[MUSIC] To understand the paradigm shifting consequences of the "Thrifty Phenotype Hypothesis" as a conceptual framework to understand the roots of type two diabetes, some historical background of our understanding of type two diabetes is needed. So, research into insulin resistance, type two diabetes and the metabolic syndrome took off in the 1960s after the first human plasma insulin assays demonstrated that the majority of cases of late-onset diabetes could not be explained sufficiently by lack of insulin. Twin studies from the 80s suggested an almost exclusive role of genetics in type two diabetes, with nearly 100% concordance rates among genetically identical monozygotic twins. The studies of Hales and Barker published in the early 90s, were therefore highly provocative to the diabetes research community, postulating that not only type two diabetes but also the key components of the metabolic syndrome representing well-established cardiovascular disease risk factors, seemed to have at least parts of their origin in early life. The notion that factors operating early in life influence these states of disease was originally devised by the Norwegian epidemiologist Anders Forsdahl in 1970. Nevertheless, the undisputable achievement of Hales and Barker was that in an unselected population sample from Hertfordshire in the U.K. they provided a direct link between low birth weight and increased risks of developing type two diabetes, hypertension, elevated triglycerides, as well as insulin resistance later in life. Therefore, the paradigm shifting potential of the studies was not only the idea of a role for fetal programming in itself, but equally as important, the notion that fetal programming could represent a significant player in the origin of type two diabetes, the metabolic syndrome and cardiovascular disease. Early criticism of the studies of Hales and Barker included the use of changing definition of markers of growth in early life and underdevelopment in different studies, such as birth weight versus ponderal index with respect to exposure, and different phenotypes such as type two diabetes, the metabolic syndrome, and insulin resistance with respect to outcome. So, alongside the diverse beliefs and conceptions regarding the aetiology of type two diabetes and the metabolic syndrome, there was a strong polarization of use in the 1980s and the 1990s concerning the roles of muscle insulin resistance, defective pancreatic insulin secretion, and elevated hepatic glucose production in the pathophysiology of type two diabetes. This debate has now been settled by uniform agreement that glucose intolerance ranging from the prediabetic states of impaired fasting and impaired glucose tolerance to overt type two diabetes constitutes a heterogeneous, dysmetabolic state, or states involved in the dysfunction of multiple organs, including liver, muscle, pancreas, adipose tissue, gut, kidney and brain. And it is of interest that the concept of fetal programming, with its ideas of organ plasticity which actually may represent the most plausible hypothesis of a common ground for the underlying aetiology and molecular mechanisms of type two diabetes. Thus, the multiple organ functions in type two diabetes, changing with time and age, and differing in magnitude between type two diabetes patients within and between societies does require a comprehensive conceptual framework, such as developmental programming to understand the clustering of these disease components and risk factors. Type two diabetes genes have appeared to be more selective in their influence of organ dysfunctions in type two diabetes with defective insulin secretion being the most important affected by the more than 50 known genotypes involved in the predisposition to type two diabetes. In contrast, despite their initial hypothesis of fetal programming of type two diabetes being associated with impaired insulin secretion, Hales and Barker and their colleagues were the first to document the association between low birth weight and insulin resistance in humans. The importance of this finding is underscored by our knowledge that insulin resistance is a very prominent and early feature of the metabolic syndrome, and consistently has been associated with fetal programming in humans, regardless of whether the exposure is low birth weight, prematurity, independent of low birth weight, gestational diabetes or a twin or zygosity status that are also known to be associated with an adverse fetal growth. So, regarding the definition of the metabolic syndrome, central points in the discussion of its raison d´être over recent years have been whether it is a real disease entity of clinical relevance. If insulin resistance is a main common denominator or cause, if it explains the risk of cardiovascular disease beyond the contributions of each of the individual components, and whether the clustering of the proposed components of the metabolic syndrome may be an artefact when observed from a stringent epidemiological perspective. What has, however, not been sufficiently emphasized in this debate is that the thrifty phenotype hypothesis, formulated with great visionary precision by Hales and Barker represents the most plausible explanation of the origin of all the components of a metabolic syndrome. The idea of an adverse fetal environment rather than genetic determinants defining origin of type two diabetes and its associated cardiometabolic risk was supported by twin studies, that reported lower birth weights among monozygotic twins with type two diabetes, compared with their genetically identical but non-diabetic co-twins. Subsequent twin studies have documented both defective insulin secretion and insulin resistance being associated with low birth weight in a complex non-genetic and age dependent manner. The age dependency may in this context represent an important issue to explain the highly age dependent states of type two diabetes, the metabolic syndrome, as well as cardiovascular disease. While the concordance estimates from population based twin studies, questioned the notion of a major genetic component in type two diabetes being in marked contrast to the earliest studies of twins from the 80s. Perhaps the most significant lesson from twin studies was the finding that zygosity and thus twin status may influence insulin secretion and insulin action in its own right. The extent to which twins develop type two diabetes in a differential age dependent manner compared with singletons is currently the unresolved, but even the finding in, at least one study, that twins have a risk of type two diabetes that is similar to a singleton with a lower birth weight, is consistent with the notion that twins may differ from singletons with respect to risk of type two diabetes. Thus, the thrifty phenotype hypothesis has challenged the role of the classical twin model in the assessment of genetic versus non-genetic risk of metabolic and cardiovascular diseases, emphasizing the enormous impact of the hypothesis. Despite low birth weight being a crude marker of an adverse intrauterine environment, it has with remarkable consistency, been associated with risk of type two diabetes, as well as impaired insulin secretion and insulin resistance in multiple studies, including population based epidemiological studies. In addition, studies of the identified genetic type two diabetes marker have confirmed the notion that the association is predominantly non-genetic. Thus, only two out of the known 50 type two diabetes genes are associated with a slightly lower birth weight. While prematurity is associated with risk of type two diabetes independently of birth weight, studies of third trimester fetal growth rate, pointed to what effects prior to or after third trimester being the most important periods during development, relevant to programming of components of the metabolic syndrome. Animal studies have provided substantial proof of concept for associations of global, as well as distinct protein undernutrition during pregnancy with glucose intolerance and physiological and metabolic defects relevant to type two diabetes in the offspring. Importantly, compared to studies of low birth weight in humans and protein undernourished rats in utero identified strikingly similar changes in the expression of key insulin signalling proteins of the glucose and of the glucose transporter GLUT4 protein in both skeletal muscle and adipose tissue. Epigenetics is defined as changing gene functions that are not due to changes in the sequence of the nucleotides of the genome. The increasing awareness of a prime role of epigenetics including DNA methylations and histone modifications as well as a prime role of regulatory small noncoding, microRNAs have provided ideas and novel tools to look for the mechanisms that underlie developing programming on multiple organ functions in type two diabetes. These technologies are forecasting groundbreaking discoveries within the years to come. Already, prominent examples of recent discoveries in the area include transcriptional regulation by promoter DNA methylation, as well as histone modifications of the pancreatic proliferation and transcription factor Pdx1 by fetal undernutrition as well as the discovery of increased expression of the microRNA-483-3p in subcutaneous adipose tissue from humans with a low birth weight as well as from rats that were undernourished by protein in utero. This may confer an increased risk of lipotoxicity with subsequently, as explained, has detrimental effects on multiple organ functions in type two diabetes, probably by regulating a factor involved in the development of adipose tissue cells, called the growth and differentiation factor three. Recent studies from our group have suggested that the key epigenetic abnormalities in developmental programming of type two diabetes could be hidden in the most immature stem cells in the body. Stem cells are responsible for the constant renewal of cells in many tissues including the adipose tissue. And recent studies have suggested that the turn over rates of cells in subcutaneous adipose tissue is quantitatively much faster than previously anticipated, and that the normal functioning stem cells are required to maintain normal functions of the adipose tissue. In a study of immature stem cells obtained from the subcutaneous tissue of low birth weight subjects, we actually did found several indications of a disproportional immaturity compared with healthy subjects born with normal birth weights. And these abnormalities included a impaired release of the key appetite regulating hormone leptin. The impaired release of leptin in these cells was associated with a reduced leptin gene expression, as well as increased leptin gene DNA methylation. So these abnormalities may be associated with reduced tissue expandability, and subsequently, as explained, lipo- toxicity, in other tissues. Furthermore, the impaired leptin release may contribute to increased risk of adiposity due to reduced appetite suppression, in response to overeating. Finally, the idea and proof of concept of an immature stem cell function in low birth weight subjects may suggest that a more general immature stem cell function in multiple organs may actually explain the multiple organ dysfunction in itself in type two diabetes. This is a present hypothetical scenario that we are studying. Biopsies obtained from the subcutaneous adipose tissue from different humans with a different risk of developing type two diabetes, are further processed in the laboratory to isolate the stem cells. The stem cells are subsequently stored in a freezer to be ready for use in later experiments. Stem cells kept in a freezer can be growth in in vitro cultures by adding different differentiation factors, and the cells with different degrees of maturity can subsequently be studied functionally, morphologically, as well as with respect to epigenetic changes. The extent to which the global epidemic of diabetes may be driven by a mismatch between being born with a low birth weight and the fast propagation of over-nutrition and physical inactivity seen over recent years in developing countries, needs to be determined in order to provide a focus for efforts to prevent metabolic diseases. Gestational diabetes, also called GDM, may be considered an early manifestation of type two diabetes that is unmasked by pregnancy-induced insulin resistance. And studies in both animals and humans have indicated that exposure to an adverse fetal environment is a significant risk factor for GDM in its own right. Besides compelling evidence of inter-generational transmission of type two diabetes and the metabolic syndrome via low birth weight as well as gestational diabetes, recognition of this has provided support for universal screening for gestational diabetes, and for pregnancy itself, being a window of opportunity to prevent type two diabetes in both the mother and the child. The relevance and importance of earlier and more effective prevention of type two diabetes is underscored by the modest effects of early detection by screening for type two diabetes in the general population on mortality as well as the absence of any significant effect of intensive, as opposed to conventional glucose control, as mentioned, on cardiovascular disease mortality in patients with overt type two diabetes. Therefore, to understand the full potential of the thrifty phenotype hypothesis as a platform to implement primary prevention of type two diabetes, there is an urgent need to determine the extent to which developmental programming influences type two diabetes in different manners, in different populations, as well as to understand the long-term effects of distinct exposures during pregnancy and the molecular mechanisms involved. Today, prevention of type two diabetes is achievable through lifestyle interventions combining healthy diet with increased physical activity. However, the most effective lifestyle intervention programs only postpone the onset of type two diabetes, defined by hypoglycemia, for an average of around two years. There is, therefore a need for more effective and sustainable prevention strategies for disease, and interventions among pregnant women provide another potential to prevent type two diabetes in a more sustainable manner in the next generations. As for the pharmacological treatment of type two diabetes today, many different treatment modalities have now become available to reduce the plasma glucose level. Our current treatment modalities include metformin to increase insulin action, insulin secretagogues such as sulfonylureas to increase insulin secretion, DPP-4 inhibitors increasing GLP-1 levels, glitazones to increase adipose tissue expandability, SGLT2 inhibitors to increase excretion of glucose in the urine, and acarbose to reduce the absorption of carbohydrates from the gastrointestinal channel. GLP-1 agonists have also become available to increase insulin secretion as well as to reduce appetite in different types of a patient with type two diabetes. Finally, we also have different types of insulin available to compensate for the reduced indigenous insulin secretion in patients with type two diabetes. And right now, extremely much research is ongoing to understand the optimal use of these different drugs in type two diabetes and further details regarding this topic is beyond the scope of the current lecture. However, it needs to be emphasized that none of the mentioned drugs have been shown to reduce the risk of diabetes complications, beyond their potential to reduce plasma glucose levels. Metformin, being the oldest class of all glucose lowering drugs, has been suggested in some studies to reduce the risk of cardiovascular disease beyond its effect on glucose in itself. However, this has been questioned in recent meta-analyses. Furthermore, GLP-1 agonist does reduce weight and blood pressure, which is very promising in type two diabetes treatment. And may, therefore, represent the class of drugs that in the future may prevent diabetes complications beyond their capability to reduce glucose. However, this has not yet been conclusively proven. So, altogether, there is an increase or increasing need for society to invest in research in type two diabetes in order for us to be able to prevent and to treat the extremely common disease in a cost-effective manner in the future. [MUSIC]
