Year: 2014
Type: dissertation
Study design: Observational Study
Abstract: Disturbances in insulin sensitivity and insulin secretion precede the manifestation of type 2 diabetes. Both genes and environment contribute to the diabetes risk. Heritability indicates the proportion to which genotype determines the variability of a trait, such as for example blood glucose concentration. The current work was done for the Hjelt institute and for the Finnish institute of Molecular Medicine (FiMM) in the University of Helsinki. Heritability of insulin sensitivity, insulin secretion and traits associated with type 2 diabetes were estimated by means of twin and family studies. The twins belonged to the Finnish Twin Cohort Study of the University of Helsinki and the families participated in the Botnia study, a project on type 2 diabetes genetics. The collecting of the material was made between the years 1992 - 2004. Insulin sensitivity was measured by means of hyperinsulinaemic euglycaemic clamp technique. Insulin secretion was measured both via oral (OGTT) and intravenous (IVGTT) glucose tolerance tests. The heritability of body mass index (BMI) and type 2 diabetes were estimated in a follow-up study of twins. Furthermore, heritability estimates of several glucose metabolism and insulin sensitivity related traits were obtained by examining Botnia study families where at least two family members had type 2 diabetes. Altogether 66 monozygotic (MZ) and 85 dizygotic (DZ) twin pairs underwent OGTT. A subset of the pairs participated also in IVGTT- and clamp studies. The follow-up study was based on information that was received from 10400 twin pairs during a maximum of 28 years of follow-up. From the Botnia-study, 5810 adults from 942 families were chosen: 1707 of them had type 2 diabetes. The average family size was 6,17. On the basis of the metabolic studies, it was concluded that the genotype determines the insulin secretion's early phase, which begins immediately after the ingestion or infusion of glucose. The heritability of this trait varied between 55% and 76%. The majority of variation in insulin sensitivity, instead, seemed to be due to non-hereditary factors, as the heritability of insulin sensitivity was only 37%. In the follow-up study, 6.3% of male and 5.1% of female twins got type 2 diabetes. BMI calculated on the basis of the data recorded at the start of the follow-up, predicted future diabetes well. On average, the hazard ratio for type 2 diabetes was 1,22 per each BMI unit and the risk began to increase already from the BMI-value of 20kg/m2. The hazard ratios for type 2 diabetes in normal weight, overweight, obese and morbidly obese twins were 0.59, 2.96, 6.80 and 13.64, respectively. When BMI and type 2 diabetes were modelled together, the heritability of BMI in men was 75%, and 71% in women. Correspondingly, the heritability of type 2 diabetes was 73% in men and 64% in women, respectively. The genetic factors influencing BMI explained only 16% of the risk for type 2 diabetes among men and 21% of the risk among women. In the Botnia study, the highest heritability estimate for type 2 diabetes, 69%, was observed among individuals aged 35 to 60 years. The heritability of the early phase of insulin secretion varied between 41% (all subjects) and 50% (non-diabetic subjects). The heritability of insulin sensitivity was the same as among twins, from 37% to 40%. Among diabetes-related traits, the highest heritability estimates were obtained for lean body mass (53% to 65%), serum HDL cholesterol concentration (52% to 61%) and suppression of free fatty acids during OGTT (63% to 76%). The variation of all insulin sensitivity and insulin secretion -related traits were smaller within than between families. It is stated as a summary of this doctoral thesis that the risk for type 2 diabetes seems to be an inherited trait. A relatively small share in this risk, on the other hand, seems to be due to genes which influence BMI. Finally, the early phase of the pancreatic insulin secretion appears to be an aspect of metabolism that encompasses promising phenotypes for genomic studies.
Source: Työväentutkimus Vuosikirja
Author: Mikko Lehtovirta
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1485110298