A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Medicine in the branch of Internal Medicine, Johannesburg, 2014 / Objective: To evaluate and compare any differences in control, i.e. HbA1C, total cholesterol, BP and BMI in a single group of Type-2 diabetes patients during two time periods, i.e. before and after specialist-supervised care. In addition, to describe differences in the use of anti-platelet and statin therapy for primary cardiovascular prophylaxis. Methods: Patients were recruited from the Diabetes Clinic at Chris Hani Baragwanath Academic Hospital (CHBAH) and the audits of two separate time periods were conducted. The first audit recorded standard of care delivered by registrars from January 2005 to December 2007. The second audit recorded care after the introduction of specialist-supervised care from September 2009 to September 2012. The patients were all insulin-requiring and were required to be seen for at least 24 months during both audit periods. The first recorded HbA1C in (i) 2005 and (ii) from September 2009 triggered the inception of a patient’s assessment periods. Data for at least 80% of parameters had to be available for a patient to be included in the audit. Results: This study showed significant differences using ANCOVA comparing final values for each audit after adjustment for their respective baseline values in respect of HbA1C (p<0.000), SBP (p<0.012) and BMI (p<0.001) after the implementation of an endocrinologist-supervised clinic. The percentage of patients reaching guideline targets, and the use of aspirin and statins, improved as well. Conclusion: This study showed a difference in the level of care delivered by the endocrinologist-supervised clinic as opposed to one which was led by registrars. However, other factors may have contributed to the outcomes, most notably that the consultation time with each patient was longer after the introduction of expert supervision in 2009.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Medicine in the branch of Internal Medicine Johannesburg, 2014 / Background Diabetes is a global epidemic. The International Diabetes Federation estimates that there are at least 285 million diabetics worldwide and this is estimated to grow to over 440 million by 2030 1 . A study was conducted at the Helen Joseph Hospital Diabetic clinic in an attempt to identify predictors of glycaemic control and to compare the level of care to the 2012 Society for Endocrinology, Metabolism and Diabetes of South Africa (SEMDSA) guidelines. Methods Patients were recruited from the Helen Joseph Hospital Diabetic clinic. To be included the patient had to be part of the coloured (mixed race) community, be willing to give informed consent, be older than 18 years, have an HBA1C taken within 6 months, have a diagnosis of Type 2 diabetes mellitus and be a clinic attendee for at least 1 year. Pregnant patients, Type 1 diabetic patients, patients with a psychotic disorder or aphasia were excluded. Data collection consisted of face-to-face interviews, review of treatment, medication knowledge evaluation, a short examination and collection of recent blood results. Statistical analysis was done by stratifying patients into two groups by using the mean HBA1C. Variables with a p < 0.1 from this analysis were used in a logistic regression model. In addition, the correlation between continuous variables were tested. A comparison was made between the level of care and the 2012 SEMDSA guidelines. v Results A total of 100 patients were recruited into the study. The mean age was 62.8 years with mean duration of diabetes of 15.8 and clinic attendance of 10.9 years. The group had very poor education level and the median income of R1200 per month was also low. The mean HBA1C was found to be 9.74%, well above the target recommended by SEMDSA. Knowledge of diabetes with respect to management and complications was very poor. Age > 50 years (OR 0.372 CI 0.06-2.26), estimated glomerular filtration rate ≥ 60 ml/min/1.73m2 (OR 0.90 CI 0.25-3.27), experiencing a microvascular complication (OR 0.73 CI 0.11-5.07) or any other diabetic complication (OR 0.56 CI 0.07-4.38) and having experienced a hypoglycaemic episode (OR 0.31 CI 0.09-1.10) predicted better glycaemic control. Duration of diabetes < 10 years (OR 1.36 CI 0.37-5.02), diastolic blood pressure ≥ 70 mmHg (OR 2.80 CI 0.80-9.78), aspirin dosage ≥ 150 mg daily (OR 6.47 CI 1.60-26.05), simvastatin dosage = 40 mg daily (OR 2.35 CI 0.31-18.10) and body mass index > 25 kg/m2 (OR 1.09 CI 0.49-2.41) all predicted a poorer glycaemic result. HBA1C was found to positively correlate with diastolic blood pressure (p = 0.0024, r = 0.31). Systolic blood pressure positively correlated with diastolic blood pressure (p < 0.0001, r = 0.56). Apart from correlating with systolic blood pressure and HBA1C, diastolic blood pressure also positively correlated with the triglyceride level (p = 0.0003, r = 0.36). Positive correlations between total cholesterol, triglycerides, HDL-C and LDL-C were found. As expected, body mass index and waist circumference correlated positively (p < 0.0001, r = 0.82). Level of care was not at the level recommended by the 2012 SEMDSA guidelines. Only 6% of patients met the waist circumference goal. Only 15% of patients achieved blood v i pressure goal. Most of the patients (86%) who qualified for aspirin did not receive it. In the group of patients receiving aspirin 33% did not qualify. According to the SEMDSA guidelines, most of the patients not receiving a statin (90%) should have been on statin therapy. Only 23.5% of patients on statins were at lipid goal. The frequency of laboratory testing did not meet SEMDSA guidelines. There were 31 (31%) patients without a urea, creatinine and electrolyte test for the previous year and 37 (37%) patients without a lipogram for the previous year. Only 21 patients had a listed urine albumin/creatinine ratio and only 33% of these had been done in the previous year. Conclusions Various new variables were identified in the search for predictors of glycaemic control. It was surprising to find that education level, monthly income, smoking status and knowledge of diabetes did not have a statistical impact on glycaemic control. Increased age, duration of diabetes, glomerular filtration rate, hypoglycaemic frequency and diabetic complications experienced were associated with improved glycaemic control. Increased diastolic blood pressure, aspirin dosage, statin dosage and body mass index were associated with worse glycaemic control. The standard of care in the clinic was found on the whole to be inferior to the level of care recommended by SEMDSA.

acase@tulane.edu / Although men with testosterone deficiency are at increased risk for type 2 diabetes (T2D), previous studies have ignored the role of testosterone and the androgen receptor (AR) in pancreatic β–cell. Our study shows that male pancreatic β–cell specific AR knockout (βARKOMIP) mice develop glucose intolerance because AR potentiates glucose-stimulated insulin secretion (GSIS) through increasing cyclic AMP (cAMP) accumulation and amplifying the insulinotropic effect of glucagon-like peptide-1 (GLP-1). Using transcriptome analysis, we find that AR-deficient islets exhibit altered expression of genes involved in inflammation and insulin secretion demonstrating the importance of androgen action in β-cell health in the male. Our recent study shows that male βARKOMIP mice exhibit impaired intraperitoneal (IP) glucose tolerance- because of impaired IP-GSIS- without alteration in oral glucose tolerance, suggesting that AR amplifies the islet-derived, but not the gut-derived GLP-1 to potentiate GSIS. Dihydrotestosterone (DHT) increases the insulinotropic effect of GLP-1, not gastric inhibitory polypeptide (GIP) and glucagon, in male insulin-secreting β-cell line 832/3 cells and wild-type male mouse islets. Accordingly, using 832/3 cells transduced with exchange factor directly activated by a cAMP (EPAC)-based fluorescence resonance energy transfer (FRET) sensor, we observe that the AR agonist dihydrotestosterone (DHT) specifically allows GLP-1, not GIP and glucagon, to increase cAMP production above level of the individual hormones. The insulinotropic effect of DHT is abolished using EPAC and PKA inhibitors as well as rapamycin indicating that DHT stimulates GSIS via a cAMP/PKA/EPAC pathway and activation of mTOR. This study identifies AR as a novel receptor that enhances β–cell function, a finding with implications for the prevention of type 2 diabetes (T2D) in aging men. / 1 / Weiwei Xu

No description available.

The purpose of this study was to explore associations between early-life factors and the development of youth onset type 2 diabetes mellitus (T2DM). Until 1990, T2DM was seldom reported in youth, however rates of youth onset T2DM are rising worldwide. This retrospective case-control study utilized repository data housed at the Manitoba Centre for Health Policy to review perinatal exposures of Manitoba youth with and without T2DM. The mean age at time of diagnosis was 13.1 years and 61% of youth onset T2DM cases were female. The majority of youth with T2DM resided in rural areas at time of diagnosis. This study found a 14-fold increase in the risk of youth onset T2DM when the mother had pre-gestational diabetes, and 6.5-fold increase in that risk if the mother had gestational diabetes. Breastfeeding was found to be protective, and a lower income quintile at time of birth was found to be more significantly associated with the development of youth onset T2DM than increasingly higher income quintiles . The findings emphasize that efforts aimed at preventing T2DM in youth must begin in the pre-conception period and continue throughout pregnancy.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 5 uppsatser.

Thesis Title Exploring new methodologies to identify disease-associated variants in African populations through the integration of patient genotype data and clinical phenotypes derived from routine health data: A case study for Type 2 Diabetes Mellitus patients in the Western Cape Province, South Africa. Abstract Introduction There is poor knowledge on the genetic drivers of disease in African populations and this is largely driven by the limited data for human genomes from sub-Saharan Africa. While the costs of generating human genomic data have gone down significantly, they are still a barrier to generating large scale African genomic data. This project is therefore a proof-of-concept pilot study that demonstrates the implementation of a cost-effective, scalable genotyped virtual cohort that can address population level genomic questions. Methods We optimised a tiered informed consent process that is suitable for the cohort study design and adapted it to conducting human genomic research in the African context. We used an existing dataset to explore statistical methods for modelling longitudinal routine health data into a standardised phenotype for genome wide association studies (GWAS). We then conducted a feasibility study and piloted the tiered informed consent process, DNA collection by buccal swab and DNA extraction from buccal swabs and peripheral blood samples. DNA samples were genotyped for approximately 2.2 million variants on the Infinium™ H3Africa Consortium Array V2. Genotyping quality control (QC) was done in Plink 1.9 and genome wide imputation on the Sanger Imputation Service. We demonstrated successful variant calling and provide aggregate statistics for known aetiological variants for type 2 diabetes and severe COVID-19 as well as demonstrating the feasibility of running nested case-control GWAS with these data. Results We demonstrate the use of routine health data to provide complex phenotypes to link to genotype data for both non-communicable diseases (diabetes) and infectious diseases (Tuberculosis, HIV and COVID-19). 459 participants consented to providing a DNA sample and access to their routine health data and were included in the feasibility study. A total of 343 DNA samples and 1782023 genotyped variants passed quality control and were available for further analysis. While most of the cohort population clustered with the 1000 genomes African population, principal component analysis showed extensive population admixture. For the COVID-19 analysis, we identified 63 cases of severe COVID-19 and 280 controls, and for the type 2 diabetes analysis we identified 93 cases and 250 controls using the routine health data of participants in the cohort. While the sample sizes were insufficient for a GWAS we were able to evaluate known type 2 diabetes mellitus and COVID-19 variants in the study population. Conclusion We have described how we conceptualised and implemented a genotyped virtual population cohort in a resource constrained environment, and we are confident that this design and implementation are appropriate to scale up the cohort to a size where novel health discoveries can be made through nested case-control studies. In the interim we demonstrate the analysis and validation of aetiological variants identified in other studies and populations.

Bien que le Diabète de Type 2 soit parfois considéré comme évitable, il est généralement irréversible et les traitements actuels sont communément inefficaces pour stopper la progression inexorable de la maladie vers un mauvais contrôle glycémique et des complications dégénératives micro- et macrovasculaires. Le DT2 est caractérisé par une altération de la sécrétion d’insuline par les cellules beta pancréatiques, combinée à une absence de réponse des organes cibles à l’insuline (insulino-résistance) incluant le foie, le tissu adipeux et le muscle squelettique. Malgré 40 ans de recherches intensives, les mécanismes moléculaires sous-jacents sont toujours largement débattus à ce jour. Le DT2 est une maladie à forte composante génétique, comme l’ont montré les études de jumeaux concordants en général pour le DT2. Au moins 2% des patients atteints de DT2 ont un diabète d’origine monogénique, survenant en général pendant l’enfance ou l’adolescence. L’une de ces formes survient spécifiquement à la naissance (diabète néonatal) et 50% de ses étiologies génétiques sont connus à ce jour. Les formes communes de DT2 survenant chez l’adulte sont polygéniques, liées à l’interaction entre des variants génétiques à effet modeste et faible pénétrance, et l’environnement ; en outre, des mécanismes « épigénétiques » seraient aussi en cause. L’identification des déterminants génétiques du DT2 a été dopée par les études d’association pangénomique (GWAS pour Genome Wide Association Studies) grâce à la mise au point de puces à ADN, qui permettent d’analyser conjointement plusieurs centaines de milliers de polymorphismes nucléotidiques simples (SNPs pour Single Nucleotide Polymorphisms) chez plusieurs centaines de milliers d’individus. Les GWAS ont permis d’identifier à ce jour une trentaine de gènes associées au risque de DT2. Le diagnostic du DT2 repose sur la mesure d’un trait continu, la glycémie à jeun. A partir de 1,25g/l, un individu est considéré diabétique. La glycémie à jeun, même chez des personnes non diabétiques, est fortement héritable, c’est-à-dire que ce paramètre métabolique est sous contrôle génétique. Nous avons ainsi utilisé la méthode des GWAS pour rechercher des loci régulant la glycémie dans des populations générales comme la population française DESIR. Nous avons mis en évidence la contribution du gène MTNR1B (codant le récepteur 2 de la mélatonine) dans la sécrétion d’insuline et la régulation de l’homéostasie glycémique. La mélatonine est l’hormone clef des rythmes circadiens de l’organisme, et il a été rapporté dans plusieurs études que la perturbation de ces rythmes est nuisible à l’homéostasie glycémique. Nous avons pu ensuite préciser quelles étaient les séquences d’ADN ayant un effet dans ce contrôle glycémique. Nous avons ainsi mis en évidence des mutations non-synonymes rares qui annihilaient la voie de signalisation de la mélatonine et qui sont associées à un risque élevé de DT2. Par ailleurs, via le consortium international MAGIC, nous avons contribué à l’identification de 16 marqueurs génétiques de la glycémie à jeun, de cinq marqueurs de la glycémie après charge de glucose, et de 10 loci intervenant dans la variance de l’hémoglobine glyquée (HbA1c, qui est un marqueur communément utilisé pour évaluer le contrôle glycémique d’un diabète traité). Ce faisant, nous avons montré que si le gène HK1 codant l’hexokinase 1 est le facteur génétique ayant le plus d’effet sur les valeurs d’HbA1c, il n’intervient pas sur les mécanismes physiologiques de la régulation de la glycémie. C’est uniquement de par les effets des variants d’HK1 sur la fonction des globules rouges (et sur le risque d’anémie) que ce gène modifie indirectement l’HbA1c. / Type 2 Diabetes is a major health care problem responsible for early morbidities and mortality. T2D prevalence inexorably increases due to dramatic changes in our way of life. T2D is preventable but no generally curable and present medications fail to prevent the worsening of glucose control and the development of complications. T2D is a systemic disease characterized by both insulin secretion defects and by insulin resistance at the levels of several tissues. Despite more than 40 years of research the aetiologies of T2D are still elusive. T2D is a multifactorial disease with a significant genetic component. However, T2D is a polygenic disorder with the effects of multiple DNA variants having a modest effect and a weak penetrance interaction with environmental factors. The identification of T2D susceptibility genes has been transformed by Genome Wide Association Studies (GWAS) which allow the analysis of hundred of thousands Single Nucleotide Polymorphisms (SNPs) in thousands of samples. Case/control GWAS have identified about 30 loci/genes, so far. However, these loci only explain a small part of T2D inheritance. T2D is defined by the measurement of the continuous trait “glycemia”. A fasting plasma glucose (FPG) higher than 7mM is considered to be abnormal. FPG is highly genetically determined and we have reanalyzed our GWAS data obtained in non diabetic general populations to identify genes that control (normal) glucose values. We first found that SNPs at MTNR1B (encoding the melatonin 2 receptor) locus regulate both FPG and insulin secretion. Melatonin is the hormone of darkness that plays a major role in circadian rhythms. The alteration of these physiological rhythms has been shown to impair glucose homeostasis. Subsequently we have screened and functionally analysed the coding part of MTNR1B in thousands of T2D cases and controls for rare lack of function mutations that strongly increase the risk for T2D. In addition via our contribution to the international consortium MAGIC we have identified 16 genetic markers modulating FPG, five controlling blood glucose after oral glucose load, and ten involved in the variance of glycated haemoglobin (HbA1c, a clinical marker of glucose control in treated diabetic patients). In this respect, we have demonstrated that if HK1 (encoding hexokinase 1) is the most potent gene controlling HbA1c, it was not at all involved in the physiology of glucose homeostasis. Instead, variant at HK1 locus act on red cell function, increase risk for anemia, and only indirectly perturb HbA1c measurement. This study shows that GWAS findings don’t mean causality and it is always mandatory to question the physiological validity of any association found through GWAS before implying a gene as causal. In this respect, the MAGIC consortium showed that among all the genes that regulate HbA1c, a large proportion is indeed directly related to red cell function. In conclusion, during my PhD, I have contributed to achieve a map of frequent SNPs regulating the major glucose control quantitative traits that define T2D. I also showed that rare DNA variants with a stronger biological impact also contribute to T2D risk. Although still of limited value for the prediction of T2D, GWAS have proven extremely useful to make progress in T2D physiology.

Yang Tao. / "November 2000." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (p. 136-152). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

La polyarthrite rhumatoïde (PR) est une maladie inflammatoire chronique d’étiologie inconnue. Les mécanismes physiopathologiques de cette maladie mettent en jeu un réseau cellulaire et cytokinique dont l’étude permet de définir des cibles thérapeutiques potentielles. L’IL-33 est une cytokine impliquée dans plusieurs maladies inflammatoires mais son rôle dans l’inflammation chronique comme la PR reste peu étudié. L’objectif de ce travail a été d’étudier le rôle de l’IL-33 et son mode d’action dans deux modèles expérimentaux d’inflammation chronique, l’arthrite au collagène (AEC) et le psoriasis induit par l’imiquimod (IMQ) chez la souris. Nous avons montré pour la première fois que l’administration d’IL-33 recombinante pendant les phases précoce et tardive de l’AEC, permet d’inhiber presque totalement les signes cliniques de la maladie. Cet effet protecteur passe par le déclenchement d’une réponse immunitaire de type 2 y compris l'expansion des ILC2, des éosinophiles et des cellules Th2. En outre, nous avons démontré que l’administration d’IL-33 dans notre modèle induit l’expansion de lymphocytes T régulateurs ST2L+ et une activité suppressive accrue. Dans un second temps, nous avons démontré que malgré l’expression de l’IL-33 dans les articulations ou la peau de souris développant une AEC ou un psoriasis induit par imiquimod, l’IL-33 endogène n’est pas nécessaire pour le développement de ces deux pathologies. En outre, l’absence de cette cytokine ne modifie pas la réponse des lymphocytes T ni dans l’AEC et ni dans le psoriasis. L'ensemble de ces résultats suggère que cette cytokine n’est pas cruciale pour le développement de l'inflammation chronique, et que la mise au point de traitement ciblant l’axe IL-33 / ST2 doit être envisagée avec précautions. / Rheumatoid arthritis (RA) is a chronic inflammatory disease that is associated with severalmediators. The physiopathological mechanisms of this disease involve cellular and cytokinenetworks whose study helps to define potential therapeutic targets. IL-33 is a cytokine involved inmany inflammatory diseases although its role in chronic inflammation such as RA remainsunclear. The aim of this work is to study the role of IL-33 and its mode of action in twoexperimental models of chronic inflammation, collagen induced arthritis (CIA) and imiquimod(IMQ) induced psoriasis. First, we showed for that the administration of recombinant IL-33 duringthe early and late phases of CIA inhibits the clinical signs of the disease in mice C57BL/6. Thisprotective effect is associated with the response type 2 including expansion of ILC2, eosinophilsand Th2 cells. Furthermore, we demonstrated that access of IL-33 in our model induced TregST2L and promotes the acquisition of regulatory phenotypes of Tregs. These Tregs achieve animportant suppressive activity leading inhibition of CIA. Secondly, despite the expression of IL-33 in the joint and skin of mice with CIA and IMQ induced psoriasis, endogenous IL-33 is notnecessary for the development of these two chronic inflammation models. In addition, the absenceof this cytokine does not alter the T cell response in the CIA or psoriasis. [...]