An excess of free intracellular calcium can reduce the efficiency of insulin-mediated glucose transport by blocking the dephosphorylation of GLUT-4. Classical isoforms of protein kinase C (PKC) can interfere with insulin signalling via serine phosphorylation of IRS-1 and the insulin receptor. Parathyroid hormone (PTH), by activating phospholipase C-beta in adipocytes, can promote a sustained increase in intracellular free calcium in these cells, while also activating classical PKCs. This may rationalize the fact that insulin resistance is a typical feature of hyperparathyroidism, as well as epidemiological evidence that regular ingestion of dairy products or of ethanol--which down-regulates PTH secretion--reduces risk for insulin resistance syndrome and diabetes. Alpha-1 adrenergic receptors of adipocytes--like PTH receptors--also activate phospholipase C-beta, and thus have an effect analogous to PTH on intracellular free calcium and PKC activity in adipocytes. This suggests that, via activation of alpha-1 adrenergic receptors, increased sympathetic activity in adipose tissue may promote insulin resistance syndrome. In fact, measures which provoke increased sympathetic output--such as diuretic use and severe salt restriction--are known to compromise insulin sensitivity, whereas alpha-1 antagonist drugs, as well as drugs that act centrally to suppress sympathetic activity, typically have a favorable effect on insulin function. When insulin resistance syndrome is associated with elevated sympathetic activity--for example, in hypertensives who are obese or on diuretic therapy--measures which down-regulate sympathetic activity, or, more specifically, alpha-1 adrenergic activity, may be warranted. These include centrally acting imidazoline analogs (moxonidine, rilmenidine) and alpha-1 antagonists (doxazosin, prazosin). Taurine and high-dose pyridoxine may represent practical nutritional strategies for moderating elevated sympathetic activity, and exercise training and low-insulin-response diets may be useful in this regard as well.