Role of heparin in realization of the hypoglycaemic action of insulin

A temporary resistance to the hypoglycaemic action of insulin has been found after preliminary binding of heparin in the blood of animals by 1 mg/200 of protamine sulphate (PS). This effect was observed after 5-30 min PS treatment before the insulin injection or endogenous increase of insulin stimulated by sugar load. PS did not influence the concentration of immunoreactive insulin in blood plasma. 2,5-ionene, a synthetic antagonist of heparin, induced temporary resistance to the hypoglycaemic action of insulin. Intravenous injection of heparin in corresponding doses after PS administration restored the hypoglycaemic effect of insulin. The results suggest that the presence in the circulation of reactive heparin may be necessary for insulin reception by the target tissue.     

Decreased sensitivity to the hypoglycemic action of insulin in animals with a lowered blood heparin concentration

It has been shown that in animals with reduced heparin blood concentration the hypoglycemic insulin action was considerably low. This was established for rats with alloxan diabetes and ageing rats with depressed anticoagulation system and atherosclerosis enhanced by prolonged atherogenic diet. With insulin injection (0.2-0.3 U/200 g), blood sugar concentration in such animals was 2-2.5 times lower than in normal ones. The compensation of endogenous heparin deficiency by an intravenous injection of heparin normalizes the reaction of animals to exogenous insulin.     

Lateral modulation of the hypoglycemic action of insulin

The results of the experimental investigation on 15 rabbits are presented here. Hypoglycemic action of the standard exogenic insulin dose strengthened after performing transcerebral lateral electrostimulation on the right side with the weak current impulse.     

Role of insulin-stimulated protein phosphorylation in insulin action

Insulin promotes both the phosphorylation and dephosphorylation of proteins in its target cells. Insulin-induced dephosphorylation has long been thought to serve an important regulatory function; the role of insulin-stimulation phosphorylation is less certain. The proteins known to be substrates for this reaction are ATP citrate (pro-3S)-lyase, acetyl-CoA carboxylase, and the ribosomal subunit S6. The evidence as to the physiological role and mechanism underlying the insulin-stimulated phosphorylation of these proteins is summarized. Present information suggests that insulin-stimulated phosphorylation may serve an important regulatory role in certain actions of insulin.     

Role of Rho-kinase in regulation of insulin action and glucose homeostasis

Accumulating evidence indicates an important role for serine phosphorylation of IRS-1 in the regulation of insulin action. Recent studies suggest that Rho-kinase (ROK) is a mediator of insulin signaling, via interaction with IRS-1. Here we show that insulin stimulation of glucose transport is impaired when ROK is chemically or biologically inhibited in cultured adipocytes and myotubes and in isolated soleus muscle ex vivo. Inactivation of ROK also reduces insulin-stimulated IRS-1 tyrosine phosphorylation and PI3K activity. Moreover, inhibition of ROK activity in mice causes insulin resistance by reducing insulin-stimulated glucose uptake in skeletal muscle in vivo. Mass spectrometry analysis identifies IRS-1 Ser632/635 as substrates of ROK in vitro, and mutation of these sites inhibits insulin signaling. These results strongly suggest that ROK regulates insulin-stimulated glucose transport in vitro and in vivo. Thus, ROK is an important regulator of insulin signaling and glucose metabolism.     

Role of magnesium in insulin action,diabetes and cardio-metabolic syndrome X

Magnesium (Mg) is one of the most abundant ions present in living cells and its plasma concentration is remarkably constant in healthy subjects. Plasma and intracellular Mg concentrations are tightly regulated by several factors. Among them, insulin seems to be one of the most important. In vitro and in vivo studies have demonstrated that insulin may modulate the shift of Mg from extracellular to intracellular space. Intracellular Mg concentration has also been shown to be effective in modulating insulin action (mainly oxidative glucose metabolism), offset calcium-related excitation-contraction coupling, and decrease smooth cell responsiveness to depolarizing stimuli. A poor intracellular Mg concentration, as found in noninsulin-dependent diabetes mellitus (NIDDM) and in hypertensive patients, may result in a defective tyrosine-kinase activity at the insulin receptor level and exaggerated intracellular calcium concentration. Both events are responsible for the impairment in insulin action and a worsening of insulin resistance in noninsulin-dependent diabetic and hypertensive patients. By contrast, in NIDDM patients daily Mg administration, restoring a more appropriate intracellular Mg concentration, contributes to improve insulin-mediated glucose uptake. The benefits deriving- from daily Mg supplementation in NIDDM patients are further supported by epidemiological studies showing that high daily Mg intake are predictive of a lower incidence of NIDDM. In conclusion, a growing body of studies suggest that intracellular Mg may play a key role in modulating insulin-mediated glucose uptake and vascular tone. We further suggest that a reduced intracellular Mg concentration might be the missing link helping to explain the epidemiological association between NIDDM and hypertension.