[Diabetic nephropathy: oral anti-diabetic agents or insulin?]. / Nefropatia diabetica: ipoglicemizzanti o insulina?

Diabetic nephropathy is a microvascular complication, as well as retinopathy and neuropathy of type 1 and type 2 diabetes mellitus. The pathogenesis directly correlates with hyperglycemia. The direct glucose toxicity, hypercoagulability, oxidative stress and endothelial dysfunctions play a role. Strict glycemic control with HbA1c levels <7% for 10 yrs is associated with a 25% microvascular end point reduction. Patients underwent pancreas transplantation, and after 10 yrs the present nephropathy and functional and structural abnormalities have regressed. Diabetic nephropathy alters the pharmacokinetic profile of almost all oral anti-diabetic agents, as well as insulin metabolism; therefore, it is imperative to determine creatinine clearance. Renal failure requires insulin therapy. Incipient diabetic nephropathy allows very limited indications to oral anti-diabetic agents because of the altered pharmacokinetic profile and side effects (hypoglycemia with secretagogues agents, lactic-acidosis with metformin and other biguanides, and hydric retention and weight gain with thiazolidinediones). Moreover, oral anti-diabetic agents reduce the percentage of HbA1c by no more than 1.5%. Insulin therapy is preferred, with a dose reduction when creatinine clearance is <60 mL/m. To control better the post-prandial glycemic peak, it is useful to use bolus insulin analogues at each meal and basal intermediate-acting insulin at bedtime to mimic the natural insulin patterns as far as possible.

Ethanol dose-dependently elicits opposing regulatory effects on hippocampal AMPA receptor GluA2 subunits through a zeta inhibitory peptide-sensitive kinase in adolescent and adult Sprague-Dawley rats.

AMPA receptor GluA2 subunits are strongly implicated in cognition, and prior work suggests that these subunits may be regulated by atypical protein kinase C (aPKC) isoforms. The present study assessed whether hippocampal and cortical AMPA receptor GluA2 subunit regulation may be an underlying factor in known age-related differences to cognitive-impairing doses of ethanol, and if aPKC isoforms modulate such responses. Hippocampal AMPA receptor GluA2 subunit, protein kinase Mζ (PKMζ), and PKCι/λ expression were elevated during adolescence compared to adults. 1 h following a low-dose (1.0-g/kg) ethanol exposure, hippocampal AMPA receptor GluA2 subunit serine 880 phosphorylation was decreased in adolescents, but was increased in adults. Age-dependent changes in GluA2 subunit phosphorylation were paralleled by alterations in aPKC isoforms, and zeta inhibitory peptide (ZIP) administration prevented ethanol-induced increases in both in adults. Ethanol-induced changes in GluA2 subunit phosphorylation were associated with delayed regulation in synaptosomal GluA2 subunit expression 24 h later. A higher ethanol dose (3.5-g/kg) failed to elicit changes in most measures in the hippocampus at either age. Similar to the hippocampus, analysis of cerebral cortical tissue also revealed age-related declines. However, no demonstrable effects were found following a low-dose ethanol exposure at either age. High-dose ethanol exposure reduced adolescent GluA2 subunit phosphorylation and aPKC isoform expression that were again accompanied by delayed reductions in synaptosomal GluA2 subunit expression. Together, these results suggest that GluA2-containing AMPA receptor modulation by aPKC isoforms is age-, region- and dose-dependently regulated, and may potentially be involved in developmentally regulated ethanol-induced cognitive impairment and other ethanol behaviors.