Published 5.12.2024
Text: Aino Latva-Rasku
Image: Lauri Nummenmaa
Editing: Viestintätoimisto Jokiranta 

 

Interest in the brain’s role as a regulator of the energy balance in our bodies has been on the rise recently. It is not only the gut hormones but also the hormones secreted by fat tissue, for example, that activate the satiety centre in our brain, thereby suppressing our appetite. In type 2 diabetes and obesity, however, these signals become attenuated. Thus, the brain works in a selfish manner in order to safeguard its own energy supply, while also modifying the metabolism of other body organs in order to maintain optimal availability of nutrients. It is interesting – and worrying – that brain metabolic alterations seem to be associated with the increased risk of the onset of memory and mental disorders, in addition to elevated blood sugar and type 2 diabetes.

Several underlying reasons for insulin resistance

Obesity and type 2 diabetes are closely associated with insulin resistance, which refers to the impaired ability of insulin to increase the storage of nutrients in cells. This phenomenon has been identified for most tissues in human bodies, such as the muscles, liver, subcutaneous and visceral fat, small intestine wall and kidneys. The phenomenon can also be measured and is manifested as the impaired ability of the insulin target tissues to transfer glucose from blood to cells after a meal.

Several underlying reasons for insulin resistance have been identified at the cellular level. The phenomenon may be explained by excessive accumulation of fatty acids inside the cells, low-grade inflammation, or disorders in the functioning of the mitochondria that produce energy for cells.

My research team has used positron emission tomography (PET) to assess the insulin sensitivity of various human tissues. The subjects are administered a glucose tracer and, at the same time, their blood insulin level is raised to correspond to the state after a meal. The tracer dose rate indicates the ability of insulin to increase the storing of glucose in a particular tissue. In obesity and type 2 diabetes, the accumulation of the tracer typically decelerates in all aforementioned tissues.

What is brain insulin resistance?

A slightly astonishing but recurrent finding in our earlier research is that, while insulin resistance is manifested as impaired cellular uptake of glucose in almost all tissues, the situation is quite the opposite in the brain. Thus, the brain’s glucose uptake increases significantly in response to an elevated blood insulin level in subjects with impaired insulin sensitivity due to, for example, a genetic risk or obesity. The control groups do not show any major alterations in metabolism. The worrying aspect is that a corresponding change can be seen already at a young age for those individuals who have been found to have an increased risk of metabolic syndrome.

Nevertheless, it is still unclear what brain insulin resistance is. Unlike most other tissues, the brain’s use of glucose is not directly dependent on the insulin level in the blood. Brain insulin resistance has often primarily referred to functional changes, in which the ability of insulin to increase the activation of various brain areas has declined. This becomes apparent when studying the response by means of functional magnetic resonance imaging (fMRI). The direct effects of insulin on the brain have been investigated in humans by using intranasal insulin. The research has shown that the ability of insulin to activate the hypothalamic area and thereby increase satiety is declined in subjects with obesity.

We do not, however, know if the metabolic alterations occur simultaneously with the impaired response to insulin, as observed in the fMRI studies, or if the changes happen via different mechanisms.

Obesity, memory disorders and severe depression

The results of our previous research suggest that the brain’s craving for glucose increases the liver’s night-time glucose production, which results in an elevated fasting blood sugar level. Causality is challenging to show, but it is possible that the brain’s increased demand for glucose also alters our eating behaviour. This does not necessarily lead to obesity but may make weight management more difficult. With a better understanding of this phenomenon, we could find new methods to treat obesity.

The way the brain uses glucose does not alter in metabolic diseases alone. In Alzheimer’s disease, the glucose uptake of the brain as a whole typically slows down but researchers have recently found that the uptake may actually accelerate prior to the decline phase. Correspondingly, both deceleration and acceleration of glucose uptake has been described in severe depression. In fact, the metabolic alterations may be a significant factor linking these diseases.

I am grateful for the grant awarded by the Sakari Alhopuro Foundation that enables me to initiate my first independent research project. In my research, I will focus on exploring how various brain alterations identified by means of different methods can be linked with each other in persons with obesity or type 2 diabetes.

 

 

 

 

Aino Latva-Rasku, MD, PhD, earned her doctoral degree in 2020 from the University of Turku with her dissertation concerning the insulin sensitivity of various tissues and the related factors. She has continued her research at the national Turku PET Centre, while also carrying out clinical work as a resident at the Outpatient Clinic of Endocrinology of Turku University Hospital (Tyks). Latva-Rasku has special interest in the alterations of brain metabolism and functioning in type 2 diabetes and obesity.