[MUSIC] As for the multifactorial etiology of type 2 diabetes, we can divide these into three major categories. Primary predisposing factors, secondary precipitating factors, as well as tertiary accelerating factors. As for the primary predisposing factors, there are two major factors that we today know are playing a role. On one side there's genetics. And we know about more than 50 types of genetic changes that are each associated with a significant increased risk of developing type 2 diabetes. Indeed there has been major breakthrough in our current understanding of the genetics of type 2 diabetes. However, it should also be said that there are more than 50 type 2 diabetes susceptibility genes known today. Actually only explain around 10 to 15% of the background risk of developing the disease in most populations. There must be other risk factors that are playing a role. Also, among the primary predisposing factors is my own research topic, which is the fetal origins of type 2 diabetes, also called developing programming factors. The underlying idea here is that there are factors occurring in pregnancy which predisposes offspring of the pregnant women to develop type 2 diabetes more than 50 years after they have been born. So now, 20 years after this idea was first promoted by Barker and Hayes, we know that this is actually a fact, it can occur. However, as for the genetic dimension, we really don't know how much it means and how much it impacts in a differential manner in different populations. I will return to that topic later. As for the secondary precipitating factors in type 2 diabetes, these include the factors that most people generally know about, including physical inactivity and energy dense diet, leading to overall and in particular, abdominal obesity. Besides, these factors also include use of medicine such as glucocorticoids, aging, pregnancy, smoking, and sleep deprivation, hyperfunctioning of endocrine diseases, as well as other comorbidities mentioned earlier. And one of these comorbidities is cancer. There's recently been intense debate about why it is that patients who have type 2 diabetes have an around 20% increased risk of developing multiple types of cancer. There have been discussions about how new glucose lowering drugs, including some types of insulin, may cause cancer in type 2 diabetes, which has of course, created a lot of fear among patients. But what we know and believe today is that the association between cancer and type 2 diabetes is due to that some patients who have cancer actually develop type 2 diabetes as a consequence of the cancer disease. The association could, to some extent, be due to the fact that cancer in general is causing a hypermetabolic state, including insulin resistance. In other cases, the coexistence of cancer and type 2 diabetes could simply be due to that patients who go to a doctor because they have diagnosed cancer or diabetes are statistically more likely also to have diagnosed the other type of disease, either the diabetes or cancer. Another somewhat unrecognized cause of type 2 diabetes is heart insufficiency. Our conventional view is that cardiac disease and heart insufficiency is a consequence of type 2 diabetes. But today, we know that a reduced left ventricular heart function may be a cause also of type 2 diabetes. Reduced left ventricular function causes low flow of blood in the periphery activation of the sympathetic nervous system, as well as it activates subclinical inflammation, and which are all known factors causing insulin resistance and subsequently affecting the risk of developing type 2 diabetes. Recent studies from nationwide Danish national prescription registers have clearly shown that the use of looped diuretics, being a proxy for heart insufficiency, in a dose dependent manner, is associated with an increased risk of later development of type 2 diabetes, supporting this hypothesis. So as for the tertiary accelerating factors, these are factors that act deleterious on glucose homeostasis in people who have established type 2 diabetes. And the most important being lipo- and glucose toxicity. Elevated plasma glucose, as well as plasma free fatty acid levels, are both key metabolic abnormalities in type 2 diabetes. Both factors also influence major organ dysfunction in type 2 diabetes, including the liver, the pancreatic beta-cell, as well as skeletal muscle. This, in turn, causes further elevation of hepatic glucose production, further impairment of the pancreatic beta-cell function, as well as further deterioration of the disposal of glucose by insulin in skeletal muscle. By these mechanisms, a vicious cycle is generated, which contributes to the deterioration of the metabolic abnormalities in type 2 diabetes over time. That is important to understand because it, to some extent, means that the development of a type 2 diabetes is a point of no return. And that we, therefore, must focus primarily on the prevention of disease instead of the cure. The major organ dysfunctions involved in the development of type 2 diabetes include the pancreas, with impaired insulin secretion, and a disproportionately elevated glucagon secretion, increased hepatic glucose production, skeletal muscle insulin resistance, and multiple abnormalities in adipose tissue. Including elevated lipolysis and release of free fatty acids and reduced storage capacity of free fatty acids in the subcutaneous adipose tissue due to reduced expandability. As well as altered release of hormones from the adipose tissue that are important for other appetite type regulations such as leptin or insulin action in vivo, such as adiponectin. Changes in body composition with respect to the amount and the distribution of adipose tissue versus muscle is an important feature of patients with type 2 diabetes and people at increased risk of type 2 diabetes. Changes in body composition with respect to the amount and distribution of adipose tissue versus muscle is an important feature in patients with type 2 diabetes and people at increased risk of developing the disease. The body composition can be measured by DEXA scanning, which is a scanner technology that uses two different X-ray sources to determine the amount of fat versus muscle tissue. In contrast to conventional X-ray technologies, DEXA is associated with a very low amount of radiation. The person wearing light clothes is placed in a whole body scanner and the examination takes less than 15 minutes. The data are processed in a computer and the results are reported in many different ways, including visual illustrations and calculations of fat versus muscle tissue in many compartments of the body. The amount of adipose tissue in the abdomen is of special interest. However, the scanner is not able to differentiate how much fat is stored in the visceral, that is, in the abdominal side, versus the subcutaneous compartment. Additional defects of organ functions in type 2 diabetes include reduced secretion and or action of the gut incretin hormones GLP-1 and GIP, as addressed previously by Jens Juul Holst. Impaired cardiovascular and heart functions may also contribute to insulin resistance in type 2 diabetes, as already explained. Furthermore, the kidneys may influence glucose homeostasis by changing the threshold of renal glucose clearance, as well as by the capacity to produce glucose by gluconeogenesis, which is also present in the kidneys. Finally, the brain is likely to play a key role in the development of type 2 diabetes, although our current knowledge about that is insufficient. However, the brain controls glucose homeostasis, directly or indirectly, via many different hormonal and neurological mechanisms, including the hypothalamus pituitary access. Patients with type 2 diabetes are also known to have an increased risk of neurocognitive disorders, including depression. And as for other comorbidities in type 2 diabetes, this may not only be a consequence of the disease caused by elevated plasma glucose levels. It may actually be considered that the neurocognitive dysfunctions in type 2 diabetes could represent a distinct read out of a common underlying risk factor of both conditions, which for instance, may be the topic that I'm going to address in my next lecture, namely, the thrifty phenotype hypothesis. [MUSIC]
