Sodium/hydrogen exchange activity in type 1 diabetes mellitus: the never-ending story.

The amiloride-sensitive Na+/H+ exchanger (NHE) mediates uphill H+ extrusion and thus causes intracellular alkalinization. The NHE plays a major role in pH homeostasis, Na+ absorption, cell volume regulation, and cell proliferation; it is activated by growth factors, mitogens, neurotransmitters, tumor promoters, and others. At intracellular pH (pHi)>7.2-7.4, the system is quiescent; when pHi falls, the rate of H+ - efflux increases in an allosteric manner to reach a maximum around pHi=6.0. The kinetics for external Na+ follows the Michaelis-Menten model with a single, binding site. The effect of intracellular H+ best fits an allosteric model with at least two binding sites. According to the postulate that erythrocyte sodium-lithium countertransport (NLCT) might be one mode of operation of the ubiquitous NHE, and following the trail of previous investigations of NLCT association with hypertension and diabetic nephropathy, several studies have confirmed elevated NHE activity in different cell types in patients with essential hypertension. However, the relation between NHE and either NLCT or hypertension remains unclear and the usefulness of NLCT activity as a risk marker for the development of essential hypertension has been now excluded. On the contrary, few publications have dealt with the physiologic NHE in diabetic nephropathy, and contrasting results have been reported. We have observed an accelerated NHE in essential hypertension and in Type 1 diabetes, however without any relationship with urinary albumin excretion rate. Furthermore, NHE activity increased in non-diabetic first-degree relatives of Type 1 diabetic patients, yet no difference could be observed between relatives of probands with diabetic nephropathy and relatives of probands with normoalbuminuria. Unlike erythrocyte NHE activity, abnormal albumin excretion was a distinctive feature of non-diabetic first-degree relatives of Type 1 diabetic patients with nephropathy. The lack of agreement among Authors, even using both the same cell and the same method, testifies to the difficulty in performing a correct patient selection and uniformly reproducible NHE measurement. We compare individual clinical characteristics among different study populations confirming previous conclusions regarding NLCT in essential hypertension: main determinant for the flux values of NHE seems to be patient selection rather than methodology. A common effort is advisable to collaborate, standardise, compare methodologies, and unify criteria of subject recruitment