It is well known that type 2 diabetes raises the risk of dementia. The reasons for this are less clear, but one explanation could be insulin resistance in the brain, according to Malin Wennstr-m, a researcher at Lund University's Molecular Memory Research Unit. She has received EUR 700,000 from the Swedish Research Council to investigate her theory.
"The goal is to find measureable biomarkers early in the development of dementia in diabetes patients and, in the long term, to develop drugs that can halt the process", says Malin Wennstr-m.
Type 2 diabetes often goes hand in hand with insulin resistance, a condition that weakens the effect of insulin on body tissue, for example in muscle and fat cells. In recent years, researchers have come to understand that cells in the brain also develop insulin resistance.
The focus of Malin Wennstr-m's research is on pericytes, a type of cell that enwraps small blood vessels in the brain. Pericytes are found throughout the body and have an important supporting function for blood vessels.
"We know that loss of pericytes is the first abnormality of the diabetic eye which can be observed clinically. Without pericytes, blood vessels become fragile and start to leak, which in time leads to poorer blood supply", says Malin Fex, a researcher at Lund University Diabetes Centre, who is also participating in the project.
One explanation as to why patients with type 2 diabetes are twice as likely to develop dementia later in life compared with non-diabetics could thus hypothetically be a loss of pericytes in the brain caused by insulin resistance.
"In one of the most common forms of dementia - vascular dementia - blood circulation in the brain is weakened, and a high proportion of Alzheimer's patients also show vascular pathology", says Malin Wennstr-m.
The research will be carried out in three phases:
In Phase A, pericytes isolated from deceased dementia patients will be cultured and studied.
"We will stimulate the pericytes with factors that we know lead to insulin resistance, for example high levels of inflammatory signal molecules, high levels of sugar and fat, and stress hormones. We will then study the response of the pericytes by measuring changes in gene expression, protein release and levels of insulin resistance. In this way, we hope to find new biomarkers that can signal insulin resistance and other changes in the pericytes", says Malin Wennstr-m.
In Phase B, the experiments will be transferred to laboratory animals. Insulin-resistant rodents with diabetes and rodents that have been exposed to chronic mild stress and systemic inflammation will be studied. The levels of biomarkers discovered in Phase A will be measured in the rodents's blood and cerebrospinal fluid. By simultaneously studying the brains of the rodent, the researchers can investigate whether the biomarkers reflect the biological processes induced by insulin resistance in the brain.
"The studies on cells give us insights into specific mechanisms, but to get a picture of what they look like in a complex biological system, we have to complement the studies with animal experiments."
In the final phase, Phase C, the discoveries that have been made will be tested in clinical studies. Working with Katarina N-gga, a doctor at the Memory Clinic in Malm-, samples of blood and spinal fluid from dementia patients and blood from individuals who have undergone a glucose tolerance test (a test that measures changes in the sugar metabolism that can be a sign of insulin resistance) will be analysed.
"Analysing cerebrospinal fluid is one of the few methods of studying changes in the human brain associated with disease", says Malin Wennstr-m, adding:
"The best outcome would be if we found markers for this in the blood. We could then easily identify at an early stage, which individuals with type 2 diabetes are at increased risk of developing dementia in the future. We would then also have a concrete target for the development of treatments to halt the process."
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