Alterações morfológicas no tecido ósseo têm sido descritas nos usuários de hipoglicemiantes orais da classe das tiazolidinedionas (TZDs). Hipotetiza-se que alguns genes relacionados com a osteogênese e osteoclastogênese podem ser influenciados pelo tratamento farmacológico, entretanto, o exato mecanismo ainda não está bem esclarecido. O objetivo do estudo foi avaliar o efeito da pioglitazona no remodelamento ósseo através de genes envolvidos na osteoclastogênese em indivíduos recentemente diagnosticados com DM2 e modelos animais, com a finalidade de identificar marcadores genéticos sensíveis de alterações ósseas. Foram convidados para participar do estudo 199 indivíduos (100 diabéticos e 99 normoglicêmicos), no ambulatório de dislipidemias do Instituto Dante Pazzanese de Cardiologia. Os indivíduos diabéticos foram tratados com pioglitazona (15, 30, 45, 45 mg/ dia/ via oral) por 16 semanas. Foram colhidas amostras de sangue, antes e após o tratamento para avaliações laboratoriais, extração de DNA genômico e de RNA total. Os polimorfismos e a expressão do mRNA nas células sanguíneas foram determinados pela PCR em tempo real através do sistema TaqMan®. Para o estudo em modelo animal após a indução da dieta hiperlipídica por 32 semanas, foram utilizados 12 camundongos machos da linhagem C57BL/J6, os quais foram divididos em três grupos: controle (n=4); diabéticos induzidos pela dieta hiperlipídica (DH, n=4) e diabéticos induzidos pela dieta hiperlipídica e tratados com pioglitazona 35mg/Kg/dia por 16 semanas (DHP, n=4). Para os grupos experimentais foram colhidos: amostras de sangue, para exames laboratoriais; fêmures, para a extração do RNA total; e tíbias, para determinação dos parâmetros histomorfométricos. Os pacientes DM2 apresentaram diminuição nas concentrações séricas de osteocalcina e na expressão de OPG e aumento na expressão de VDR em comparação ao grupo NG (p<0,05). A expressão de RANKL e IL6 foi maior entre as mulheres, enquanto que a expressão de PPARG foi maior entre os homens com DM2 em comparação ao grupo NG (p=0,032). Pacientes DM2 antes do tratamento apresentaram glicemia e expressão do mRNA de IL6 negativamente associados ao cálcio ionizado, enquanto que as transcrições de TNFA e VDR foram associadas positivamente e negativamente com bALP respectivamente (p<0,05). O tratamento com pioglitazona reduziu a glicemia de jejum, glicemia pós-prandial, insulina, HOMA-IR, triglicerídeos, VLDL-C, tALP e bALP e aumentou a HDL, tACP, TNF-&#945; e a transcrição de OPG (p<0,05). A glicemia basal associou-se positivamente com o cálcio ionizado. A expressão basal de OPG foi associado negativamente com tALP, enquanto que a expressão basal de TNFA foi associada positivamente com tALP e negativamente com tACP. A expressão basal IL6 foi associada positivamente com tALP, enquanto que a expressão basal de VDR foi associada negativamente com osteocalcina e positivamente com bALP em resposta ao tratamento (p<0,05). O polimorfismo RANK rs1805034 foi associado com redução na transcrição do gene RANK nos indivíduos DM2 e com o remodelamento ósseo após o tratamento com pioglitazona (p<0,05). O polimorfismo RANKL rs9525641 foi associado com aumento da transcrição gênica de RANKL nos indivíduos NG e DM2 e melhora da resposta farmacológica nos indivíduos DM2 tratados com pioglitazona (p<0,05). O polimorfismo rs3102735 do gene OPG foi associado com aumento da formação óssea nos indivíduos DM2 antes e após o tratamento (p<0,05). O genótipo CG do polimorfismo OPG rs2073618 foi associado com alteração da transcrição de OPG no grupo DM2 pré e pós-tratamento (p<0,05). O polimorfismo PPARG rs1801282 foi associado com menor risco para o desenvolvimento de diabetes (p<0,05). O polimorfismo PPARG rs2972162 foi associado com melhora da resistência insulínica nos indivíduos DM2 tratados com pioglitazona (p=0,017). O polimorfismo ESRI rs9340799 foi associado com redução da formação óssea nos indivíduos DM2 (p=0,038). Nos camundongos, após a indução da dieta hiperlipídica por 32 semanas, observou-se aumento do peso, da glicemia, do colesterol total, da expressão do mRNA de RANK, RANKL, IL6 e TNFA em fêmures e aumento de Tb.Sp e diminuição de BV/TV em comparação ao grupo controle (p<0,05). O tratamento com pioglitazona diminuiu a expressão de TNFA (p=0,028). As medidas histomorfométricas não alteraram-se após o tratamento (p>0,05). Os resultados sugerem que o estado hiperglicêmico e o tratamento influenciam os marcadores bioquímicos e moleculares. Os polimorfismos dos genes RANK, RANKL, OPG e ESRI parecem estar envolvidos no remodelamento ósseo independentemente da hiperglicemia e do tratamento e os polimorfismos do gene PPARG parecem estar envolvidos com menor risco para desenvolver diabetes e com a melhora da resistência insulínica em resposta ao tratamento com pioglitazona. / Morphological changes in bone tissue have been reported in users of oral hypoglycemic class of thiazolidinediones (TZDs). It is hypothesized that some genes related to osteogenesis and osteoclastogenesis may be influenced by pharmacological treatment, however, was not aware exact mechanism. The study aims was to evaluate pioglitazone effect on bone remodeling through genes involved in osteoclastogenesis in individuals newly diagnosed with DM2 and animal models, in order to identify sensibles genetics markers of bone alterations. Were invited to participate in study 199 patients (100 diabetics and 99 normoglycemic), in dyslipidemia ambulatory of Institute Dante Pazzanese of Cardiology. Diabetic subjects were treated with pioglitazone (15, 30, 45 or 45 mg /day/oral) for 16 weeks. Blood samples were collected before and after treatment for laboratory evaluations, extraction of genomic DNA and total RNA. Polymorphisms and mRNA expression in blood cells was determined by real time PCR using TaqMan® system. For study in animal model after 32 weeks of fat diet induction, was used 12 male mice C57BL/J6, which were divided into three groups: control (n=4); induced diabetic fat diet (DH, n=4) and induced diabetic fat diet and treated with pioglitazone 35mg/Kg/day for 16 weeks (DHP, n=4). For experimental groups were collected: blood samples for laboratory tests; femurs, for extraction of total RNA; and tibias, to determine histomorphometric parameters. DM2 patients showed decrease in serum osteocalcin and OPG expression and increased VDR expression compared to NG group (p<0.05). RANKL and IL6 expression were higher among women, whereas PPARG expression was higher among men with DM2 compared to NG group (p=0,032). DM2 patients before treatment showed blood glucose and IL6 mRNA expression negatively associated with ionized calcium, whereas TNFA and VDR transcription are positively and negatively associated with bALP respectively (p<0.05). Pioglitazone treatment reduced fasting glucose, postprandial glucose, insulin, HOMA-IR, triglycerides, VLDL-C, tALP and bALP and increased HDL, tACP, TNF-&#945; and OPG transcription (p<0.05). Basal blood glucose was positively associated with ionized calcium. Basal OPG expression was negatively associated with tALP, whereas basal TNFA expression was positively associated with tALP and negatively with tACP. Basal IL6 expression was positively associated with tALP, whereas basal VDR expression was negatively associated with osteocalcin and positively with bALP in response to treatment (p<0.05). RANK rs1805034 polymorphism was associated with RANK gene transcription reduction in subjects with DM2 and bone remodeling after treatment with pioglitazone (p<0.05). RANKL rs9525641 polymorphism was associated with increased RANKL gene transcription in NG and DM2 subjects and pharmacological response improvement in DM2 subjects treated with pioglitazone (p<0.05). OPG rs3102735polymorphism was associated with increased bone formation in DM2 subjects before and after treatment (p<0.05). CG genotype of OPG rs2073618 polymorphism was associated with OPG transcription change in DM2 group before and after treatment (p<0.05). PPARG rs1801282 polymorphism was associated with lower risk for diabetes development (p<0.05). PPARG rs2972162 polymorphism was associated with insulin resistance improvement in DM2 subjects treated with pioglitazone (p=0,017). ESRI rs9340799 polymorphism was associated with reduced bone formation in DM2 subjects (p=0,038). In mice, after 32 weeks of fat diet induction, was observed increase weight, blood glucose, total cholesterol and RANK, RANKL, IL6 and TNFA mRNA expression in femurs and Tb.Sp increase and BV/TV decrease compared to control group (p<0.05). Treatment with pioglitazone decrease TNFA (p=0,028). Histomorphometrics measurements not change after treatment (p>0.05). Results suggest that hyperglycemic state and treatment influence biochemical and molecular markers. RANK, RANKL, OPG and ESRI polymorphisms seens to be involved in bone remodeling regardless of hyperglycemia and treatment and PPARG gene polymorphisms seens to be associated with lower risk for diabetes development and with insulin resistance improvement in response to treatment with pioglitazone.

Le diabète est une maladie chronique avec une progression alarmante. L’insuline-résistance et la diminution de la masse fonctionnelle des cellules beta, associée à l'inflammation des îlots, sont les principaux défauts impliqués dans la pathogenèse du diabète de type 2 (DT2). La compréhension des mécanismes impliqués dans l'inflammation des îlots pancréatiques, et l'identification de cibles moléculaires à visée anti-inflammatoire, sont des approches intéressantes pour le traitement du diabète. La glycogène synthase kinase 3 (GSK3), est une sérine-thréonine kinase qui régule des fonctions cellulaires essentielles. Cette enzyme a été récemment décrite comme un régulateur important de l'inflammation dans différentes conditions pathologiques. Cependant, l'implication potentielle de GSK3beta dans l'inflammation des îlots au cours du diabète reste inexplorée. Le but de ce travail était d'étudier l'implication de GSK3beta dans l'inflammation des îlots pancréatiques et d'évaluer l'impact de l'inhibition de GSK3beta dans l’amélioration de l’hyperglycémie du rat diabétique Goto-Kakizaki. Le rat Goto-Kakizaki (GK) est un modèle spontané de DT2, avec une hyperglycémie chronique apparaissant au sevrage, une masse beta cellulaire réduite et une altération profonde de la sécrétion d'insuline en réponse au glucose. Peu après le sevrage, l'inflammation se développe dans les îlots du rat GK et participe au dysfonctionnement des cellules beta. Nous avons traité les rat GK mâles avec du chlorure de lithium (LiCl), un inhibiteur de GSK3. Le traitement chronique de jeunes rats GK a permis d’éviter l’installation de l’hyperglycémie chronique qui se développe normalement dans ce modèle chez les adultes. A la fin du traitement, la glycémie basale des rats GK traités par le LiCl était fortement réduite, en comparaison avec celle des rats GK non traités. Ces améliorations étaient associées à une réduction de l'expression des cytokines et des chimiokines pro-inflammatoires dans les îlots. L’inhibition de GSK3 a également diminué la fibrose des îlots et rétabli partiellement la sensibilité à l’insuline et la sécrétion d'insuline induite par le glucose chez les rats GK. De plus, des études ex vivo sur des îlots humains et des îlots de rats Wistar, exposés à un environnement inflammatoire en culture, ont révélé l'implication directe de GSK3 dans la réponse inflammatoire autonome des îlots. Ceci était entre autres associée à l’activation du facteur de transcription STAT3. En conclusion, nous montrons pour la première fois que GSK3beta est impliquée dans l’inflammation des îlots pancréatiques humains et de rongeurs. L’inhibition de GSK3beta atténue fortement l’inflammation insulaire, et prévient l’installation de l’hyperglycémie chronique chez le rat GK. L’ensemble des résultats de ce travail nous permet de proposer GSK3beta comme une cible potentielle pour le développement de traitements anti-inflammatoires dans le contexte du diabète de type 2 / Diabetes Mellitus (DM) is a chronic disabling disease with epidemic dimension. It is now established that islet inflammation is associated with defective functional beta cell mass in type 2 diabetes. The understanding of the mechanisms that govern diabetes-associated inflammation in pancreatic islets, and the identification of molecular targets to dampen inflammation are important steps to address this pathological condition. GK rat is a spontaneous model of type 2 diabetes with impaired beta cell function and mass, closely associated with islet inflammation. Glycogen Synthase Kinase 3 (GSK3) is a multi-tasking serine-threonine kinase which regulates crucial cellular functions. In recent years, GSK3beta has been found to be an important regulator of inflammation in different diseased conditions. However, the potential role of GSK3beta in the context of islet inflammation remains unexplored. In this study, we tested the potential of lithium, an inhibitor of GSK3, in improving islet inflammation and glucose metabolism in the GK rat. In vivo, treatment of young GK rats prevented the development of overt diabetes which normally occurs in adult individuals. Lithium improved the glycemic status of the GK rats after few weeks of treatment. At the end of the protocol, GK rats treated with lithium had a blood glucose levels that were significantly lower than that of age-matched untreated GK rats, which were overtly diabetic at this stage. Lithium treatment resulted in reduced expression of pro-inflammatory cytokines and chemokines, decreased fibrosis and reduced macrophage infiltration in the islets. Lithium partially restored the pancreatic insulin content, the insulin sensitivity and the glucose induced insulin secretion in the GK rats. Moreover, ex vivo studies in non-diabetic human and rat islets exposed to inflammatory environment in culture, revealed the direct implication of GSK3 in the islet autonomous inflammatory response. Moreover, we showed that GSK3 controls the islet inflammatory response at least in part by regulating the activity of the pro-inflammatory transcription factor STAT3. Taken together, our results identified GSK3 as a viable target to treat diabetes-associated inflammation, and could have potential clinical application in the treatment of diabetes and metabolic syndrome

This research explored health decision-making processes among people recently diagnosed with type 2 diabetes. Our analysis suggested that diagnosis with type 2 was followed by a period of intense emotional and cognitive disequilibrium. Subsequently, the informants were observed to proceed to health decision-making which was affected by three separate and interrelated factors: knowledge, self-efficacy, and purpose. Knowledge included cognitive or factual components and emotional elements. Knowledge influenced the degree of upset or disequilibrium the patient experienced, and affected a second category, agency: the informants’ confidence in their ability to enact lifestyle changes. The third factor, purpose, summarized the personal and deeply held reasons people gave as they made decisions concerning their health, eating and exercising. We propose this model, grounded in informant stories, as a heuristic, to guide further inquiry. From these stories, the patient is seen as more active and the interrelated influences of knowledge, agency, and purpose, synergistically interact to explain changes in health behaviors.

The prevalence of diabetes mellitus (DM) continues to be a global concern among health care practitioners. Without collaboration and interventions, this chronic disease, which poses a significant financial burden for health care institutions, will continue to be problematic. Promoting the use of glycemic control measures among diabetic patients is an intervention, which has the potential to reduce diabetic complications and improve outcomes. The purpose of this doctoral project was to explore available evidence through a systematic review of the best practices for glucose management. The chronic care model served as the theoretical framework. The evidence based practice question was, What is the current evidence supporting the utilization of a computer-based glucose management system (CBGMS) for inpatient diabetic adults in acute and critical care settings? A systematic review was conducted, yielding 532 studies in which 3 of the studies related to CBGMSs published from 2008 to 2017 were critically appraised. The John Hopkins Nursing Evidence Appraisal Tool with specific inclusion and exclusion criteria was utilized. Participants were adult patients (aged 18 and over) with DM in inpatient care settings who were English speaking. Interventions included the traditional paper-based sliding scale regimen versus the utilization of a CBGMS. Outcome measures included decreased length of stay, reduced cost, and glucose optimization. A conclusion was the implementation of a CBGMS has the potential to improve patient outcomes with additional research that exhibits overall benefits and implement into practice. Thus, implementation of a CBGMS can lead to positive social change by aiding in a change in practice that will ultimately ameliorate patient health outcomes.

Les agrumes très consommés au niveau mondial, représente des sources de caroténoïdes tels que la β-cryptoxanthine, qui contribuent avec les flavonoïdes (hespéridine) aux effets santé de ces fruits et en particulier dans la prévention du diabète de type 2 (DT2). Le DT2 est une pathologie mondiale en croissance exponentielle. L’objectif général de ce travail est par conséquent d’étudier les propriétés nutrition-santé de concentrés de jus de clémentine, obtenus par une technologie membranaire innovante et spécifiquement enrichis en β-cryptoxanthine (βCX) et hespéridine (HES) mais également en pectines. Le devenir digestif de ces phytomicronutriments, garants de la qualité nutritionnelle des concentrés a évalué dans un premier temps en couplant le modèle de digestion in vitro aux cellules intestinales de type Caco-2. Pour une meilleure vision physiologique des mécanismes associés aux premières étapes de la digestion, des modèles de digestion, statique et dynamique, sont comparés. La bioaccessibilité et l’absorption intestinale des caroténoïdes sont fortement influencées par la teneur et structure des pectines. Dans un second temps, les activités biologiques (disglycémie, dislipidémie, inflammation) impliquées dans la prévention du DT2 sont évaluées in vivo chez le rat après administration du concentré d’agrume. L’étude a démontré qu'un aliment à base d'agrume spécifiquement enrichi en βCX et HES est efficace dans la prévention du syndrome métabolique/DT2, soulignant le rôle possible de la βCX et de sa bioconversion en rétinoïdes. Une étude in vitro complémentaire sur macrophages murins révèle des effets anti-inflammatoires synergiques des 2 phytomicronutriments. / Citrus fruits, which are widely consumed worldwide, represent sources of carotenoids such as βCX, which contribute with flavonoids (HES) to the health effects of these fruits, particularly in the prevention of type 2 diabetes (T2D). T2D is a worldwide pathology that is growing exponentially. The general objective of this work is therefore to study the nutritional and health properties of clementine juice concentrates obtained by innovative membrane technology and specifically enriched in both βCX and HES but also in pectins. The digestive behaviour of these phytomicronutrients, guarantors of the nutritional quality of the concentrates, was first assessed by coupling the in vitro digestion model with the Caco-2 intestinal cells. For a better physiological vision of the mechanisms associated with the first stages of digestion, models of static and dynamic digestion are compared. The bioavailability and intestinal absorption of carotenoids are strongly influenced by the content and structure of pectins. In a second step, the biological activities (disglycemia, dislipidemia, inflammation) involved in the prevention of T2D are evaluated in vivo in rat after administration of the citrus concentrate. The study demonstrated that a citrus food specifically enriched in βCX and HES is effective in preventing metabolic syndrome/T2D, highlighting the possible role of βCX and its retinoid bioconversion. A complementary in vitro study on murine macrophages reveals synergistic anti-inflammatory effects of the two phytomicronutrients.

Individuals with type 2 diabetes mellitus (T2DM) are at risk for developing life-threatening comorbidities such as cardiovascular disease (CVD). As a consequence, T2DM is associated with increased morbidity and mortality and decreased quality of life, thus highlighting the importance of prevention of T2DM. Further, the prevalence of T2DM is substantially greater in rural populations compared to urban populations, making rural individuals particularly appropriate targets for T2DM prevention. T2DM is a largely preventable disease that is associated with modifiable risk factors such as poor diet, sedentary lifestyle, and obesity. Lifestyle interventions to improve these modifiable risk factors have been used to decrease the risk of developing T2DM. There is little evidence that supports lifestyle interventions as a means to decrease T2DM risk in rural populations with prediabetes, the precursor of T2DM. The purpose of this dissertation was to determine whether rural-living individuals with prediabetes would improve modifiable risk factors, specifically diet quality by following a lifestyle intervention; thereby, decreasing their risk of developing T2DM. Specific aims for this dissertation were to, 1) examine and synthesize data from dietary interventions used to reduce risk of T2DM in rural populations on order to identify gaps and guide future research, 2) critically evaluate validity and reliability of indices used to determine diet quality in research, and 3) determine the effect of a risk reduction program on improving diet quality and glucose control (as a measure of T2DM risk) in rural adults with prediabetes and CVD risk factors. Specific aim one was achieved by a review and synthesis of literature focused on lifestyle and dietary interventions used in rural populations to decrease the risk of developing T2DM. Common goals in these studies were a decrease in weight, decrease in dietary fat and calories, and an increase in physical activity. Decreased weight and increased physical activity were demonstrated in all eight studies, and a decrease in T2DM incidence was also demonstrated in one of the studies. However, diet quality was not adequately assessed in the majority of the studies. Furthermore, none of the studies were randomized controlled trials and only half used a control group. It was concluded that research using a more robust design is needed to determine the effect of lifestyle changes, specifically diet, on T2DM risk in rural populations. Specific aim two was addressed by a critical analysis of six common indices of dietary quality. Validity and reliability of the Healthy Eating Index, the Alternative Healthy Eating Index, the DASH diet score, the Diet Quality Index-Revised, the Healthy Diet Indicator, and the Diet Quality Score were examined. Five of the six indices are valid and reliable tools for measure diet quality but all five rely on an extensive food frequency questionnaire that may be burdensome for participants. The Diet Quality Score does not provide adequate evidence to support its use in research. It was concluded that a short, reliable, and validated diet screener may be useful in research. Specific aim three was addressed by a secondary data analysis of a longitudinal, randomized controlled study of rural residents with CVD risk factors and prediabetes. Diet quality, measured by the Mediterranean Diet Adherence Screener (MEDAS), and glucose control, measured by hemoglobin A1c, were analyzed in a subpopulation of 62 participants with prediabetes. Neither diet quality nor glucose control improved between baseline, four month, and 12 month post intervention. The reliability and validity of the MEDAS in this population is not known and may have been a factor in the lack of intervention effect related to diet quality. Participants were also not informed of their prediabetes status, thus it is not known if this knowledge would have made an impact on the outcomes of the study. In addition, the small sample size limits the statistical power to determine changes between the intervention and control groups. It was concluded that further research is needed to determine if a high quality diet will reduce T2DM risk in this rural population Considering the disproportionate prevalence of T2DM in rural populations compared to their urban counterparts, the results of this dissertation demonstrate a continued need for interventions that decrease modifiable risk factors associated with this disease. Interventions that target obesity, poor diet quality, and sedentary lifestyles in at-risk rural populations that are culturally tailored are needed to decrease risk of developing T2DM and the comorbidities associated with this preventable disease.

The prevalence of type 2 diabetes (T2D) continues to rise and is predicted to increase to 30 million people by 2030 in the United Sates alone. African Americans (AA) have one of the highest prevalence rates of T2D among all ethnic groups. African American Women (AAW) are 100% more likely to develop T2D compared with their white counterparts. The aim of this study was to quantitatively investigate the relationship of the perceptions of AAW not previously identified that could lead to a reduction in risk of T2D among AAW. A cross-sectional study of 183 AAW 20 to 65 years old was conducted to identify any correlation among the variables, using validated surveys. The participants were recruited via flyers and online. The health belief model and the theory of planned behavior served as the theoretical framework. Spearman's rho correlation was used to determine the strength of the correlations. The majority of respondents had moderate to high lifestyle and behavior changes relative to diet (59%) and blood sugar testing (93%), as well as low participation for exercise (62%). The majority of the AAW had low awareness of T2D severity (72%), low interference to daily activities (88%), and low social support for diabetes management (74%). A significant correlation was observed between healthy diet and severity, interference, outcome expectancies, and self-efficacy (p < .001). A significant relationship was found between exercise and severity, interference, outcome expectancies, and self-efficacy (p < .001). This study may inspire social change by creating awareness among healthcare workers regarding educational resources, environmental changes, and community interventions to reduce the economic burden associated with health care costs, to mitigate T2D, and to reduce health disparity.

African American men are more likely to have diagnosed or undiagnosed diabetes than non-Hispanic White Americans and are less likely to adhere to treatment. Culture in the African American community plays a key role in how this community copes with illness and the health care system. The purpose of this study was to examine the lived experiences of social and cultural determinants of Type 2 diabetes self-management among African American men. Bandura's social cognitive theory provided the theoretical framework for the study. The research question sought to identify cultural and social factors that contribute or protect how African American men manage Type 2 diabetes. The study had a qualitative research design with a phenomenological approach. A purposive sample of 11 African American men ages 48 to 76 with Type 2 diabetes volunteered to participate in in-depth interviews. Interviews were audiotaped, transcribed, inductively coded, and analyzed for emergent themes using NVivo 12 software. Thematic analyses led to the development of 8 themes and 8 subthemes. The lived experiences of the participants were classified into personal factors (self-efficacy, knowledge, outcomes, expectations, and attitudes); environmental factors (modeling, social norms, perceived support, facilitation, dietary choices, and accessibility); and behavioral factors, which differed in terms of consumption, goal setting, and behavior toward health care. Positive social change implications of the study may include further education on disease management, recommendations to healthcare professionals, community stakeholders, and African American families on specific factors that can enhance knowledge, attitudes, and behaviors to improve management of Type 2 diabetes among African American men.

Tarmfloran spelar en viktig roll för människorshälsa genom att bl.a. reglera värdens immunitet, producera näringsämnen och stärkatarmbarriären. Dysbios i tarmfloran har associerats med flera sjukdomar,inklusive diabetes typ 2. Metformin är förstahandsvalet av läkemedel mot diabetestyp 2 och har en pleotropisk effekt. Det finns stöd för att tarmarna är ettbetydande målorgan för metformin, dels för att intravenös administrering av metforminger sämre effekt än oral. Syftet med denna litteraturstudie var därför attundersöka om metformin har effekter på tarmflorans sammansättning hos människormed diabetes typ 2. Resultatet är baserat på fem olika studier hämtade frånPubmed. Alla studierna ger stöd åt att metformin förändrar tarmfloranssammansättning och indikerar även att tarmfloran är involverad i metforminsbehandlingseffekter och biverkningar. Hur omfattande förändringarna var ochvilka taxa som påverkades varierade, troligen p.g.a. olika studiedesigner. Resultatentyder på att metformin ökar den relativa förekomsten av Escherichia, Akkermansiamuciniphila och SCFA-producerande taxa, inklusive Blautia. Indikationer fanns också på att metformin minskar den relativaförekomsten av Intestinibacter.Slutsatsen är att metformin förändrar tarmflorans sammansättning, men att flerstudier krävs för att bekräfta både de taxonomiska och funktionella förändringarna.Det finns också ett behov av mer kunskap om hur resultat påverkas avsekvenserings- och statistikmetoder för att lättare kunna göra jämförelser mellan studier. / The gut microbiota has important impact on hosthealth by regulating host immunity, providing nutrients and strengthening ofthe gut integrity. A gut microbiota dysbiosis has been associated with severaldiseases, including type 2 diabetes. Metformin is the drug of first choiceagainst type 2 diabetes and has pleiotrophic effects. It has been suggestedthat the intestines is a important target of metformin because intravenousadministration exerts smaller therapeutic effects than oral. The aim of thislitterature study was to investigate if metformin alters the gut microbiotacomposition in humans. The result is based on five studies collected from Pubmed.All studies support that metformin treatment is associated with an altered gutmicrobiota and may be involved in terapeutic and side effects of metformin. Theamplitude of the metformin-induced alterations and affected taxa differed amongthe studies, probably due to large differences in study designs. Main findingssuggest that metformin increase the relative abundance of Escherichia, Akkermansiamuciniphila and SCFA-producing taxa as Blautia.Metformin also might decrease the relative abundance of Intestinibacter. In conclusion, metformin alters the gutmicrobiota, but more studies are needed to determine the taxonomic andfunctional alterations during metformin treatment. There is also a need of moreknowledge of how results are affected by sequencing and statistical methods.

Globally, the prevalence of Type 2 diabetes is rising. The most affected populations are those that have undergone recent and rapid transition towards a Western lifestyle, characterised by energy-dense diets and physical inactivity.¶ Two major hypotheses have attempted to explain the variation in diabetes prevalence, both between and within populations, beyond the contributions made by adult lifestyle. The thrifty genotype hypothesis proposes that some populations are genetically well adapted to surviving in a subsistence environment, and are predisposed to develop diabetes when the dietary environment changes to one that is fat and carbohydrate rich. The programming hypothesis focuses on the developmental environment, particularly on prenatal and early postnatal conditions: nutritional deprivation in utero and early postnatal life, measured by low birthweight and disrupted child growth, is proposed to alter metabolism permanently so that risk of diabetes is increased with subsequent exposure to an energy-dense diet. Both hypotheses emphasise discord between adaptation (genetic or developmental) and current environment, and both now put forward insulin resistance as a likely mechanism for predisposition.¶ Diabetes contributes significantly to morbidity and mortality among Australia’s Indigenous population. Indigenous babies are more likely to be low birthweight, and typical patterns of child growth include periods of faltering and rapid catch-up. Although there have been numerous studies in other populations, the programming hypothesis has not previously been tested in an Australian Indigenous community. The framework of the programming hypothesis is thus expanded to consider exposure of whole populations to adverse prenatal and postnatal environments, and the influence this may have on diabetes prevalence.¶ The present study took place in Cherbourg, a large Aboriginal community in southeast Queensland with a high prevalence of diabetes. Study participants were adults with diagnosed diabetes and a random sample of adults who had never been diagnosed with diabetes. Data were collected on five current risk factors for diabetes (general and central obesity, blood pressure, age and family history), in addition to fasting blood glucose levels. A lifestyle survey was also conducted. Participants’ medical records detailing weight growth from birth to five years were analysed with regard to adult diabetes risk to determine whether childhood weight and rate of weight gain were associated with subsequent diabetes. Adult lifestyle factors were xiialso explored to determine whether variation in nutrition and physical activity was related to level of diabetes risk.¶ Approximately 20% of adults in Cherbourg have diagnosed diabetes. Prevalence may be as high as 38.5% in females and 42% in males if those who are high-risk (abnormal fasting glucose and three additional factors) are included. Among those over 40 years, total prevalence is estimated to be 51% for females and 59% for males.¶ Patterns of early childhood growth may contribute to risk of diabetes among adults. In particular, relatively rapid weight growth to five years is associated with both general and central obesity among adult women. This lends some qualified support to the programming hypothesis as catch-up growth has previously been incorporated into the model; however, although the most consistent association was found among those who gained weight more rapidly, it was also found that risk is increased among children who are heavier at any age.¶ No consistent associations were found between intrauterine growth retardation (as determined by lower than median birthweight and higher than median weight growth velocity to one and three months) and diabetes risk among women or men. A larger study sample with greater statistical power may have yielded less ambiguous results.¶ Among adults, levels of physical activity may be more important than nutritional intake in moderating diabetes risk, although features of diet, such as high intake of simple carbohydrates, may contribute to risk in the community overall, especially in the context of physical inactivity. A genetic component is not ruled out. Two additional areas which require further investigation include stress and high rates of infection, both of which are highly relevant to the study community, and may contribute to the insulin resistance syndrome.¶ Some accepted thresholds indicating increased diabetes risk may not be appropriate in this population. Given the relationship between waist circumference and other diabetes risk factors and the propensity for central fat deposition among women even with low body mass index (BMI), it is recommended that the threshold where BMI is considered a risk be lowered by 5kg/m2 for women, while no such recommendation is made for men.¶ There are a number of social barriers to better community health, including attitudes to exercise and obesity, patterns of alcohol and tobacco use and consumption of fresh foods. Some of these barriers are exacerbated by gender roles and expectations.¶