Effects of Age and Obesity on Brain Insulin Sensitivity (Aging)

Insulinsensitivität Des Menschlichen Zentralnervensystems Mit Fortschreitendem Alter: Kernspintomographische Untersuchung Mit Intranasaler Gabe Von Insulin

Obesity and especially type 2 diabetes (T2D) increases the risk of neurocognitive dysfunctions including adverse effects on brain structure and function. Recent evidence from clinical studies have shown that T2D almost doubles the risk for dementia. As the population gets older, age-related chronic diseases, as T2D, become more prevalent. Scientific evidence is emerging that there are several links between metabolic and neurocognitive functions. Impaired insulin action (i.e. insulin resistance), the main hallmark of T2D, has been suggested as a likely shared common pathophysiological mechanism. However, the neural processes that determine how insulin resistance is are connected to the onset and progression of T2D and dementia remain unclear. In this context, the overall aim is to study brain insulin resistance to disentangle age-related and obesity related brain insulin resistance in healthy normal and overweight/obese persons at the age of 20 to 70 years . To this end, the investigators will assess brain insulin action using intranasal insulin/placebo during functional Magnetic Resonance Imaging (fMRI). Additionally, structural changes and cognitive processes will be assessed as secondary variables.

fMRI measurement will be performed before and after administration of 160 U of human insulin or placebo as nasal spray. Changes in regional brain activity will be quantified by cerebral blood flow and blood oxygenation dependent (BOLD) signal to assess regional brain insulin sensitivity. Brain insulin sensitivity will be compared between eight groups (young normal weight men and women, young overweight/obese men and women, old normal weight men and women, old overweight/obese men and women). Persons are categorized into normal weight and overweight/obese based on the Body Mass Index (BMI). Age groups are build based on a median split.

Insulin sensitivity will be estimated from a frequent-sampling 75 g oral glucose tolerance test (oGTT) using the Matsuda formula. Correlation of regional brain insulin sensitivity by intranasal insulin will be performed with whole-body insulin sensitivity based on oGTT. Changes in regional cerebral blood flow from before to after intranasal insulin administration will be assessed by functional magnetic resonance imaging (fMRI).

Correlation of the change in regional brain insulin sensitivity by intranasal insulin with the simultaneous change of the autonomous nervous system (measured by heart rate variability).

Correlation of the change in regional brain insulin sensitivity by intranasal insulin with cognitive measures addressed by neuropsychological testing.

Brain response to food cues assessed by functional magnetic resonance imaging. Food cues will be rated for palatability on a visual analogue scale.

Inclusion Criteria: Body-Mass Index (BMI) between 19-35 kg/m2 HbA1c ≤6.0% normal glucose tolerance during 75g oral glucose tolerance test (OGTT) Exclusion Criteria: Not removable metal parts in or on the body manifest cardiovascular disease claustrophobia recent surgery (less than 3 months) Simultaneous participation in other studies Acute disease or infection within the last 4 weeks neurological and psychiatric disorders treatment with centrally acting drugs hemoglobin Hb <13g / dl Hypersensitivity to any of the substances used