Is insulin resistance caused by defects in insulin's target cells or by a stressed mind?

Abstract

The importance of understanding insulin action is emphasized by the increasing prevalence of insulin resistance in various populations and by the fact that it plays an important pathophysiological role in many common disorders, for example, diabetes, obesity, hypertension and dyslipidemia. The primary factors responsible for the development of insulin resistance are so far unknown, although both genetic and environmental factors are involved. The genetic defects responsible for the common forms of insulin resistance, for example, in type 2 diabetes, are largely unidentified. Some studies from our group as well as by other investigators suggest that cellular insulin resistance is reversible and that it may be secondary to factors in the in vivo environment. These may include insulin-antagonistic action of hormones like catecholamines, glucocorticoids, sex steroids and adipokines as well as dysregulation of autonomic nervous activity and they could contribute to the early development of insulin resistance. Some of these factors can directly impair glucose uptake capacity and this might be due to alterations in key proteins involved in insulin's intracellular signaling pathways. This article briefly summarizes proposed mechanisms behind cellular and whole-body insulin resistance. In particular, we question the role of intrinsic defects in insulin's target cells as primary mechanisms in the development of insulin resistance in type 2 diabetes and we suggest that metabolic and neurohormonal factors instead are the main culprits.

Prenatal viral exposure followed by adult stress produces glucose intolerance in a mouse model

“…However, the relationships are complex and both hyper-and hypocortisolism may arise as a consequence of fetal programming of the HPA axis during intrauterine life. Nonetheless, although not scrutinised in our present work, such a relationship between fetal events and adult-onset diabetes is intriguing, given the role of glucocorticoids and stress in the pathogenesis of type 2 diabetes [19].…”

Neuroendocrine mechanisms in insulin resistance

“…In addition, release of adrenaline from the adrenal medulla is regulated largely by autonomic nerve activity. Sympathoadrenal activation will have profound metabolic effects including insulin resistance (3,13). For more long-term communication the brain can use the hypthalamo-pituitary hormonal systems and other neurohormonal pathways.…”

“…Nonetheless, the ability of counter-regulatory hormones, including glucagon, adrenaline, cortisol and growth hormone, to increase blood glucose can contribute to insulin resistance and development of type 2 diabetes if there is an inappropriately large response (13) Insulin resistance in the pathobiology of type 2 diabetes Insulin resistance is an important component of the pathophysiological processes that underlies the development of type 2 diabetes, and it is likely to play a role in development of other conditions such as dyslipidemia, hypertension and atherosclerosis.…”

“…For example, high levels of glucose and free fatty acids will have detrimental effects in some tissues, e.g. muscle and liver (13). As obesity is a very important component in the metabolic syndrome and also is a major risk factor for the development of type 2 diabetes, adipose-related mechanisms are of interest.…”

“…Cortisol exerts its metabolic effects via effects on gene transcription, and the glucocortiocoid receptor belongs to the family of nuclear hormone receptors acting as transcription factors in the cell nucleus. Cortisol impairs glucose uptake in peripheral tissues like fat and muscle and this can involve impaired translocation to the plasma membrane of glucose transporter 4 (GLUT4) (13). Previous results on human fat cells suggest that there are differences in glucocorticoid effects between the visceral and subcutaneous adipose depots (49).…”