Characteristics of Prediabetes, predictors of progression and strategies to prevent Type 2 Diabetes Mellitus in a multiethnic population in the United Kingdom

Executive Summary: Type 2 Diabetes Mellitus (T2DM) is a chronic multi factorial disorder linked to obesity that is associated with increased morbidity and mortality. T2DM poses a major public health problem with the prevalence expecting to reach 4 million in the United Kingdom by the year 2025. Upto 50% of people may have established complications at the time of diagnosis of T2DM. However, T2DM is preceded by a latent phase of Prediabetes (PDM) which provides a window of opportunity for primary prevention. PDM is often known as impaired glucose metabolism (IGM) or impaired glucose regulation (IGR). PDM is a collective term for impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and those with combined IFG and IGT. The reported prevalence of these conditions is variable throughout the world. This thesis seeks to address key questions on identification of IGR, determine factors predicting progression to T2DM and thus propose prevention strategies in a mixed ethnic population in the UK using data from the ADDITION Leicester and ADDITION PLUS studies. ADDITION Leicester is a sub study of the multinational multi centre study-ADDITION Europe. ADDITION study is a randomised controlled trial evaluating the benefits of a multi factorial cardiovascular disease risk factor intervention in a cohort of patients with screen detected T2DM. The prevalence of PDM was 16% in the study population with IFG, IGT and combined IFG and IGT being 2.8%, 11% and 2.2% respectively. People of South Asian (SA) origin have a significantly higher adjusted prevalence of PDM compared to those of White European (WE) origin (OR: 1.57; 95% CI: 1.24 to 1.98). A risk score tailored to the local population (Leicester risk assessment score) was robust in identifying those at risk of developing T2DM and PDM as well those progressing from PDM to T2DM at 12 months. Subjects with PDM have a unique phenotype placing their cardiovascular disease (CVD) risks between T2DM and normal glucose tolerance. Novel markers of CVD such as Interleukin 6, Adiponectin, Leptin and C-reactive protein are also raised in those with PDM compared to normal. The risk of progression from PDM to T2DM at 12 months is higher for SA compared to WE (OR: 3.09, 95% CI- 1.58 to 6.02). The diabetes progression rate (cases/100 person-years) for IFG, IGT and combined IFG and IGT were 5.51, 3.13 and 14.46 respectively. The risk of progression for SA people occurs at a lower cut off for BMI and waist circumference. A meta analysis of 13,314 patients from 22 studies with PDM revealed a pooled progression rate (cases per 100 person-years) (95% CI) to be 6.29 (4.29- 9.22), 7.48 (5.00-11.18) and 7.86 (5.51- 11.20) for people with IFG, IGT and combined IFG+IGT respectively. Presence of CVD, central obesity measured both by waist circumference and BMI, triglycerides, fasting plasma glucose (FPG) and HbA1c significantly predict progression to T2DM at 12 months. Presence of metabolic syndrome with more than 2 additional criteria significantly predicts progression to T2DM. In terms of adipocytokines, TNFα is the only marker, after adjusting for confounders that is significantly associated with progression to T2DM. In terms of follow up of this cohort, we propose a two step method using FPG >6 mmol/L as a screening tool to identify people who can subsequently be screened using an OGTT, reducing the number of OGTT needed to 23.5%. Our findings suggest using a structured screening programme with a risk score used in parallel to the recommended opportunistic screening for T2DM. The need for ethnic specific cut-off for obesity has been established. Factors such as presence of metabolic syndrome, HbA1c >6%, presence of a single diabetes range glucose value and pre-existing CVD may be used in risk stratification of individuals with PDM. These factors may also be used to guide those who may benefit from Metformin in addition to established life style interventions for PDM. Our findings provide a contemporary and prospective data on the prevalence of PDM in a multi ethnic UK population and factors predicting progression from PDM to T2DM. A robust strategy using a self assessed risk score is proposed to identify those at risk of developing PDM and T2DM. A step wise ethnic specific algorithm using anthropometric measures is also recommended to enable follow up of those with PDM. These findings have important implications for public health in informing strategies to address the emerging pandemic of T2DM

Characteristics of prediabetes, predictors of progression and strategies to prevent Type 2 Diabetes Mellitus in a multiethnic population in the United Kingdom

Executive Summary: Type 2 Diabetes Mellitus (T2DM) is a chronic multi factorial disorder linked to obesity that is associated with increased morbidity and mortality. T2DM poses a major public health problem with the prevalence expecting to reach 4 million in the United Kingdom by the year 2025. Upto 50% of people may have established complications at the time of diagnosis of T2DM. However, T2DM is preceded by a latent phase of Prediabetes (PDM) which provides a window of opportunity for primary prevention. PDM is often known as impaired glucose metabolism (IGM) or impaired glucose regulation (IGR). PDM is a collective term for impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and those with combined IFG and IGT. The reported prevalence of these conditions is variable throughout the world. This thesis seeks to address key questions on identification of IGR, determine factors predicting progression to T2DM and thus propose prevention strategies in a mixed ethnic population in the UK using data from the ADDITION Leicester and ADDITION PLUS studies. ADDITION Leicester is a sub study of the multinational multi centre study-ADDITION Europe. ADDITION study is a randomised controlled trial evaluating the benefits of a multi factorial cardiovascular disease risk factor intervention in a cohort of patients with screen detected T2DM. The prevalence of PDM was 16% in the study population with IFG, IGT and combined IFG and IGT being 2.8%, 11% and 2.2% respectively. People of South Asian (SA) origin have a significantly higher adjusted prevalence of PDM compared to those of White European (WE) origin (OR: 1.57; 95% CI: 1.24 to 1.98). A risk score tailored to the local population (Leicester risk assessment score) was robust in identifying those at risk of developing T2DM and PDM as well those progressing from PDM to T2DM at 12 months. Subjects with PDM have a unique phenotype placing their cardiovascular disease (CVD) risks between T2DM and normal glucose tolerance. Novel markers of CVD such as Interleukin 6, Adiponectin, Leptin and C-reactive protein are also raised in those with PDM compared to normal. The risk of progression from PDM to T2DM at 12 months is higher for SA compared to WE (OR: 3.09, 95% CI- 1.58 to 6.02). The diabetes progression rate (cases/100 person-years) for IFG, IGT and combined IFG and IGT were 5.51, 3.13 and 14.46 respectively. The risk of progression for SA people occurs at a lower cut off for BMI and waist circumference. A meta analysis of 13,314 patients from 22 studies with PDM revealed a pooled progression rate (cases per 100 person-years) (95% CI) to be 6.29 (4.29- 9.22), 7.48 (5.00-11.18) and 7.86 (5.51- 11.20) for people with IFG, IGT and combined IFG+IGT respectively. Presence of CVD, central obesity measured both by waist circumference and BMI, triglycerides, fasting plasma glucose (FPG) and HbA1c significantly predict progression to T2DM at 12 months. Presence of metabolic syndrome with more than 2 additional criteria significantly predicts progression to T2DM. In terms of adipocytokines, TNFα is the only marker, after adjusting for confounders that is significantly associated with progression to T2DM. In terms of follow up of this cohort, we propose a two step method using FPG >6 mmol/L as a screening tool to identify people who can subsequently be screened using an OGTT, reducing the number of OGTT needed to 23.5%. Our findings suggest using a structured screening programme with a risk score used in parallel to the recommended opportunistic screening for T2DM. The need for ethnic specific cut-off for obesity has been established. Factors such as presence of metabolic syndrome, HbA1c >6%, presence of a single diabetes range glucose value and pre-existing CVD may be used in risk stratification of individuals with PDM. These factors may also be used to guide those who may benefit from Metformin in addition to established life style interventions for PDM. Our findings provide a contemporary and prospective data on the prevalence of PDM in a multi ethnic UK population and factors predicting progression from PDM to T2DM. A robust strategy using a self assessed risk score is proposed to identify those at risk of developing PDM and T2DM. A step wise ethnic specific algorithm using anthropometric measures is also recommended to enable follow up of those with PDM. These findings have important implications for public health in informing strategies to address the emerging pandemic of T2DM.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Molecular Characterization of Foot-and-Mouth Disease Virus Type C of Indian Origin

Comparison of nucleotide sequences of the partial 1D region of foot-and-mouth disease type C viruses of Indian origin with those of European, South American, and Southeast Asian viruses revealed that the Indian viruses form a distinct genotype. The vaccine strain C IND/51/79 belongs to this genotype and may be a prototype strain of this genotype

Independent Effect of Ethnicity on Glycemia in South Asians and White Europeans

OBJECTIVE: HbA[subscript 1c] levels are higher in most ethnic groups compared with white Europeans (WEs) independent of glycemic control. This comparison has not been performed between South Asians (SAs) and WEs. We analyzed the independent effect of ethnicity on HbA[subscript 1c] and fasting and 2-h plasma glucose (FPG and 2hrPG, respectively) between these groups. RESEARCH DESIGN AND METHODS: Analysis of the ADDITION-Leicester study, in which 4,688WEs and 1,352 SAs underwent oral glucose tolerance testing, HbA[subscript 1c], and other risk factor measurements. RESULTS: Significant associations with HbA[subscript 1c] included ethnicity, FPG, 2hrPG, and homeostasis model assessment of β-cell function (P < 0.001); age and sex (P < 0.01); and fasting insulin and potassium (P < 0.05). After adjusting for these and other risk factors, SAs demonstrated higher HbA[subscript 1c] (6.22 and 6.02%, mean difference 0.20%, 0.10–0.30, P < 0.001), FPG (5.15 and 5.30 mmol/L,mean difference 0.15 mmol/L, 0.09–0.21, P < 0.001), and 2hrPG (5.82 and 6.57mmol/L, mean difference 0.75 mmol/L, 0.59–0.92, P < 0.001) compared with WEs, respectively. CONCLUSIONS: HbA[subscript 1c], FPG, and 2hrPG levels were higher in SAs independent of factors affecting glycemic control

Selected baseline demographics of ADDITION-Leicester cohort investigated, separated by ethnicity and sex.

<p>Continuous variables presented as mean (standard deviation) or geometric mean (95% confidence intervals) after initial log transformation of non-normally distributed variables. Low HDL defined <1.0 and 1.3 mmol/l in males and females respectively.</p>*<p>p<0.001,</p>‡<p>p<0.01,</p>†<p>p<0.05.</p

Receiver operating characteristic curves of the triglyceride-to-HDL cholesterol ratio (THR) to detect insulin resistance, defined as cohort HOMA-IR≥75th percentile, in White European and South Asian men and women.

<p>Receiver operating characteristic curves of the triglyceride-to-HDL cholesterol ratio (THR) to detect insulin resistance, defined as cohort HOMA-IR≥75th percentile, in White European and South Asian men and women.</p

The Association of triglycerides-to-HDL ratio (THR) tertiles with markers of insulin resistance (IR).

<p>The cut-points for tertiles of THR were as follows. White European men: <0.83, 0.83 to 1.50, ≥1.51; White European women: <0.67, ≥0.67 to <1.14, ≥1.14; South Asian men: <0.91, ≥0.91 to <1.70, ≥1.70; South Asian women: <0.73, ≥0.73 to <1.18, ≥1.18. Continuous variables presented as geometric mean (95% confidence intervals) including adjustments for age, BMI, LDL-cholesterol and SBP. P-values for trend across the tertiles:</p>*<p>p<0.001,</p>‡<p>p<0.01,</p>†<p>p<0.05.</p><p>Key: HOMA1-IR = Homeostasis model assessment of insulin resistance, IR = Insulin resistance, QUICKI = quantitative insulin sensitivity check index THR = triglyceride-to-HDL ratio.</p