We studied the relation of serum insulin levels to plasma lipid levels and blood pressure in two groups drawn from among 247 healthy, normotensive nonobese subjects with normal glucose tolerance. One group of 32 subjects was defined as having hyperinsulinemia (serum insulin, >2 SD above the mean) and then compared with 32 normoinsulinemic subjects (serum insulin within 1 SD of the mean) matched for age (mean, 39 years), sex (22 men and 10 women), and body-mass index (24.7). The two groups had similar patterns of smoking, drinking, and physical exercise.

Diabetes mellitus (DM) is the major cause of end-stage renal disease (ESRD) globally, and novel treatments are urgently needed. Current therapeutic approaches for diabetic nephropathy (DN) are focussing on blood pressure control with inhibitors of the renin-angiotensin-aldosterone system, on glycaemic and lipid control, and life-style changes. In this review, we highlight new molecular insights aiding our understanding of the initiation and progression of DN, including glomerular insulin resistance, dysregulation of cellular substrate utilisation, podocyte-endothelial communication, and inhibition of tubular sodium coupled glucose reabsorption. We believe that these mechanisms offer new therapeutic targets that can be exploited to develop important renoprotective treatments for DN over the next decade.

We showed before that in neonatal rat cardiac myocytes partial inhibition of Na⁺/K⁺-ATPase by nontoxic concentrations of ouabain causes hypertrophic growth and transcriptional regulations of genes that are markers of cardiac hypertrophy. In view of the suggested roles of Ras and p42/44 mitogen-activated protein kinases (MAPKs) as key mediators of cardiac hypertrophy, the aim of this work was to explore their roles in ouabain-initiated signal pathways regulating four growth-related genes of these myocytes,i.e. those for c-Fos, skeletal α-actin, atrial natriuretic factor, and the α₃-subunit of Na⁺/K⁺-ATPase. Ouabain caused rapid activations of Ras and p42/44 MAPKs; the latter was sustained longer than 90 min. Using high efficiency adenoviral-mediated expression of a dominant-negative Ras mutant, and a specific inhibitor of MAPK kinase (MEK), activation of Ras-Raf-MEK-p42/44 MAPK cascade by ouabain was shown. The effects of the mutant Ras, an inhibitor of Ras farnesylation, and the MEK inhibitor on ouabain-induced changes in mRNAs of the four genes indicated that (a) skeletal α-actin induction was dependent on Ras but not on p42/44 MAPKs, (b) α₃ repression was dependent on the Ras-p42/44 MAPK cascade, and (c) induction of c-fos or atrial natriuretic factor gene occurred partly through the Ras-p42/44 MAPK cascade, and partly through pathways independent of Ras and p42/44 MAPKs. All ouabain effects required extracellular Ca²⁺, and were attenuated by a Ca²⁺/calmodulin antagonist or a protein kinase C inhibitor. The findings show that (a) signal pathways linked to sarcolemmal Na⁺/K⁺-ATPase share early segments involving Ca²⁺ and protein kinase C, but diverge into multiple branches only some of which involve Ras, or p42/44 MAPKs, or both; and (b) there are significant differences between this network and the related gene regulatory pathways activated by other hypertrophic stimuli, including those whose responses involve increases in intracellular free Ca²⁺ through different mechanisms.

Oxidative stress has been implicated in the pathophysiology of diabetic nephropathy. Studies in experimental animal models of diabetes strongly implicate oxidant species as a major determinant in the pathophysiology of diabetic kidney disease. The translation, in the clinical setting, of these concepts have been quite disappointing, and new theories have challenged the concepts that oxidative stress per se plays a role in the pathophysiology of diabetic kidney disease. The concept of mitochondrial hormesis has been introduced to explain this apparent disconnect. Hormesis is intended as any cellular process that exhibits a biphasic response to exposure to increasing amounts of a substance or condition: specifically, in diabetic kidney disease, oxidant species may represent, at determined concentration, an essential and potentially protective factor. It could be postulated that excessive production or inhibition of oxidant species formation might result in an adverse phenotype. This review discusses the evidence underlying these two apparent contradicting concepts, with the aim to propose and speculate on potential mechanisms underlying the role of oxidant species in the pathophysiology of diabetic nephropathy and possibly open future more efficient therapies to be tested in the clinical settings.