A central aim in drug development is to ensure that the new drug is efficacious and safe in the intended patient population. Mathematical models describing the pharmacokinetic-pharmacodynamic (PK-PD) properties of a drug are valuable to increase the knowledge about drug effects and disease and can be used to inform decisions. The aim of this thesis was to develop mechanism-based PK-PD-disease models for important safety and efficacy biomarkers used in anti-diabetic drug development. Population PK, PK-PD and disease models were developed, based on data from clinical studies in subjects with varying degrees of renal function, non-diabetic subjects with insulin resistance and patients with type 2 diabetes mellitus (T2DM), receiving a peroxisome proliferator-activated receptor (PPAR) α/γ agonist, tesaglitazar. The PK model showed that a decreased renal elimination of the metabolite in renally impaired subjects leads to increased levels of metabolite undergoing interconversion and subsequent accumulation of tesaglitazar. Tesaglitazar negatively affects the glomerular filtration rate (GFR), and since renal function affects tesaglitazar exposure, a PK-PD model was developed to simultaneously describe this interrelationship. The model and data showed that all patients had decreases in GFR, which were reversible when discontinuing treatment. The PK-PD model described the interplay between fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c) and haemoglobin in T2DM patients. It provided a mechanistically plausible description of the release and aging of red blood cells (RBC), and the glucose dependent glycosylation of RBC to HbA1c. The PK-PD model for FPG and fasting insulin, incorporating components for β-cell mass, insulin sensitivity and impact of disease and drug treatment, realistically described the complex glucose homeostasis in the heterogeneous patient population. The mechanism-based PK, PK-PD and disease models increase the understanding about T2DM and important biomarkers, and can be used to improve decision making in the development of future anti-diabetic drugs.

No description available.

Antro tipo cukrinis diabetas yra viena iš aktualiausių dabartinės medicinos problemų, kurios etiopatogenetinis pagrindas ypač glaudžiai siejasi su visuomenės papročiais ir gyvenimo būdu (WHO, 2006). Su gyvenimo būdu susietų rizikos veiksnių plėtra XX amžiuje įgavo epideminio pobūdžio metabolinių sutrikimų išraišką tarp atskirų, bet sąlyginai identiškai gyvenančių, individų grupių (King H. et al., 1998; Wild S. et al., 2004). Nepalankių socialinių ir ekonominių veiksnių įtaka ypač skatina metabolinių sutrikimų, kurie pasireiškia kaip metabolinis sindromas ir 2 tipo cukrinis diabetas, gausėjimą. Pasirinkus hipotezę, kad šiuolaikinės civilizacijos įpirštas gyvenimo būdas yra palankus 2 tipo cukrinio diabeto manifestavimui, prognozuojama, kad 2030 metais šia liga sirgs apie 366 milijonai planetos gyventojų (Wild S. et al., 2004). Metabolinių sutrikimų visuma įvardinta kaip „cukrinis diabetas” tampa vis dažnesne regėjimo sutrikimų, aklumo, kojų amputacijų, inkstų funkcijos nepakankamumo, blogos gyvenimo kokybės, prarasto darbingumo bei ankstyvesnio mirtingumo priežastimi. Tai – liga, esanti penktoje vietoje pagal mirtingumą po užkrečiamų, širdies ir kraujagyslių ligų, vėžio ir nelaimingų atsitikimų (Roglic G. et al., 2005). Lietuvoje cukrinio diabeto problema tampa vis aktualesnė, didėja sergančiųjų šia liga skaičius. Jei 1966 m. šalyje tebuvo suskaičiuotas 3561 sergantysis cukriniu diabetu (Sideraite Š., 1998), tai 1997 m. sausio 1 d. jau buvo užregistruoti 26896 sergantieji šia... [toliau žr. visą tekstą] / Diabetes mellitus is one of the main health issues in Lithuania. Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia, resulting from defects in insulin secretion, insulin action or both. The disease is associated with significant increased risk of long–term microvascular and macrovascular complications. The number of cases of diabetes worldwide in 2000 among adults 20 years of age is estimated to be 171 million. Diabetes is becoming a world pandemic with an estimated increase till 366 million cases by 2030, especially in developing countries. The number of people with diabetes is increasing due to population growth, aging, urbanization, and increasing prevalence of obesity . The aim of our study to assess clinical, laboratory data, risk factors and quality of life of new type 2 diabetes mellitus cases. A case–control study included 234 cases with newly confirmed diagnose of type 2 diabetes mellitus in 2001 and 468 controls who were free of the disease. Cases and controls were matched by gender and age (+5 yr.). Ratio of case and controls was 1:2. Two questionnaires were used in this study (1st one – to collect information on possible risk factors of type 2 diabetes mellitus, the 2nd one – EQ–5D questionnaire – to measure quality of life for patients with newly diagnosed type 2 diabetes mellitus). Variables were retained in models as confounders when inclusion changed the value of the odds ratio (OR) by more than 10% in any exposure category. The... [to full text]

Coronary heart disease is the single greatest contributor to mortality within developed countries in our time. Type 2 diabetes mellitus and obesity, both of which are potent risk factors for coronary heart disease, are common conditions with rapidly rising rates of prevalence both globally and in Australia. Within Australia, Indigenous Australians suffer from disproportionately high rates of diabetes, obesity and coronary heart disease, the reason for which lies, in part, with changes in dietary intake and decreased levels of physical activity over the past 200 years. These disease trends have led to a substantially reduced life expectancy from an increase in excess cardiovascular deaths in Indigenous Australians. Assessment of cardiovascular risk in Indigenous Australians is complicated by ethnic differences in cardiovascular risk factors and their prevalence. There is also evidence that Indigenous Australians are genetically predisposed to diabetes. Current cardiovascular risk stratification algorithms are suboptimal, significantly underestimating risk in Indigenous Australians. This thesis aimed to address these issues. Firstly, to evaluate the efficacy of a lifestyle intervention programme to sustainably improve markers of health outcome in a cohort of Indigenous Australians who were overweight or had type 2 diabetes mellitus by improving diet and physical activity levels. Secondly, to evaluate the utility of anthropometric markers of obesity, ultrasound markers of atherosclerotic burden and serum C-reactive protein as additional cardiovascular risk stratification tools. The Healthy Lifestyle Programme (HELP) was a two year prospective intervention study designed and implemented with substantial input from the Indigenous community. The primary intervention consisted of a series of educational workshops delivered predominantly by Indigenous health workers advocating improving diet and increasing physical activity. To complement these workshops, facilities were established within the community to support dietary improvement and increased physical activity. Sustainable changes to markers of cardiovascular outcome, including significant reductions in central obesity and blood pressure were demonstrated over time. A slowing in the deterioration of renal function as marked by albuminuria was also detected. These beneficial changes were accompanied by increased physical activity and improved dietary intake. In a substudy, individuals with the apolipoprotein E4 genotype, who were dyslipidaemic at baseline, benefited from lipid profiles that improved significantly during the course of the study. Changes in blood pressure and central obesity detected during the course of the project are likely to have significant clinical impact on health outcomes considering their sustained nature. Evaluating ultrasound imaging based markers of cardiovascular risk, carotid artery intimal medial thickness was a more reliable measure of risk based on its firm correlation with established cardiovascular risk factors compared to brachial artery flow mediated vasodilatation. Carotid artery intimal medial thickness may be the better surrogate marker to improve cardiovascular risk stratification in the Indigenous population. Examining anthropometric markers of obesity, body mass index and waist circumference but not waist hip ratio correlated well with traditional cardiovascular risk factors. Furthermore, both body mass index and waist circumference predicted insulin resistance fairly well using threshold values derived from receiver operating characteristics curve analyses. Both body mass index and waist circumference were simple to perform with a high degree of reproducibility between observers and will likely be valuable additional cardiovascular risk stratification tools. Raised inflammatory stress, as marked by elevated serum C-reactive protein levels, was found in individuals with diabetes or obesity. C-reactive protein levels did not correlate with carotid artery intimal medial thickness, suggesting that C-reactive protein raises cardiovascular risk by means other than increasing atherosclerotic burden. Genotyping a small random sample of our the C-reactive protein gene promoter region. This SNP was found to independently increase serum C-reactive protein in the Framingham cohort. A genetic basis for increased inflammatory stress may contribute to coronary heart disease in Indigenous Australians. In summary, a community centred lifestyle intervention programme was efficacious in producing sustainable improvement in markers of health outcome. Examination of additional cardiovascular risk markers in the Indigenous community have provided evidence for using carotid artery intimal medial thickness, waist circumference, body mass index and serum C-reactive protein levels to improve cardiovascular risk stratification. These additional tools would allow for more specific resource allocation to target individuals at highest cardiovascular risk for preventative management. C-reactive protein gene polymorphisms, their contribution to circulating C-reactive protein levels and cardiovascular outcomes warrants further investigation in the Indigenous population. A more proactive risk management plan, which includes a lifestyle intervention component, may yield the greatest improvement in long term health outcomes if targeted at younger members of the Indigenous community.

Coronary heart disease is the single greatest contributor to mortality within developed countries in our time. Type 2 diabetes mellitus and obesity, both of which are potent risk factors for coronary heart disease, are common conditions with rapidly rising rates of prevalence both globally and in Australia. Within Australia, Indigenous Australians suffer from disproportionately high rates of diabetes, obesity and coronary heart disease, the reason for which lies, in part, with changes in dietary intake and decreased levels of physical activity over the past 200 years. These disease trends have led to a substantially reduced life expectancy from an increase in excess cardiovascular deaths in Indigenous Australians. Assessment of cardiovascular risk in Indigenous Australians is complicated by ethnic differences in cardiovascular risk factors and their prevalence. There is also evidence that Indigenous Australians are genetically predisposed to diabetes. Current cardiovascular risk stratification algorithms are suboptimal, significantly underestimating risk in Indigenous Australians. This thesis aimed to address these issues. Firstly, to evaluate the efficacy of a lifestyle intervention programme to sustainably improve markers of health outcome in a cohort of Indigenous Australians who were overweight or had type 2 diabetes mellitus by improving diet and physical activity levels. Secondly, to evaluate the utility of anthropometric markers of obesity, ultrasound markers of atherosclerotic burden and serum C-reactive protein as additional cardiovascular risk stratification tools. The Healthy Lifestyle Programme (HELP) was a two year prospective intervention study designed and implemented with substantial input from the Indigenous community. The primary intervention consisted of a series of educational workshops delivered predominantly by Indigenous health workers advocating improving diet and increasing physical activity. To complement these workshops, facilities were established within the community to support dietary improvement and increased physical activity. Sustainable changes to markers of cardiovascular outcome, including significant reductions in central obesity and blood pressure were demonstrated over time. A slowing in the deterioration of renal function as marked by albuminuria was also detected. These beneficial changes were accompanied by increased physical activity and improved dietary intake. In a substudy, individuals with the apolipoprotein E4 genotype, who were dyslipidaemic at baseline, benefited from lipid profiles that improved significantly during the course of the study. Changes in blood pressure and central obesity detected during the course of the project are likely to have significant clinical impact on health outcomes considering their sustained nature. Evaluating ultrasound imaging based markers of cardiovascular risk, carotid artery intimal medial thickness was a more reliable measure of risk based on its firm correlation with established cardiovascular risk factors compared to brachial artery flow mediated vasodilatation. Carotid artery intimal medial thickness may be the better surrogate marker to improve cardiovascular risk stratification in the Indigenous population. Examining anthropometric markers of obesity, body mass index and waist circumference but not waist hip ratio correlated well with traditional cardiovascular risk factors. Furthermore, both body mass index and waist circumference predicted insulin resistance fairly well using threshold values derived from receiver operating characteristics curve analyses. Both body mass index and waist circumference were simple to perform with a high degree of reproducibility between observers and will likely be valuable additional cardiovascular risk stratification tools. Raised inflammatory stress, as marked by elevated serum C-reactive protein levels, was found in individuals with diabetes or obesity. C-reactive protein levels did not correlate with carotid artery intimal medial thickness, suggesting that C-reactive protein raises cardiovascular risk by means other than increasing atherosclerotic burden. Genotyping a small random sample of our the C-reactive protein gene promoter region. This SNP was found to independently increase serum C-reactive protein in the Framingham cohort. A genetic basis for increased inflammatory stress may contribute to coronary heart disease in Indigenous Australians. In summary, a community centred lifestyle intervention programme was efficacious in producing sustainable improvement in markers of health outcome. Examination of additional cardiovascular risk markers in the Indigenous community have provided evidence for using carotid artery intimal medial thickness, waist circumference, body mass index and serum C-reactive protein levels to improve cardiovascular risk stratification. These additional tools would allow for more specific resource allocation to target individuals at highest cardiovascular risk for preventative management. C-reactive protein gene polymorphisms, their contribution to circulating C-reactive protein levels and cardiovascular outcomes warrants further investigation in the Indigenous population. A more proactive risk management plan, which includes a lifestyle intervention component, may yield the greatest improvement in long term health outcomes if targeted at younger members of the Indigenous community.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.

Thesis (Ph. D.)--West Virginia University, 2004. / Title from document title page. Document formatted into pages; contains xiv, 287 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 261-282).

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Objetivo: Avaliar o efeito da intervenção dietética individualizada sobre o diagnóstico nutricional e controle metabólico em diabéticos tipo 2 sedentários Casuística e Métodos: Trata-se de um ensaio clínico controlado e prospectivo com 80 adultos, de ambos dos sexos, com Diabetes Mellitus tipo 2 divididos em GI (grupo intervenção: 40 indivíduos submetidos à intervenção dietética e a utilização de hipoglicemiante) e GC (grupo controle: 40 indivíduos submetidos à medicação hipoglicemiante). Foi realizada intervenção dietética individualizada por três meses baseando-se nas recomendações da American Diabetes Association (2002). Foram analisadas as variáveis antropométricas: massa corporal total (MCT), estatura com determinação do Índice de Massa Corporal (IMC) e perímetro da cintura (PC); as variáveis bioquímicas glicemia, colesterol total, LDL-colesterol, HDL-colesterol, triglicerídeos (TG) e hemoglobina glicada (HbA1c) e as variáveis dietéticas energia, proteínas, carboidratos, lipídeos, colesterol e fibras alimentares. Para estatística inferencial foi utilizado o Anova two-way com nível de significância de 95%. Resultados: Na análise intergrupos, o GC apresentou aumento nas variáveis: MCT (&#916;%=0,78; p=0,014), IMC (&#916;%=0,76; p=0,012), PC (&#916;%=0,75; p=0,019) enquanto que o GI apresentou redução nas variáveis: MCT (&#916;%=-3,71; p<0,001), IMC (&#916;%=-3,77; p<0,001), PC (&#916;%=-3,98; p<0,001). Na comparação da média do IR intergrupos, observou-se diferença nas variáveis: energia (p<0,001), lipídeos (p=0,012), gorduras saturadas (p<0,001); colesterol dietético (p=0,006); fibras alimentares (p=0,001); glicemia (p<0,001), colesterol total (p<0,001), LDL-colesterol (p<0,001) e HbA1c (p<0,001).Conclusão: A intervenção dietética foi eficiente em melhorar o perfil antropométrico e o controle metabólico dos diabéticos tipo 2 sedentários. / Objective: To evaluate the effect of individualized dietary intervention on nutritional diagnosis and metabolic control in sedentary subjects with type 2 diabetes. Materials and methods: This controlled clinical trial, investigated 80 adults, of both sexes, with type 2 diabetes. Patients were divided into intervention group (IG: 40 individuals subjected to intervention and hypoglycemic drug) and control group (CG: 40 individuals subjected only hypoglycemic drug). Individualized dietary intervention was conducted, for three months, based on the American Diabetes Association (2002). The anthropometric variables evaluated included: total body mass (TBM) and height to calculate body mass index (BMI), and waist circumference (WC): biochemical variables assessed were: blood glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides (TG), and glycated hemoglobin (HbA1c): In addition, the intake of energy, protein, carbohydrate, lipid, cholesterol, and dietary fibers. For inferential statistics two-way ANOVA was used with significant level of 95%.Results: In the intergroup analysis, the CG showed increase in TBM (&#916;%=0.78; p=0.014), BMI (&#916;%=0.76; p=0.012), WC (&#916;%=0.75; p=0.019); whereas IG decreased TBM (&#916;%=-3.71; p<0.001), BMI (&#916;%=-3.77; p<0.001), WC (&#916;%=-3.98; p<0.001). In comparing the mean RI intergroups, there was difference in the variables: energy/day (p<0.001), lipids (p=0.012), saturated fats (p<0.001), cholesterol (p=0.006), dietary fibers (p=0.001); blood glucose (p<0.001), total cholesterol (p<0.001), LDL-cholesterol (p<0.001), and HbA1c (p<0.001). Conclusions: The dietary intervention was efficiently the improvement the anthropometric and metabolic control of type 2 sedentary diabetics.

A nefropatia diabética (ND) é uma complicação microvascular freqüente, que acomete cerca de 40% dos indivíduos com diabete melito (DM). A ND associa-se a significativo aumento de morte por doença cardiovascular. É a principal causa de insuficiência renal terminal em países desenvolvidos e em desenvolvimento, representando, dessa forma, um custo elevado para o sistema de saúde. Os fatores de risco para o desenvolvimento e a progressão da ND mais definidos na literatura são a hiperglicemia e a hipertensão arterial sistêmica. Outros fatores descritos são o fumo, a dislipidemia, o tipo e a quantidade de proteína ingerida na dieta e a presença da retinopatia diabética. Alguns parâmetros de função renal também têm sido estudados como fatores de risco, tais como a excreção urinária de albumina (EUA) normal-alta e a taxa de filtração glomerular excessivamente elevada ou reduzida. Alguns genes candidatos têm sido postulados como risco, mas sem um marcador definitivo. O diagnóstico da ND é estabelecido pela presença de microalbuminúria (nefropatia incipiente: EUA 20-199 μg/min) e macroalbuminúria (nefropatia clínica: EUA ≥ 200 μg/min). À medida que progride a ND, aumenta mais a chance de o paciente morrer de cardiopatia isquêmica. Quando o paciente evolui com perda de função renal, há necessidade de terapia de substituição renal e, em diálise, a mortalidade dos pacientes com DM é muito mais significativa do que nos não-diabéticos, com predomínio das causas cardiovasculares. A progressão nos diferentes estágios da ND não é, no entanto, inexorável. Há estudos de intervenção que demonstram a possibilidade de prevenção e de retardo na evolução da ND principalmente com o uso dos inibidores da enzima conversora da angiotensina, dos bloqueadores da angiotensina II e do tratamento intensivo da hipertensão arterial. Os pacientes podem entrar em remissão, ou até mesmo regredir de estágio. A importância da detecção precoce e da compreensão do curso clínico da ND tem ganhado cada vez mais ênfase, porque a doença renal do DM é a principal causa de diálise no mundo e está associada ao progressivo aumento de morte por causas cardiovasculares. / Diabetic nephropathy (DN) is a frequent microvascular complication, which affects about 40% of diabetes mellitus (DM) patients. DN is associated with an increased cardiovascular death rate. DN is the major cause of kidney failure in developing as well as in developed countries, and it is, therefore, associated with increased health system costs. The more defined risk factors for the development and progression of DN are sustained hyperglycemia and hypertension. Other putative risk factors are smoking, dyslipidemia, the amount and source of protein in the diet, and the presence of diabetic retinopathy. Some renal function parameters have also been studied as risk factors, such as high normal urinary albumin excretion (UAE) and extremely high or low glomerular filtration rate levels. Some candidate genes have been analyzed as risk factors, but without any definitive marker. DN diagnosis is established by the presence of microalbuminuria (incipient nephropathy: UAE 20-199 μg/min), and macroalbuminuria (overt nephropathy: UAE ≥200 μg/min). As DN progress, the chance of death from coronary artery disease increases. When patients progress to kidney failure with uremia, renal replacement therapy becomes necessary, and when on dialysis, diabetic patients have higher mortality rates in comparison to non-diabetic ones, primarily from cardiovascular causes. DN progression through stages is not always the rule. Intervention studies demonstrate that DN prevention and remission are possible, mainly with angiotensinconverting enzyme inhibitors, angiotensin-II receptor blockers, and intensive hypertension treatment. The importance of the earlier detection, and the understanding of clinical course of DN, have progressively grown, because it is the leading cause of dialysis in the world, and is associated with increased cardiovascular mortality.

This thesis deals with the topic of "Physical Activity of Seniors with Type 2 Diabetes Mellitus". The theoretical part characterizes terms relating to old age, its symptoms and health problems associated with it; type 2 diabetes mellitus; physical activity playing an essential role in the prevention; and non-pharmacological treatment of this disease. The practical part focuses on monitoring physical activities of seniors with type 2 diabetes mellitus. To collect the data for the research a standardized IPAQ long questionnaire was used. A selected group was monitored using Yamax Digiwalker SW 700 pedometers as regards to the number of steps they made. The obtained results were analyzed and compared with the recommendations for physical activities.