Twenty-year Follow-up of the Inter99 Cohort

BACKGROUND Type 2 Diabetes (T2D) affecting globally more than 400 million people represents one of the most significant global health challenges of our time. However, despite huge research investments, there are still limited insights into its complicated etiology and pathophysiology during the life-course. T2D is furthermore defined by arbitrary glycemic thresholds, which inadequately captures the diversity of clinical presentations and sub-phenotypes with differential complications and damages in multiple organs including small and large vessels, heart, kidney, liver and nerve tissue, often present already at the time of disease onset.

The heterogeneity of phenotypes in T2D is likely rooted in differential genetic, prenatal, and postnatal non-genetic etiologies between individuals. As for genetics, the known 568 T2D susceptibility variants are estimated to account for 18% of the putative genetic contribution to T2D. The totality of data from human famine catastrophes conclusively confirm the initial reports from Hertfordshire, UK, of an adverse intrauterine environment associated with low birth weight (LBW) playing a significant role in the development of T2D. The concept of fetal and early life developmental programming has been confirmed, validated and mechanistically examined in multiple animal studies. Studies in humans and animals have provided compelling evidence of an adverse fetal environment contributing to virtually all the known multiple organ defects influencing glucose homeostasis. Furthermore, emerging evidence consistently suggest that LBW and an adverse fetal environment play a direct and independent role in the development of important complications in T2D including cardiovascular disease, hypertension, dyslipidemia and vascular dysfunctions. Vascular stiffness reflected by elevated pulse-wave-velocity are early signs of micro- and/or macrovascular disease in patients with and without T2D. The fact that T2D patients often have a significant burden of vascular and metabolic complications already at diagnosis, indicates that factors influencing risk of T2D at the same time represent direct causes of co-morbidities that it is otherwise considered as complications to hyperglycemia. Accordingly, a distinct subgroup of T2D patients, as a result of an adverse fetal environment, may be affected by diabetic complications to a larger extent than patients with T2D due to other factors. Indeed, it was reported that LBW accounts for most of the excess cardiovascular disease (CVD) mortality in T2D. Moreover, LBW is associated with smaller kidneys with fewer nephrons and increased risk of chronic kidney disease. Another study reported increased risk of cardiac autonomic function (heart rate variability) in children, which is a known risk factor of CVD morbidity and mortality. Patients with T2D are at increased risk of developing NAFLD, which may progress to non-alcoholic stereo hepatitis (NASH), overt liver cirrhosis and liver cancer. NAFLD and NASH are clinically silent and under-diagnosed diseases with a global prevalence of 25-30% and is associated with increased risk of CVD in a non-genetic manner. Recent unpublished data from our group showed a threefold increased liver fat content in young, non-diabetic LBW men when studied before and after 4 weeks of a high carbohydrate challenge diet.

AIM To give a detailed phenotypical cardiometabolic description of the population-based Inter99-cohort, in order to examine associations of size at birth and prematurity, as proxies for the early fetal environment, concurrent lifestyle factors and genetic risk with the age-specific incidence of T2D and CVD, and its complications and co-morbidities, among Danish citizens aged 50-80 years.

HYPOTHESIS

1. An adverse fetal environment (LBW and/or prematurity) is associated with increased risk of developing a more severe T2D sub-phenotype with increased morbidity and mortality from micro- and macro vascular complications as well as cardiometabolic co-morbidities including NAFLD, compared with T2D patients born at term with a normal birth weight.
2. An adverse fetal environment is associated with increased morbidity and mortality from a range of micro- and macrovascular manifestations, as well as NAFLD, typically referred to as diabetes complications, even among elderly non- diabetic people with or without prediabetes (impaired glucose tolerance or impaired fasting glucose).