is increasing over the world along with obesity. By making changes in lifestyle secondary effects may be reduced. Aim: The aim of the literature review is to compile and illustrate research that describes different nursing strategies in encountering and motivating patients with type 2 diabetes to lifestyle-changes. Method: A literature review using a qualitative analyses approach based on ten scientific articles. Result: Three areas were identified: To motivate lifestyle changes, The importance of a good treatment. By motivating and educating nurse´ may contribute to supporting the patient in lifestyle changes. To succeed in changes a relation build upon nurse-patient are needed, where every patient is seen as a unique individual. Conclusion: Further nurse-education is necessary to make the patients apply self care with good results. Nurses must have the ability to help the patients to self-care.

Både nationellt och internationellt ses en stark ökning av typ 2 diabetes vilket har bidragit till att sjukdomen blivit en av de huvudsakliga orsakerna till för tidig sjukdom och död i de flesta länder. Sjukdomsdebuten kryper allt lägre ned i åldrarna och kräver att individen utför en adekvat egenvård för att undvika att drabbas av komplikationer. Syftet med denna systematiska litteraturstudie var att beskriva kvinnors upplevelse av att hantera egenvården vid typ 2 diabetes. Studien baseras på tio vetenskapliga artiklar som analyserats med kvalitativ induktiv analysmetod. Analysen resulterade i fem kategorier som visade sig påverka kvinnors upplevelse av att hantera sin egenvård: Upplevelsen av att tvingas anpassa sig, Upplevelsen av motivation, Upplevelsen av vårdgivares stöd, Upplevelsen av omgivningens förståelse och Upplevelsen av att hantera sina känslor. Kvinnor påverkas i stor utsträckning av den information och det bemötande de får av vårdgivare både efter att ha fått diagnosen och vidare. För att kvinnor ska stärkas i sin egenvårdskapacitet bör stöd och information anpassas till kvinnans aktuella livssituation. Familjen har stor betydelse för kvinnors upplevelse av att hantera egenvården vilket kräver att omvårdnaden även bör innefatta familjen. Vidare forskning bör fokusera på familjens upplevelse när någon i familjen drabbas av typ 2 diabetes.

Background: Self-care is a multi-dimensional concept and has different definitions. Amongthe definitions, Orem’s definition of self-care is more consistent. Orem (1995) argues that,self-care is a personal activity to take care and maintain of own self health and illness andprevention of disease related complications. Aim: The aim of the paper was to investigate the factors that contribute to self-care behavioramong patients with Type 2 DM as argued in the literature. Method: data was collected from the following electronic databases: CINAHL, PubMed,LibHub, SweMed and Google Scholar-to find full texts. Data was analyzed through CriticalAppraisal Skill Programme. To ensure validity and reliability the author were blinded toreduce study bias and articles were selected according their quality. Result: 31 relevant studies were included in the review, among the major findings of the studywere; Age, Social support/network, high income level, high educational attainment and longType 2 DM diagnosis history had a positive predictor in Type 2 DM patients self-carecontributing factors. Conclusion: To improve a Type 2 DM patients self-care activities the present study concludedthat Demographic, Socio-Economic and Social support factors are among the positivecontributors in patients of Type 2 DM successful Self-Care activities. Key words; Blood glucose self-monitoring, self-administration, Self-care, self-medication,Type 2 Diabetes. / The aim of the paper was to investigate the factors that contribute to self-care behavior among patients with Type 2 DM as argued in the literature.