Long-term effects of fenofibrate on lipoproteins and surrogate markers of macrovascular and microvascular disease in people with type 2 diabetes

Background and aims. Diabetic dyslipidemia is a highly atherogenic triad of increased triglycerides, decreased HDL cholesterol, and small dense LDL. Fibrates have a beneficial effect on diabetic dyslipidemia, and they have reduced cardiovascular events in randomized trials. Fenofibrate has reduced albuminuria and markers of low-grade inflammation and endothelial dysfunction. The present studies were undertaken to characterize the alterations of VLDL and LDL subclasses and to investigate the binding of LDL to arterial wall in type 2 diabetes. Further purpose was to elucidate the effects of fenofibrate on several lipoprotein subclasses, augmentation index (AIx), carotid intima-media thickness (IMT), and renal function. Subjects. 239 type 2 diabetic subjects were recruited among participants of the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study at the Helsinki centre. The patients were randomized to fenofibrate (200mg/d) or placebo for 5 years. Additionally, a healthy control group (N = 93) was recruited. Results. VLDL1 triglycerides increased in similar proportion to total triglycerides in type 2 diabetic patients and control subjects. Despite the increase in total apoCIII levels, VLDL apoCIII was decreased in diabetic patients. Enrichment of LDL with apoCIII induced a small increase in binding of LDL to arterial wall proteoglycan. Intrinsic characteristics of diabetic LDL, rather than levels of apoCIII, were responsible for increased proteoglycan binding of diabetic LDL with high apoCIII. Fenofibrate reduced triglycerides, increased LDL size, and shifted HDL subclasses towards smaller particles with no change in levels of HDL cholesterol. High levels of homocysteine were associated with lower increase of HDL cholesterol and apoA-I during fenofibrate treatment. Long-term fenofibrate treatment did not improve IMT, AIx, inflammation, or endothelial function. Fenofibrate decreased creatinine clearance and estimated glomerular filtration rate. No effect on albuminuria was seen with fenofibrate. Instead, Cystatin C was increased during fenofibrate treatment. Conclusions. 1) Elevation of VLDL 1 triglycerides was the major determinant of plasma triglyceride concentration in control subjects and type 2 diabetic patients. 2) LDL with high apoCIII showed multiple atherogenic properties, that were only partially mediated by apoCIII per se in type 2 diabetes 3) Fenofibrate demonstrated no effect on surrogate markers of atherosclerosis. 4) Fenofibrate had no effect on albuminuria and the observed decrease in markers of renal function could complicate the clinical surveillance of the patients. 5) Fenofibrate can be used to treat severe hypertriglyceridemia or in combination therapy with statins, but not to increase HDL levels.

Familial aggregation of type 1 diabetes and diabetic nephropathy in Finland

Type 1 diabetes (T1D) is a common, multifactorial disease with strong familial clustering. In Finland, the incidence of T1D among children aged 14 years or under is the highest in the world. The increase in incidence has been approximately 2.4% per year. Although most new T1D cases are sporadic the first-degree relatives are at an increased risk of developing the same disease. This study was designed to examine the familial aggregation of T1D and one of its serious complications, diabetic nephropathy (DN). More specifically the study aimed (1) to determine the concordance rates of T1D in monozygotic (MZ) and dizygotic (DZ) twins and to estimate the relative contributions of genetic and environmental factors to the variability in liability to T1D as well as to study the age at onset of diabetes in twins; (2) to obtain long-term empirical estimates of the risk of T1D among siblings of T1D patients and the factors related to this risk, especially the effect of age at onset of diabetes in the proband and the birth cohort effect; (3) to establish if DN is aggregating in a Finnish population-based cohort of families with multiple cases of T1D, and to assess its magnitude and particularly to find out whether the risk of DN in siblings is varying according to the severity of DN in the proband and/or the age at onset of T1D: (4) to assess the recurrence risk of T1D in the offspring of a Finnish population-based cohort of patients with childhood onset T1D, and to investigate potential sex-related effects in the transmission of T1D from the diabetic parents to their offspring as well as to study whether there is a temporal trend in the incidence. The study population comprised of the Finnish Young Twin Cohort (22,650 twin pairs), a population-based cohort of patients with T1D diagnosed at the age of 17 years or earlier between 1965 and 1979 (n=5,144) and all their siblings (n=10,168) and offspring (n=5,291). A polygenic, multifactorial liability model was fitted to the twin data. Kaplan-Meier analyses were used to provide the cumulative incidence for the development of T1D and DN. Cox s proportional hazards models were fitted to the data. Poisson regression analysis was used to evaluate temporal trends in incidence. Standardized incidence ratios (SIRs) between the first-degree relatives of T1D patients and background population were determined. The twin study showed that the vast majority of affected MZ twin pairs remained discordant. Pairwise concordance for T1D was 27.3% in MZ and 3.8% in DZ twins. The probandwise concordance estimates were 42.9% and 7.4%, respectively. The model with additive genetic and individual environmental effects was the best-fitting liability model to T1D, with 88% of the phenotypic variance due to genetic factors. The second paper showed that the 50-year cumulative incidence of T1D in the siblings of diabetic probands was 6.9%. A young age at diagnosis in the probands considerably increased the risk. If the proband was diagnosed at the age of 0-4, 5-9, 10-14, 15 or more, the corresponding 40-year cumulative risks were 13.2%, 7.8%, 4.7% and 3.4%. The cumulative incidence increased with increasing birth year. However, SIR among children aged 14 years or under was approximately 12 throughout the follow-up. The third paper showed that diabetic siblings of the probands with nephropathy had a 2.3 times higher risk of DN compared with siblings of probands free of nephropathy. The presence of end stage renal disease (ESRD) in the proband increases the risk three-fold for diabetic siblings. Being diagnosed with diabetes during puberty (10-14) or a few years before (5-9) increased the susceptibility for DN in the siblings. The fourth paper revealed that of the offspring of male probands, 7.8% were affected by the age of 20 compared with 5.3% of the offspring of female probands. Offspring of fathers with T1D have 1.7 times greater risk to be affected with T1D than the offspring of mothers with T1D. The excess risk in the offspring of male fathers manifested itself through the higher risk the younger the father was when diagnosed with T1D. Young age at onset of diabetes in fathers increased the risk of T1D greatly in the offspring, but no such pattern was seen in the offspring of diabetic mothers. The SIR among offspring aged 14 years or under remained fairly constant throughout the follow-up, approximately 10. The present study has provided new knowledge on T1D recurrence risk in the first-degree relatives and the risk factors modifying the risk. Twin data demonstrated high genetic liability for T1D and increased heritability. The vast majority of affected MZ twin pairs, however, remain discordant for T1D. This study confirmed the drastic impact of the young age at onset of diabetes in the probands on the increased risk of T1D in the first-degree relatives. The only exception was the absence of this pattern in the offspring of T1D mothers. Both the sibling and the offspring recurrence risk studies revealed dynamic changes in the cumulative incidence of T1D in the first-degree relatives. SIRs among the first-degree relatives of T1D patients seems to remain fairly constant. The study demonstrates that the penetrance of the susceptibility genes for T1D may be low, although strongly influenced by the environmental factors. Presence of familial aggregation of DN was confirmed for the first time in a population-based study. Although the majority of the sibling pairs with T1D were discordant for DN, its presence in one sibling doubles and presence of ESRD triples the risk of DN in the other diabetic sibling. An encouraging observation was that although the proportion of children to be diagnosed with T1D at the age of 4 or under is increasing, they seem to have a decreased risk of DN or at least delayed onset.

Dyslipidaemia, glucose intolerance and cardiovascular disease mortality and morbidity in Europeans and Asians

Dyslipidaemia, a major risk factor of cardiovascular disease (CVD), is prevalent not only in diabetic patients but also in individuals with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). The aims of this study were: 1) to investigate lipid levels in relation to glucose in European (Study I) and Asian (Study II) populations without a prior history of diabetes; 2) to study the ethnic difference in lipid profiles controlling for glucose levels (Study III); 3) to estimate the relative risk for cardiovascular mortality (Study IV) and morbidity (Study V) associated with dyslipidaemia in individuals with different glucose tolerance status. Data of 15 European cohorts with 19 476 subjects (I and III) and 13 Asian cohorts with 19 763 individuals (II and III) from 21 countries aged 25-89 years, without a prior history of diabetes at enrollment, representing Asian Indian, Chinese, European, Japanese and Mauritian Indian, were compared. The lipid-CVD relationship was studied in 14 European cohorts of 17 763 men and women which provided with follow-up data on vital status, with 871 CVD deaths occurred during the average 10-year follow-up (IV). The impact of dyslipidaemia on incidence of coronary heart disease (CHD) in persons with different glucose categories (V) was further evaluated in 6 European studies, with 9087 individuals free of CHD at baseline and 457 developed CHD during follow-up. Z-scores of each lipid component were used in the data analysis (I, II, IV and V) to reduce the differences in methodology between studies. Analyses of cardiovascular mortality and morbidity were performed using Cox proportional hazards regression analysis adjusting for potential confounding factors. Within each glucose category, fasting plasma glucose (FPG) levels were correlated with increasing levels of triglycerides (TG), total cholesterol (TC), TC to high-density lipoprotein (HDL) ratio and non-HDL cholesterol (non-HDL-C) (p<0.05 in most of the ethnic groups) and inversely associated with HDL-C (p<0.05 in some, but not all, of the populations). The association of lipids with 2-h plasma glucose (2hPG) followed a similar pattern as that for the FPG, except the stronger association of HDL-C with 2hPG. Compared with Central & Northern (C & N) Europeans, multivariable adjusted odd ratios (95% CIs) for having low HDL-C were 4.74 (4.19-5.37), 5.05 (3.88-6.56), 3.07 (2.15-4.40) and 2.37 (1.67-3.35) in Asian Indian men but 0.12 (0.09-0.16), 0.07 (0.04-0.13), 0.11 (0.07-0.20) and 0.16 (0.08-0.32) in Chinese men who had normoglycaemia, prediabetes, undiagnosed and diagnosed diabetes, respectively. Similar results were obtained for women. The prevalence of low HDL-C remained higher in Asian Indians than in others even in individuals with LDL-C < 3 mmol/l. Dyslipidaemia was associated with increased CVD mortality or CHD incidence in individuals with isolated fasting hyperglycaemia or IFG, but not in those with isolated post-load hyperglycaemia or IGT. In conclusion, hyperglycaemia is associated with adverse lipid profiles in Europeans and Asians without a prior history of diabetes. There are distinct patterns of lipid profiles associated with ethnicity regardless of the glucose levels, suggesting that ethnic-specific strategies and guidelines on risk assessment and prevention of CVD are required. Dyslipidaemia predicts CVD in either diabetic or non-diabetic individuals defined based on the fasting glucose criteria, but not on the 2-hour criteria. The findings may imply considering different management strategies in people with fasting or post-load hyperglycaemia.

Inpatient hospital care and its costs among type 1 diabetic patients in Finland : a nationwide longitudinal study

Background. In Finland, the incidence of type 1 diabetes mellitus (T1DM) is the highest in the world, and it continues to increase steadily. No effective preventative interventions exist either for individuals at high risk or for the population as a whole. In addition to problems with daily lifelong insulin replacement therapy, T1DM patients with long-lasting disease suffer from various diabetes related complications. The complications can lead to severe impairments and reductions in functional capacity and quality of life and in the worst case they can be fatal. Longitudinal studies on the costs of T1DM are extremely rare, especially in Finland. Typically, in these studies, distinctions between the various types of diabetes have not been made, and costs have not been calculated separately for the sexes. Aims. The aim of this study was to describe inpatient hospital care and costs of inpatient care in a cohort of 5,166 T1DM patients by sex during 1973-1998 in Finland. Inpatient care and costs of care due to T1DM without complications, due to T1DM with complications and due to other causes were calculated separately. Material and Methods. The study population consisted of all Finnish T1DM patients diagnosed before the age of 18 years between January 1st in 1965 and December 31st in 1979 and derived from the Finnish population based T1DM register (N=5,120 in 1979 and N=4,701 in 1997). Data on hospitalisations were obtained from the Finnish Hospital Discharge Register. Results. In the early stages of T1DM, the majority of the use of inpatient care was due to the treatment of T1DM without complications. There were enormous increases in the use of inpatient care for certain complications when T1DM lasted longer (from 9.5 years to 16.5 years). For women, the yearly number of bed-days for renal complications increased 4.8-fold, for peripheral vascular disease 4.3-fold and for ophthalmic complications 2.5-fold. For men, the corresponding increases were as follows: 5-fold, 6.9-fold and 2.5-fold. The yearly bed-days for glaucoma increased 8-fold, nephropathy 7-fold and microangiopathy 6-fold in the total population. During these 7 years, the yearly numbers of bed-days for T1DM without complications dropped dramatically. The length of stay in inpatient care decreased notably, but hospital visits became more frequent when the length of duration of T1DM increased from 9.5 years to 16.5 years. The costs of treatments due to complications increased when T1DM lasted longer. Costs due to inpatient care of complications in the cohort 2.5-folded as duration of T1DM increased from 9.5 years to 16.5 years, while the total costs of inpatient care in the cohort dropped by 22% due to an 80% decrease in the costs of care of T1DM without complications. Treating complications of female patients was more expensive than treating complications of men when T1DM had lasted 9.5 years; the mean annual costs for inpatient care of a female diabetic (any cause) were 1,642 , and the yearly costs of care of complications were 237 . The corresponding yearly mean costs for a male patient were 1,198 and 167 . Treating complications of female patients was more expensive than that of male patients also when the duration of diabetes was 16.5 years, although the difference in average annual costs between sexes was somewhat smaller. Conclusions. In the early phases of T1DM, the treatment of T1DM without complications causes a considerable amount of hospital bed-days. The use of inpatient care due to complications of T1DM strongly increases with ageing of patients. The economic burden of inpatient care of T1DM is substantial.

Statistical analysis of the associations of hereditary factors with the risk of Type 1 diabetes and Diabetic Nephropathy based on the familial data collected through ascertaiment from population-based registers

In genetic epidemiology, population-based disease registries are commonly used to collect genotype or other risk factor information concerning affected subjects and their relatives. This work presents two new approaches for the statistical inference of ascertained data: a conditional and full likelihood approaches for the disease with variable age at onset phenotype using familial data obtained from population-based registry of incident cases. The aim is to obtain statistically reliable estimates of the general population parameters. The statistical analysis of familial data with variable age at onset becomes more complicated when some of the study subjects are non-susceptible, that is to say these subjects never get the disease. A statistical model for a variable age at onset with long-term survivors is proposed for studies of familial aggregation, using latent variable approach, as well as for prospective studies of genetic association studies with candidate genes. In addition, we explore the possibility of a genetic explanation of the observed increase in the incidence of Type 1 diabetes (T1D) in Finland in recent decades and the hypothesis of non-Mendelian transmission of T1D associated genes. Both classical and Bayesian statistical inference were used in the modelling and estimation. Despite the fact that this work contains five studies with different statistical models, they all concern data obtained from nationwide registries of T1D and genetics of T1D. In the analyses of T1D data, non-Mendelian transmission of T1D susceptibility alleles was not observed. In addition, non-Mendelian transmission of T1D susceptibility genes did not make a plausible explanation for the increase in T1D incidence in Finland. Instead, the Human Leucocyte Antigen associations with T1D were confirmed in the population-based analysis, which combines T1D registry information, reference sample of healthy subjects and birth cohort information of the Finnish population. Finally, a substantial familial variation in the susceptibility of T1D nephropathy was observed. The presented studies show the benefits of sophisticated statistical modelling to explore risk factors for complex diseases.

Long-term clinical outcome after liver transplantation

With transplant rejection rendered a minor concern and survival rates after liver transplantation (LT) steadily improving, long-term complications are attracting more attention. Current immunosuppressive therapies, together with other factors, are accompanied by considerable long-term toxicity, which clinically manifests as renal dysfunction, high risk for cardiovascular disease, and cancer. This thesis investigates the incidence, causes, and risk factors for such renal dysfunction, cardiovascular risk, and cancer after LT. Long-term effects of LT are further addressed by surveying the quality of life and employment status of LT recipients. The consecutive patients included had undergone LT at Helsinki University Hospital from 1982 onwards. Data regarding renal function – creatinine and estimated glomerular filtration rate (GFR) – were recorded before and repeatedly after LT in 396 patients. The presence of hypertension, dyslipidemia, diabetes, impaired fasting glucose, and overweight/obesity before and 5 years after LT was determined among 77 patients transplanted for acute liver failure. The entire cohort of LT patients (540 patients), including both children and adults, was linked with the Finnish Cancer Registry, and numbers of cancers observed were compared to site-specific expected numbers based on national cancer incidence rates stratified by age, gender, and calendar time. Health-related quality of life (HRQoL), measured by the 15D instrument, and employment status were surveyed among all adult patients alive in 2007 (401 patients). The response rate was 89%. Posttransplant cardiovascular risk factor prevalence and HRQoL were compared with that in the age- and gender-matched Finnish general population. The cumulative risk for chronic kidney disease increased from 10% at 5 years to 16% at 10 years following LT. GFR up to 10 years after LT could be predicted by the GFR at 1 year. In patients transplanted for chronic liver disease, a moderate correlation of pretransplant GFR with later GFR was also evident, whereas in acute liver failure patients after LT, even severe pretransplant renal dysfunction often recovered. By 5 years after LT, 71% of acute liver failure patients were receiving antihypertensive medications, 61% were exhibiting dyslipidemia, 10% were diabetic, 32% were overweight, and 13% obese. Compared with the general population, only hypertension displayed a significantly elevated prevalence among patients – 2.7-fold – whereas patients exhibited 30% less dyslipidemia and 71% less impaired fasting glucose. The cumulative incidence of cancer was 5% at 5 years and 13% at 10. Compared with the general population, patients were subject to a 2.6-fold cancer risk, with non-melanoma skin cancer (standardized incidence ratio, SIR, 38.5) and non-Hodgkin lymphoma (SIR 13.9) being the predominant malignancies. Non-Hodgkin lymphoma was associated with male gender, young age, and the immediate posttransplant period, whereas old age and antibody induction therapy raised skin-cancer risk. HRQoL deviated clinically unimportantly from the values in the general population, but significant deficits among patients were evident in some physical domains. HRQoL did not seem to decrease with longer follow-up. Although 87% of patients reported improved working capacity, data on return to working life showed marked age-dependency: Among patients aged less than 40 at LT, 70 to 80% returned to work, among those aged 40 to 50, 55%, and among those above 50, 15% to 28%. The most common cause for unemployment was early retirement before LT. Those patients employed exhibited better HRQoL than those unemployed. In conclusion, although renal impairment, hypertension, and cancer are evidently common after LT and increase with time, patients’ quality of life remains comparable with that of the general population.

Innate immune system and adiponectin in diabetic nephropathy in type 1 diabetes

Introduction: The pathogenesis of diabetic nephropathy remains a matter of debate, although strong evidence suggests that it results from the interaction between susceptibility genes and the diabetic milieu. The true pathogenetic mechanism remains unknown, but a common denominator of micro- and macrovascular complications may exist. Some have suggested that low-grade inflammation and activation of the innate immune system might play a synergistic role in the pathogenesis of diabetic nephropathy. Aims of the study: The present studies were undertaken to investigate whether low-grade inflammation, mannan-binding lectin (MBL) and α-defensin play a role, together with adiponectin, in patients with type 1 diabetes and diabetic nephropathy. Subjects and methods: This study is part of the ongoing Finnish Diabetic Nephropathy Study (FinnDiane). The first four cross-sectional substudies of this thesis comprised 194 patients with type 1 diabetes divided into three groups (normo-, micro-, and macroalbuminuria) according to their albumin excretion rate (AER). The fifth substudy aimed to determine whether baseline serum adiponectin plays a role in the development and progression of diabetic nephropathy. This follow-up study included 1330 patients with type 1 diabetes and a mean follow-up period of five years. The patients were divided into three groups depending on their AER at baseline. As a measure of low-grade inflammation, highly sensitive CRP (hsCRP) and α-defensin were measured with radio-immunoassay, and interleukin-6 (IL-6) with high- sensitivity enzyme immuno-assay. Mannan-binding lectin and adiponectin were determined with time-resolved immunofluorometric assays. The progression of albuminuria from one stage to the other served as a measure of the progression of diabetic nephropathy. Results: Low-grade inflammatory markers, MBL, adiponectin, and α-defensin were all associated with diabetic nephropathy, whereas MBL, adiponectin, and α-defensin per se were unassociated with low-grade inflammatory markers. AER was the only clinical variable independently associated with hsCRP. AER, HDL-cholesterol and the duration of diabetes were independently associated with IL-6. HbA1c was the only variable independently associated with MBL. The estimated glomerular filtration rate (eGFR), AER, and waist-to-hip ratio were independently associated with adiponectin. Systolic blood pressure, HDL-cholesterol, total cholesterol, age, and eGFR were all independently associated with α-defensin. In patients with macroalbuminuria, progression to end-stage renal disease (ESRD) was associated with higher baseline adiponectin concentrations. Discussion and conclusions: Low-grade inflammation, MBL, adiponectin, and defensin were all associated with diabetic nephropathy in these cross-sectional studies. In contrast however, MBL, adiponectin, and defensin were not associated with low-grade inflammatory markers per se. Nor was defensin associated with MBL, which may suggest that these different players function in a coordinated fashion during the deleterious process of diabetic nephropathy. The question of what causes low-grade inflammation in patients with type 1 diabetes and diabetic nephropathy, however, remains unanswered. We could observe in our study that glycemic control, an atherosclerotic lipid profile, and waist-to-hip ratio (WHR) were associated with low-grade inflammation in the univariate analysis, although in the multivariate analysis, only AER, HDL-cholesterol, and the duration of diabetes, as a measure of glycemic load, proved to be independently associated with inflammation. Notably, all these factors are modifiable with changes in lifestyle and/or with a targeted medication. In the follow-up study, elevated serum adiponectin levels at baseline predicted the progression from macroalbuminuria to ESRD independently of renal function at baseline. This observation does not preclude adiponectin as a favorable factor during the process of diabetic nephropathy, since the rise in serum adiponectin concentrations may remain a mechanism by which the body compensates for the demands created by the diabetic milieu.

Glycemic Control in Diabetic Pregnancies: Effects on Fetal and Maternal Outcome

Background: Both maternal and fetal complications are increased in diabetic pregnancies. Although hypertensive complications are increased in pregnant women with pregestational diabetes, reports on hypertensive complications in women with gestational diabetes mellitus (GDM) have been contradictory. Congenital malformations and macrosomia are the main fetal complications in Type 1 diabetic pregnancies, whereas fetal macrosomia and birth trauma but not congenital malformations are increased in GDM pregnancies. Aims: To study the frequency of hypertensive disorders in gestational diabetes mellitus. To evaluate the risk of macrosomia and brachial plexus injury (Erb’s palsy) and the ability of the 2-hour glucose tolerance test (OGTT) combined with the 24-hour glucose profile to distinguish between low and high risks of fetal macrosomia among women with GDM. To evaluate the relationship between glycemic control and the risk of fetal malformations in pregnancies complicated by Type 1 diabetes mellitus. To assess the effect of glycemic control on the occurrence of preeclampsia and pregnancy-induced hypertension in Type 1 diabetic pregnancies. Subjects: A total of 986 women with GDM and 203 women with borderline glucose intolerance (one abnormal value in the OGTT) with a singleton pregancy, 488 pregnant women with Type 1 diabetes (691 pregnancies and 709 offspring), and 1154 pregnant non-diabetic women (1181 pregnancies and 1187 offspring) were investigated. Results: In a prospective study on 81 GDM patients the combined frequency of preeclampsia and PIH was higher than in 327 non-diabetic controls (19.8% vs 6.1%, p<0.001). On the other hand, in 203 women with only one abnormal value in the OGTT, the rate of hypertensive complications did not differ from that of the controls. Both GDM women and those with only one abnormal value in the OGTT had higher pre-pregnancy weights and BMIs than the controls. In a retrospective study involving 385 insulin-treated and 520 diet-treated GDM patients, and 805 non-diabetic control pregnant women, fetal macrosomia occurred more often in the insulin-treated GDM pregnancies (18.2%, p<0.001) than in the diet-treated GDM pregnancies (4.4%), or the control pregnancies (2.2%). The rate of Erb’s palsy in vaginally delivered infants was 2.7% in the insulin-treated group of women and 2.4% in the diet-treated women compared with 0.3% in the controls (p<0.001). The cesarean section rate was more than twice as high (42.3% vs 18.6%) in the insulin-treated GDM patients as in the controls. A major fetal malformation was observed in 30 (4.2%) of the 709 newborn infants in Type 1 diabetic pregnancies and in 10 (1.4%) of the 735 controls (RR 3.1, 95% CI 1.6–6.2). Even women whose levels of HbA1c (normal values less than 5.6%) were only slightly increased in early pregnancy (between 5.6 and 6.8%) had a relative risk of fetal malformation of 3.0 (95% CI 1.2–7.5). Only diabetic patients with a normal HbA1c level (<5.6%) in early pregnancy had the same low risk of fetal malformations as the controls. Preeclampsia was diagnosed in 12.8% and PIH in 11.4% of the 616 Type 1 diabetic women without diabetic nephropathy. The corresponding frequencies among the 854 control women were 2.7% (OR 5.2; 95% CI 3.3–8.4) for preeclampsia and 5.6% (OR 2.2, 95% CI 1.5–3.1) for PIH. Multiple logistic regression analysis indicated that glycemic control, nulliparity, diabetic retinopathy and duration of diabetes were statistically significant independent predictors of preeclampsia. The adjusted odds ratios for preeclampsia were 1.6 (95% CI 1.3–2.0) for each 1%-unit increment in the HbA1c value during the first trimester and 0.6 (95% CI 0.5–0.8) for each 1%-unit decrement during the first half of pregnancy. In contrast, changes in glycemic control during the second half of pregnancy did not alter the risk of preeclampsia. Conclusions: In type 1 diabetic pregnancies it is extremely important to achieve optimal glycemic control before pregnancy and maintain it throughout pregnancy in order to decrease the complication rates both in the mother and in her offspring. The rate of fetal macrosomia and birth trauma in GDM pregnancies, especially in the group of insulin-treated women, is still relatively high. New strategies for screening, diagnosing, and treatment of GDM must be developed in order to decrease fetal and neonatal complications.

Physical activity and diabetic complications in patients with type 1 diabetes

Type 1 diabetes is associated with the risk for late diabetic complications which are divided into microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (cardiovascular disease, CVD) diseases. The risk for diabetic complication can be reduced by effective treatment, most importantly the glycaemic control. Glycaemia in type 1 diabetes is influenced by the interplay between insulin injections and lifestyle factors such as physical activity and diet. The effect of physical activity in patients with type 1 diabetes is not well known, however. The aim of this thesis was to investigate the physical activity and the physical fitness of patients with type 1 diabetes with special emphasis on glycaemic control and the diabetic complications. The patients included in the study were all part of the nationwide, multicenter Finnish Diabetic Nephropathy (FinnDiane) Study which aims to characterise genetic, clinical, and environmental factors that predispose to diabetic complications in patients with type 1 diabetes. In addition, subjects from the IDentification of EArly mechanisms in the pathogenesis of diabetic Late complications (IDEAL) Study were studied. Physical activity was assessed in the FinnDiane Study in 1945 patients by a validated questionnaire. Physical fitness was measured in the IDEAL Study by spiroergometry (cycle test with measurement of respiratory gases) in 86 young adults with type 1 diabetes and in 27 healthy controls. All patients underwent thorough clinical characterisation of their diabetic complication status. Four substudies were cross-sectional using baseline data and one study additionally used follow-up data. Physical activity, especially the intensity of activities, was reduced in patients affected by diabetic nephropathy, retinopathy, and CVD. Low physical activity was associated with poor glycaemic control, a finding most clear in women and evident also in patients with no signs of diabetic complications. Furthermore, low physical activity was associated with a higher HbA1c variability, which in turn was associated with the progression of renal disease and CVD during follow-up. A higher level of physical activity was also associated with better insulin sensitivity. The prevalence of the metabolic syndrome in type 1 diabetes was also lower the higher the physical activity. The aerobic physical fitness level of young adults with type 1 diabetes was reduced compared with healthy peers and in men an association between higher fitness level and lower HbA1c was observed. In patients with type 1 diabetes, a higher physical activity was associated with better glycaemic control and may thus be beneficial with respect to the prevention of diabetic complications.

Diabetic cardiomyopathy and post-infarct ventricular remodelling : Effects of levosimendan in a rodent model of type II diabetes

Type 2 diabetes is a risk factor for the development of cardiovascular disease. Recently, the term diabetic cardiomyopathy has been proposed to describe the changes in the heart that occur in response to chronic hyperglycemia and insulin resistance. Ventricular remodelling in diabetic cardiomyopathy includes left ventricular hypertrophy, increased interstitial fibrosis, apoptosis and diastolic dysfunction. Mechanisms behind these changes are increased oxidative stress and renin-angiotensin system activation. The diabetic Goto-Kakizaki rat is a non-obese model of type 2 diabetes that exhibits defective insulin signalling. Recently two interconnected stress response pathways have been discovered that link insulin signalling, longevity, apoptosis and cardiomyocyte hypertrophy. The insulin-receptor PI3K/Ak pathway inhibits proapoptotic FOXO3a in response to insulin signalling and the nuclear Sirt1 deacetylase inhibits proapoptotic p53 and modulates FOXO3a in favour of survival and growth. --- Levosimendan is a calcium sensitizing agent used for the management of acute decompensated heart failure. Levosimendan acts as a positive inotrope by sensitizing cardiac troponin C to calcium and exerts vasodilation by opening mitochondrial and sarcolemmal ATP-sensitive potassium channels. Levosimendan has been described to have beneficial effects in ventricular remodelling after myocardial infarction. The aims of the study were to characterize whether diabetic cardiomyopathy associates with cardiac dysfunction, cardiomyocyte apoptosis, hypertrophy and fibrosis in spontaneously diabetic Goto-Kakizaki (GK) rats, which were used to model type 2 diabetes. Protein expression and activation of the Akt FOXO3a and Sirt1 p53 pathways were examined in the development of ventricular remodelling in GK rats with and without myocardial infarction (MI). The third and fourth studies examined the effects of levosimendan on ventricular remodelling and gene expression in post-MI GK rats. The results demonstrated that diabetic GK rats develop both modest hypertension and features similar to diabetic cardiomyopathy including cardiac dysfunction, LV hypertrophy and fibrosis and increased apoptotic signalling. MI induced a sustained increase in cardiomyocyte apoptosis in GK rats together with aggravated LV hypertrophy and fibrosis. The GK rat myocardium exhibited decreased Akt- FOXO3a phosphorylation and increased nuclear translocation of FOXO3a and overproduction of the Sirt1 protein. Treatment with levosimendan decreased cardiomyocyte apoptosis, senescence and LV hypertrophy and altered the gene expression profile in GK rat myocardium. The findings indicate that impaired cardioprotection via Akt FOXO3a and p38 MAPK is associated with increased apoptosis, whereas Sirt1 functions in counteracting apoptosis and the development of LV hypertrophy in the GK rat myocardium. Overall, levosimendan treatment protects against post-MI ventricular remodelling and alters the gene expression profile in the GK rat myocardium.