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Metabolic and genetic influence on glucose metabolism in type 2 diabetic subjects—experiences from relatives and twin studies

https://doi.org/10.1016/S1521-690X(03)00041-1Get rights and content

Abstract

Based on our investigations in first-degree relatives, in twins in general, and in monozygotic twins discordant for type 2 diabetes, we have studied the inheritance of glucose intolerance, insulin resistance and insulin secretion in order to evaluate the role of genes versus environment in the development of type 2 diabetes. Insulin resistance in type 2 diabetes is mainly linked to glucose disposal in skeletal muscle, i.e. reduced glycogen synthesis. In order to investigate the genetic component responsible for the reduced glycogen synthase activity and reduced glucose transport, we also investigated cultured myotubes based on in vivo skeletal muscle biopsies.

The results obtained in our own studies are discussed in comparison with the international literature.

We conclude that both genetic and environmental factors play a role in the development of type 2 diabetes (hyperglycaemia), and that only subjects who are genetically disposed to insulin resistance and who possess β-cells which are unable to compensate for the degree of insulin resistance seem to develop type 2 diabetes. Variables of two gene alleles disposing to insulin resistance have been identified, and their role is discussed. The most important environmental factor seems to be obesity, but intrauterine malnutrition also plays a role. The cellular mechanism responsible for obesity/lipid-induced diabetes mellitus is discussed with specific emphasis on the role of accumulation of long-chain AcylCoA and triglycerides in liver, muscle and β-cells.

Section snippets

Characterization of glucose metabolism in type 2 diabetic subjects

Type 2 diabetes (T2D) is the most common type of diabetes today, and about 250 million people worldwide seem to suffer from this devastating disease. More than 80% of T2D subjects are obese; these subjects are especially characterized by abdominal obesity. Therefore, in this chapter, we concentrate mainly on the typical form, which seems to be linked to a lifestyle of overnutrition, mainly by saturated fat, and reduced physical activity. In the following, we refer to this type of disease when

Classical twin studies

Twin studies have been used extensively in medical research to determine the potential role of genes versus environment in the aetiology of human disease. Monozygotic (MZ) twins are genetically identical and should theoretically be concordant for diseases with a genetic aetiology. Dizygotic (DZ) twins, on the other hand, have 50% of their genes in common and are genetically as different as ordinary siblings. Differences in phenotypic appearance among MZ twin pairs are consequently due to

Genes versus environment in the aetiology of type 2 diabetes mellitus

T2D has traditionally been considered to have a major genetic component, primarily due to twin studies reporting concordance rates in the range of 50–92% among MZ twins.7., 8., 9., 10. Most studies including DZ twins have reported a significantly lower concordance rate among DZ twins, indicating a major genetic component in the aetiology of T2D.7., 8., 10., 11., 12. The incomplete concordance among MZ twins, even in selected studies, implies a role for an environmental component.

We recently

Lessons from studies on glucose metabolism in first-degree relatives and non-diabetic monozygotic co-twins of type 2 diabetic patients

Due to the fact that many of the defects of glucose homeostasis in diabetes may be secondary to hyperglycaemia33., 34., many research groups have focused on studies in non-diabetic persons at risk of T2D. Given the putative impact of genetics for the development of T2D, particular attention has been paid to studies of first-degree relatives of T2D patients as well as studies of non-diabetic genetically identical co-twins of twins with T2D (i.e. MZ twin pairs discordant for T2D). Both groups

Intracellular genetic defects: lessons from cultured myotubes

During recent decades, a large number of studies have searched for the genetic causes of insulin resistance in human skeletal muscle by in vivo studies of MZ and DZ twins and glucose-tolerant first-degree relatives of T2D subjects. Enzyme activities, the expression of key proteins in glucose metabolism and the insulin-signalling cascade were studied in in vivo muscle biopsies as described above. However, it is still uncertain whether the observed changes represent adaptive compensation at the

Impact of the prenatal environment on metabolic defects in type 2 diabetes

During the last decade, a large number of studies have reported an association between low birth weight and the risk of developing T2D.20., 75., 76. Our findings of a significantly lower birth weight in twins with overt T2D, as compared with both their genetically identical and non-identical co-twins, demonstrate that the association between low birth weight and T2D is not entirely explained by any putative association between a gene causing both low birth weight and T2D.

The extent to which an

Conclusion

T2D is a complex disease characterized by several metabolic abnormalities. Fasting and postprandial hyperglycaemia is only one feature characterizing these subjects. Hyperglycaemia develops owing to the combination of reduced insulin-stimulated glucose clearance in the periphery (skeletal muscle) and slightly increased hepatic glucose production. Hyperglycaemia develops in order to compensate for the reduced insulin-mediated uptake, and plasma glucose continues to increase until the

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