The number of individuals affected by Type 2 diabetes
mellitus (T2DM) is increasing rapidly nearly everywhere in the world. Insulin
resistance, which means reduced impact of insulin in its target tissues,
especially in the liver, skeletal muscle and adipose tissue, is the defining
hallmark of T2DM. Insulin resistance in these tissues manifests as impaired
ability to take up glucose and fatty acids from blood after a meal, increased
production of glucose and triglycerides into the blood circulation by the liver
and increased release of free fatty acids into the blood by adipose tissue.

This thesis work focuses on studying insulin resistance
using a cross-sectional cohort of a wide range of individuals of different ages
and body mass index (BMI). P.Pro12Ala polymorphism of the PPARG gene reduces
diabetes risk, and the aim of this study was to determine whether this variant
affects liver insulin sensitivity. Further goals were to study associations
between insulin sensitivity in different tissues and to develop inexpensive and
fast models to identify muscle and whole-body insulin resistance. Moreover,
possible benefits of resistance training to liver and adipose tissue insulin
sensitivity among elderly women were evaluated.

It was found that overweight and obese carriers of the
p.Pro12Ala polymorphism of the PPARG gene display higher insulin-stimulated
liver glucose uptake when compared to carriers of the common p.Pro12Pro
genotype. It was discovered that insulin resistance is more likely to be
present simultaneously in skeletal muscle and adipose tissue than in the liver,
and that insulin sensitivity is affected by obesity, sex and age. The developed
regression models based on serum metabolomics for identifying whole-body and
skeletal muscle insulin resistance correlated with insulin sensitivity better
than the currently used fasting surrogate markers for insulin resistance.
Moreover, it was revealed resistance training does not affect adipose tissue
glucose uptake but instead improves insulin suppression of endogenous glucose
production in elderly women and may thus prevent glucose levels rising too high
after a meal.

In conclusion, this thesis work shows that genetic mutations
can alter tissue insulin sensitivity, and insulin resistance tends to be
simultaneously present in several tissues. The newly developed models for
identifying insulin resistance may improve the possibility of finding persons
at risk of diabetes and ultimately cardiovascular disease. In addition,
resistance training is an effective tool for improving diabetes and
cardiovascular disease risk factors.