Insulin: new roles for an ancient hormone

Abstract

Recent research has greatly expanded the domain of insulin action. The classical action of insulin is the control of glucose metabolism through the dual feedback loop linking plasma insulin with plasma glucose concentrations. This canon has been revised to incorporate the impact of insulin resistance or insulin deficiency, both of which alter glucose homeostasis through maladaptive responses (namely, chronic hyperinsulinaemia and glucose toxicity). A large body of knowledge is available on the physiology, cellular biology and molecular genetics of insulin action on glucose production and uptake. More recently, a number of newer actions of insulin have been delineated from in vitro and in vivo studies. In sensitive individuals, insulin inhibits lipolysis and platelet aggregation. In the presence of insulin resistance, dyslipidaemia, hyper-aggregation and anti-fibrinolysis may create a pro-thrombotic milieu. Preliminary evidence indicates that hyperinsulinaemia per se may be pro-oxidant both in vitro and in vivo. Insulin plays a role in mediating diet-induced thermogenesis, and insulin resistance may therefore be implicated in the defective thermogenesis of diabetes. In the kidney, insulin spares sodium and uric acid from excretion; in chronic hyperinsulinaemic states, these effects may contribute to high blood pressure and hyperuricaemia. Insulin hyperpolarises the plasma membranes of both excitable and non-excitable tissues, with consequences ranging from baroreceptor desensitisation to cardiac refractoriness (prolongation of QT interval). Under some circumstances insulin is vasodilatory-the mechanism involving both the sodium-potassium pump and intracellular calcium transients. Finally, by crossing the blood-brain barrier insulin exerts a host a central effects (sympatho-excitation, vagal withdrawal, stimulation of corticotropin releasing factor), collectively resembling a stress reaction. Description and understanding of these new roles, their interactions, the interplay between insulin resistance and hyperinsulinaemia, and their implications for cardiovascular disease have only begun.

Relationship between QT interval and cardiovascular risk factors in healthy young subjects

“…28 In diabetic patients, the association between glycaemia and QTc may be also QT interval in young subjects G Leotta et al mediated by insulin-resistance and chronic hyperinsulinaemia, since insulin increases sympathetic activity and hyperpolarizes plasma membrane of cardiac myocytes. 29 A positive relationship between QTc duration and fasting glucose has been previously demonstrated in a large population-based study 16 and in the elderly. 30 In women aged 52-88 years with normal fasting glucose, QTc was prolonged as a function of progressive worsening of glucose tolerance.…”

Different postprandial acute response in healthy subjects to three strawberry jams varying in carbohydrate and antioxidant content: a randomized, crossover trial

“…Accordingly, after the jam ingestion, insulin also increased, in response to the elevation of blood glucose concentration [22,28,29]. The intake of simple sugars, such as In this study, the results confirm that total cholesterol, HDL-c, LDL-c (only with LS jam), and TG concentrations decreased during the first 30 min after consumption of the three different types of jams, which might be partly attributed to the fact that insulin promotes the transfer of LDL-c from peripheral blood to liver, reducing the circulating LDL-c concentrations [35,36].…”

“…These findings are important, because the result is a lower availability of FFA in plasma, but more FFA to be accumulated into the adipocyte. Additionally, insulin induced stimulation of glucose metabolism in fat cells increasing the availability of glycerol to re-esterify FFA and to accumulate into the adipocytes as TG [29]. Moreover, fructose may play an important effect on hepatic de novo lipogenesis, hereby also insulin resistance, increasing TG concentration.…”

In Vivo Mutagenesis of the Insulin Receptor

“…Insulin Resistance The cornerstone of current theories on the pathogenesis of type 2 diabetes is that skeletal muscle, the main site of insulin-dependent glucose disposal, is intrinsically unable to respond to insulin, either as a result of genetic predisposition or as a consequence of environmental factors (4). Indeed, an impairment of insulin-dependent glucose uptake and phosphorylation is an early step in the development of type 2 diabetes (12).…”

“…Insulin resistance is found in the main insulin target tissues (muscle, adipose cells, liver) of patients with overt diabetes. However, this is a consequence of chronic hyperinsulinemia and glucotoxicity (4). The question of whether insulin resistance represents a generalized impairment of insulin action or is initially restricted to specific organs has remained unclear, as has its relationship to impaired ␤-cell function.…”